PHARMACOLOGY

It is science that deals with effects of drugs on living systems

It is divided into several branches like pharmacokinetics, pharmacodynamics,
pharmacotherapeutics, chemotherapy and toxicology etc.
Pharmacokinetics : Pharmacodynamics:
It means movement of drug within the body; it It is the study of drugs - their mechanism of
includes processes of absorption (A), distribution action, pharmacological actions and their adverse
(D), metabolism (M) and excretion (E). effects. It covers all the aspects relating to
It means 'what the body does to the drug* 'what the drug does to the body1.

ROUTES OF DRUG ADMINISTRATION:

Most of drugs can be administered by different routes.
Intradermal
Routes of drug administration
Subcutaneous

Intra venom
Local Systemic
Intraarterial
4 intramuscular
Topical Intra-articular Intrathecal Enteral Parenteral
(skin and (through GIT) •intravenous Intra -articular
mucous •Intramuscular
membranes) 1 * Subcutaneous
•Sublingual
Oral Rectal • Transdormal
•Nasal
•Inhaialionai Fig, 1J Injectable routes of drug adnwncstration.

LOCAL ROUTES: SYSTEMIC ROUTES

It is simplest mode of administration of a drug at Drugs administered by this route enter the blood
site where desired action is required. and produce systemic effects
Systemic side effects are minimal.
(A)Topical Drug is applied to skin or mucous (A) Enteral Routes
membrane at various sites for localized action. They include oral, sublingual and rectal routes.
1. Oral cavity: Oral Route. It is the most common and acceptable
As suspension, e.g. nystatin; as a troche, e.g. route for drug administration. Dosage forms are
clotrimazole (for oral candidiasis); as a cream tablet, capsule, powder, syrup, linctus, mixture,
2, GI tract: suspension, etc.
As tablet which is not absorbed, eg. neomycin
(for sterilization of gut before surgery). Tablets could be coated (covered with a thin film
3. Rectum and anal canal: of another substance) or uncoated . They are also
->As an enema (administration of drug into the available as chewable (albendazole), dispersible
rectum in liquid form): (aspirin), mouth dissolving (ondansetron) and
Evacuont enema (for evacuation of bowel): For sustained release forms.
example, soap water enema - soap acts as a Capsules have a soft or hard shell.
lubricant and water stimulates rectum.
->As a suppository (administration of the drug in (B) Sublingual Route
a solid form into the rectum) The preparation is kept under the tongue.
e g. bisacodyl suppository for evacuation of The drug is absorbed through the buccal mucous
bowel . membrane and enters systemic circulation
 directly, e.g. nitroglycerin(for acute attack of
4. Eye, ear and nose; angina) and buprenorphine.
As drops, ointment and spray (for infection,
allergic conditions, etc.), e.g. gentamicin - eye (C) Rectal Route.
and ear drops. Drugs can be given in form of solid or liquid.
5. Vagina: 1.Suppository: It can be used for local (topical)
As tablet, cream, pessary, etc. (for vaginal effect as well as systemic effect, e.g.
candidiasis). indomethacin for rheumatoid arthritis.
6.Urethra:
As jelly, e.g. lignocaine. 2. Enema : Retention enema can be used for local
7.Skin: effect as well as systemic effect.
As ointment, cream, lotion, powder, eg. The drug is absorbed through rectal mucous
clotrimazole (antifungal) for cutaneous candidiasis. membrane and produces systemic effect,
e.g. diazepam for status epilepticus in children
(B) Intra-arterial route: This route is rarely methylprednisolone enema in ulcerative colitis.
employed. It is mainly used during diagnostic
studies, such as coronary angiography and for the (D) Parenteral Routes
administration of some anticancer drugs, e.g. for Routes of administration other than enteral route
treatment of malignancy involving limbs. are called parenteral routes.

(C) Administration of the drug into deep tissues (E) Inhalation

by injection, e.g. administration of triamcinolone Volatile liquids and gases are given by inhalation
directly into the joint space in rheumatoid for systemic effects, e.g. general anaesthetics.
arthritis.
(F) Injections(below)

ORAL IV INTRAMUSCULAR (IM) SUBCUTANEOUS INTRADERMAL

(PER OS or PO) PARENTERAL

INHALATION SUBLINGUAL RECTAL TOPICAL OTIC OPHTHALMIC

 INJECTIONS
Intradermal Subcutaneous (s.c.) Intramuscular (i.m.) Intravenous (i.v.) Intrathecal
Route. Route. Route. Route.
The drug is The drug is Drugs are injected Route. Drugs are Drug is
injected into injected into the into large muscles, injected directly into injected into
layers of skin, subcutaneous tissue such as deltoid, the blood stream subarachnoid
eg. BCG of the thigh, gluteus maximus and through a vein. space, e.g.
vaccination and abdomen, arm, e.g. vastus lateralis, e.g. lignocaine
drug sensitivity adrenaline, insulin, paracetamol, Advantages (spinal
tests. etc. diclofenac, etc. ->Bioavailability is anaesthesia),
A volume of 5-10 ml 100%. antibiotics
It is painful and Advantages can be given at a ->Quick onset of (amphotericin
a small amount of Self -administration time. action, so it is the B). etc.
the drug can be of drug is possible, route of choice in
administered. e.g. insulin. Depot Advantages : emergency, e.g.
preparations can be is more intravenous diazepam
inserted into the rapid as compared to to control convulsions
subcutaneous oral route. ->Mild in status epilepticus.
tissue, e.g. irritants, depot ->Large volume of
norplant for injections, soluble fluid can be
contraception. substances and administered, e.g.
suspensions can be intravenous fluids in
Disadvantages : given by this route. patients with severe
-^It is suitable only dehydration.
for non -irritant Disadvantages •^Highly irritant
drugs. Aseptic conditions are drugs, e g. anticancer
needed. drugs can be given
->Drug absorption is -Untramuscular because they get
slow, hence not (i.m.) injections are diluted in blood.
suitable for painful and may cause ->Hypertonic solution
emergency. abscess. can be infused by
intravenous route,
->Self -administration e.g. 20% mannitol in
is not possible. cerebral oedema.

-> There may be Disadvantages

injury to nerves. ^Local irritation may
cause phlebitis.
->Self- administration
is usually not
possible.
-^Strict aseptic
conditions are
needed .
 PHARMACOKINETICS

Pharmacokinetics is derived from two words: Pharmacon meaning drug and kinesis
meaning movement.
It includes: absorption (A), distribution (D), metabolism (M), excretion (E).

All these processes involve movement of drug molecule through various biological
membranes.
Passive diffusion: Active transport: Facilitated diffusion: Filtration: Endocytosis:
It is a bidirectional Drug molecules move This is a type of Filtration The drug is
process. from a region of carrier -mediated depends on the taken up by the
The drug molecules lower to higher transport and does molecular size cell through
move from a region concentration against not require energy. and weight of vesicle
of higher to lower the concentration The drug attaches to the drug. formation.
concentration until gradient. It requires a carrier in the If drug
equilibrium is energy, e.g. membrane, which molecules are Absorp tion of
attained. transport of facilitates its smaller than the vitamin B12-
sympathomimetic diffusion across the pores, they are intrinsic factor
amines into neural membrane. filtered easily complex in the
tissue, transport of through the gut is by
choline into membrane. endocytosis.
cholinergic neurons
and absorption of
levodopa from the
intestine
DRUG ABSORPTION
Movement of a drug from the site of administration into the blood stream is known
as absorption.
FACTORS INFLUENCING DRUG ABSORPTION:
Physicochemical Route of drug pH and Food Presence of Area of the Gastrointestinal
properties of drug: administration: ionization other drugs absorbing and other
surface diseases:

l.Physicochemical properties of drug:

Physical Lipid- soluble Particle Disintegration time: Dissolution Formulations:
state: and unionized size; It is the time taken time: Pharmacologically
Liquid form form: Drugs with for the formulation It is the time inert substances
of drug is of the drug smaller (tablet or capsule) taken for the like lactose.
better is better particle size to break up into particles to go starch, calcium
absorbed absorbed arc small particles and into solution. sulphate, gum, etc.
than solid than water absorbed its variation may ore added to
formulations. soluble and better than affect the Shorter the formulations as
ionized form. larger ones. bioavailability time, better is binding agents.
the These are not
absorption. totally inert and
may affect the
absorption of drug
Route of drug pH and Food Presence of Presence of Area of the Gastrointestinal
administration: ionization: food in the other drugs: absorbing and other
A drug Strongly stomach can Concurrent surface: diseases:
administered by acidic affect the administrate Normally, In gastroenteritis,
intravenous route (heparin) and absorption of some n of two or drugs are there is increased
bypasses the strongly basic drugs. more drugs better peristaltic
process of (aminoglyco si Food decreases may affect absorbed in movement that
absorption as it des) drugs the absorption of their small decreases drug
directly enters usually rifampicin, absorption, intestine absorption. In
the circulation. remain levodopa, etc., e.g. ascorbic because of achlorhydria,
Some drugs are ionized at all hence they should acid a larger absorption of iron
highly polar pH, hence be taken on an increases the surface from the gut is
compounds, ionize they are empty stomach for absorption of area reduced.
in solution and poorly better effect. oral iron.
are not absorbed absorbed Milk and milk
through GI products decrease
tract. the absorption of
tetracyclines.

BIOAVAILABILITY

It is fraction of a drug that reaches systemic circulation from a given dose.

Intravenous route of drug administration gives 100% bioavailability as it directly
enters the circulation.

Other factors that affect bii of a are:

First- pass metabolism (First- pass effect, Hepatic diseases: Enterohepatic cycling:
presystemic elimination): They result in a Some drugs are excreted
decrease in drug via bile but after
When drugs are administered orally, they have to metabolism, thus reaching intestine they
pass via gut wall ->portal vein -Oliver ->systemic increasing the are reabsorbed n liver n
circulation. bioavailability of drugs bile n intestine and the
that undergo high first- cycle is repeated such
During this passage, certain drugs get pass metabolism, eg. recycling is called
metabolized and are removed or inactivated pro pranolol and enterohepatic circulation
before they reach systemic circulation. lignocaine. and it increases
This process is known as first-pass metabolism. bioavailability as well as
The net result is a decreased bioavailability of the duration of action of
the drug and diminished therapeutic response the drug.
S ystemic eirculaiion Factor* atfectmg bioavadabibty of a drug
1. Physrcochem+cal properties of the drug
2 Route of drug admmislralion
3. pH and wUation
4 Food
5 . Presence of other drugs
6. Arse of absorbing surface
7 Gastrointestinal and other diseases

8 Fjrst^aw metabolrsm
9 Hepatic diseases
10 Enlerohepalic cycling
Fig. 1.4 First pass metabolism. Plot between plasma concentration and time to calculate bloavsIUbllrty

BIOEQUIVALENCE:
Many different pharmaceutical companies can manufacture same compound (with
same dose as well as dosage form) e.g. phenytoin is available as tab. Dilantin as
well as Tab. Eptoin.
If the difference in bioavailability of these two preparations (same drugs, same
dose, same dosage forms) is less than 20%, these are known to be biaequivalent.
these are biologically equal i.e. will produce similar plasma concentrations.

DRUG DISTRIBUTION

Distribution is defined as reversible transfer of drugs between body -fluid

compartments .
After absorption, a drug enters systemic circulation and is distributed in body
fluids.
Apparent Volume of Distribution :
Apparent volume of distribution (aVd) is defined as hypothetical volume of body
fluid into which a drug is uniformly distributed at a concentration equal to that in
plasma, assuming body to be a single compartment.
Total administered amount of drug
aV . = ,
Concentration of the drug in plasma
Drugs with high molecular weight (e.g. heparin) or extensively bound to plasma
protein (eg. warfarin) are largely restricted to vascular compartment, hence their
oVd is low.
Drug Reservoirs or Tissue Storage :
Some drugs are concentrated or accumulated in tissues or some organs of the
body, which can lead to toxicity on chronic use,
e g. tetracyclines - bones and teeth; thiopen tone and DDT - adipose tissue;
chloroquine - liver and retina; digoxin - heart etc...
Blood-Brain Barrier Placental Barrier
The capillary boundary that is present between Drugs administered to a pregnant woman can
blood and brain is called blood—brain barrier (BBB). cross placenta and reach fetus.
Passage across placenta is affected by lipid
In the brain capillaries, the endothelial cells are solubility, degree of plasma protein binding,
joined by tight junctions. presence of transporters.
Only the lipid-soluble and unionized form of drugs substances with high molecular weight like
can pass through BBB and reach the brain. insulin cannot cross the placental barrier
Lipid -insoluble and ionized particles do not cross the
BBB

PLASMA PROTEIN BINDING

Many drugs bind to plasma proteins like albumin, 1 acid glycoprotein, etc...
Clinical importance of plasma protein binding:
->Drugs that are highly bound to plasma proteins have a low volume of distribution.
-> Plasma protein binding delays the metabolism of drugs.
->Bound form is not available for filtration at glomeruli .
Hence, excretion of highly plasma protein bound drugs by filtration is delayed.

Highly protein bound drugs have a longer duration of action, e.g. sulphadiazine is
less plasma protein bound and has a duration of action of 6 hours, whereas
sulphadoxine is highly plasma protein bound and has a duration of action of 1
week.

In case of poisoning, highly plasma protein bound drugs are difficult to be removed
by haemodialysis.
Ab&urption
Drug Enters circulation

Binds to plasma protein ( acidic drugs to

albumin, basic drugs to acid glycoprotein)

Free form (pharma* < * Bound form (cannot exert pharmacological

cologically active ) action, acts as a ‘temporary store’ of the drug)

In disease states like anaemia, renal failure, chronic liver diseases, etc. plasma
albumin levels are low (hypoalbuminaemia).
there will be a decrease in bound form and an increase in free form of drug,
which con lead to drug toxicity.
Plasma protein binding can cause -> displacement interactions.
More than one drug can bind to same site on plasma protein.
The drug with higher affinity will displace one having lower affinity and may result
in a sudden increase in free concentration of drug with lower affinity.
CLINICAL IMPORTANCE OF PLASMA PROTEIN BINDING
• Duration of action: Drugs with high PPB are usually long acting
• Distribution: High PPB drugs stay in plasma, thus have low Vd .
* Displacement: Highly PPB drug can be displaced by another highly bound drug

• Dialysis: It is not effective for drugs having high PPB

 BIOTRANSFORMATION (DRUG METABOLISM)

Chemical alteration of drug in a living organism is called biotransformation.

The metabolism of a drug usually converts lipid -soluble and unionized compounds
into water-soluble and ionized compounds, hence not reabsorbed in renal tubules
and are excreted.
If parent drug is highly polar (ionized), then it may not get metabolized and is
excreted as such.
Sites:
Liver is main site for drug metabolism, other sites are GI tract, kidney, lungs,
blood, skin and placenta.
The end result of drug metabolism is inactivation, but sometimes a compound with
pharmacological activity may be formed as shown below:
Active drug to inactive metabolite: Active drug to active Inactive drug (prodrug)
This is the most common type of metabolic metabolite to active metabolite
transformation. Codeine -^Morphine Levodopa ^Dopamine
Phenobarbitone-> Hydroxyphenobarbitone Diazepam ->Oxazepam Prednisone ->
Phenytoin -> p- Hydroxyphenytoin Prednisolone

Prodrug:
It is an inactive form of a drug, which is converted to an active form after
metabolism.
Uses of Prodrugs (Advantages):
1. To improve bioavailability: Parkinsonism is due to To prolong the To improve To provide
deficiency of dopamine. Dopa mine itself cannot be duration of action: taste: site-
used since it does not cross BBB. So, it is given in Phenothiazines Clindamycin has spacific
the form of a prodrug, levodopa. have a short a bitter taste, drug
Levodopa crosses BBB and is then converted into duration of action, so clindamycin delivery:
dopamine. whereas esters of palmitate sus Flow chart
|
» Levodopa
Dopa devarboxyhw phenothiazine pension has below
Levodopa | * Dopamine
(fluphenazine) been developed
BBB
have a longer for paediatric
duration of action use to improve
the taste

TO PROVIDE SITE-SPECIFIC DRUG DELIVERY SYSTEM:

,, . .
Methenamine
acidic pH of urine
1
_ ,, , . , . . .
Formaldehyde (acts as urinary antiseptic)
Metabolism may occur with help of microsomal (present in smooth endoplasmic
reticulum) or non -microsomal enzymes.
Microsomal enzymes (monooxygenases, cytochrome P45O and glucoronyl
transferase) may be induced or inhibited by other drugs whereas non -microsomal
enzymes are not subjected to these interactions.
 Metabolic Reactions

Phase 1 Phase II
(Both microsomal as well as non- microsomal)
• Oxidation
l
* Hydroxylation Microsomal Non-microsomal
- Dealkylation • Glucuronide • Glutathione
- Deamination
• Reduction
conjugation
(Most common •
conjugation
Acetylation
• Hydrolysis phase H reaction) • Methylation
• Sulfation

Table 1.1 Phase I reactions

Oxidation Addition of oxygen/removal of Phenytoin, phenobarbitone, pento¬
hydrogen barbitone. propranolol
Reduction Removal of oxygen/addition of Chloramphenicol, methadone
hydrogen
Hydrolysis Break down of compound by -
Esters procaine, succinylchoiine
addition of water Amides - lignocaine, procainamide
Cyclization Conversion of straight chain Proguarul
compound into nng structure
Decyclization Breaking up of the ring structure Phenobarbitone, phenytoin
of the drug

Phase II Reactions :
If phaseImetabolite is polar, it is excreted in urine or bile.
Many metabolites are lipophilic and undergo subsequent conjugation with an
endogenous substrate, such as glucuronic acid, sulphuric acid, acetic acid or amino
acid.
These conjugates are polar, usually water-soluble and inactive.
Not all drugs undergo phaseIand phase II reactions in that order.
In case of isoniazid (INH), phase II reaction precedes phaseIreaction
Table 1.2 Phase H reactions Drug Drug Drug Drug
(INH)
Conjugation reaction Enzyme Examples
Glucuronidation UDP glucuronosyf transferase • Aspirin
• Morphine
Acetylation N-acetyftransferase • Isoniazid
• DapsOne
Sulphaton Sulphotransferase • Paracetamol
• Methyldopa
Methylation Transmethylase • Adrenaline
• Dopamine
Glutathione conjugation Glutathione transferase • Paracetamol
Glycine conjugation Acyl CoA glycine transferase • Salicylates Fig. 1.5 Phases of biotransfcrmation.
 DRUG EXCRETION

Removal of drug and its metabolite from body is known as drug excretion.
The main channel of excretion of drugs is kidney; others include lungs, bile,
faeces, sweat, saliva, tears, milk, etc...
Kidney: Lungs: Bile: Skin: Metals like Milk:
The processes Alcohol and Some drugs arsenic and mercury are Drugs taken by
involved in the volatile general are secreted excreted through skin. lactating women
excretion of drugs via anaesthetics, in bile. They may appear in
kidney are gio merular such as ether. are Saliva: Certain drugs milk. They may
filtration, passive halothane, isoflu reabsorbed in like potassium iodide. or may not
tubular reabsorption rane, the gut while phenytoin, adversely affect
and active tubular sevoflurane and a small metronidazole and the breast fed
secretion. Glomerular ether are portion is lithium are excreted in infant. Drugs like
filtration and active excreted via excreted in saliva. penicillins.
tubular secretion lungs. faeces, e.g. erythromycin,
facilitate drug tetracyclines. Salivary estimation of etc. are safe for
excretion, whereas Faeces: Drugs lithium may be used for use but
tubular reabsorption like purgatives, noninvasive monitoring amiodarone is to
decreases drug eg. senna, of lithium therapy. be avoided in
excretion cascara, etc. mothers during
are excreted in breast feeding.
faeces

PHARMACOKINETIC PARAMETERS

The important pharmacokinetic parameters are bioavailability, volume of

distribution, plasma half-life (tl/2) and clearance.
PLASMA HALF-LIFE (tl/2) CLEARANCE

It is time required for plasma concentration of a Clearance (CL) of a drug is defined as that
drug to decrease by 50% of its original value. volume of plasma from which the drug is removed
in unit time.
Plasma half-life of lignocaine is 1 hour and for Rate of elimination
aspirin it is 4 hours. Clearance = — ——
Plasma concentration of the drug

Clinical Importance of Plasma Half-Life. (a) First order kinetics

->It helps to determine duration of drug action, (b) 0 order kinetics
-^determine frequency of drug administration,
-^estimate time required to reach steady state.
(At steady state, amount of drug administered is
equal to the amount of drug eliminated in dose
interval)
First order kinetics Zero-order kinetics:
A constant fraction of the drug in the body is A constant amount of a drug in the body is
eliminated per unit time. eliminated per unit time.
For example, assume drug ‘A‘ with plasma tl/2 of For example, ethanol is eliminated from the body
1 hour following first -order kinetics of elimination at the rate of about 10 mL/h.
and having an initial plasma concentration of 100 Assume a drug 'B' with an initial plasma
mcg/ml concentration of 200 mcg/mL and eliminated at a
1 hour 1 hour constant amount of 10 mcg per unit time. The
100 mcg/mL 50 mcg/ml 25 mcg/mL concentration will be 190 mcg/mL after 1 hour
V* 'A
and 100 mcg/mL after 10 hours. So, half-life is
The rate of drug elimination is directly
10 hours.
proportional to its plasma concentration. 1 hour 1 hour
200 mcg/mL 190 mcg/niL 180 mcg/ml
10 mcg 10 mcg
The tl/2 of the drugs following first- order
If its concentration is increased to 300 mcg/mL,
kinetics will always remain constant.
concentration will be 290 mcg/mL after 1 hour
(as constant amount 10 mcg per unit time is
The drug will be almost completely eliminated in
eliminated)
four to five plasma half -lives if administered at a
The rote of elimination is independent of plasma
constant rate at each half-life.
drug concentration
Most of the drugs follow first-order kinetics.

First Order Kinetics (Linear kinetics) Zero Order Kinetics (Non linear Kinetics)
Constant fraction of drug to eliminated Constant amount of the drug is eliminated per
per unit lime. unit time.
2 Rate of elimination ts proportional to Rate of elimination is independent of plasma
plasma concentration concentration.
3. Clearance remains constant Clearance is more at low concentrations and less
al high concentrations
4 Half life remains constant Half life is fess al tow concentrations and more at
high concentrations Drugs showing ltrs /pseudo HfO order kinetics

Most of the drugs follow first order Very few drugs follow pure zero order kinetics Zrm Zero twiiur kirwln* 'him n tn
kinetics. e g alcohol W WiULie in
A A kuhoi and A-^iirm
Any drug at high concentration (when metabolic T Theophylline
or elimination pathway ts saturated) may show T Tolbutamide
zero order kinetics. P^wer Wmrylci n

Fig. 1.6 (A) Plasma half life of a drug after single intravenous injection. (B) Steacy state: achieved
after approximately four to five half-lives during repeated administration at a constant rate.
 PHARMACODYNAMICS

Pharmacodynamics (Greek pharmacon: drug; dynamis: power).

It covers all aspects relating to 'what the drug does to the body'.
It is study of drugs - their mechanism of action, pharmacological actions and
adverse effects
Types of effects of a drug:
Stimulation: Depression: Irritation: Cytotoxic: Replacement:
Some drugs act by Some drugs Certain Drugs are selectively When there is a
increasing the act by agents on toxic for the deficiency of
activity of specific decreasing the topical infecting endogenous substances,
organ/system, e.g. activity of application organism/cancer they can be replaced by
adrenaline specific can cause cells, e.g. drugs, e.g. insulin in
stimulates the organ/system, irritation of antibiotics/anticancer diabetes mellitus,
heart resulting in an e g. alcohol, the skin and drugs. thyroxine in cretinism
increase in heart barbiturates, adjacent and myxoedema, etc.
rate and force of general tissues
contraction. anaesthetics,
etc. depress
the central
nervous
system.

Mechanism of drug action:

(a) Non- receptor mediated
(b) Receptor mediated

NONRECEPTOR -MEDIATED MECHANISM OF ACTION OF DRUGS

1. By physical action: 2. By chemical action: 3. Through enzymes: 4. Through ion
Osmosis Some drugs act by -> Antaeids are weak Some drugs act by channels :
exerting an osmotic effect, bases - they inhibiting the enzyme Some drugs directly
eg. 20% mannitol in cerebral neutralize gastric acid activity. bind to ion channels
oedema and acute congestive - useful in peptic and alter flow of
glaucoma. ulcer. -> Angiotensin -converting ions, e g. local
enzyme (ACE) inhibitors, anaesthetics block
Adsorption: Activated like iron, such as captopril, sodium channels in
charcoal adsorbs toxins; copper, mercury, etc. enalapril, etc. act by neuronal membrane
hence, it is used in the are eliminated from inhibiting ACE. They are to produce local
treatment of drug poisoning. the body with the help used in the treatment anaesthesia.
of chelating agents. of hypertension,
Demulcent: Cough syrup congestive heart Through antibody
produces a soothing effect in These agents trap failure, etc. production: Vaccines
pharyngitis by coating the metals and form produce their effect
inflamed mucosa. water-soluble com b. Xanthine and by stimulating the
plexes, which are hypoxanthine are formation of
Radioactivity Radioactive rapidly excreted from oxidized to uric acid by antibodies, e.g.
isotopes emit rays and the body, e.g. the enzyme xanthine vaccine against
destroy the tissues, e.g. 1311 dimercaprol (BAL) in oxidase, which is tuberculosis (BCG),
in hyperthyroidism arsenic poisoning, inhibited by allopurinol. oral polio vaccine,
desferrioxamine in iron Allopurinol (competitive etc.
poisoning and d- inhibitor) is used in the
penic illumine in copper treatment of chronic
poisoning. gout to reduce the
synthesis of uric acid.

RECEPTOR-MEDIATED MECHANISM OF ACTION OF DRUGS:

Receptors are macromolecules, present either on cell surface, cytoplasm or in the
nucleus with which drug binds and interacts to produce cellular changes.
Drug (D) + Receptor (R) * Drug-rcccptor complex > Response
Affinity: The ability Agonist: A drug that is Partial Inverse agonist:
of drug to get bound capable of producing agonist: It has full affinity towards the
to receptor is known pharmacological action after A drug that receptor but produces effect
as affinity. binding to receptor is called binds to the opposite to that of an agonist,
an agonist. receptor but e.g. benzodiazepines (BZDs)
Intrinsic activity: The Agonist has high affinity high produces an produce antianxiety and
ability of drug to intrinsic activity (e.g. effect less anticonvulsant effects by
produce morphine and adrenaline). than that of interacting with BZD receptors,
pharmacological action an agonist is but -carbolines act as inverse
after combining with Antagonist: A drug that called agonist at BZD receptor and
the receptor is known prevents binding of agonist to partial produce anxiety and
as intrinsic activity of its receptor or blocks its agonist. convulsions.
the drug. effect/s is called an It inhibits
antagonist. the effect Inverse agonist has affinity
It does not by itself produce of agonist. intrinsic activity
any effect. Partial
Competitive antagonist has agonist has
high affinity without intrinsic affinity less
activity intrinsic
activity
Receptor families:
Ligand-gated ion channels G protein- coupled Enzymatic Receptor -regulating gene
(inotropic receptors) receptors (GPCRs; receptors expression (transcription
metabotropic factors) or the nuclear
receptors) receptor
1.Ligand -Gated Ion Channels (Inotropic Receptors).
Examples are nicotinic (NM) acetylcholine receptors at neuromuscular junction,
GABA (gamma amino butyric acid) and glutamate receptors in CNS.
Binding of agonist to Opens the ion channels Flow of ions
inotropic receptors (Na*, K*, Ca1+, Ci-) * through channels

Tissue Hyperpolarization/
response Depolarization
2. & Protein -Coupled Receptors (GPCRs, Metabotropic Receptors).
GPCRs are trans membrane receptors which control cell function via adenylyl
cyclase, phospholipase C. ion channels, etc.
They are coupled to intracellular effectors through & proteins.
G proteins are membrane proteins and have three subunits (alpha .beta, gamma)
with GDP bound to subunit.
Binding of Coupling of G protein GDP bound to a subunit
agonist to receptors to the receptors exchanges with GTP

Dissociation of G protein
subunits from occupied
receptor. a-GTP also
dissociates from (Jy subunit

a-GTP and fry subunits

are released

Stimulation of GTPasc
lenzyme/ion
Bind to target
associated with a subunit channel
I
GTP GDP
l
Effects produced depends the
on

I,
a subunit associates with fly subunit
type of G protein (G1( Gh Gq and
Go>» which associates with agonist
occupied receptor (see Mow)

G, G, Pt
l® I© I©/©
Adcnylyi cyclase Adcnvlyl cyclase Phospholipase C Enzymes and ion channels,

I
TcAMP,
l TlPj and TdAG.
e.g. all GPCRs

IcAMP.
e.g. |S- adrenergic e.g. aradrencrgic e.g. muscarinic (M^
receptors receptors in smooth muscle receptors

3. Transmembrane Enzyme-Linked Receptors.

Transmembrane enzyme -linked receptors have enzymatic activity in their
intracellular portion. The enzyme is mainly tyrosine kinase, e.g. receptor tyrosine
kinases for insulin, epidermal growth factor, etc.)
 Binding of agonist (eg. Stimulates intrinsic kinase
insulin) to extracellular
Dimerization
activity in intracellular
of the receptor
domain of receptors part of the receptor

I
Phosphorylation of tyrosine residues
on the receptor and other intracellular
proteins ( when insulin/EGF, etc. are agonists >

Tissue Gene Activates intracellular

response transcription signalling pathways

Nuclear Receptors
Regulate Sene Expression.
Examples; receptors for thyroxine, vitamins A and D, sex steroids and
glucocorticoids.
Steroids -> bind to receptors in cytoplasm -> steroid -receptor complex -Emigrates
to nucleus ->binds to specific site on bNA -> regulate protein synthesis ->
response .

THERAPEUTIC INDEX
Therapeutic index (TI) is an index of drug safety.

Median lethal dose (LD?0 ) of die drug

Median effective dose (EDW) of the drug

Therapeutic range
Log dose *
Dose-response curves of therapeutic effect (A) and adverse effect (B).
 Combined effect of drugs
A combination of two or more drugs can result in an increase or a decrease in
response
Increased Response Decreased response
1. Additive effect: In antagonism, effect of one drug is decreased
Combined effect of two or more drugs is equal to or abolished in the presence of another drug.
sum of their individual effect.
Effect of drugs A* B = Effect of drug A Effect Physical antagonism:
of drug B The opposing action of two drugs is due to their
For example, combination of ibuprofen and physical property, e.g. adsorption of alkaloids by
paracetamol as analgesic activated charcoal - useful in alkaloid poisoning.

2.Potentiation (supra -additive): Chemical antagonism:

The enhancement of action of one drug by an opposing action of two drugs is due to their
other drug which is inactive is called potentiation. chemical property, e.g. antacids are weak bases;
Effect of drugs A* B >Effect of drug A they neutralize gastric acid and are useful in
Effect of drug B peptic ulcer; chelating agents complex metals and
Levodopa* carbidopa; are useful in heavy metal poisoning (dlmercaprol
acetylcholine *physostigmine . in arsenic poisoning).
Carbidopa and physostigmine inhibit breakdown of
levodopa and acetylcholine, respectively, thus Physiological (functional) antagonism:
enhancing their effects. Here, two drugs act at different receptors or
by different mechanisms on same physiological
3. Synergism: system and produce opposite effects,
When two or more drugs are administered e.g. insulin and glucagon an blood sugar;
simultaneously, their combined effect is greater adrenaline and histamine on bronchial smooth
than that elicited by either drug alone. muscle - histamine produces bronchoconstriction
For example, sulphamethoxazole + trimethoprim; (via histamine receptors), whereas adrenaline
pyrimethamine *sulphadoxine produces bronchodilatation by acting through
adrenergic ( beta 2) receptors - hence,
adrenaline helps to reverse bronchospasm in
anaphylactic shock.

Receptor antagonism:
The antagonist binds to same receptor as the agonist and inhibits its effects.
It can be competitive or noncompetitive

Competitive antagonism:
In competitive antagonism, both agonist and the antagonist bind reversibly to same
site on the receptor.

16
Equilibrium type of competitive antagonism Nonequilibrium antagonism
It can be overcome (reversible) by increasing The antagonist binds to the same site on the
concentration of agonist. receptor as agonist but binding is irreversible.
The log DRC of the agonist shows a rightward The antagonist forms strong covalent bond with the
parallel shift in the presence of competitive receptor, e.g. phenoxybenzamine is an irreversible
antagonist antagonist of adrenaline at receptors.

Non-competitive antagonism:
The antagonist binds to a different site on receptor and prevents the agonist from
interacting with the receptor.
In this type, the antagonistic effect cannot be overcome by increasing the
concentration of the agonist. There is a flattening of the ORC in noncompetitive
antagonism, e g. diazepam and bicuculline

Agonist + noncompetitive antagonist (increasing dose)

Fig. 1.12 Noncompetitive antagonism. (Adapted from Alfred Gilman Sr. and Louis S. Goodman;
Goodman 8 Gilman's The Pharmacological Basis of Therapeutics, I2e.)
 TOLERANCE
It means need for larger doses of a drug to produce a given response' .
Tolerance develops to nasal decongestant effect of ephedrine on repeated use.
Patients on organic nitrates for angina develop tolerance on long-term therapy.

drug drug effect

Tolerance is commonly seen with drugs like morphine, alcohol, amphetamine, etc
(a) Types of tolerance:
Tokrancc

I *
Natural IoEerance Acquired tolerance

Genetically determined reduced/ l

It develops on repeated exposure to a
lack of response to a drug
drug, sometimes tolerance develops
only to certain effects, e.g. on repeated
use of morphine, tolerance develops
Species tolerance Racial tolerance to its euphoriant effect but not to its
Some species are tolerant to Some races show tolerance miotic effect
certain drug?, eg. rabbits to certain drugs, c.g. blacks
can tolerate large doses of are tolerant to mydriatic?
atropine
(b) Mechanism of development of tolerance:
1) Pharmacokinetic tolerance Cross -tolerance:
(dispositional tolerance): The phenomenon of tolerance exhibited by closely related (structural
and mechanistic) drugs is called cross- tolerance, eg. among nitrates,
It is due to reduced con among apioids, between ether and alcohol.
centration of drug at site of
-
action may be as a result of Tachyphylaxis (tachy =rapid; phylaxis protection; acute tolerance):
decreased absorption, Repeated use of certain drugs at short intervals may result in rapid
increased metabolism and decrease in pharmacological response.
excretion. This is known os tachyphylaxis or acute tolerance, e g. tyramine.
ephedrine and amphetamine.
For example: rifampin induces
metabolizing enzyme of oral These drugs act by releasing noradrenaline from adrenergic nerve
contraceptives, enhances their endings. Repeated administration of the drug causes gradual depletion
metabolism, leading to of the neurotransmitter and hence reduction in the response
contraceptive failure.
/
/

Respone
, 1
t9.t lows of ephedra oh BP
Pfa- 113 Tach^aMB- flP, PW*
 AUTONOMIC NERVOUS SYSTEM PHARMACOLOGY
Autonomic nervous system Somatic nervous system
Aufo self: nomos governing, this system 3 Somatic nervous system is under
mvoluniniy and maintains homeostasis voluntary control Nervous system
Each autonomic fibre ts nwde up of two Each somatic fibre ci made 141 oi
neurons arranged in senes angle motor neuron, which
connects CNS Io skeletal
rnusctes
Central nervous system Peripheral nervous system
(CNS) (PNS)
Effector ceil Motor
nerve
Ganglia V Skeletal muscle

1— *10 {neuromuscular
junction) Autonomic nervous Somatic nervous
Neuroeffector junction
1
* •Postgangiicne fibre
system (ANS) system
L * Preganglionic fibre
*
It innervates the bean, smooth muscles and It innervates skeletal muscte
exocnrio glands Sympathetic system Parasympdthdic system
it controls visceral functions such as circulation, it controls skeletal muscle tone
digestion and excretion

parasympathetic
nerves

sympathetic
nerves

sympathetic
nerves

Ach Acetylcholine [NJ Nicotinic acetylcholine receptor

E Epinephrine [M] Muscarinic acetylcholine receptor
NE Norepinephrine [a] Norepinephrine receptor subtype
I/? ] Norepinephrine receptor subtype

CHOLINERGIC DRUG: Act on receptor by ach

ADNERGIC DRUG: Act on receptor stimulated by nor -epinephrine
Cholinergic Receptors
 CHOLINERGIC SYSTEM

Acetylcholine (ACh) is -> neurotransmitter in cholinergic system

The neurons that synthesize, store and release ACh are called cholinergic neurons

SYNTHESIS OF ACETYLCHOLINE :
Choline enters -> cholinergic neuron by carrier- mediated transport, where it
reacts with acetyl -CoA with help of choline acetyltransferase (ChAT) to form
ACh.
The ACh is then stored in storage vesicles.
It is released into synaptic cleft when an action potential reaches nerve terminals.
The released ACh interacts with cholinergic receptors on effector cell and
activates them.
In the synaptic cleft, ACh is rapidly hydrolysed by acetylcholinesterase (AChE)
enzyme.

aii . HO-C-
ch\^ch, q Acetic Acid
+ N-CH2CHj-O-C-CH3
EtetoMndanMcWn ¥
fa Cho*re

CH2CH3OH
Aevtylc hoNnortof»•

CHOLINESTERASES
ACh is rapidly hydrolysed to choline and acetic acid by enzyme cholinesterases.
There are two types of cholinesterase:

True cholinesterase or AChE: Pseudocholinesterase or butyrylchalinesterase:

It is found in cholinergic neurons, ganglia, RBCs It is found in plasma, liver and glial cells.
and neuromuscular junction (NMJ). Pseudocholinesterase can act on a wide variety of
It rapidly hydrolyses ACh and methacholine. esters including ACh (hydrolysis is slow) but does
not hydrolyse methacholine.
 Sympathetic stimuUUon Orfan Parasympathetic stimulation
Heart

* HR
CHARACTERISTICS OF THE
AUTONOMIC NERVOUS SYSTEM
’foc 1 FOC
Pupil SYMPATHETIC PARASYMPATHETIC
Mydriasis Miosis NERVOUS SYSTEM NERVOUS SYSTEM

DIALATES PUPILS CONSTRICTS PUPILS

INHIBITES SALIVARY GLANDS STIMULATES SALIVARY GLANDS

Bfonchodilaiatron 4 Bronchospasm
ACCELERATES HEART RATE SLOWS HEART RATE

Cl motility DELATES BRONCHI CONSTRICTS BRONCHI

decreases and
sphincter tone CONVERTS GLYCOGEN STIMULATES STOMACH
increases TO GLUCOSE FOR AND INTESTINES AND
IMMEDIATE ENERGY BILE RELEASE

INHIBITS BLADDER CONTRACTION CONTRACTS BLADDER

Rfl. 2-2 Effects of sympattwtic and parasympathoiK! stimuiaiian on various organs HR, heart
rate; FOC. force 01 contraction. GH. gastroiniestinai trad,

CHOLINERGIC RECEPTORS
They are divided broadly into two types - muscarinic and nicotinic.
Muscarinic receptor subtypes with their location(s)

t 1 t
M, M, M, ,
M and M
• Gastric glands • Heart • Smooth muscles • CNS
• Autonomic ganglia • Exocrine glands
• CNS • Endothelial cells
Nicotinic receptor subtypes with their bcationB)
I
Nn nm
• Autonomic ganglia • Neuromuscular junction (NM|)

. • Adrenal medulla
CNS

CHARACTERISTICS OF MUSCARINIC AND NICOTINIC RECEPTOR SUBTYPES:

Receptor type(s) Intracellular effects Response
Mt and Ms T Inositol triphosphate (IPJ • Increases learning and memory
and T diacylglycerol • Promotes glandular secretion and
(DAG) smooth muscle contraction
M, I Cyclic adenosine Hyperpolarization
monophosphate (cAMP), • Depresses SA node
opening of K ‘ channels • Depresses AV node
• Decreases atrial and ventricular
contraction
Nn Opening of ion channels Depolarization
(Na\K‘) • Release of adrenaline and nor¬
adrenaline from adrenal medulla
Nm Opening of ion channels • Depolarization
(Na\K') • Skeletal muscle contraction
 CHOLINERGIC DRUG

CHOLINERGIC DRUGS

Choline esters Alkaloids

Acetylcholine Muscarine
Methacholine Pilocarpine
Carbamates
Reversible
J
Acridine
. Irreversible
L
Carbamates Organophosphates
Carbachol Arecoline
Bethanechol Physostigmine Tacrine Carbaryl* Dyflos (DFP)
(Eserine) (Sevin) Echothiophate
Neostigmine Propoxur* Malathion*
Pyridostigmine (Baygon) Diazinon*
(TIK-20)
* Insecticides Edrophonium
£ Nerve gases Rivastigmine Tabun £
for chemical Donepezil Sarin £
warfare Galantamine Soman c

Trick :
Directly acting:
Kohli(Choli) comes directly on ABP news in cor with methali and musa.
Alkaloids: APM

Reversible:
Lipid soluble: Water soluble
Galantamine Neostigmine
Rivastigmine Edrophonium
Physostigmine
Donepezil
Tacrine
Choli and lip* ki ga ri phasi - do taxi
lagi - fir pani peeya
Irreversible:
Organophosphates :
Choli calls indirectly apne paa or maa ko bulaya in eco with tabu,sara,soma in
organization
 ACHETVLCHOLINE
ACh produces muscarinic and nicotinic effects by interacting with respective
receptors on effector cells.
MUSCARINIC ACTIONS:
(a)Cardiovascular system->
Heart:

XI HR (negative chronotropic effect)

II FOC (negative inotropic effect)

|| A-V conduction (negative dromotropic effect)

Fig. 2.5 The effect of acetylcholine (ACh) on blood vessels.

(b)Smooth muscles:
Gastrointestinal tract:
T Tone of the gut

T Peristaltic movements

T Gl secretions

— Relaxes the sphincter (may cause defecation)

Fig. 2.6 Effects of acetylcholine {ACh) on gasiiwitestinai (Gt) tract

Urinary bladder:
Contracts the detrusor muscle

AO,

Relaxes trigone and sphincter (causes urination)

Fig. 2,7 Effects of acetylcholine (ACh) on urinary bladder.

Bronchus:

Contracts the bronchial smooth muscle (bronchospasm)

ACh -® '
Increases tracheobronchial secretion - therefore,
q 7 cholinergic drugs are contraindicated in asthmatics

Fig. 2.8 The effect of acetylcholine (ACh) on bronchi.

(c) Exocrine glands:
Increase in salivary, lacrimal, sweat, bronchial, gastric and other gastrointestinal
(GI) secretions.

(d)Eye
ACh does not produce any effect on topical administration because of its poor
penetration through tissues.
 Sphincter papillae Ciliary muscle

Suspensory Comea
ligament
Lens
iris
Canal of Schlemm

papillae
Fig. 2.9 Autonomic innervation of the eye.

NICOTINIC ACTIONS^
To elicit nicotinic actions, larger doses of ACh are required.
Autonomic ganglia: Skeletal muscles: Actions on CNS:
Higher doses of ACh produce dangerous At high Intravenously administered ACh
muscarinic effects especially on heart. concentration, ACh does not cause any central effects
initially produces because of its poor penetration
Hence, prior administration of atropine twitching, through the blood-brain barrier
is necessary to elicit nicotinic actions. fasciculations (B8B).
Higher doses of ACh stimulate both followed by
sympathetic and parasympathetic prolonged
ganglia depolarization of
NMJ and paralysis.

CHOLINOMIMETIC ALKALOIDS
They mimic the actions of ACh; examples are pilocarpine, muscarine and arecoline.
Pilocarpine: Muscarine:
Pilocarpine is a cholinomimetic It is an active ingredient of poisonous mushroom. Amanita muscaria
alkaloid obtained from Pilocarpus and Inocybe species. Some types of mushroom poisoning are explained
plant. as follows:
Mushroom poisoning
It is a tertiary amine.
It produces muscarinic and 1 1 1
Rapid onset type Hallucinogen type Delayed onset type
nicotinic effects by directly Caused by hweybe species. Caused by Amaniui muHaria Caused byAmir/HM phalloides.
interacting with the receptors. It is characterized by and species. Toxin Toxin is amatoxin. It results in
It has predominant muscarinic excessive muscarinic is muscimol. It produces delayed gastroenteritis, hepatic
effects, vomiting, diarrhoea, mainly central effects. and renal damage. It does not
actions .
bradycardia, salivation. There is no specific antidote; respond to atropine and is
USES: sweating, bronchospasm, atropine is contraindicated, treated withthiactic acid,
-> Pilocarpine 0.5%-4% solution is hypotension, etc. (due to Supportive care should Supportive care is required,
used topically in the treatment toxin muscarine). It be given-
responds to tv. atropine.
of open -angle glaucoma and
acute congestive glaucoma.
-> It is used alternatively with
mydriatics to break adhesions
between the iris and lens.
Pilocarpine is used as a
sialagogue (drug used to augment
salivary secretion)
 1
ANTICHOLINESTERASES

They inhibit -> enzyme cholinesterase that is responsible far hydrolysis of ACh.
Thus, ACh is not metabolized, gets accumulated at muscarinic and nicotinic sites
and produces cholinergic effects.
Hence, anticholinesterases are called indirectly acting cholinergic drugs

Anticholinesterases

Reversible Irreversible

Carbamates | Acridine i Carbamates j Organophosphates

7—1 Dyflos(DFP)
Physostigmine Tacrine Carbaryl*
(Eserine) (Sevin) Echothiophate
Neostigmine Propoxur' Malathion*
Pyridostigmine (Baygon) Diazinon*
(T1K20)
Edrophonium
Rivastigmine Tabun £
Donepezil Sarin c
Galantamine Soman f

Use of NeostlgminefPyridostigmine

Muscarinic Nicotinic
[without atropine) (with atropine)
Postoperative paralytic ileus Mysthenia gravis
Postoperative urinary retention Cobra bite
Reversal of non-depolarizing
muscle relaxants

Physostigmine Neostigmine Pyridostigmine .

(Eserine)
It is a It is a synthetic anticholinesterase agent. All features are same
tertiary amine Its actions are pronounced on NMJ, gastrointestinal as neostigmine.
and has good tract (GIT) and urinary bladder than on cardiovascular
penetration system (CVS) or eye. Pyridostigmine has a
through On skeletal muscle, it has both direct and indirect longer duration of
tissues. actions . action and can be given
Its actions twice daily in sustained
are similar to Indirect Actions. By inhibiting cholinesterases, release form; hence, it
those of other neostigmine increases ACh concentration at NMJ. is preferred to
cholinergic neostigmine in
agents . Direct Actions. Because of structural similarity with myasthenia gravis.
ACh (i.e. quaternary ammonium compound), neostigmine
also directly stimulates NM receptors at NMJ. Even though
Thus, it improves muscle power in patients with pyridostigmine is less
myasthenia gravis. Neostigmine does not cross BBB and potent than
has no central side effects. Therefore, neostigmine is neostigmine, it is
preferred to physostigmine in myasthenia gravis. better tolerated by
It is available for oral, s.c., i.v. and i.m. myasthenic patients.
administration.
 ADVERSE EFFECTS OF ANTICHOLINESTERASES:
They are due to overstimulation of both muscarinic and nicotinic receptors -
increased sweating. Salivation, Nausea & vomiting, abdominal cramps, bradycardia,
diarrhoea, tremors and hypotension.
THERAPEUTIC USES OF REVERSIBLE ANTICHOLINESTERASES;
Eye: Myasthenia Postoperative Curare poisoning and reversal Belladonna Alzheimer's
Glaucoma gravis urinary retention of nondepolarizing poisoning disease
and paralytic neuromuscular blockade
ileus

GLAUCOMA
Aqueous humour formed by ciliary process is drained mainly through trabecular
meshwork
Glaucoma is optic nerve damage with loss of visual function that is frequently
associated with raised IOP.
Normal IOP varies between 10 and 20 mm Hg.
Management of this disorder is almost always directed at lowering the existing
IOP either by improving drainage or decreasing the formation of aqueous humour

Action of muscarinic agonists on eye can be depicted as follows:

Acetylcholine ( Lv.), pilocarpine, physostigmine

Mt receptors
I
Contract sphincter Contract ciliary muscle -► Spasm
pupilhe (miosis) of accommodation

I
Open the trabecular meshwork around the canal of Sehlemm

Facilitate drainage of aqueous humour and reduce

intraocular pressure (1OP) in glaucoma
Ciliary muscle contraction -> Relaxation of suspensory ligaments of lens
I .
Bulging of lens

Vision fixed
i
for near distance

ACUTE CONGESTIVE GLAUCOMA; CHRONIC SIMPLE GLAUCOMA;

It is usually precipitated by mydriatics in people It is a genetically predisposed condition
with narrow iridocorneal angle and shallow affecting -> patency of trabecular meshwork.
anterior chamber.
Acute congestive glaucoma is a medical The IOP rises gradually.
emergency . Pharmacotherapy is definitive treatment in a
Once the attack is controlled, treatment is majority of cases
surgical or laser iridetomy.
 Acute congestive (narrow-angle) Chronic simple (wide-angle)
glaucoma glaucoma
Osmotic agents p -Blockers' (topical)
• Mannitol (20%) i.v. • Timolol (0.25%)
• Glycerol (50%) oral • Belaxdol (0.25%)
• Carteolol (1%)
Carbonic anhydrase inhibitor Prostaglandins
• Acetazoiamide. i.v., oral • Latanoprost (0.005%), topical
p- Blockers Carbonic anhydrase inhibitors
• Timolol (0.5%), topical • Dorzolamide (2%). topical
• Bnnzotamide. topical
• Acetazoiamide, oral
MrOtiCS « Adrenergic agonists
• Pilocarpine (2%), topical • Dipivefnn (0.1%). topical
• Apractonidine(t%), topical
Prostaglandins Miotics
• Latanoprost (0.005%), topical • Pilocarpine (0.5%), topical
'Propranolol is not used in glaucoma as it anesthetizes cornea due to its membrane stabilizing
effect

Group Drug* Mechanism Adverse effect Special points

1 MIOTICS
-
Directly Acting
muscannicagoru&t
Pilocarpine Increase
outflow
trabecular Blurred vision due to
induced myopia
* Pilocarpine is short
acting and can result m
-
AChE inhibitor Physostigmine • Headache and brow fluctuations in (OP
Echothtophate patn * Miches increase the risk of
• AChE inhibitors can lead retinal tears tn susceptible
to cataract formalism individuals
* Can cause punctal
stenosis of nasolacrimal
system
2 BETA BLOCKERS
Non-selective Timolol * Formation of • Allergic blepharo¬ * Should be avoided m
(p*pj blocked Levobunolol
Carleok)! Metipranatd
aqueous humor conjunctivitis
• Precipitates asthma
--
Asthma
Bradycardia
• Transient stinging and -CHF

- CardiaselecUve BeldxOui
burning tn eye -Betaaolot
Diabetes
it
less likely ip
*
(ft) blockers preopdate asthma but is
fess efficacious
3 PGF ANALOGS LatanopfOs! T Uveoscferai outflow *Iris pigmentation * Drug of choice for POAG
Brmataprosi * Growth of eyelashes
Travoprosi • Macular edema in
Tafluprost aphakics (Latanoproslt
Unoprostone * Reactivation of uveitis
(Latanoprosi)

4 a AGONISTS Apr&ctomdme * Aqueous formation • Lid retraction • Brimprudme is fess hkely

Bnmonidine * Dry Mouth to cause ocular allergy
* Ocular burning find • These can cause CN5
allergic conjunctivitis depression and ^pnoa In
neonates and are contra -
indicated m children
« 2 years
5 AGONISTS Drprvetnne * Trabecular and * Conjunctival hyperemia
Adrenaline uveosc feral outflow (Red Eye)
* Ocular atergy
- -

6 CARBONIC DorzOlamide « Aqueous formation • Ocular afergy

ANHYDRASE Brmzoiamide • Corneal edema
INHIBITORS * Bitter taste

Tricks:
Baap CM hai mera
B=Beta blockers P= prostaglandins analogue M= miotics
Alpha agonist C= carbonic anhydrase inhibitors
Beta blockers:
 TABLA
.
Timolol betaxololol,levobunolol
DRUGS USED IN GLAUCOMA

|Aqueous Mcrsw •AqijwiPfl Quito*

Alpha agonist *ackers T “1
q^gonnts Carbonic anhydntM rnhtbUor*
DAB * Bnfflonidww * AceLazdamide
?
• Apfaciond'no •Dorzoterntbo » t
bipivefrine, Apraclonidine, Brimonidine •BnnzolanMda Trabecular t Uveo-»derai
outflow outflow
[ *
Prostaglandin analogues: *
Cardlot&iecltve Non-sctective
Millet 'VtpontiH
•BefsxGltV * Timofey
TABLA trial -LerobuwW Ptfocaff)^ Dtptv(ltr^TW
’
•Carrot - Phyaa^tt^minv
Travoprost,bimatoprost, latanoprost

Carbonic anhydrase inhibitors:

DAB
barzalamide
Brinzolamide

Miotics:
PPE
MYASTHENIA GRAVIS
Myasthenia gravis is an autoimmune disorder where antibodies are produced against
NM receptors of NMJ resulting in a decrease in number of NM receptors.

In myasthenia, there is marked muscular weakness varying in degree at different

times .
MYASTHENIA GRAVIS IS DIAGNOSED BY:
Typical signs and Edrophonium test - edrophonium (2-10 mg) given slow Demonstration of
symptoms - weakness intravenously shows dramatic improvement of circulating antibodies to
and easy fatigability. symptoms in patients with myasthenia gravis but not NM receptors.
in other muscular dystrophies; it is also useful to
differentiate myasthenic crisis from cholinergic
crisis.
 TREATMENT:
Neostigmine is a synthetic anticholinesterase agent.
On skeletal muscle, it has both direct and indirect actions.
Indirect Actions Direct Actions.
By inhibiting cholinesterases, neostigmine increases Because of structural similarity with ACh
ACh concentration at NMJ. (i.e. quaternary ammonium compound), neostigmine
also directly stimulates NM receptors at NMJ.
Thus, it improves muscle power in patients with myasthenia gravis.
Neostigmine does not cross BBB and has no central side effects.
Therefore, neostigmine is preferred to physostigmine in myasthenia gravis.
It is available for oral, s.c., i.v. and i.m. administration.

Long-term use or overdose of anticholinesterases leads to cholinergic crisis (severe

muscular weakness and neuromuscular paralysis due to prolonged depolarization).

This may be differentiated from myasthenic crisis (severe weakness due to

exacerbation of myasthenia) by injecting a small dose of edrophonium (2 mg, i.v.).

-> If patient shows improvement in muscle power -> myasthenic crisis.

If muscular weakness deteriorates n cholinergic crisis.

• Ventilator should be kept ready before injecting edrophonium as it may

aggravate cholinergic crisis, which is dangerous.

CORTICOSTEROIDS AND OTHER IMMUNOSUPPRESSANTS like azathioprine or

cyclophosphamide are useful in the induction and maintenance of remission.

(c) Postoperative Urinary Retention and Paralytic Ileus :

Neostigmine is used because it increases tone of smooth muscle and relaxes the
sphincters.

* Tone of the detrusor musde

*
Tone

। Peristalsis
Retakes ingone and sphincter
[helps in voiding of urine]

Rg. 2.13 Effects Of neostigmine on smooth muscles of gut and unnary tract

(d) Curare Poisoning and Reversal of Nondepolarizing Neuromuscular Blockade:

Edrophonium or neostigmine is used.
Antagonize neuromuscular blockade by increasing concentration of ACh at NMJ.
Prior administration of atropine is a must to block muscarinic side effects.

(e) Belladonna Poisoning :

Physostigmine is preferred because it reverses both central and peripheral effects
of atropine p
 ORGANOPHOSPHORUS INSECTICIDES | IRREVERSIBLE ANTICHOLINESTERASE

All organophosphorus (OP) compounds except echothiophate have no therapeutic

applications.
Echothiophate is rarely used in resistant cases of glaucoma.

OP compounds have only toxicological importance.

OP poisoning is one of most common poisoning all over world.
Common OP compounds are parathion, malathion, dyflos, etc.
They irreversibly inhibit cholinesterases and cause accumulation of ACh at
muscarinic and nicotinic sites.
Wh* birth t «d<)OK

SIGNS AND SYMPTOMS:

Muscarinic effects: Nicotinic effects: Central effects:
Profuse sweating, salivation, lacrimation, Twitchings, Headache, restlessness,
increased tracheobronchial secretions, fasciculations, muscle confusion, convulsions,
bronchospasm, vomiting, abdominal cramps, weakness and paralysis coma and death are
miosis, bradycardia, hypotension, are due to prolonged usually due to respiratory
involuntary urination and defecation. depolarization , failure.

DIAGNOSIS OP poisoning can be diagnosed by:

History of exposure Characteristic signs and symptoms Estimating cholinesterase activity in
blood, which is decreased
TREATMENT:
General measures: Specific measures:
1. Remove the contaminated clothes; wash skin with soap and water. Atropine
2. Gastric lavage should be continued till returning fluid is clear. Oximes
3. Airway should be maintained.
4. Artificial respiration is given, if necessary.
5. Diazepam should be used cautiously by slow i.v. injection to control
convulsions .
HO-O
ch™;ch3 Oximes OP compounds
?n^ch2chto-c-ch3 > +
JT CH3
W- r y Llir
* 'EsteflcSite' ru ru nu
UMjUrijUn Anionic site Esteratic site
 1. ATROPINE:
Atropine is first drug to be given in OP poisoning.
Inject atropine 2 mg i.v. stat and it should be repeated every 5-10 minutes
doubling dose, if required, till patient is fully atropinized
(fully dilated, nonreactive pupils, tachycardia, etc.).
Atropine should be continued for 7-10 days.
OP poisoning

I Airopine
Mt ACh (agonist) Muscarinic receptors (anLavon

2. OXIMES;
Atropine is not effective for reversal of neuromuscular paralysis.
Neuromuscular transmission can be improved by giving cholinesterase reactivators
such as pralidoxime and obidoxime.
Pralidoxime is administered intravenously slowly in a dose of 1-2 g.

Anionic site Esteratic site

OP compounds inactivate cholinesterases by phosphorylating esteratic site of the
enzyme
Oximes bind with high affinity to anionic site, react with phosphorus atom of the
OP compound, dephosphorylate -> enzyme, and reactivate it.
Early administration of oximes is necessary before phosphorylated enzyme under
goes aging (loses alkyl groups) and becomes resistant to reactivation.

Uses of cholinergic drugs

Muscarinic uses Nicotinic uses

I J
Glaucoma Alzhiemefs Belladona Reversal of Mysthenia gravis Cobra bite
* Pilocarpine •Tacnne •Poisoning muscle relaxants •Neostig¬
• Physostigmine •Oonepezil •Physostigmine •Neostigmine mine
•Ecothiophate •Rivashgmme •Pyridostigmine •Pyridostig¬

Sjogren
•Gallantamne

Postoperative Diagnosis of
I
Diagnosis
—I mine

Treatment
syndrome bronchial hyper •Edrophonium •Neostigmine
•Pilocarpine reactivity •Pyridostigmine
•Cewimehne * Melhachohne
I —
Paralytic ileus
—;
Urinary retention
* Bethanecbol •Bethanechol
• Neostigmine •Neostigmine
 ANTICHOLINERGICS

ANTICHOLINERGIC DRUGS
(Muscarinic antagonists. Airopinic drugs. Parasympatholytic*}

Antisecretary-antispasmodics

Quaternary comps. Tertiary amines

Propantheline Dicyclomine
Oxyphenonium VnlcthamAlu
Cidinium Pirenzepinc
Pipenzolate methyl bromide
Isopropamide
Glycopyrrolate
Natural alkaloids: aIka ne aarti ko hy bola( alkaloids, atropine, hyoscine)
Semisynthetic: homma ka hathi (homatropine, hyoscine butyl bromide. atropine
methonitrate, tiotropium, ipratropium)
Synthetic: antisecretory-antispasmodic : GOCIP
Mydriatics: my city
Antiparkinsonian: aunty ka BP theek hai
Vasicoselective : vase tofu laaya

MECHANISM OF ACTION.
Both natural and synthetic drugs competitively block muscarinic effects of ACh
(competitive antagonism).

ATROPINE:
Atropine is prototype drug and chief alkaloid of belladonna.
It is a tertiary amine.
It blocks actions of ACh on all muscarinic receptors.
Atropine is administered by topical (eye), oral and parenteral routes.
PHARMACOKINETICS:
Atropine, scopolamine and most of synthetic tertiary amines are well absorbed
from conjunctiva and GI tract.
Are widely distributed all over body.
Cross BBB; partly metabolized in liver and partly excreted unchanged in urine
ATROPINE SUBSTITUTES:
Atropine acts on all subtypes of muscarinic receptors.
Atropine substitutes have selective or relatively selective action on a particular
organ, hence produce less adverse effects than atropine.
 PHARMACOLOGICAL ACTION OF ATROPINE:
| { Secretion ol
exocrine glands
Control tremor and
rigidity of pdrhirrMntsm

•Passive mydriasis
•Cydoplegia
•Loss of hghl reflex

Relaxes bronchial
smooth muscle, but
dries up all secretions
Fig, 2.14 Ar;iton$ ol atropine LH. unwary Hack RS. respiratory system

Eye: Effects of atropine on eye arc depicted as follows

Atropine

1
Paralysis of constrictor pupillav Paralysis of ciliary muscle leading to loss of
(blockade of receptors) accommodation {blockade of M, receptors)
+
Passive mydriasis
+
Cycloplegia

Effects on eye last for 7-10 days following topical administration of atropine.

THERAPEUTIC USES OF ATROPINE AND TPS SUBSTITUTES:

Ophthalmic Preanaesthetic Sialorrhoea Chronic Antispasmodic Urinary Poisoning Vagolytic
uses medication obstructive disorder and
pulmonary parkinsoinism
disease
(COPD)
1. Ophthalmic uses:
As mydriatic and cycloplegic -> for refraction testing.
-> Atropine, homatropine, cyclopentolate or tropicamide are used topically.
-
> The action of atropine lasts for 7-10 days.
Tropicamide is preferred mydriatic as it has a short duration of action.
-
> In children, atropine is preferred because of its greater efficacy.
2. As preanaesthetic medication:
-> Atropine or glycopyrrolate is used.
They are used prior to administration of general anaesthetics: To prevent vagal
bradycardia during anaesthesia.

3. Sialorrhoea:
Synthetic derivatives (glycopyrrolate) are used to decrease excessive salivary
secretion, eg. in heavy metal poisoning and parkinsonism.

4. Chronic obstructive pulmonary disease (COPD) and bronchial asthma:

Ipratropium bromide and tiotropium bromide are used in COPO and bronchial
asthma.
They are administered by metered dose inhaler or nebulizer.
They produce bronchodilatation without affecting mucociliary clearance, hence are
preferred to atropine.

5. Anticholinergics are useful as antispasmodic:

Useful in dysmenorrhoea, intestinal and renal colic.
They are less effective in biliary colic.

6. Urinary disorders:
Oxybutynin and flavoxate hove more prominent effect on bladder smooth muscle,
hence are used to relieve spasm after urologic surgery.

7. Poisoning:
-> In OP poisoning, atropine is the life-saving drug
•> In some types of mushroom poisoning (Inocybe species), atropine is drug of
choice
•> Atropine is used in curare poisoning with neostigmine to counteract the
muscarinic effects of neostigmine.

8. As vagolytic:
Atropine is used to treat sinus bradycardia and partial heart block due to
increased vagal activity.
It improves A-V conduction by vagolytic effect.

9. Parkinsonism:
Centrally acting anticholinergic drugs such as benzhexol (trihexy phenidyl),
benztropine, biperiden, procyclidine, etc. are preferred agents for prevention and
treatment of drug- induced parkinsonism.
They are also useful in idiopathic parkinsonism, but less effective than levodopa.
They control tremor and rigidity of parkinsonism.
 ADVERSE EFFECTS AND CONTRAINDICATIONS:
GIT: Eye: Photophobia, Urinary tract: CNS: CVS: Acute
Dryness of headache, blurring Difficulty in Large doses Tachycardia, belladonna
mouth and of vision; in elderly micturition and produce palpitation poisoning
throat, persons with urinary restlessness, and (Below)
difficulty in shallow anterior retention excitement, hypotension .
swallowing, chamber, they may especially in delirium and
constipation, etc precipitate acute elderly men hallucinations.
congestive with enlarged
glaucoma. prostate .

ACUTE BELLADONNA POISONING

It is more common in children.
The presenting features include fever, dry and flushed skin, photophobia, blurring
of vision, difficulty in micturition, restlessness, excitement, confusion,
disorientation and hallucinations.
Severe poisoning may cause respiratory depression, cardiovascular collapse,
convulsions, coma and death.

Treatment of belladonna poisoning (Atropine poisoning):

It is mainly symptomatic.
1. Hospitalization.
2. Gastric lavage with tannic acid in case poison was ingested.
3. Tepid sponging to control hyperpyrexia.
4. Diazepam to control convulsions.
5. The antidote for severe atropine poisoning is physostigmine (1-4 mg). It is
injected intravenously slowly. It is a tertiary amine - counteracts both peripheral
and central effects of atropine poisoning. Hence, physostigmine is preferred to
neostigmine .
 ADRENERGIC RECEPTORS

All adrenergic receptors are G -protein coupled receptors and regulate production
of intracellular second messengers.

Presynaptic

Postsynaptic
Effect of activation of a Effect of activation of Effect of activation of a Effect of
1 receptors: presynaptic a 2 -receptors: 2 -receptors on various activation of
Blood vessels: Mediate negative feedback secretions P 1-
Constriction control on NA secretion Beta cells of islets of receptors
(i.e. stimulation of a 2- Langerhans in pancreas: Heart:
GI sphincter (anal): receptors decreases release of Decrease in insulin Cardiac
Increase in tone NA from sympathetic nerve secretion stimulation
endings)
Urinary sphincter: Ciliary epithelium: Kidney:
Increase in tone Effect of activation of Reduction of aqueous Promote renin
postsynaptic vascular a 2- humour secretion release
Radial muscle (iris): receptors Mediate stimulatory
Contraction (mydriasis) effects: Vasoconstriction and Sympathetic nerve
venoconstriction endings Decrease in NA
release
Stimulatory effects due Inhibitory effects due to Effect of activation of p
to activation of p 2- activation of p 2 -receptors 3 -receptors
receptors Bronchial, uterine (pregnant), Adipose tissue: Lipolysis
Liver Stimulation of vascular and bladder smooth
glycogenolysis muscles: Relaxation
Skeletal muscle:
Contraction In GI smooth muscle, activation
Ciliary epithelium: of both alpha- and p -
Increase in secretion of receptors causes relaxation
aqueous humour

Uptake of K *
into celh
Radial muscle of Glycofen
Pi—> Qucow
-

Kidney ffconcW Ptegnjni CapJUn« (tfycogenolysiM

wnooih muMle uterus

Adipose tissue
 ADRENERGIC DRUG CLASSIFICATION

-> Adrenergic Drugs (Sympathomimetics)

-> The sympathomimetic drugs mimic effects of sympathetic stimulation
-> They ore also referred to as adrenergic agonists.
ADRENERGIC DRUGS
(Sympathomimetics) ->Pressor agents:
Pm ka pending kaam
-^cardiac stimulants:
DIA
->nasal decongestants
Pox nose PP
->bronchodilators:
Its forme terol
->uterine relaxant
RITS
anorectics
FAST
-tens stimulants:
MAD

Adrenergic agonists Receptor action Therapeutic uses

1 . Directly acting
• Adrenaline aj-, p, . p? and An.-urfiytaciic shock. Cardiac arrest, to
pj-agonis! prolong Duration of local anaesthe¬
sia. to control Epistaxis and other
capdiary oozing. Branchial asthna
(acute) {ABC DE}
• Noradrenakne ar, a?- and ^-agonist Hypotensive states

* Isoprenahie Pt- and p^agontat Heart block, cardiac arrest

• Debut amnio Relatively selective Cardiogenic shock due to acute
|i- agonist myocardial mtarcton (Mi) , con¬
gestive cardiac failure (CCF) or
cardiac surgery
• Salbutamol Selective -agonists Bronchial asthma, to suppress pre
(Albutoroi) mature labour (as uterine
• Levalbutercl relaxant)
• Pirbuterol
• Terbutaline
• Saimeteroi
• Formoterol
• Ritodnne Selective fa-agonists: Ulenne relaxants
- IsoJtsuprme main action on ulerus
,
• Phenylephrine Selective a agonists Vasopressor agents, nasal
• Msthoxarmne decongestants, as mydriatic
(phenylephrine), allergic or
vasomotor rhinitis
a, + -agonists Nasal decongestants (m stimuia-
• Oxymetazoine tton|; structural damage can
• Xyfometazoine occur due to intense vasccorv
strict ion («y stimulation)
2 Indirectly acting
• Amphetamine They act by releasing NA m Narcolepsy, attention-deficit
* Methamphet - the por^hery; NA, DA hyperactivity disorder (ADHD)
amine and 5 hydroxytrypta
* Methylpl-ienidate mine (5-HT) oentraly
3 Mixed acting
• Ephedrine « . and |ij. (direct Intravenous ephedrine is used (or
action) + releases NA the treatment of hypotension due
(indirect action) to spinal anaesthesia
• Dopamine ui« . P1 and Di + Cardiogenic shock, CCF with
releases NA oliguria
 adrenaline

Direct- Acting Sympathomimetics Adrenaline (Epinephrine):

al-, aZ-, fll-, p 2- and p 3 -Agonist.
It is a catecholamine, which is secreted mainly by adrenal medulla.
Adrenaline is a direct- acting, nonselective adrenergic agonist.

PHARMACOLOGICAL ACTIONS:
1.Cardiovascular system;
HEART: BLOOD VESSELS AND BP;
Adrenaline is a powerful cardiac stimulant. Blood vessels of skin and mucous
It acts mainly by interacting with pl -receptors and produces membranes
various effects. (a 1-receptors) are constricted
They are as follows: by adrenaline.
-^Increase in heart rate - increase rate of spontaneous
depolarization in SA node (positive chronotropic effect) It also constricts renal,
->Increase in myocardial contractility (positive inotropic effect) mesenteric, pulmonary and
-^Increase in conduction velocity (positive dromotropic effect) splanchnic vessels, but dilates
-^Increase in cardiac output blood vessels of skeletal muscle
->Increase in automaticity Cardiac work and its oxygen and coronary vessels (02).
requirement is markedly increased

2. Respiratory system:
Adrenaline rapidly relaxes (02) bronchial smooth muscle.
It is a potent bronchodilator but has a short duration of action.
It inhibits release of inflammatory mediators from mast cells ( pZ).
It also reduces secretions and relieves mucosal congestion by vasoconstrictor
effect ( al).

3. CNS: In therapeutic doses, adrenaline does not cross BBB; hence, CNS effects
are minimal. But in high doses, it may cause headache, restlessness and tremor.

4. GIT: It relaxes smooth muscle of gut ( a and pZ).

It reduces intestinal tone and peristaltic movements but effects are transient.

5. Bladder; it relaxes detrusor muscle ( p 2) and contracts sphincter (al).

As a result, it may cause difficulty in urination

PHARMACOKINETICS:
-^Adrenaline is not suitable for oral administration because of its rapid inactivation
in GI mucosa and liver.
->Adrenaline can be given subcutaneously.
->In anaphylactic shock, absorption of s.c. adrenaline is poor; hence, it is given
intramuscularly.
->In cardiac arrest, it is given intravenously. It does not cross BBB, and the
metabolites are excreted in urine.
ADVERSE EFFECTS AND CONTRAINDICATIONS:
->The adverse effects of adrenaline are an extension of its pharmacological
actions.
->They are tachycardia, palpitation, headache, restlessness, tremors and rise in
BP.
The serious side effects are cerebral haemorrhage and cardiac arrhythmias.
In high concentration, adrenaline may cause acute pulmonary oedema due to shift
of blood from systemic to pulmonary circulation.
Adrenaline is contraindicated in most of cardiovascular diseases such as
hypertension, angina, cardiac arrhythmias and congestive cardiac failure (CCF).
-> In patients on p -blockers, it may cause hypertensive crisis and cerebral
haemorrhage due to unopposed action on vascular a 1-receptors

THERAPEUTIC USES OF ADRENALINE (ABCDE)

(1) Anaphylactic shock:
Adrenaline is life-saving drug in anaphylactic shock.
Adrenaline 0.3-0. 5 mL of 1:1000 solution (1 mg/mL) is administered
intramuscularly.
It rapidly reverses manifestations of severe allergic reactions.
Adrenaline produces following effects:
p, mediated eardiac stimulation (T heart rate and Tforcc of contraction)
+
ct, -mediated vasoconstriction —* T peripheral resistance,
These actions help to TbP.
a a,-mediated vasoconstriction — imucosal oedema (1laryngeal oedema ).
a —
p. stimulation bronchodilalion
1 release of mediators from mast cells.
a li is physiological antagonist of histamine.
(2) Bronchial asthma:
Adrenaline is a powerful bronchodilator and has rapid onset but short duration of
action.
It is rarely used for acute asthma.
Its use has declined because of its dangerous cardiac stimulant effect.
The beneficial effects of adrenaline in bronchial asthma
Adrenaline 0.3-0. 5 mL of 1:1000 solution is given subcutaneously.
It can be given by nebulization (as inhalation).
Adrenaline

Inhibits the release of

inflammatory
mediators from mast
cells (histamine, LTs,
bradykinin, PGF2ij, PAF)

Decreases secretions

Relieves mucosal
I
oedema and congestion
Fig. 2.22 Effects of adrenaline in bronchial asthma. LTs, leukotrienes: PGFju, prostaglandin
Fjo: PAF. platelet-activating factor.
(3) Cardiac resuscitation:
In treatment of cardiac arrest due to drowning or electro cution, adrenaline is
injected intravenously in 1:10,000 (0.1 mg/mL) concentration along with other
supportive measures such as external cardiac massage.

(4) Prolongs Duration of local anaesthesia:

Adrenaline (1:100,000) with lignocaine. Adrenaline, by its vasoconstrictor effect
(a 1) delays absorption of the local anaesthetic and prolongs the duration of local
anaesthesia .

(5) Controls Epistaxis and other capillary oozing:

Adrenaline is used as a local haemostatic to control bleeding following tooth
extraction and during surgical procedures in nose, throat, larynx, etc. because of
its vasoconstrictor effect.

ALPHA ADRENERGIC BLOCKING DRUGS

u ADRENERGIC BLOCKING DRUGS

Non equilibrium type Equilibrium type

(Competitive antagonists)
b-haloalkylamlne I
Phenoxybenzamine !
Non selective u, Selective Selective
Prazosin Yohimbine |
1 Terazosin
Ergot alkaloids Imidazoline Miscellaneous
I Doxazosin
Ergotamine Phentolaminc I Chlorpromazine
< AUuzo^in
Tamsulosin

Hydrogenated ergot alkaloids

Dihydroergotamine (DHE)
Dih yd roergotoxine
(Codergocrine)

Zosin: Non -selective:

Selective: Ergot amine nature release toxin
Pro tera dost alfu tamsu Phen tol amine
Yo him bine Phen oxy benz amine
Chlor pro maa zine
 (3) Cardiac resuscitation:
In treatment of cardiac arrest due to drowning or electro cution, adrenaline is
injected intravenously in 1:10,000 (0.1 mg/mL) concentration along with other
supportive measures such as external cardiac massage.

(4) Prolongs Duration of local anaesthesia:

Adrenaline (1:100,000) with lignocaine. Adrenaline, by its vasoconstrictor effect
(al) delays absorption of the local anaesthetic and prolongs the duration of local
anaesthesia.

(5) Controls Epistaxis and other capillary oozing:

Adrenaline is used as a local haemostatic to control bleeding following tooth
extraction and during surgical procedures in nose, throat, larynx, etc. because of
its vasoconstrictor effect.

ALPHA ADRENERGIC BLOCKING DRUGS

.» ADRENERGIC BLOCKING DRUGS

Non equilibrium type Equilibrium type

(Competitive antagonists)
|’-haloalkylamlne
Phenoxybenzamine
Non selective . Oj Selective
Yohimbine

Miscellaneous
Chlorpromazine

Hydrogenated ergot alkaloids

Dihydroergotamine (DHE)
Dthvd roergotoxine
(Codcrgocrinc)

Zosin: Non-selective:
Selective : Ergot amine nature release toxin
Pro tera dost alfu tamsu Phen tol amine
Vo him bine Phen oxy benz amine
Chlor pro maa zine

5
(3) Cardiac resuscitation:
In treatment of cardiac arrest due to drowning or electro cution, adrenaline is
injected intravenously in 1:10,000 (0.1 mg/mL) concentration along with other
supportive measures such as external cardiac massage.

(4) Prolongs Duration of local anaesthesia:

Adrenaline (1:100,000) with lignocaine. Adrenaline, by its vasoconstrictor effect
(al) delays absorption of the local anaesthetic and prolongs the duration of local
anaesthesia.

(5) Controls Epistaxis and other capillary oozing:

Adrenaline is used as a local haemostatic to control bleeding following tooth
extraction and during surgical procedures in nose, throat, larynx, etc. because of
its vasoconstrictor effect.

ALPHA ADRENERGIC BLOCKING DRUGS

u ADRENERGIC BLOCKING DRUGS

1
Non equilibrium type

l^haloalkylamine j r
Phenoxybenzamine p 1
Non selective

Id 1
Ergot alkaloids Imidazoline
*1
Miscellaneous
E rg<>ta m ine Phen tola m me Chlorpromazine
Ergotoxine
Hydrogenated ergot alkaloids
Dihydroergotamine (DHE)
Dihydroergotoxine
(Codergocrine)

Zosin: Non -selective;

Selective: Ergot amine nature release toxin
Pra tera dost alfu tamsu Phen tol amine
Vo him bine Phen oxy benz amine
Chlor pro rnaa zine
THERAPEUTIC USES OF a -BLOCKERS
1. PHEOCHROMOCYTOMA:
It is a tumour of adrenal medulla, which releases large amounts of adrenaline and
NA.
The signs and symptoms include a sudden and paroxysmal rise in BP with headache,
palpitation and excessive sweating.
The diagnosis of pheochromocytoma is usually made by estimating catecholamines,
VMA and other metabolites in blood and urine (normal VMA: 4-8 mg per 24 hours
urine sample), CT and MRI scan.

The definitive treatment for pheochromocytoma is surgery.

2. Hypertensive emergencies;
Intravenous phentolamine can be used in following conditions, because of its rapid
onset of action: To control hypertensive episodes intraoperatively during surgery of
pheochromocytoma .
To control hypertensive crisis due to clonidine withdrawal.
To control hypertensive crisis due to cheese reaction'.

3. Essential hypertension;
Among a -blockers, selective 1-antagonists are preferred to non-selective
arlblockers in treatment of mild -to -moderate hypertension.
Selective a 1-antagonists cause less tachycardia and have favourable effects on
lipid profile.

4. Benign prostatic hyperplasia;

Selective a 1-blockers are used in BPH; they decrease tone of smooth muscle in
neck of bladder and prostate resulting in reduction in resistance to urinary flow.
Prazosin, doxazosin, terazosin and alfuzosin are particularly useful in patients who
also have hypertension.
Tamsulosin is preferred for BPH in normotensive patients

5. Tissue necrosis;
Phentolomine is infiltrated locally to prevent tissue necrosis due to extravasation
of a -agonists.

6. Male sexual dysfunction:

Local injection of phentolamine with papaverine may be used in the treatment of
male sexual dysfunction.
 BETA ADRENERGIC BLOCKING DRUGS

|i ADRENERGIC BLOCKING DRUGS

mifiicr
Non selective (pt + pj flfM Cardioselectlve (pj
Metoprolol
Atenolol
Acebulolol
Without ISA With ISA With a blocking Bisoprolol
property Esmolol
Propranolol Pindolol
Sota lol Labetalol Betaxolul
Timolol 'ISA: Intrinsic Carvcdilot Celiprolol
^sympathomimetic activity' Nebivolol
GENERAT1ONWISE CLASSIFICATION
p ADRENERGIC BLOCKING DRUGS

THERAPEUTIC USES OF fl -BLOCKERS

1. Hypertension -
fl -Blockers ore useful for all grades of hypertension.
These drugs are preferred especially in patients with angina, MI or cardiac
arrhythmias .
The advantages of fl -blockers are as follows -
Sodium and water retention is rare
Cheaper
Have a long duration of action
Well tolerated.

2. Angina prophylaxis and MI:

fl -Blockers reduce myocardial 02 demand by de creasing heart rate, myocardial
contractility and arterial pressure.
They improve exercise tolerance and reduce frequency of anginal episodes.
Use of fl -blockers early in acute phase of MI may limit infarct size.
Long-term use of fl -blockers may reduce mortality and reinfarction.
3. Cardiac arrhythmias:
fl -Blockers are mainly used in atrial arrhythmias such as atrial fibrillation, atrial
flutter and paroxysmal supraventricular tachycardia (PSVT) but rarely for
ventricular arrhythmias

4. Congestive cardiac failure :

Chronic use of fl -blockers such as carvedilol, metoprolol and bisoprolol has shown
to reduce mortality rate in chronic heart failure.

5. Pheochromocytoma:
fl -Blockers are used to control cardiac manifestations of pheochromocytoma, but
should not be given alone

6. Glaucoma :
fl -Blockers decrease IOP by reducing -> production of aqueous humour.
Timolol, carteolol, levobunolol, betaxolol, etc. are used topically in glaucoma.
Timolol is ->most frequently used fl -blocker in glaucoma.
Betaxolol is a selective fl 1-blocker; hence, systemic adverse effects
(cardiovascular and pulmonary) are rare.

7. Prophylaxis of migraine:
Propranolol and metoprolol are effective in reducing the frequency of migraine
headache.

8. Hyperthyroidism:
The signs and symptoms of hyperthyroidism such as tachycardia, palpitation,
tremor and anxiety are reduced due to blockade of - preceptors

9. Essential tremors:
Oral propranolol may give some benefit in patients with essential tremors.

10. Acute anxiety states:

fl -Blockers are useful in controlling the symptoms of acute anxiety such as
palpitation, tachycardia, tremor and sweating.

11. Alcohol withdrawal:

Propranolol may produce some benefit in the treatment of alcohol withdrawal.

12. Hypertrophic obstructive cardiomyopathy:

Propranolol decreases outflow resistance.

13. Dissecting aortic aneurysm:

fl -Blockers are useful in the management of dissecting aortic aneurysm -> they
decrease cardiac contractility and the rate of development of pressure during
systole .
 ADVERSE EFFECTS OF BLOCKERS.
CVS: Respiratory CNS: Metabolic: Muscular
system; weakness
Bradycardia, heart block and Sleep Recovery from and
may precipitate congestive heart Blockade of disturbances, hypoglycaemia tiredness:
failure in patients with low- 02 -receptors hallucinations, (induced by
cardiac reserve. in bronchial fatigue and antidiabetic drugs) These are
smooth mental is delayed by due to
Blockade cf vascular //2- muscle can depression. //blockers. reduced
receptors causes unopposed tri - cause severe blood flow
action, reduces further blood bronchospasm //Blockersmay to skeletal
supply and may worsen peripheral in patients mask warning signs muscle.
vascular disease. with asthma and symptoms of
and COPD. hypoglycaemia ,
// -Blockers can exacerbate
Prinzmetal angina (variant angina)
due to unopposed a 1 -oction,
hence are contraindicated .
 AUTACOIDS
Autacoids are produced by cells and act locally. Hence, they are also called 'local
hormones'.
Various autacoids are histamine, serotonin (5 -hydroxytryptamine [5-HT]),
prostaglandins (PGs), leukotrienes, angiotensin, kinins and platelet - activating factor
(PAF)

HISTAMINERGIC AGONISTS AND ANTAGONISTS

HISTAMINERGIC AGONISTS

H, ANTAGONISTS
(Conventional antihistaminics)

Highly sedative Moderately sedative MUdly sedative Second generation

Pheniramine Chlorpl lenira mine (nonsedating) anti¬
Diphenhyd ra m inc histamines
Dimcnhydritiate Cyproheptadine Dexchlorpheniramine
Medozinc Tnprolidinc Fexofenadine
Promethazine Loratadine
I lydroxyzinc Cinnarizinc Clemastine
Dedoratadlne
Cetirizine
Levoceti nzine
Azelastine
Mizolastine
Ebastine
Highly sedative: Moderately sedative Mildly sedative

Hy Priya DI DI CM in CP tripti chlo dex Lora

clean kro Desi
Fem me
CET

HISTAMINE AND ANTIHISTAMINES;

Histamine is a biogenic amine present in many animal and plant tissues.
It is mainly present in storage granules of mast cells in tissues like skin, lungs,
liver, gastric mucosa and placenta.
It is one of -> mediators involved in inflammatory and hypersensitivity reactions.
 M«l cell

•AG48 region
- Btle «ih
*
Food (cr*b, fith) * Release ol htitimme

•Pmp: Morphine, d K,
dertron, hydr AJAtine. etc.
Itching, ufliurii, fiirthing,
hypotrnvon. Udtyardia,
broncho^pAsm, nng pcn?d?rn<i etc.

H H) -Receptors Smooth muscle contraction,

I increase in capillary permeability
S
T * Hj Receptors |Gastric acid secretion
A
M
I
Hj-Presynaptic |cAMP * Histamine levels in brain.
autoreceptors lungs, skin, gastric mucosa
N
E H4- Receptors Chemotaxis, cytokine secretion

MECHANISM OF ACTION OF H1 - BLOCKERS :

Hl - Antihistamines antagonize the effects of histamine by competitively blocking
the Hl -receptors (competitive antagonism).
Histamine (agonist) >| Ii, -Receptors p Antihistamines (antagonists)

First -generotion hl -blockers Second -generation hl -blockers

Pharmacological Actions Antihistamines (antagonists) : Have no anticholinergic effects.
1. Hl -blockers cause CNS depression, sedation and drowsiness. Lack antiemetic effect.
Certain antihistamines have antiemetic, local anaesthetic and anti¬ Do not cross blood-brain barrier
parkinsonian effects. (BBB), hence cause minimal/no
drowsiness.
2. They have antiallergic action; hence, most of manifestations of Do not impair psychomotor
typeIreactions are suppressed. performance .
Are relatively expensive.
3. They have anticholinergic actions - cause dryness of mouth,
blurring of vision, constipation, urinary retention.

FIRST -GENERATION Hl -BLOCKERS:

1. Allergic diseases:
Hl -antihistamines are used to prevent and treat symptoms of allergic reactions.
For example, pruritus, urticaria, dermatitis, rhinitis, conjunctivitis and angioedema
of lips respond to these drugs.
2. Common cold:
They produce symptomatic relief by sedative and anticholinergic actions.
3. Pre -anaesthetic medication:
Promethazine is used for its sedative and anticholinergic effects.
4. As antiemetic:
Promethazine, diphenhydramine, dimenhydrinate, etc. are useful for prophylaxis of
motion sickness because of their anticholinergic action.
These drugs are useful in drug- induced and postoperative vomiting.
Promethazine, in combination with other antiemetics, is used to control vomiting
due to cancer chemotherapy and radiation therapy.
I

5 . Parkinsonism-
Imbalance between dopamine (DA) and acetylcholine (Ach) in basal ganglia produces
parkinsonism.
Promethazine, diphenhydramine or orphenadrine are used to control tremor,
rigidity (central action) and sialorrhoea of parkinsonism due to their anticholinergic
and sedative properties.
Promethazine and diphenhydramine are useful for treatment of idiopathic and
drug- induced parkinsonism.
6 .Hl -blockers
They are used to control mild blood transfusion and saline infusion reactions
(chills and rigors) and as adjunct in anaphylaxis.
7.Sedative and hypnotic:
Hl -antihistamines (e g. promethazine and diphenhydramine) are used to induce
sleep, especially in children during minor surgical procedures.

SECOND-GENERATION Hl -BLOCKERS:
Route and
Drug duration of action important features
Cetirizine p.o.. 12-24 hours « H- blocker; inhibits histamine release;
achieves good concentration in the skm;
poorly crosses BBB; may cause drowsiness
• Drug interactions rare
Levocetirizine p.o., 12-24 hours More potent and produces less adverse effects
than cetirizine
Loratadine p.o., 24 hours Long acting, nonsedating agents
Desloratadine « Cardiac arrhythmias have been noticed in
Mizolasbne animals treated with ebastine
Ebastine • No cardiac arrhythmias wrlh loratadine
and desJoratadmo
* Loratadine may rarely cause seizures
Fexofenadine p.o., 12-24 hours • Active metabolite of terfenadne
• Nonsedating agent
* Arrhythmias rare; avoid In patients with
prolonged QT interval
Azeiastme Tbpicai (nasal • Hr blocker; inhibits histamine release
spray, eye drops}, « Produces active metabolite
12-24 hours * Has a rap+d onset and long duration of action
• Taste atleratfon. burning sensation in the
nose, drowsiness
Rupatadme p.o. Hi। -blocker + blocks actions of platelet -activating
factor
 SEROTONIN

5 -hydroxy tryptamine (serotonin) is synthesized from tryptophan.

It is produced by hydroxylation followed by decarboxylation of tryptophan; steps
similar to catecholamine synthesis.
It is similarly stored in vesicles and its action is terminated by reuptake.
It acts by activation of several serotonin receptors (5- HT1 - HT7 receptors)
Receptors

5HT, 5 5HT, sht4

shtia 5 HTi^D
Preiynaptlc Cause constriction of cra¬ Responsible for most of the Inotropic receptor (all Present In GIT
autoreceplor nial vessels direct actions of serotonin others 5 HT receptors are Responsible for the
G-proiem coupled receptors) increase in peristalsis

Modulates the realse Ketansenn and Mediates most of the reflex

nt an sarin
of serotonin (antagonists) are useful as and indirect actions of wo
antihypertensive agents tonin

Partial agonist of this

Agonist* al this receptor Clozapine and risperidone Antagonists like ondanse- Agonists (cisapride,
receptor {buspifone. (iumJinpfan naratnplan) are atypical antipsychotic iron, gratnsclrw and tro- mosapnde renzapnde
tsaptrune gopifMG) are useful for the treat- agents that act through pisetron are the agents of fogaserod) are useful in
are useful as antian* ment of acute migraine antagonistic activity at ths choice for chemalherapy the treatment of gastroe¬
xloty drug* attacks recuptcx induced vomiting sophageal reflux disease

5-HYDROXY TRYPTAMINE (S-HT) ANTAGONISTS

ERGOT ALKALOIDS
Ergot alkaloids occur naturally in a fungus, Claviceps purpurea.
The most important compounds and their therapeutic uses are:
Action Use with Adverse
Drug on receptor Effects route effects
Ergotamine Partial agonist/ Contraction of Acute \tomiting.
(natural antagonist smooth muscles - migrane diarrhoea;
alkaloid) al 5 HTt blood vessels (oral, subfen- overdosage -
and 5-HT? uterus, gut and gml, rectal) severe vaso¬
receptors other viscera spasm
grene
— * gan-

Dihydroergob • Predominant • Smooth muscle Acute Nausea,

amine (semi- a -blockade contract ion migraine vomiting
synthetic) • Weak & HT and less than (oral, LmM
u agonistic ergotamine s.c.)
action • Less vasocon¬
strictor effect
(safer than
ergotamine for
parenteral use)
Ergometrine • Partial agonist • Major action* Postpartum Nausea.
(ergonovine: al 5-HT7and contraction of haemor vomiting, use
natural weak action at myometrium rhage nBP
alkaloid) u -receptors Vasoconstric (i,m„ U)
No a-antagonstlc tion Is minimal
action
 SEROTONIN

5 -hydroxy tryptamine (serotonin) is synthesized from tryptophan.

It is produced by hydroxylation followed by decarboxylation of tryptophan; steps
similar to catecholamine synthesis.
It is similarly stored in vesicles and its action is terminated by reuptake.
It acts by activation of several serotonin receptors (5- HT1 - HT7 receptors)
Receptors

5HT, 5 5HT, sht4

shtia 5 HTi^D
Preiynaptlc Cause constriction of cra¬ Responsible for most of the Inotropic receptor (all Present In GIT
autoreceplor nial vessels direct actions of serotonin others 5 HT receptors are Responsible for the
G-proiem coupled receptors) increase in peristalsis

Modulates the realse Ketansenn and Mediates most of the reflex

nt an sarin
of serotonin (antagonists) are useful as and indirect actions of wo
antihypertensive agents tonin

Partial agonist of this

Agonist* al this receptor Clozapine and risperidone Antagonists like ondanse- Agonists (cisapride,
receptor {buspifone. (iumJinpfan naratnplan) are atypical antipsychotic iron, gratnsclrw and tro- mosapnde renzapnde
tsaptrune gopifMG) are useful for the treat- agents that act through pisetron are the agents of fogaserod) are useful in
are useful as antian* ment of acute migraine antagonistic activity at ths choice for chemalherapy the treatment of gastroe¬
xloty drug* attacks recuptcx induced vomiting sophageal reflux disease

5-HYDROXY TRYPTAMINE (S-HT) ANTAGONISTS

ERGOT ALKALOIDS
Ergot alkaloids occur naturally in a fungus, Claviceps purpurea.
The most important compounds and their therapeutic uses are:
Action Use with Adverse
Drug on receptor Effects route effects
Ergotamine Partial agonist/ Contraction of Acute \tomiting.
(natural antagonist smooth muscles - migrane diarrhoea;
alkaloid) al 5 HTt blood vessels (oral, subfen- overdosage -
and 5-HT? uterus, gut and gml, rectal) severe vaso¬
receptors other viscera spasm
grene
— * gan-

Dihydroergob • Predominant • Smooth muscle Acute Nausea,

amine (semi- a -blockade contract ion migraine vomiting
synthetic) • Weak & HT and less than (oral, LmM
u agonistic ergotamine s.c.)
action • Less vasocon¬
strictor effect
(safer than
ergotamine for
parenteral use)
Ergometrine • Partial agonist • Major action* Postpartum Nausea.
(ergonovine: al 5-HT7and contraction of haemor vomiting, use
natural weak action at myometrium rhage nBP
alkaloid) u -receptors Vasoconstric (i,m„ U)
No a-antagonstlc tion Is minimal
action
 ERGOT ALKALOIDS ARE CONTRAINDICATED IN
Ischaemic heart disease, hypertension, peripheral vascular disease and renal
disease.
Ergotamine and dihydroergotamine are used for the treatment of acute attack of
migraine.
-> Dihydroergotoxine (codergocrine) is useful for the treatment of dementia.
-> Bromocriptine is useful in Parkinsonism, hyperprolactinemia and acromegaly.
DRUG THERAPY OF MIGRAINE
Migraine is a common and debilitating condition, attack consists of an initial visual
disturbance (the aura), severe throbbing headache often with photophobia, nausea
and vomiting.
Management of migraine
1— I
I
Drugs for acute attack Drugs for prophylaxis
•Bela blockers
- Timolol
Propanolol i Drug of i । ice)

- Nadolol
-

Paracetamol or NSAlDs •Calcium Channel blockers

- Flunarizine

I - (Miazem
- Verapamil
Not controlled - Nimodipme
•Tncyckc anlideprossants
Triplans (or ergotamine + caffeine) -- Amitriptyline
Imrpramine

| Not controlled
- Nor-tnptyhne
•Inliepitepiics
- Topiramate
- Valproate
Opioids or Dropendoi
(if opioid tolerant patents)
- Gabapentin
•MelhysergKie

| Not controlled

Propofol
•Cyproheptadine
* Cion
•
Wine
C andeiart an
(Ref CMOT 2015 p 956)
•Botulinum toxin A

Nonsteroidal Anti - inf lammatory Antiemetics Ergotamine: Triptans:

Drugs. (Oral or Parenteral). (below)
Oral/sublingual/suppository
Nonsteroidal anti-inflammatory They are used to treat preparation is used at onset of
drugs (NSAlDs) are used alone nausea and vomiting pain or warning symptoms.
or in combination. associated with attack. It is used in moderate to
They provide symptomatic severe migraine.
relief but should not be taken They also improve
on a long-term basis, e g. absorption of oral MECHANISM OF ACTION:
paracetamol, aspirin, medications used to treat It acts as a partial agonist at
ibuprofen, naproxen, diclofenac migraine, e.g. 5-HT1B/1D receptors in
and mefenamic acid. metoclopramide, cranial blood vessels
They are useful in mild and domperidone,
moderate migraine. prochlorperazine, constriction of dilated cranial
blood vessels, decreases
 promethazine and inflammation and extravasation
diphenhydramine of plasma into perivascular
space ,

TRIPTANS.
Selective 5-HT1B/1D agonists, include sumatriptan, rizatriptan, eletriptan,
almotriptan, zolmitriptan. naratriptan, frovatriptan, etc. ]
They are used in moderate and severe migraine.

MECHANISM OF ACTION OF TRIPTANS (SELECTIVE 5-HT1B/1D AGONISTS):

Abnormal dilatation
=> Cerebral ischaemia <=> Migraine attack
of cranial blood vessels
_ .
Tnptans
Selective 5-HT
=> agonists
Constrict dilated Restore cerebral
cranial blood vessels blood flow
and arteriovenous
shunts

PROPHYLAXIS OF MIGRAINE (NOTE ABCD):

Anticonvulsants:
For example, gabapentin, sodium valproate and topiramate are used for migraine
prophylaxis.

Beta-blockers:
Propranolol, timolol, atenolol, metoprolol, etc.
Propranolol is more effective than other -blockers; requires prolonged treatment.

Calcium channel blockers (CCBs):

For example, verapamil and flunarizine.
They reduce the frequency of attacks.
Flunarizine is selective for cerebral calcium channels; it also has Na channel¬
blocking effect.
CCBs should not be co -administered with -blockers.

Antidepressants:
TCAs like amitriptyline help to reduce attacks of migraine; exact mechanism of
action of antimigraine effect is not clear. TCAs produce undesirable side effects
on prolonged therapy.
 PROSTAGLANDINS

PGs ore -> products of long -chain fatty acids.

Arachidonic acid is -> precursor for bio -synthesis of all PGs.
The enzyme involved in -> formation of PGs from arachidonic acid is
cyclooxygenase (COX).
The main PGs are PGE2, PGF2 and PGI2,

There are two forms of COX, called COX-1 and COX- 2:

most tissues such as BV, kidney Inducible during

stomach and platelets; COX is inflammation by
the enzyme responsible for the cytokines and inflammatory
biosynthesis of various PGs mediators (endotoxins)
pgi2 pge2 pgd2 txa2 PGE.
pgi2
TXA;
Other mediators
* Vasodilatation Lowers * Gl protection • Vasodilatation Platelet (TNF-a, ILs.
•Inhibition of IOP * Platelet function • Broncho aggregation bradykintn)
platelet •Kidney function constriction Regulation at
aggregation •Regulation of of blood •Pain
blood flow flow •inflammation
•Fever
PREPARATIONS, FORMULATIONS & USES OF PROSTAGLANDIN ANALOGUES:

Preparations Formulations/route Uses

• Dinoprostone (PGEJ • Vaginal tab • induction of labour
• Vaginal gel • Midterm abortion
• Termination of pregnancy
• Dinoprost (PGF^J Intra amniobc injection Mid-term abortion
• Carboprost (15-methyl • Mid-term abortion
PGFaJ • Contra? of PPH
• Gemeprost (PGEJ Vaginal pessary Cervical priming in early
pregnancy
 • Alprostadil (PGET) • intravenous infusion • To maintain the patency of
* Intracavemous ductus arteriosus m neonates
injection with congenital heart disease
until surgery
• Erectile dysfunction
• Misoprostol (PGE,| Oral, vaginal pessary • Peptic ulcer
* Abortion, PPH
• Epoprostend (PGy Intravenous infusion Pulmonary hypertension
• Treprastinil (PGIJ
* lloprosl (PGy
* Latanoprost (PGF7j Topcal (eye drops) Glaucoma
• Bmatoprost (PGFjJ
• Unopfostone (PGF.j
• Travoprost (PGF.J
THERAPEUTIC uses OF PROSTAGLANDINS IN OBSTETRICS:
1. Abortion: 2.Induction of 3. PPH:
PGs stimulate uterine contractions and cause ripening of cervix. labour: Carboprost
->Dinoprostone (vaginal) is used for induction of mid -trimester PGs can be used to (i.m.) and
abortion, missed abortion and hydatidiform mole. soften cervix for misoprostol
induction of labour. (oral) can be
-^Misoprostol (oral or vaginal) can be used in combination with used to
mifepristone or methotrexate to induce abortion in early control PPH.
pregnancy.

->Carboprost (i.m.) is used to induce abortion in second

trimester of pregnancy.

(PGE1) and dinoprost (PGF2 ) are also useful for

inducing abortion
ADVERSE EFFECTS:
They are nausea, vomiting, diarrhoea, fever, flushing, hypotension and backache
due to uterine contractions.
Injections are painful due to sensitization of nerve endings.
Pyrexia
Sensitization of
Peripheral nerves (pain)
To prevent HPeripheral,
Platelet Pulmonary and coronary
aggregation resistance (PCI2)

Promote healing of To maintain the Patency of

Peptic ulcer increase ductus arteriosus in neonates with
Peristaltic movements, congenital heart disease until surgery
Purging effect (diarrhoea)
Pulmonary
hypertension

Erectile dysfunction Glaucoma

Abortion
Cervical Primmg
Induction of labour
Postpartum haemorrhage
Fig . 6J Effects and uses of prostaglandins
-
Note: PGs tn the figure, actons/uses with plenty o' P s and a single G
 NONSTEROIDAL ANTIINFLAMMATORY DRUGS

NONSTEROIDAL ANTIINFLAMMATORY DRUGS/ANTIPYRETIC-ANALGESICS

Preferential cox -2 Selective cox -2 Non- selective cox Analgesic -anti -pyreties
Inhibitors inhibitors
Payal and meenu PEC SAFE PP MAN
preferential ccx2 coxib A=kin
inhibitor khati hai F=M
E-PET
P-OP
PRO-P-INK

NSAIDs act by inhibiting COX enzyme and thus prostaglandin synthesis.

These drugs act as antipyretic, analgesic and anti-inflammatory agents.
Prostaglandins play a protective role in stomach and non- selective COX inhibitors
can cause GI toxicity (peptic ulcer) on lang term use.

MECHANISM OF ACTION :
COX is enzyme responsible for biosynthesis of various PGs.
There are two well recognized isoforms of COX. COX-1 and COX-2.
->COX-1 is constitutive, found in mast tissues such as blood vessels, stomach and
kidney.
PGs have important physiological role in many tissues

->COX-2 is induced during inflammation by cytokines and endotoxins and

is responsible for production af prostanoid mediators of inflammation.

->Aspirin and most of NSAIDs inhibit both COX-1 and COX-2 isoforms; thereby
decrease PGs and thromboxane synthesis.
 The anti-inflammatory effect of NSAIDs is mainly due to inhibition of COX- 2.
Aspirin causes irreversible inhibition of COX activity.
Rest of the NSAIDs causes reversible inhibition of the enzyme.

PHARMACOLOGICAL ACTIONS OF ASPIRIN AND OTHER NSAIDS:

(AAAAAGUV)

1 Analgesic effect: 2. Antipyretic effect: 3. Anti¬ 4. Antiplatelet 5. Acid-base

inflammatory (antithrombotic) and electrolyte
NSAIDs are mainly Thermoregulatory effect: effect: balance:
used for relieving centre is situated in
musculoskeletal the hypothalamus. Anti¬ Aspirin in low doses In therapeutic
pain, inflammatory (50-325 mg/day) doses,
dysmenorrhoea and Fever occurs when effect is irreversibly inhibits salicylates
pain associated there is a disturbance seen at high platelet TXA2 cause
with inflammation in hypothalamic doses synthesis and respiratory
or tissue damage. thermostat. (aspirin: 4-6 produces antiplatelet alkalosis, which
g/day in effect, which lasts is compensated
Analgesic effect is NSAIDs reset divided for 8-10 days, i.e. by excretion
mainly due to hypothalamic doses). life time of of bicarbonate
peripheral thermostat and reduce platelets. (compensated
inhibition of PG elevated body These drugs respiratory
production. temperature during produce only Aspirin in high doses alkalosis).
fever. symptomatic (2-3 g/day) inhibits
They also increase They promote heat loss relief. both PGI2 and TXA2 In toxic doses,
pain threshold by by causing cutaneous synthesis, hence respiratory
acting at vasodilatation and They antiplatelet effect is centre is
subcortical site. sweating. suppress lost. depressed and
signs and can lead to
These drugs They do not affect symptoms of Aspirin should be respiratory
relieve pain without normal body inflammation withdrawn 1 week acidosis.
causing sedation, temperature . such as pain, prior to elective Later, there is
respiratory tenderness, surgery because of uncompensated
depression, The antipyretic effect swelling, risk of bleeding. metabolic
tolerance or is mainly due to vasodilatation acidosis
dependence. inhibition of PGs in and leukocyte
They ore less hypothalamus infiltration
efficacious than but they do
opioids as The dose of aspirin for not affect
analgesics. antipyretic effect is 2- the
3 g/day. progression
Aspirin produces of underlying
analgesia at doses disease.
of 2-3 g/day.
 6.GIT:
Aspirin irritates -> gastric mucosa and produces nausea, vomiting and
dyspepsia.
The salicylic acid formed from aspirin also contributes to these effects.
Aspirin also stimulates CTZ and produces vomiting.
Inhibits PGs in the Increase in
gastric mucosa HCI production

Loss of Gastric irritation,

protective action peptic ulcer

w Exists in Enters the

Aspirin
pH unionized form mucosal cell
stomach

• Acute ulcers
|pH 7.1

Ionized and
• Erosive gastritis Incomes indiHusible
• Haemorrhage ( within themucosal cells)

7.CVS;
Prolonged use of aspirin and other NSAIDs causes sodium and water
retention.
They may precipitate CCF in patients with low cardiac reserve.
They may also decrease -> effect of antihypertensive drugs.
8 . Urate excretion:
Salicylates, in therapeutic doses -> inhibit urate secretion into renal tubules and
increase plasma urate levels.
In high doses, salicylates inhibit -> reabsorption of uric acid in renal tubules and
produce uricosuric effect

ADVERSE EFFECTS:
SIT: Hypersensitivity: In people with Reye's syndrome;
Nausea, vomiting, dyspepsia, It is relatively more G6PD deficiency, Use of salicylates
epigastric pain, acute gastritis, common with aspirin. administration of in children with
ulceration and 61 bleeding. salicylates may viral infection
Manifestations are skin cause haemolytic may cause hepatic
Ulcerogenic effect is major rashes, urticaria, anaemia . damage with
drawback of NSAIDs, which is rhinitis, bronchospasm, fatty infiltration
prevented/minimized by taking: angioneurotic oedema and
(a) NSAIDs after food . and rarely anaphylactoid encephalopathy -
(b) Buffered aspirin reaction. Reye's syndrome.
(preparation of aspirin with Hence, salicylates
antacid) . are
(c) Proton -pump inhibitors/H2- contraindicated in
blockers /misoprostol with children with viral
NSAIDs. infection.
(d) Selective COX -2 inhibitors.
Nonsteroidal anti-inflammatory drugs and their important features:
Table 6.5 Nonsteroidal anti-inflammatory drugs and Their important features
Route and
formulations
Drug with oral dose Other points
1. Ibuprofen Oral and topical gel • It has moderate anti-inflammatory effect
Dose: 400-600 mg • 1t is better tolerated than aspinn
t.d.s. • ft can be used in children
Route and
formulations
Drug with oral dose Other points
2. Diclofenac Oral. i.m„ rectai. • It has potent anti-inflammatory effect
topical gel and • It gets concentrated in synovial fluid,
ophthalmic hence preferred in inflammatory condi¬
preparation tions (arthritis) of joint
(eye drops) • Incidence of hepatotoxicity is more
Dose: 50 mg b.d, • Combination of diclofenac with miso¬
or 100 mg sus¬ prostol (PGE- analogue! Is available,
tained release which reduces Gi irritation and peptic ulcer
preparation o.d.
3. Aceclofenac Oral Same as diclofenac
Dose: 100 mg b.d.
or 200 o.d.
4. Indomethacin Oral, eye drops and • It is a nonselective COX inhibitor
Note: it has suppository • It has potent anti inflammatory effect
Extra mecha¬ Dose: 50 mg t.d.s. • It inhibits migration of neutrophils to
nism of action inflamed area
Extra uses • It is very effective in ankylosing spondylitis,
Extra side acute gout and psoriatic arthritis
effects • It has prominent Gl side effects
• CNS side effects are severe headache,
confusion, hallucinations, etc.
• It is contraindicated in epileptics,
psychiatric patients and dnvers
5. Piroxicam Oral, i.m. and • It has potent anti -inflammatory effect
topical gel • It is long acting
Dose: 20 mg o.d. • Increased incidence of peptic ulcer and
bleeding
6. Ketorolac Oral, I.m.. i.v.. oph¬ • It has potent analgesic effect and
thalmic prepara¬ efficacy is almost equal to morphine
tion and trans- • Il relieves pain without causing respira¬
dermal patch tory depression, hypotension and drug
Dose: 10-20 mg dependence
q.i.d. • It is used in renal colic, postoperative and
metastatic cancer pain
7. Mefenamic acid Oral • It has analgesic, antipyretic and weak
Dose; 250-500 nig anti-inflammatory effect
ti.d. • It is used in dysmenorrhoea. osteoarthri¬
tis. rheumatoid arthritis
 SELECTIVE COX- 2 INHIBITORS:
Some of COX -2 inhibitors ore parecoxib, etoricoxib, etc.
Parecoxib is a prodrug of valdecoxib and is administered parenterally, celecoxib
and etoricoxib are given by enteral route.
Selective COX-2 inhibitors.
e.g. etorkoxib. parecoxib, celecoxib

Gastric friendly Kidney Heart

GI irritation and Inhibit COX-2 I hgher incidence of cardiovascular
peptic ulcer are rare I thrombotic events
They mainly inhibit PGb; TXA2
Na+. HtO retention
' is unaffected
4 This may be responsible for
Oedema increased risk of cardiovascular
events

Table 6.6 Differences between nonselecttve COX and selective COX-2 inhibitors
Nonselective COX inhibitors Selective COX-2 inhibitors
• Analgesic effect + • Analgesic effect +
• Antipyretic effect + • Antipyretic effect +
• Anti 'inflammatory effect + • Anti-inflammatory effect *
• Antjplatetet effect + • Mo antiptateiel effect
• GI side effects are marked + + • GJ side effects are less (less ulcerogenic
• Renal toxicity + potential)
(sodium and water retention) • Renal toxicity +
.
Note + present: + + . effect is more.

PARACETAMOL (ACETAMINOPHEN)
^Paracetamol is effective by oral and parenteral routes.
->It is well absorbed, widely distributed all over body, metabolized in liver by
sulphate and glucuronide conjugation.
->The metabolites are excreted in urine.
USES; Adverse Effects:
l.As antipyretic: 1. Side effects are rare, occasionally
To reduce body temperature during fever. causes skin rashes and nausea.
2. As analgesic: 2. Hepatotoxicity: With acute overdose or
To relieve headache, toothache, myalgia, chronic use.
dysmenorrhoea. etc. 3. Nephrotoxicity is commonly seen on
3. It is preferred analgesic and antipyretic: in patients chronic use.
with peptic ulcer, haemophilia, bronchial asthma and
children.
 ACUTE PARACETAMOL POISONING
Acute overdosage mainly causes hepatotoxicity ->
symptoms are nausea, vomiting, diarrhoea, abdominal pain, hypoglycaemia,
hypotension, hypoprothrombinaemia, coma, etc.
Death is usually due to hepatic necrosis.

MECHANISM OF TOXICITY AND ITS TREATMENT:

The toxic metabolite of paracetamol is detoxified by conjugation with glutathione
and gets eliminated.

High doses of paracetamol cause depletion of glutathione levels.

In the absence of glutathione, toxic metabolite (N-acetyl-p-benzo-quinoneimine
[NAPQI]) binds covalently with proteins in liver and kidney and causes necrosis.

Alcoholics and premature infants are more prone to hepatotoxicity.

N- acetylcysteine or oral methionine replenishes glutathione stores of liver and
protects liver cells.

Activated charcoal is administered to decrease absorption of paracetamol from

gut, Haemodialysis may be required in cases with acute renal failure.
Liver

Fig. 6.5 Mechanism of paracetamol toxicity and its treatment NAPQI, N acetyl-p benzo-
Quinoneimine

Table 67 Differences between aspirin and paracetamol

Aspirin Paracetamol (acetaminophen)
1 . It is a salicylate derivative 1, It is a para-aminophenol derivative
2. It has analgesic, antipyretic and potent 2. It has potent antipyretic and analgesic
anti-inflammatory effects effects with poor anti-inflammatory
3. It causes Gi station (nausea, vomiting, activity
peptic ulcer and bleeding) 3 It usually does not produce gastric
4. In large doses, it produces acid-base irritation
and electrolyte imbalances 4. It does not produce acid-base and
5. It has antiplatelet action electrolyte imbalances
6. It has no specific antidote 5. It has no antiplateiel action
7. It is contraindicated in peptic ulcer, 6. W- acetylcysteine is the antidote
people with bleeding tendency, bron¬ 7, Paracetamol is the preferred analgesic
chial asthma and m children with viral and antipyretic in patients with peptic
infection ulcer, bronchial asthma and in children
 TREATMENT OF GOUT
Gout is a disorder of purine metabolism in which plasma urate concentration is
raised either due to overproduction or impaired excretion of uric acid.
It is characterized by intermittent attacks of acute arthritis produced by
deposition of sodium urate crystals in joints.
Primary hyperuricaemia may be Secondary hyperuricaemia can occur in leukaemias, chronic
idiopathic or due to enzyme defects renal failure and during drug therapy (thiazides, loop
diuretics, pyraz inamide, levodopa, cytotoxic agents, etc.)
ANTIRHCUUATOID DRUGS

1
NSAIDs
Otchkinr I
Uricosuric*
1 -—1
Synlhwl* Inhibitor* '
Glucocorticoid*
Probenixid Atlupunnitl
SuHinpytj hfbmosb t

Non -biological drugs: Biological agents: II-1 antagonist:

Cute =chloroquine A=adalimumab Anna kinra
P- penicillamine C-cetrolizumab
A=azathiaprine E= etanercept
G=gold salts Inhibitors^ infliximab
L= leflunomide
1= immunosuppressant
Mallika=methotrexate
Sehrawat= sulfasalazine

TREATMENT OF ACUTE ATTACK OF GOUT:

1. Nonsteroidal Anti- 2.CoIchicine. 3.Glucocorticoids.
Inflammatory It is an alkaloid.
Drugs To relieve an acute Glucocorticoids are
attack, NSAIDs like It is neither an analgesic nor a uricosuric effective, produce
naproxen, indomethacin, agent, although it relieves pain in acute attack rapid response and
piroxicam, diclofenac, of gout. are reserved for
aceclofenac and etoricoxib cases not responding
are used. Deposition of urate crystals in joint -> to NSAIDs and
They are better tolerated Chemotactic factors produced -> migration of colchicine.
than colchicine. neutrophils into joint -> release factors which Prednisolone and
contribute to inflammation. methylprednisolone

15
 It is administered either orally ar are used systemically
intravenously. in gout
It is rapid acting but poorly tolerated.
They are nausea, vomiting, diarrhoea and
abdominal pain.
Chronic use may lead to myopathy, alopecia,
aplastic anaemia and agranulocytosis.

TREATMENT OF CHRONIC GOUT:

1.Uricosuric agents:
They inhibit active tubular reabsorption of uric acid in proximal tubules and
increase excretion of uric acid, eg. probenecid and suIphinpyrazone.
They are rapid acting but poorly tolerated.
High fluid intake is advised to prevent formation of urate crystals in urine.

SULPHINPYRAZONE is an alternative to probenecid.

Uricosuric drugs should not be given within 3 weeks of an acute attack of gout.
They mobilize uric acid from tophaceous deposits, hence there is fluctuation in
serum uric acid levels which can precipitate an acute attack.
These drugs are contraindicated in patients with renal failure.
Side effects: are rare, but GI toxicity (nausea, vomiting) and skin rashes may
occur.

2.Uric Acid Synthesis Inhibitors:

Xanthine Hypoxanthine Uric acid

Xanthine oxidase Xanth me oxidase

3 . Allopurinol:
Allopurinol prevents -> synthesis of uric acid by inhibiting enzyme xanthine
oxidase, thus reduces plasma urate levels.
Its active metabolite, alloxanthine, is a non-competitive inhibitor of xanthine
oxidase enzyme.

It reduces urate crystals in kidney, joints and soft tissue.

There is an increase in levels of xanthine and hypoxanthine in plasma which are
effectively excreted in urine.
Allopurinol is administered orally and is drug of choice for asymptomatic gout.
It is used in chronic gout as well as hyperuricaemia associated with cancer
chemotherapy, radiation or renal disease.

It should not be started within 3 weeks of an acute attack of gout, as it may

precipitate another attack.
Allopurinol is also useful in kala-azar.
 TREATMENT OF RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA) is a chronic multisystem autoimmune disease,
main characteristic feature is persistent inflammatory synovitis of peripheral
smaller joints.

Pain and swelling of joints are mainly due to PGs, whereas cytokines are
responsible for progressive damage to joints leading to deformity.
1. Disease-modifying antirheumatic drugs (DMARDs)
(i ) Nonbiologics
Methntrexaie, azathioprine, cyclophosphamide, cyclosporine, chloroquine, hy¬
droxychloroquine. sulphasalazine, lelhinomide, gold salts, dpenicillamine.
(ii ) Hiologia
(a) TNF-a antagonists: Etanercept, infliximab, adalimumab
(bi IL-I antagonist: Anakinra
(c) T-cell modulating agent: Abatacept
(d) B- lymphocyte dep kt er: Rituximab
2. NSAtDs: Aspirin, ibuprofen, diclofenac, naproxen, piroxicam, etoricoxib.
3. Glucocorticoids: Prednisolone, triamcinolone, methylprednisolone,
-
M Methotrexate A - Anakinra, abatacept
-
E Etanercept 1. - Leflunomide
D - D- Penicillamine S - Sulphasalazine
-
I Infliximab
C - Chloroquine and hydroxychloroquine
R - Rituximab
Gold compounds
Sote: Mnemonic tor I>MARI )s M L l> I (A Hi iokl ( E, I, A and R arc biologies).

SULPHASALAZINE :
It is used alone in mild disease or in combination with other drugs in severe cases.
It causes remission in active RA and is also used for chronic inflammatory bowel
disease.
It is administered orally and is split in gut by colonic bacteria.
COMMON SIDE EFFECTS are nausea, vomiting, diarrhoea, headache, skin rashes
and leukopaenia

Table 6 8 Biologies and (heit important features

Adverse
Sulphaulazine
Drug Route MOA effects Uses
* Etanercept s.c. TNF a Opportunistic Rheumatoid
• Infliximab antagonists inflations arthritis, psona
• AdaWn- alckiding SiS, Crohn Sulphapvridinc 5* Amino ulicyik acid
umab tito&ciJosis disease,
• Goknumab ankylosing
spondylitis
Absorbed into tinuliUnn Producei Uka] anti -mfUmmatory
Anakjnra s.c. IL-1 antagonist Oppoduni st ic Rheumatoid
infections,
manly
resjxalory
arthritis
I
Inhibit* production of superoxide and
activity in Ihe pit

I
inHjmmjiory cyiokinn fU Vied tn ukmtivc colilis
Abalaoopt Lv, infusion Inhibits T call OppOrtuntSbC Rivnimatotd
and TN1--Q1 by innniKytcs
activation infections arthritis
Rituximab Lv. infusion Depletes Skin rashes Used with metho
peripheral B trexate m
lymphocytes resistant cases Beneficial effect in rheumatoid arthritis
of rheumatoid
arthritis
Note MOA. mec^ansrri of acton
 CLASSIFICATION OF ANTIHYPERTENSIVE DRUGS

DRUGS AFFECTING CARDIOVASCULAR SYSTEM:

Hypertension is a common cardiovascular disease affecting worldwide population.
A persistent and sustained high blood pressure has damaging effects on heart,
brain, kidneys and eyes.
Hypertension could be:
1. Primary or essential hypertension:
It is most common type There is no specific underlying cause.
2. Secondary hypertension:
It can be due to renal, vascular, endocrine disorders, etc..

CLASSIFICATION OF ANTIHYPERTENSIVE DRUGS

ANTIHYPEAt ENSIVE DRUGS (1)

Otureties Rerun- ar^krtan.in Sympathetic

•ystem inhibitor. tnhtbiiorv

Thiazides High ceiling Pot sparing

1 1 edrenergic u+
Ih dmchlonrthM/idc runiM*midr SpironuUch mt* blockers adrenergic
VhMrthaiikknw (others) Eplcrunone Pruprarmlol
Endapa mide A milliridr LabrUkil
Metoprolol
Almnkil ('anrdilol
(other*)

ACE inhibitors Angiotensin (AT, J Direct renin

receptor blockers inhibitor
Giph>rnl -adrenergic Central
UVila prd l.OMirlan Ali&kiren blockers sympatholytic s
i
I iMTHiprii CAndesarwi Prazosin Clomdinc
!’enrklopnJ VaKirtan Terazosin Mcth\ldop4
Kamtpnl TelmiMrun llo^a/iKin
It»Mnopril Irhvxarbin nwiUoUnunc
Quinapril CHmoarton Pfeenmvbm/jmiik' Gw?J
IraniInto pit

ANTIHYPERTENSIVE DRUGS (2)

Calcium channel biockera Vasodilators

Phenyl- Benzothiazepine Dihydropyndmes Arteriolar dilator

I
Arteriolar +
alkylamine Diltiazcm Nifedipine Hydralazine vonoditat or
Verapamil Fekxlipine Minoxidil Nitroprusside
Amlodipine Diazoxfde mkI
Nitrendipine
1acidipinc
1rrcanidipine
Benidipine
April me AC laaya ream train se 1-NGO mein sir ki taang toot Sympathetic
chura ke.uski kapti queen ne naali me gai.sir bole Io aarab candy or tell inhibitors:
fake di,.kyuki AC mein parindo ki me wall pe oil kisne geeraya tha Pra tera
laashe fasi thi. 1-NGO mein sir ki taang- ATI doka(doxa)
April mein AC : ACE. pril receptor blockers Zosin-> a
Raam: ramipril LoJosartan adrenergic
Train ;trandopril Arab :irbesartan blockers
Kapti; captopril Candy :candesartan
Naali: enalapril Walkvalsartan B- adrenergic
Parindo: perindopril OiLOImesartan blockers;
Laashe: lisinopril PAM
Propranolol
Vasodilators: Atenolol
Aarti ka or Meenakshi ka di1,hydra Metoprolol
Calcium channel blockers: per aagya pr vinod ne arti ko night
Kale chane chordho ladke or falo ka m propose krdiya Central
raja aam Io use clean kro knife se sympatholytics:
kaat ke lassi banake pee loge toh AartLarteriodilator Clonidine
chehre pe nikhar aayega ar aloe vera Meenakshi ka dil: minoxidil Methyldopa
ko delete krdoge zindgi se Hydra: hydralazine CM
Vinod ne aartharterio+venodilator
Ladke;lercanidipine Night m propose: nitroprusside
Falo:felodipine
Aam Io; amlodipine
Clean: cilnidipine
Knife: nifedipine
Lassi Jacidipine
Nikhaar:nicardipine
Vera verampil
Delete diltiazem

1. ANGIOTENSIN CONVERTING ENZYME INHIBITORS

ACE inhibitors ore frequently used os first -line antihypertensive drugs.

MECHANISM OF ACTION
Inhibit generation of angiotensin Decrease in aldosterone Decrease in sympathetic nervous
II resulting in: Dilatation of production system activity.
arterioles
i decrease in Na and H2O Inhibit degradation of bradykinin
Decrease peripheral vascular retention (potent vasodilator) by ACE.
resistance (PVR) |sed BP. ised BP
Stimulate synthesis of vasodilating
prostaglandins through bradykinin.

AHskiren
 Aliskiren
Angiotensin I

Angiorensinogen > Angiotensin I Angiotensin-converting enzyme ACE inhibitors |

Angiotensin II

Aldosterone T Sympathetic
release activity
Constriction of blood vessel

Na* and H2O

? Total peripheral resistance
retention
Cardiac
hypertrophy and
TBP remodelling

PHARMACOKINETICS:
-> ACE inhibitors are usually given orally.
-> In hypertensive emergency, enalaprilat can be given intravenously.
-> Food reduces absorption of captopril; hence, it should be given 1 hour before
meals.
->ACE inhibitors poorly cross the blood-brain barrier (BBB). are metabolized in the
liver and excreted in urine.

ADVERSE EFFECTS AND CONTRAINDICATIONS:

Mnemonic: CAPTOPRIL
1.Cough (dry cough):
Appearance of intractable cough is an indication to stop the drug.
It subsides following discontinuation of drug.
2. A ngioedema:
Swelling in nose, lips, mouth, throat, larynx and glottis.
There can be airway obstruction - patient's airway should be protected.
3. Proteinuria can occur rarely. The drug should be discontinued.
4 Teratogenic effect (growth retardation, foetal hypotension, renal failure and
neonatal death) - hence contraindicated in pregnancy.
5. Hypotension may occur following the first dose of ACE inhibitor -
This can be marked in patients who are volume depleted or have congestive heart
failure (CHF).
6. Neutropenia is rare.
7. Rashes.
8. Itching: Discontinuation of drug is not required.
9. Loss of taste sensation (dysgeusia).
 THERAPEUTIC USES OF ACE INHIBITORS:
Hypertension : Acute MI: CHF: Diabetic Scleroderma
ACE inhibitors are used in ACE inhibitors should ACE inhibitors nephropathy: renal crisis:
all grades of hypertension. be started within 24 should be ACE inhibitors ACE
They decrease hours in patients with prescribed to and angiotensin inhibitors
cardiovascular and MI all patients II receptor prevent the
cerebrovascular morbidity with impaired blockers (ARBs) effects of
and mortality (fatal and LV function are the angiotensin
nonfatal myocardial preferred drugs II in the
infarction (MI), fatal and in diabetic renal artery;
nonfatal stroke, CHF and nephropathy in thus, they
sudden death) hypertensive as are effective
well as in the
normotensive treatment of
patients . scleroderma
renal crisis.

2.DIRECT RENIN INHIBITOR: ALISKIREN

Aliskiren
1©
Renin
Angiotensinogen Angiotensin I
Aliskiren, by inhibiting renin
I
decreases levels of angiotensinI and angiotensin II.
->It is useful in hypertension in combination with diuretics, ACE inhibitors or ARBs
(increased antihypertensive efficacy).
->It is administered orally.
-> Adverse effects include diarrhoea, abdominal pain, headache and angioedema.
3. DIURETICS:
Mechanism of Action of Thiazides
 These are used in uncomplicated mild to moderate hypertension and have a long
duration of action.
They should be administered in a low dose, i.e. 12.5 mg of chlorthalidone or
hydrochlorothiazide .
If the antihypertensive response is not adequate, dose can be increased up to 25
mg/day,
Advantages of Thiazides: Adverse Effects:
long duration of action (administered once daily). They ore hypokalaemia,
->Are cheap. hyperglycaemia, hyperuricaemia,
->Are well tolerated by elderly patients. hyperlipidaemia, hypercalcaemia,
Have synergistic effect when used in combination with other impotence and decreased libido.
antihypertensive drugs

4.CALCIUM CHANNEL BLOCKERS:

MECHANISM OF ACTION:
Voltage-sensitive Ca2 channels are of five subtypes: L, N, T, P and R.
L-type is predominantly present in cardiac and smooth muscle cells.
CCBs block voltage- sensitive L-type CaI+ channels by
binding to ar subunit

Prevent entry of Ca:’ into the cell

No excitation-contraction coupling in the

heart and vascular smooth muscle
1. Variant angina:
It is due to coronary spasm. Amlodipine, nifedipine SR and diltiazem can be used
prophylactically. They relieve pain effectively by attenuating the coronary
vasospasm.
2.Supraventricular arrhythmias:
Verapamil is useful for supraventricular arrhythmias because of its depressant
action on SA and AV nodes.
3. Hypertension:
OHPs, diltiazem and verapamil are used in hypertension. They control blood
pressure by their vasodilatory effect. They can be safely used in hypertensive
patients with asthma, hyperlipidaemia and renal dysfunction.
4.Hypertrophic cardiomyopathy;
Verapamil is the preferred CCB, as it improves diastolic function.
5. Migraine:
Verapamil is useful for prophylaxis of migraine. Another CCB. flunarizine. is more
effective than verapamil in reducing the frequency of migraine attacks
Table 3.5 Adverse effects of calcium channel blockers
Nifedipine Verapamil Diltiazem
• Hypotension • Constipation • Headache
• Palpitation • Sinus bradycardia • Hypotension
• Reflex tachycardia • Oedema; may precipitate • Bradycardia
• Oedema CCF In patients with low • Oedema
• Flushing cardiac reserve • AV block occurs rarely
• Fatigue • AV block and headache.
• Dizziness rarely
• Sedation
5.SYMPATHOLyTICS
Adrenergic Blockers
P- Blockers are effective in all grades of hypertension.
Selective p-blockers (block only p 1), e g atenolol, metoprolol, esmalol and
betaxolol
-> Nonselective p -blockers (block both pi and p2). e.g. propranolol and timolol

Fig. 3.3 Mechanism of antihypertensive effect of p-blockers.

1. Variant angina:
It is due to coronary spasm. Amlodipine, nifedipine SR and diltiazem can be used
prophylactically. They relieve pain effectively by attenuating the coronary
vasospasm.
2.Supraventricular arrhythmias:
Verapamil is useful for supraventricular arrhythmias because of its depressant
action on SA and AV nodes.
3. Hypertension:
OHPs, diltiazem and verapamil are used in hypertension. They control blood
pressure by their vasodilatory effect. They can be safely used in hypertensive
patients with asthma, hyperlipidaemia and renal dysfunction.
4.Hypertrophic cardiomyopathy;
Verapamil is the preferred CCB, as it improves diastolic function.
5. Migraine:
Verapamil is useful for prophylaxis of migraine. Another CCB. flunarizine. is more
effective than verapamil in reducing the frequency of migraine attacks
Table 3.5 Adverse effects of calcium channel blockers
Nifedipine Verapamil Diltiazem
• Hypotension • Constipation • Headache
• Palpitation • Sinus bradycardia • Hypotension
• Reflex tachycardia • Oedema; may precipitate • Bradycardia
• Oedema CCF In patients with low • Oedema
• Flushing cardiac reserve • AV block occurs rarely
• Fatigue • AV block and headache.
• Dizziness rarely
• Sedation
5.SYMPATHOLyTICS
Adrenergic Blockers
P- Blockers are effective in all grades of hypertension.
Selective p-blockers (block only p 1), e g atenolol, metoprolol, esmalol and
betaxolol
-> Nonselective p -blockers (block both pi and p2). e.g. propranolol and timolol

Fig. 3.3 Mechanism of antihypertensive effect of p-blockers.

JJ- Blockers may precipitate CCF and bronchospasm in susceptible individuals.
They can cause sexual dysfunction in males and nightmares.
They must be used with caution in diabetes patients receiving hypoglycaemic drugs.

CENTRALLY ACTING SYMPATHOLYTICS

Clonidine:
Clonidine is a centrally acting antihypertensive drug.
MECHANISM OF ACTION
->Clonidine is effective orally; it is highly lipid soluble and rapidly crosses the BBB.
->It has a short duration of action, requires twice a day administration.

Transdermal patch of clonidine controls BP for a week.

ADVERSE EFFECTS
Dryness of mouth and eyes, sedation, depression, bradycardia, impotence, nausea,
dizziness, parotid gland swelling and pain are the adverse effects of clonidine.
Postural hypotension may occur.

IlHR, IJCO UPVR

IBP IBP
Fia. 3.4 Mechanism of action of ctonidine.

a-Methyldopa:
It is a centrally acting sympatholytic agent.
Mechanism of Action:
a-Methyldopa — a-Methyldopamine — a-Methylnoradrenaline —» Stimulates
a^VMC

Adverse Effects:
UBP
— — iHR. 1PVR Central .ympMhetk

These include nasal stuffiness, headache, sedation, mental depression, dryness of

outflow

mouth, bradycardia, impotence, gynaecomastia, hepatitis and rarely haemolytic

anaemia.
 A -ADRENERGIC BLOCKER:
tt- Blockers

Nonsclective bloikrrs (U| and a3) Selective (a() blockers

• Phrnoxybenzamine * Prazosin
• Phentuhminc •Terazosin, doxazosin

Block both «| and ol receptors Block selectively ar vascular receptors by

in Ihe blood vesiek competitive mechanism

• Vasodilatation and fall in BP Vasodilation and fall in BP

(due to ar blockade) (cl receptors are not blocked, hence
• T ^Noradrenaline release due there is no increase in the level of NA;
to presynaptic CQ-blockade therefore, tachycardia is minimal)
(tachycardia is prominent)

6. VASODILATORS:
K
" Hyperpolarization
* Minoxidil 1 Activate k4 channels —* of vascular
•Diazoxide I (K4 channel openers)

—: * ] W-
K" efflux
smooth muscle
I
X
Vasodilatation

llBlood pressure
Minoxidil: Diazoxide.
It is a powerful arteriolar dilator. It is used in treatment of hypertensive
It is effective orally emergencies .
It causes reflex tachycardia, Na and water It is administered intravenously and has a
retention. Hence, minoxidil is used with a p- blocker long duration of action (6-24 hours).
and a diuretic. It also relaxes uterine smooth muscle.

Topical minoxidil is used to promote hair growth in Adverse effects are reflex tachycardia.
male type of baldness. hyperglycaemia, sodium and water retention.

Sodium Nitroprusside:
It is a powerful arteriolar and venodilatar (balanced arteriovenous dilator).

<
-
NO arteriolar and venodilatation

Liver Excreted
Cyanide Thiocyanate > slowly in
urine
 Sodium nitroprusside
I

Generates nitric oxide [NO]

Relaxes vascular
smooth muscle
Vasodilatation

Fig. 3.5 Mechanism of action and effects of sodium nitroprusside.

HYPERYENSIVE CRISIS
HYPERTENSIVE CRISIS;
Hypertensive emergency is characterized by a very high blood pressure (systolic
180 and/or diastolic 120 mm Hg) with progressive end organ damage such as
retinopathy, renal dysfunction and/or hypertensive encephalopathy.

It is a medical emergency
If there is no end organ damage, it is hypertensive urgency.
For hypertensive urgency, oral clonidine, labetalol or a OHP (e g. amlodipine) is
used.
In a patient with hypertensive emergency, the BP should be reduced by not more
than 25% over 1 hour

then to 160/100 mm Hg over next 2-6 hours

normal over next 48 hours .

The drugs are administered intravenously - e.g. labetalol, nicardipine,
nitroglycerin, sodium nitroprusside, furosemide (hypertensive crisis with acute
pulmonary oedema), clevidipine, esmolol (in patients with aortic dissection),
hydralazine, fenoldopam, enalaprilat, phentolamine (hypertensive crisis in
pheochromocytoma) .
 ANTIANGINAL DRUGS

Angina pectoris is a symptom of ischaemic heart disease,

PATHOPHYSIOLOGY
Angina occurs due to imbalance in oxygen supply and oxygen demand by
myocardium.
~
I
O; supply O> demand 1
• Coronary atherosclerosis • TT Heart rale
• Coronary' vasospasm • Ventricular hypertrophy
• Coronary thrombosis • FT Ventricular contractility
• TT Ventricular wall tension
Treatment

TOj supply XO? demand

L Restore the coronary blood flow by: By reducing work load on the heart
(a) Percutaneous intervention (a) Decrease preload (mainly):
(PCI) including stenting Nitrates
(b) Coronary artery bypass (b) Decrease after load: CCBs> K 4
graft (CABG) channel openers
2* Relieve the vasospasm by drugs: (c) Decrease heart rate and
CCBf nitrates contractility: [J- Adrenergic
3. Break the thrombi using thrombolytic blockers
agents: Streplokinase/urokinase
4. Prevent thrombus formation by using
antiplatdet drugs
ANTIANGINAL DRUGS

Nitrates p-blockers Calcium channel Pot. channel Other

blocker* opener antianginal
drugs

Short acting | Long acting Propranolol Verapamil Nicorandil । Trimetazidine

Glyceryl trinitrate Isosorbide Metoprolol Dlltiazem Ranolazine
Isosorbide dinitrate Atenolol Amlodipine Ivabradine
dinitratc (oral) (others) Nitrendipine Oxyphcdrinv
(sublingual) Isosorbide (others) Dipyridamole
mononitrate
Erythritol
tetronitrate
PenLuTV thrited
tetranitrate

ORGANIC NITRATES
Organic nitrates are prodrugs - they release nitric oxide (NO).
Nitrates are mainly venodilators. also cause arteriolar dilatation, thus reduce both
preload and afterload.
 MECHANISM OF ACTION:
Nitrates

|Denitrated tn the smooth muscle cell

Release nitric oxide

Stimulate guanylyl cyclase

Increased U iMP

Dephosphorylation of myosin light chain kinase (MI CK I

Decrease in Ca2, concentration in the cytosol

Relaxation of vascular smooth muscle fibres

Venodiltlalion Arleriohr dilatation Dilatation of large

(predominant effect! coronary vessels and
collateral vessels
Peripheral pooling of blood XX PVR

Increased blood flow to

XX Venous return Io the hear* X Aftcrload ischaemic area due Io
redistribution of coronary
XX Preload blood flow

XX Left and right I

end diaMohi ventricular volume Increased CL delivery to
ischaemic area
XX (lardwc work

XI Oj requirement of myocardium
( X O> demand)

Re ief ol
anginal pain

THERAPEUTIC USES OF NITRATES:

1 Angina
For acute attack of angina; For prophylaxis of angina:
Nitroglycerin is drug of choice. Longer acting nitrate preparations ore used -
For an acute attack, nitroglycerin is commonly isosorbide mononitrate orally; isosorbide dinitrate
administered sublingually with an initial dose of 0.5 orally; nitroglycerin oral sustained-release
mg that usually relieves pain in 2-3 minutes. preparation/ointment/disc/patch.
Patient is advised to spit out tablet as soon as the TransdermaI nitroglycerin produces prolonged
pain is relieved to avoid side effects effect, up to 24 hours
(hypotension and head ache).
If the pain is not relieved, tablet can be repeated
after 5 minutes but not more than three tablets
in 15 minutes.
 2. Variant angina (Prinzmetal angina):
It is due to coronary vasospasm.
Episodes of coronary vasospasm are treated with nitrates; for prophylaxis,
nitrates and CCBs (amlodipine, nifedipine SR and diltiazem) are effective.

3. Unstable angina
Antiplatelet Anticoagulants: Nitrates : b Blockers: CCBs:
agents: Low- Low-molecular- Nitroglycerin They (atenolol, Amlodipine, nifedipine SR,
dose aspirin, weight heparin, (sublingual) is metoprolol) are diltiazem or verapamil are
clopidogrel ore unfractioned usually effective. routinely used if symptoms persist
used. heparin or administered in in patients on nitrates
fondaparinux. Intravenous unstable angina and p- blockers or if p-
nitroglycerin is unless blockers are
administered if contraindicated. contraindicated.
pain persists or
recurs.

4. MI:
For management of acute AU, intravenous infusion of nitroglycerin is useful for
persistent or recurrent ischaemic pain and treatment of LV failure.

5. Hypertensive emergency:
Intravenous infusion of nitroglycerin is used because of rapid onset of action.

6.Cyanide poisoning:
In cyanide poisoning, oxygen carrying capacity of blood is not affected.
Cyanide inhibits cytochrome oxidase and prevents oxygen utilization by cells.
All tissues suffer from anoxia (histotoxic type of anoxia).

->Amyl nitrite and sodium nitrite are used in treatment of cyanide poisoning.
Nitrites rapidly convert haemoglobin to methaemoglobin.
Methaemoglobin combines with cyanide to form nontoxic cyanomethaemoglobin.
•^Intravenous sodium thiosulphate converts cyanomethaemoglobin to sodium
thiocyanate, which is rapidly excreted in urine.
Amyl nitrite and

Haemoglobin
(nontoxic)
—
sodium nitrite
* Methaemoglobin Cyanomethaemoglobin
i.v. sodium
thiosulphate
Cyanide
Sodium thiocyanate
Cytochrome (rapidly excreted in urine)
oxidase
 Potassium Channel Openers (Potassium Channel Activator):
Nicorandtl is administered orally. It causes arteriolar and venodilation, and also
improves coronary blood flow

Nkorjndtl Releases NO
Haemoglobin
| 4— Sod. nitrite (10 ml of 3% solution i.v.)
Methaemoglobin
| 4— Cyanide

Cyanomethaemoglobii]
Hyperpolarization Relaxation of vascular
I4— Sod. thiosulfale (50 ml of 25ao solution i.v.)
smooth muscle
Methaemoglobin + Sod. thiocyanate
Venodilation Arterial dilation 1
I
1Preload
1
1Afterload
Excreted iu mine

PHARMACOTHERAPY OF ACUTE MYOCARDIAL INFARCTTON

1. Antiplatelet agent:
Aspirin, 162 mg or 325 mg orally (chewed and swallowed), is administered at once
to a patient with suspected or definite MI.
If the patient is allergic to aspirin, clopidogrel 300 mg is administered.
Antiplatelet agent should be continued once daily.
2. Analgesia:
Intravenous morphine 10 mg for relief of pain.
Antiemetics like promethazine 25-50 mg slow i.v. to prevent opioid -induced
vomiting.
3. Nitrates:
Intravenous nitroglycerin for recurrent or persistent pain and to treat LV failure.
4. Low flow oxygen therapy
(2-4 L/minute) if there is decreased oxygen saturation.

5. Reperfusion therapy:
Primary percutaneous coronary intervention (PCI) or thrombolytic therapy.
Primary PCI, if facilities are available.
Thrombolytic therapy: Streptokinase, alteplase, tenecteplase, reteplase or
urokinase is used to restore coronary patency and reperfusion of infarcted area.

6. Anticoagulants:
Low-molecular-weight heparin or unfractionated heparin is given to prevent
reinfarction and thromboembolic complications.
 DRUGS USED IN CONGESTIVE CARDIAC FAILURE

Function of heart is to pump on adequate amount of blood to various tissues.

In CCF. there is an inadequate or inefficient contraction of heart leading to
reduced CO.
In initial stages of CCF, compensatory mechanisms that try to maintain the CO
are as follows:
Increased sympathetic activity. Increased renin- Myocardial hypertrophy and
angiotensm-aldosterone remodelling
activity .

Backward - Forward failure:

failure: narrowed arterioles
distended veins with T ahedoad
with T preload

•Nitrates
• ACE inhibitors
• ACE inhibitors •ARBs
•ARBs * Other vasodilators
(reduce afterload)
(reduce preload)

•Digitalis
•Dobutamine
(increase CO)

•Dopamine Reduced renal Increased

(increases renal blood flow renin¬
blood flow) angiotensin
activity

* Diuretics decrease
Na\ H?O
(promote Na\ retention ACE inhibitors
H2O excretion) ARBs

Oedema

DRUGS FOR CONGESTIVE HEART FAILURE

Inotropic drugs Diuretic* Akio atatone

antagcntati

1 1 POE 3
Cardiac Sympatho
mimetics Inhibitors
High ceiling | Thiazide like
SpttunobihHk*
Furwmidc I Hydrochlom- Fplewnone
iXgnMn IXfaiMmfar j liumnntw Bumetanidr thu/idr
(XubJin iXfpjminc Milrinone MHoLvone [vadrmergic
Xipjmide btockm
Ranin ang totentln mhtbHora
Vasodilator* Mvti*proM
BwtproM
r
ACE inhibitors Angiotensin AT, Vonodilators Arteriolar +
Xcbtvokil
Can cdilol
receptor Mocker* vonodI titor
Eiukpril
Ramipn! 14MHan tmutr^k* Sod
(nthrrM Ondr^rLin RcMirbkle nih<»pnn*>dc
KithvrQ dmktr.ile

Arteriolar dilator
H>l rhmphoilieM<TJK AC ( .\npi4ctitin uNuitiinp I tydrali/inr
 1. Diuretics :
A majority of patients with CHF are started on diuretics.
Promote •Improve cardiac
Diuretics — silt and — iCircufating iprd£>ad function
volume
water •Decrease dyspnoea
excretion and peripheral
oedema
•Relief of symptoms
of congestion

2.Cardiac Glycosides:
Source Glycosides
Digitalis purpurea (leaf) Digitoxin
Digitalis lanata (leaf) Digoxin, digitoxin
Strophanthus gratus (seed) Strophanthin-G (ouabain)

MECHANISM OF ACTION OF CARDIAC GLYCOSIDES

NaK-ATPase is a membrane-bound enzyme which is called digitalis receptor. It is
also called sodium pump.

Pharmacological Actions
1. Cardiac 2. Extracardiac
Cardiac: Extracardiac:
1. Myocardial contractility: 1.Gastrointestinal tract (GIT);
Digitalis increases the force of contraction of the Digitalis can produce anorexia, nausea,
myocardium (positive inotropic effect). This effect is more vomiting and occasionally diarrhoea.
prominent in the failing heart. Nausea and vomiting are due to
stimulation of chemoreceptor trigger
2. Heart rate: zone (CTZ) and a direct action on the
In patients with CCF, digitalis reduces the heart rate gut.
(negative chronotropic effect) by direct and indirect
actions. In small doses, digitalis decreases heart rate by 2. Kidney:
stimulation of vagus. In toxic doses, it can increase In patients with CCF, digitalis causes
sympathetic activity thus increasing heart rate. diuresis (increased urine output).

3. Electrophysiological actions: 3. Central nervous system (CNS):

At therapeutic concentrations, digoxin decreases In high doses, it can cause central
automaticity and increases resting membrane potential by sympathetic stimulation, confusion,
vagal action in atria and AV node. It also prolongs ERP and blurring of vision, disorientation, etc.
decreases conduction velocity in AV node. This may lead to
bradycardia and AV block. At higher concentrations, digoxin
can increase automaticity in cardiac tissue by direct action
as well as by increasing sympathetic activity. This can
result in atrial and ventricular arrhythmias.

4 ECG:
Digitalis produces prolongation of P-R interval, inversion of
T wave and depression of ST segment.

Fig. 3.13 Beneficial effects of digitalis in CCF. CO. cardiac output.

ADVERSE EFFECTS:
Digoxin has a narrow margin of safety.
Monitoring of serum digoxin, electrolyte levels and electrocardiogram (ECG) are
important during digitalis therapy.
Cardiac Extracardiac
Digitalis can cause any type of arrhythmias. 1.6IT: Early symptoms of toxicity are anorexia,
The most common are ventricular premature nausea and vomiting, which are due to 61
beats, ventricular tachycardia. irritation and CTZ stimulation.
2.CNS effects include headache, confusion,
It can also cause AV block, atrial tachycardia, restlessness, disorientation, weak ness, visual
atrial fibrillation, atrial flutter and even severe disturbances, altered mood and hallucinations.
bradycardia . 3.Skin rashes and gynaecomastia can occur
occasionally.

TREATMENT OF DI6OXIN TOXICITY

1. Shift patient to intensive care unit (ICU).
2. Stop digoxin and potassium-depleting diuretics (thiazides/loop diuretics).

3. Potassium chloride (KCI) orally or intravenously is the drug of choice far

tachyarrhythmias, when serum K level is normal/low.

4. Supraventricular arrhythmias are treated with oral or intravenous propranolol.

5. Intravenous lignocaine is the drug of choice for ventricular arrhythmias because

it has: Relatively low incidence of toxicity. A rapid onset and short duration of
action, so its action wears off immediately after stopping the infusion. No action
on AV nodal conduction velocity, hence, does not intensify the AV block in digitalis
toxicity.

6. AV black and bradyarrhythmias are treated with atropine and cardiac pacing.

7. Digoxin antibodies (Digibind):

It is used only in case of serious digitalis toxicity.
It neutralizes circulating digoxin/digitoxin and rapidly reverses the taxicity, but it
is expensive.
 RENAL PHARMACOLOGY I DIURETICS

Diuretics are drugs that promote excretion of Na and water in urine.

DIURETICS

High ceiling Medium Weak/adjunctive diuretics

(loop diuretics) efficacy Carbonic Osmotic Potassium
L (thiazides) anhydrase diuretics sparing
inhibitor O diuretics
C P

SITE OF ACTION
 1. CARBONIC ANHYDRASE INHIBITORS
MECHANISM OF ACTION -»
In PCT cell
It is initiated by Na'.H* Exchanger
Na enters -> cell from tubular lumen in exchange for hydrogen ions from inside
cell
I
The hydrogen ion secreted to the lumen combine with bicarbonate to form carbonic
acid which is rapidly dehydrated to carbon dioxide and water with the help of
carbonic anhydrase.
I
Carbon dioxide produced by dehydration of carbonic acid enter the proximal tubule
cell by simple diffusion where it is rehydrated back to carbonic acid
I
Dissociation of carbonic acid , the hydrogen ion is available for transport by
sodium hydrogen exchanger and HCO3 is transported out of cell by basolateral
membrane transporter and the sodium ion is reabsorbed in interstitium cell in
exchange with potassium ion with the help of sodium potassium transporter

Sodium bicarbonate reabsorption and hydrogen ion excretion is dependent on

carbonic anhydrase activity
This enzyme can be inhibited by diurectics .
proximal convoluted
Lumen tubule cell
Interstitium

K*

HCOJ 4- H*

H2O CO1 CO2 H2O

* *

USES
Acetazolamide is not used as diuretic because of its low efficacy.
It is used in the following:
1. Glaucoma: Carbonic anhydrase inhibitors 2. To alkalinize 3. Acute mountain sickness:
decrease intraocular pressure (IOP) by urine in 2. acidic Acetazolamide can be used both for
reducing formation of aqueous humour. drug poisoning symptomatic relief and prophylaxis of
Acetazolamide is used in acute congestive acute mountain sickness. It is better
glaucoma by oral and i.v. routes. to administer it prophylactically . The
Topical carbonic anhydrase inhibitors beneficial effect may be due to a
(dorzolamide and brinzolamide) are used in decrease in pH and formation of
chronic simple glaucoma cerebrospinal fluid.
 ADVERSE EFFECTS
These include hypersensitivity reactions (skin rashes, fever, nephritis, etc.),
drowsiness, paraesthesia, hypokalaemia, metabolic acidosis, headache and renal
stones.

2.OSMOTIC DIURETICS
2.OSMOTIC DIURETICS:
These include mannitol, glycerol and isosorbide.
Mannitol: Glycerol:
Mannitol is administered intravenously Glycerol can be used orally to
It is neither metabolized in body nor significantly reduce IOP in acute congestive
reabsorbed from renal tubules. glaucoma .
It is pharmacologically inert and is freely filtered at the
glomerulus.

MECHANISM OF ACTION.
Osmotic diuretics draw water from tissues by osmotic action.

This results in increased excretion of water and electrolytes.

Their site of action is in the loop of Henle and proximal tubule
20% Mannitol, i.v. infusion

I
Increases osmolality of plasma

I
Shift of fluid (osmotic effect) from the intracellular
compartment (ICC) to extracellular fluid (ECF)
| ICC -> ECF |
I
Expansion of ECF volume

l
Increases glomerularfiltration rate (GFR);
In addition, mannitol is freely filtered at the glomerulus

I
Increases osmolality of tubular fluid

Inhibits
l
reabsorption of water;
J,passive reabsorption of NaCl

The
I effect is:
net

• Increase in urine volume

• Increased urinary excretion of Na\ K+, Ca3\ Mg'\ CT\ HCO^ and POj
 USES:
1. Mannitol is used to 2. Mannitol 20% (i.v.), 3.Mannitol is used to 4. Mannitol is
reduce the elevated glycerol 50% (oral) and prevent acute renal useful to maintain
intracranial tension (ICT) isosorbide (oral) are used to shutdown in shock, the osmolality of
following head injury or reduce the elevated IOP in cardiovascular sur ECF after dialysis.
tumour. It draws fluid acute congestive glaucoma. gery, haemolytic
from the brain into the They draw fluid from the transfusion reactions,
circulation by osmotic eye, by osmotic effect, into etc
effect, thus lowering ICT. blood - IOP is decreased.

Adverse Effects
1. Too rapid and too much quantity of i.v. mannitol can cause marked expansion of
ECF volume which can lead to pulmonary oedema.
2. Headache, nausea and vomiting may occur.
3. Glycerol can cause hyperglycaemia.
3.LOOP DIURETICS

3.Loop Diuretics (High-Ceiling Diuretics)

The important loop diuretics are furosemide, bumetanide ond torsemide.
MECHANISM OF ACTION
Site of action is -> thick ascending limb of loop of Henle (site 2).

Loop diuretics bind to luminal side of Na-K-2CI cotransporter and block its
function.

There is an increased excretion of Na and Cl in urine

1
The tubular fluid reaching DCT contains large amount of No .
Hence, more Na exchanges with K , leading to K loss.
Furosemide has weak carbonic anhydrase-inhibiting activity, hence, increases the
excretion of HCO3 .
Loop diuretics also increase the excretion of Ca2 and Mg2 ,
 The loop diuretics are rapidly absorbed through gastrointestinal tract.
Furosemide and bumetanide are administered by oral, i.v. and i.m. routes.
Torsemide is given orally and intramuscularly.
Furosemide has a rapid onset of action within 2-5 minutes of i.v.; 10-20 minutes
after i.m. and 30-40 minutes after oral administration.
The duration of action of furosemide is short (2-4 hours).
Uses:
During initial stages of renal and Intravenous furosemide, Loop diuretics Furosemide is not
cardiac oedema, loop diuretics are along with isotonic saline may be used in preferred in
preferred. (to prevent volume cerebral oedema uncomplicated
They are also useful in hepatic depletion), is used in but i.v. mannitol primary hypertension
oedema - vigorous diuresis should hypercalcaemia as it is the preferred because of its short
be avoided to prevent hepatic promotes the excretion drug.. duration of action.
coma. of Ca2 in urine.
Acute pulmonary oedema - loop diuretics act in following way:
Intravenous furosemide T PG synthesis and release T Renal blood
flow

T Systemic venous capacitance due to vasodilation

Results in shift of blood from central pulmonary to

systemic vessels, X left ventricular filling pressure

Produces quick relief from pulmonary oedema

ADVERSE EFFECTS OF LOOP DIURETICS
1. Electrolyte disturbances: are the common adverse effects seen with loop
diuretics. They are as follows:
(a) Hypokaiaemia It is the most important adverse effect. It can cause fatigue,
muscular weakness and cardiac arrhythmias. Hypokaiaemia can be prevented by
using a combination of loop diuretic with potassium -sparing diuretic. It can be
treated by K supplementation.
(b) Hyponatraemia: Loop diuretics can cause depletion of sodium from the body.
(c) Hypocalcaemia and hypomagnesaemia: These are due to the increased urinary
excretion of Ca2 and Mg2 , respectively. Hypomagnesaemia can predispose to
cardiac arrhythmias.

2. The metabolic disturbances include:

(a) Hyperglycaemia: This can occur due to decreased insulin secretion.
(b) Hyperuricaemia: These drugs decrease the renal excretion of uric acid and may
precipitate attack of gout.
(c) Hyperlipidaemia They increase plasma triglycerides and LDL cholesterol levels.
3. Ototoxicity manifests as deafness, vertigo and tinnitus and is due to damage
to hair cells in inner ear. The symptoms are usually reversible on stoppage of
 Therapy. The risk of ototoxicity is increased in patients with renal impairment and
in those receiving other ototoxic drugs like cyclosporine and aminoglycosides.
4. Hypersensitivity:
Skin rashes, eosinophilia, photosensitivity, etc. may occur.

4.THIAZIDES
4.Thiazides (Senzothiadiazides) and Thiazide -Related Diuretics
Thiazides are medium-efficacy diuretics.
Mechanism of Action:
Thiazides inhibit Na-CI symport in early distal tubule (site 3) and increase Na and
Cl excretion
There is increased delivery of Na to late distal tubule.
There is increased exchange of Na-K which results in K loss.
Lumen EadV distal tubule Interetitium

USES:
Hypertension: 2. Oedema: 3. Hypercalciuria :
Thiazides are used in Thiazides are used in combination with loop Thiazides are used in
the treatment of diuretics in severe CHF. They are not very calcium nephrolithiasis as
essential hypertension effective in hepatic oedema. Most thiazides, they reduce the urinary
except metolazone, are not effective when excretion of calcium.
glomerular filtration rate (GFR) is law.
Adverse Effects
1. Thiazides cause electrolyte disturbances which include hypokalaemia,
hyponatraemia, hypomagnesaemia and hypercalcaemia.
(a) Hypokalaemia is more common with thiazides than loop diuretics because of
their long duration of action.
(b) Hypercalcaemia is due to decreased urinary excretion of Ca2 .
2. The metabolic disturbances are similar to that of loop diuretics -
hyperglycaemia, hyperlipidaemia and hyperuricaemia.
3. They may cause impotence; hence, thiazides are not the preferred
antihypertensives in young males.
4. Others: Skin rashes, photosensitivity, gastrointestinal disturbances like nausea,
vomiting and diarrhoea can occur.
 5.Potassium-Sparing Diuretics (Aldosterone Antagonists): Spironolactone
Spironolactone is an aldosterone antagonist.
It is a synthetic steroid and structurally related to aldosterone.

Aldosterone enters -> cell and binds to specific mineralocorticoid receptor (MR) in
the cytoplasm of late distal tubule and CD cells (site 4).

The hormone receptor complex (MR- AL) enters cell nucleus, where it induces
synthesis of aldosterone-induced proteins (AIPs).
I
The net effect of AIPs is to retain sodium and excrete potassium

Spironolactone competitively blocks MR and prevents the formation of AIPs.

Therefore, spironolactone promotes Na excretion and K retention.
Spironolactone is most effective when circulating aldosterone levels are high.
It also increases Ca2 excretion.

Fig. 4.5 The mechanism of action of spironolactone. MR, mineralocorticoid receptor;

AL. aldosterone: AIPs, aldosterone-induced proteins.

USES:
1. In oedematous 2. CCF: Spironolactone is 3.Spironolactone is 4. Resistant
conditions often used in moderate - often used with hypertension due to
associated with severe heart failure thiazides/ loop primary
secondary because it blocks the diuretics: Serum hyperaldosteronism
hyperaldosteronism effects of aldosterone. It potassium level is (Conn's syndrome).
(CCF, hepatic prevents hypokalaemia, maintained and
cirrhosis and ventricular remodel ling and antihypertensive
nephrotic syndrome retards the progression of efficacy is enhanced
the disease.
ADVERSE EFFECTS:
Hyperkalaemio is the major adverse effect of aldosterone antagonists.
 RESPIRATORY SYSTEM
DRUGS USED IN TREATMENT OF COUGH:
Cough is a protective reflex, intended to remove irritants and accumulated
secretions from the respiratory passages.
The drugs used in the symptomatic treatment of cough are as follows:
DRUGS FOR COUGH

Secretion enhancers Mucolytics Opioids

KICK ABCD Nos capine
NH4CL Bro m hex ine Dextro methor phan
Plant product M Bro x al
(guai taarphensin)
Tolu baal som

PHARYNGEAL DEMULCENTS
Syrups, lozenges, or liquorice may be used when cough arises due to irritation
above the larynx.

They increase salivation and produce protective soothing effect on the inflamed
mucosa.

Syrup is a concentrated solution of sugar containing the drug to mask the bitter
taste of the drug.
Lozenge, solid dosage form placed in the mouth and sucked; it dissolves slowly to
liberate the active ingredient. It soothes the irritated mucosa af the throat, eg.
dyclonine (local anaesthetic) lozenge for sore throat.
 mucolytics

These agents break thick tenacious sputum and lower the viscosity of sputum, so
that sputum comes out easily with less effort.
Bromhexine Acetylcysteine and Carboci steine
It is a semisynthetic agent used orally. Acetylcysteine is a mucolytic used as an aerosol in
It has potent mucolytic and mucokinetic the treatment of cough. Acetylcysteine and
(increase the volume of bronchial secretion and carbocisteine
decrease viscosity of the sputum) effects. 1
Open disulphide bonds in mucoproteins of sputum
Bromhexine liberates lysosomal enzymes I
Sputum becomes thin and less viscid
Digest the mucopolysaccharides |
. Cough becomes less tiring and productive.
Decreases viscosity of sputum
The side effects are nausea, vomiting and
Cough becomes less tiring and productive. bronchospasm.
The side effects are rhinorrhoea and Carbocisteine is administered orally.
lacrimation . It may cause gastric irritation, hence should be
avoided in patients with peptic ulcer.

BRONCHIAL ASTHMS
DRUGS USED IN THE TREATMENT OF BRONCHIAL ASTHMA:
In bronchial asthma, there is impairment of airflow due to contraction of bronchial
smooth muscle (bronchospasm), swelling of bronchial mucosa (mucosal oedema) and
increased bronchial mucus secretion.
There is inflammation and hyperresponsiveness of airways.
DRUGS FOR BRONCHIAL ASTHMA
1 1 1 1
Leukotriene
•ntagonnti
MiBi cell Ifibilizerv
I
Monidukast Sod. cromoglycate I
Zafirlukast Ketotifen

Bronchodilators

Sympathomimetic® Methylxanthlnes
Salbutamol Theophylline
Terbutaline Aminophyltinc
Bambuterol Choline
Salmeterol theophyllinate
Formotcrol Hydroxyethyl
theophylline
Dowphyhinu

Bro -bronchodilators
leuko teri- leukotriene antagonist
Aunty laygee-anti-IGE antibody
Mast- mast cell stabilizer
Corn - corticosteroids
1 SYMP ATHOMIMETICS
MECHANISM OF ACTION:

Sympathomimetic* — ft ** cAMP • Bronchodilafation

• Inhibit the release of
histamine, SRS-A
(LTCt and LTDp
from mast cells
Act by stimulating receptors • Promote mucociliary
in the bronchial smooth muscle clearance
and mast cells
Adrenaline (Nonselective Sympathomimetic):
It produces prompt and powerful bronchodilatation by acting through £2-
adrenergic receptors.
It is useful tn acute attack of asthma (not responding to other drugs) - 0.2-0.5
mL of 1:1000 solution given subcutaneously.
Its use has declined because of its dangerous cardiac side effects.
Table 6.9 Selective ^-agonists
Salbutamol and terbutaline Salmeterol Formoterol
Selective p7-agonists: On Long-acting selective Long-acting selective
inhalation, they have a rapid p-agonist: It is pre¬ ^-agonist: It has a
onset (within 1-5 minutes) and ferred for moderate rapid onset of action; it
short duration of action; they to severe, persistent is preferred for moder¬
are preferred for acute attack asthma; It is not suit¬ ate to severe persistent
of asthma able for acute attack asthma due to its long
Route and dose: Inhalation, as it has a slow on¬ duration of action
salbutamol 100-200 mcg set of action Route and dose: Inhala¬
every 6 hours, or as and Route and dose: Inhala¬ tion. 12-24 mcg twice
when required through tion. 60 mcg twice daily
metered-dose inhaler (MDI) daily
to terminate an acute attack;
other routes of administration
are oral, i.m. and i.v.

2 . ANTICHOLINERGICS:
Ipratropium bromide and tiotropium bromide are atropine substitutes.

They selectively block the effects of acetylcholine in bronchial smooth muscle and
causebronchodilatation.
They do not affect mucociliary clearance.
They have a slow onset of action and are less effective than sympathomimetic
drugs in bronchial asthma.
These anticholinergics are preferred bronchodilators in COPb and can also be used
in bronchial asthma.
They are administered by inhalotional route, and act primarily on larger airways..
Combined use of ipratropium with 2 -adrenergic agonists produces greater and more
prolonged bronchodilatation, hence used in acute severe asthma.
3 .LEUKOTRIENE-RECEPTOR ANTAGONISTS
These drugs competitively block effects of cysteinyl leukotrienes (LTC4 and LTD4)
on bronchial smooth muscle.
They produce bronchodilatation, suppress bronchial inflammation and decrease
hyperreactivity.
They are well absorbed after oral administration, highly bound to plasma proteins
and metabolized extensively in the liver.
They are effective for prophylactic treatment of mild asthma and moderate
persistent asthma (in combination with other drugs).
-
They are well tolerated, produce few adverse effects headache, skin rashes and
rarely eosinophilia.
Montelukast
Cysteinyl - Leukotrienes - LTC4 and
Zafirlukast
LT i- receptors LTD4 (agonists)
(antagonists) .

4.MA ST CELL STABILIZERS:

Sodium cromoglycate (cromolyn sodium) and ketotifen are mast cell stabilizers.
They are not bronchodilators.
They inhibit -> release of various mediators -> histamine. LTs, PGs, PAF, etc. by
stabilizing mast cell membrane
Onset of action is slow.
Sodium cromoglycate is not effective orally as it is poorly absorbed from gut.
In bronchial asthma, sodium cromoglycate is given by inhalation.
Uses
1. Allergic asthma: As a prophylactic agent to prevent bronchospasm induced by
allergens and irritants.
2. It can also be used in allergic conjunctivitis, allergic rhinitis, allergic
dermatitis, etc. by topical route as a prophylactic agent.
Adverse Effects:
Systemic side effects are rare: it may cause symptoms of local irritation - cough,
bronchospasm, headache, nasal congestion, etc.
 5 GLUCOCORTICOIDS:
Glucocorticoids induce synthesis of 'lipocortin', which inhibits phospholipase A2 and
thereby prevent formation of various mediators such os PGs, TXA2

Glucocorticoids have Antiallergic, anti-inflammatory, immunosuppressant effects

They: 1. Suppress inflammatory response to AG: AB reaction.
2. Decrease mucosal oedema.
3. Reduce bronchial hyperreactivity.

6 .Anti-IgE Monoclonal Antibody: Omalizumab

Omalizumab prevents -> binding of IgE to mast cell,

prevents mast cell degranulation.

It has no effect on IgE already bound to mast cells.
It is administered parenterally.
It is used in moderate to severe asthma and allergic disorders such as nasal
allergy and food allergy.

7.INHALATIONAL DEVICES:
Pressurized metered -dose Dry powder inhalers- Nebulizers-
inhaler (PMDI)- Spinhaler and Rotahaler. useful in acute severe
It is a handheld device which A capsule (rotacap) containing the drug asthma, COPD and for
can be used alone or with in fine powder form is placed in the delivering drug in young
spacer. Rotahaler. children and elderly.
It has a pressurized The drug is delivered in the
container (canister) with drug form of a mist which can
and other substances as easily reach the airways.
solution or suspension. They are expensive but do
not require coordination
A specific amount of drug is unlike Pmdi
delivered as a fine aerosol
into the air ways.
The small particles reach the
smaller airways whereas
large ones are deposited in
the oral cavity (minimized by
using spacer).

Proper coordination is
required between use of
device and breathing
(difficult for children and
elderly).
Patient has to be trained on
correct use of device.
 STATUS ASTHMATICUS
Treatment of Acute Severe Asthma (Status Asthmaticus)
1. Humidified oxygen inhalation.
2. Nebulized 02 -adrenergic agonist (salbutamol 5 mg/ terbutaline 10 mg)
+ anticholinergic agent (ipratropium bromide 0.5 mg).
3. Systemic glucocorticoids: Intravenous hydrocortisone 200 mg i.v. stat followed
by i.v. hydrocortisone 100 mg q6h or oral prednisolone 30-60 mg/day depending on
the patient's condition.
4. Inj salbutamol 0.4 mg i.m.
5. Intravenous fluids to correct dehydration.
6. Potassium supplements: To correct hypokalaemia produced by repeated doses of
salbutamal/terbutaline.
7. Sodium bicarbonate to treat acidosis.
8. Antibiotics to treat infection.

Drugs to be avoided in Patients with Bronchial Asthma

1. NSAIDs like aspirin, ibuprofen and diclofenac (paracetamol can be used).
2. 0- Adrenergic blockers.
3. Cholinergic agents.
 EMETICS AND ANTIMETICS

Nouseo and vomiting are protective reflexes that help to remove toxic substances
from gastrointestinal tract (SIT).
-> They are symptoms of altered function but are not diseases.
-> Nausea denotes feeling of impending vomiting, whereas vomiting refers to
forceful expulsion of the contents of stomach and upper intestinal tract through
mouth.
MECHANISM OF VOMITING:
-
STN SUBTHALAMIC NUCLEUS. CVZ- CHEMORECEPTOR TRIGGER ZONE
< CNS ?

ANTIEMETICS:
The drugs that are used to prevent or control vomiting are called antiemetics.
ANTIEMETICS
 1 5-HT3-Receptor Antagonists:
Ondansetron is -> prototype drug.
Their antiemetic effect is mainly due to blockade of 5 -HT3- receptors on vagal
afferents in the gut (peripheral action).
They also block 5 -HT3-receptors in CTZ and solitary tract nucleus (central
action).
Anticanccr drugs and radiotherapy

I
Tissue damage (in the guO

!
Release of serotonin (5-HT) from enterochromaffin cells of intestinal mucosa

I
Stimulates vagal affcrcnts in the gut through 5-HTj receptors

i antagonists |
\block^z Impulses to CTZ and STN

I
Induce vomiting
Pharmacokinetics : Uses: Adverse Effects:
5-HT3 antagonists are well absorbed 5-HT3 antagonists are the most 5-HT3 antagonists are
after oral administration. effective agents for prevention and well tolerated.
The metabolites are excreted in urine treatment of chemotherapy- induced They may cause
and faeces. nausea and vomiting (CINV). headache, dizziness
These agents are also available for They are also effective in and diarrhoea.
intravenous administration. hyperemesis of pregnancy,
Transdermal patch of granisetron is postoperative, postradiation and
available for prevention of cancer drug- induced vomiting but they are
chemotherapy -induced vomiting. ineffective against motion sickness.

Z Prokinetic Drugs:
Drugs that promote coordinated movement of GIT and hasten gastric emptying are
called prokinetic drugs.
They include metoclopramide, domperidone, mosapride, itopride, cisapride and
levosulpiride.
Metoclopramide and domperidone are used as antiemetics.

METOCLOPRAMIDE DOMPERIDONE
Central Actions: It is less potent and less efficacious than
The antiemetic effect of metoclopramide is mainly due metoclopramide.
to blockade of D2 -receptors in CTZ. At high It poorly crosses BBB. hence, extrapyramidal
concentration, it also blocks 5 -HT3- receptors in CTZ. side effects are rare.
 Metoclopramide It is usually administered orally, but its oral
bioavailability is low because of extensive
first pass metabolism; metabolized in liver
5-HT4-agonism Dj-antagonism 5-HTr antagonism in the gut and metabolites are excreted in urine.

Domperidone is a preferred antiemetic in

children, as it rarely produces EPS.
t f ACh secretion from the myenteric motor neurons

It counteracts vomiting induced by levodopa

The effects of metoclopramide on upper 61 tract:
ar bromocriptine without affecting their anti¬
1. Increase in tone of lower oesophageal sphincter
parkinsonian effect ns it poorly crosses BBB.
(LES).
2. Increase in tone and amplitude of antral
It is preferred over metoclopramide to treat
contractions .
vomiting induced by these drugs.
3. Relaxation of pyloric sphincter.
The important side effects are dryness of
4. Increase in peristalsis of small intestine.
mouth, diarrhoea, headache, skin rashes,
galactorrhoea and menstrual irregularities.
Metoclopramide and levodopa:
Metoclopramide crosses BBB, blocks D2 -receptors in
the basal ganglia, thus interfering with the anti¬
parkinsonian effect of levodopa.
Hence, it is not used to treat levodopa -induced
vomiting.

USES
1. As an antiemetic: Metoclopramide is effective for
prevention and treatment of:
(a) Disease-associated vomiting.
(b) Drug- induced vomiting (not used to control levodopa -
induced vomiting).
(c) Postoperative vomiting,
(d) Cancer chemotherapy -induced vomiting

2. Gastroesophageal reflux disease (GERD):

Metoclopramide produces symptomatic relief in patients
with reflux oesophagitis by increasing the tone of LES.

3. To stimulate gastric emptying before general

anaesthesia in emergency surgeries.

4. Metoclopramide has been used in treatment of

intractable hiccups.

ADVERSE EFFECTS.
They are drowsiness, dizziness and diarrhoea.
Acute dystonias (spasm of muscles of face, tongue,
neck and back) can occur.
Other extrapyramidal symptoms (EPS tremor, rigidity,
etc.) are due to blockade of 02 -receptors in basal
ganglia (drug-induced parkinsonism).

Table 7.1 Antiemetics with their uses and side effects

Drugs Uses Important side effects
1. 5 -HI receptor
j Cancer chemotlterapy-induced Headache, dizziness and
antagonists vomiting, radiation sickness diarrhoea
and postoperative vomiting
2. Prokinetic drugs • Drug induced, disease • Drowsiness, dizziness,
• Metoclopramide induced, postoperative, diarrhoea, acute
• Domperidone cancer chemotherapy- dystonias and other
induced vomiting and extrapyramidal symp¬
radiation sickness toms (EPS)
• Preferred antiemetic in • Dryness ol mouth,
children and levodopa diarrhoea and
induced vomiting headache
3. Antihistamines Motion sickness, morning Drowsiness and dryness
sickness. Meniere disease, of mouth
drug induced, postoperative,
radiation sickness and
cancer chemotherapy-
induced vomiting
4. Anticholinergics Motion sickness Sedation, dryness of
(scopolamine) mouth, blurred vision
and urinary retention
5. Neuroleptics Drug induced, disease- EPS. sedation, dystonic
induced. postoperative, reactions and ortho
cancer chemolhorapy- static hypotension
induced and radiation-
induced vomiting
6. Neurokinin (NKt)- Cancer chemotlier apy- Dizziness, diarrhoea
receptor antagonist rnduced vomiting and fatigue
7. Dronabinol Vomiting due to cytotoxic drugs Sedation, dysphoria.
arid radiation sickness hallucinations and drug
dependence
8. Glucocorticoids Adjuvant antiemetic along Metabolic disturbances
(adjuvant antiemetics) with ondansetron or
metoclopramide in cancer
chemotherapy - induced
vomiting
9. Benzodiazepines Psychogenic and anticipatory Sedation and drowsiness
(adjuvant antiemetics) vomiting
 antidiarrhoeal agents
'Diarrhoea' denotes passage of unusually loose or watery stools at least three
times or more in a 24 -hour period (WHO).
DRUGS FOR DIARRHOEA

Antimicrobial Probiotics
drugs
Lactobacillus sp.
Norfloxacin Bifidobacterium
Ciprofloxacin bifidum
Ofloxacin Strep,faecatis
Rifaximin Enterococcus sp.
Cotrimoxazolc Bacillus clausii
Tetracycline Saccharomyces
Erythromycin botdardii
Metronidazole

Nonspecific

—
1
Absorbants

ispaghula
antldlarrhoeal drugs

Antlsecretory
drugs
Racecadotril
Mcthy [cellulose Bismuth subsalicylate
Anticholinergics
Octreotide
l Oral Rehydration Solution (ORS).
In acute diarrhoea, it is important to maintain water and electrolyte balance with
proper fluid replacement (rehydration).
WHO -ORS contains :
sodium chloride -> 2.6 g
potassium chloride 4 15g
sodium citrate -> 2.9 g
glucose -> 13.5 g.

It has to be dissolved in 1 L of water.

-> Sodium and potassium are administered to replace -> losses.
-> Sodium is transported along with glucose by sodium glucose cotransporter in
ileum.
-> Citrate, a base, corrects acidosis.
ORS decreases stool volume and vomiting.
It is also effective in cholera.
ORS is also useful in heat stroke and maintenance of hydration in bum patients.
In case of severe diarrhoea with dehydration, intravenous fluids are indicated.
WHO recommends the use of zinc supplement (10-14 days) with ORS in acute
diarrhoea in children. It decreases intestinal secretions, promotes regeneration of
intestinal epithelium and reduces duration and severity of diarrhoea.
octreotide. CODEINE.
It is an analogue of somatostatin which is It is a natural opium alkaloid. It decreases GI
useful in secretory diarrhoea due to motility and produces constipation.
hormone -secreting tumours of the SIT
and pancreas. Loperamide .
It is an opiate analogue and has more potent
It inhibits secretion of 5-HT, vasoactive antidiarrhoeal effect than morphine.
intestinal peptide (VIP), gastrin, insulin, By interacting with p- opioid receptors in gut,
etc. It is administered either loperamide reduces GI motility and increases the anal
intravenously or subcutaneously. sphincter tone.
It can be used to treat diarrhoea in
patients with AIDS. It decreases secretion induced by cholera toxin and
Racecadotril; some toxins of Escherichia coli.
Racecadotril (prodrug) It is orally effective and has a rapid onset of action.
I It poorly penetrates BBB and has no abuse potential.
active metabolite The usual dose of loperamide is 4 mg stat and then 2
1 mg after each loose stool, but the maximum dose
enkephalinase inhibitor should not exceed 16 mg in 24 hours.
I It has been used in both acute and chronic
inhibits degradation of enkephalins in
diarrhoeas.
intestinal mucosa
1
increases concentration of enkephalins in
intestinal mucosa It can also be used in travellers* diarrhoea.
The toxic effects are skin rashes, headache and
decrease in intestinal secretion paralytic ileus.
It is used in acute secretory diarrhoeas. It should not be used in children younger than 4
It can be used in children. years.
Side effects are nausea, vomiting and
drowsiness.

PHARMACOTHERAPY OF INFLAMMATORY BOWEL DISEASE

IBD includes Crohn disease and ulcerative colitis, which are characterized by
diarrhoea, bleeding, abdominal discomfort, anaemia and weight loss.
1.SULPHASALAZINE:
It is a prodrug and is composed of sulphapyridine and 5 -aminosalicylic acid
(5- ASA).
On oral administration, sulphasalazine reaches colon, where it is broken down by
colonic bacteria to S-ASA and sulphapyridine.
The released 5- ASA acts locally by inhibiting the production of inflammatory
mediators.
Sulphapyridine gets absorbed and causes side effects like nausea, vomiting and
headache.
Allergic side effects are skin rashes, fever, hepatitis, pancreatitis, pneumonitis,
etc.
 2.Glucocorticoids:
Glucocorticoids ore used for short-term treatment of moderate to severe IBD.
Various glucocorticoids used in IBD are prednisolone (oral), methylprednisolone
(oral, parenteral), hydrocortisone (enema, suppository) and budesanide (oral).

Prolonged use of glucocorticoids can lead to hypothalamic-pituitary-adrenal axis

suppression and other side effects like osteoporosis, peptic ulcer, infections and
hyperglycaemia.

LAXATIVES (PURGATIVES. CATHARTICS)

Laxatives are drugs that facilitate evacuation of formed stools from the bowel ,
Purgatives cause evacuation of watery stools.
1.STOOL SOFTENERS (EMOLLIENT LAXATIVES)
Docusates: Liquid Paraffin (Note the 'Ls').
Common docusate salts are Liquid paraffin is a mineral oil and is administered orally.
dioctyl sodium
sulphosuccinate (DOSS) and It softens stools.
dioctyl calcium
sulphosuccinate . It also has a Lubricant effect which helps in smooth defaecation.

They lower surface tension It is useful in patients with cardiac disease because it prevents
of stool, thereby cause straining during defaecation.
accumulation of fluid and ADVERSE EFFECTS OF LIQUID PARAFFIN:
fatty substance, thus Lipid pneumonia may occur due to entry of drug into lungs; hence, liquid
softening the stools. paraffin should not be given at bed time and in lying down position.

These agents act within 1-3 Long-term use may cause malabsorption of vitamins A, D, E and K
days. (fat -soluble vitamins).

They are administered orally Leakage of faecal matter through anal sphincter may lead to soiling of
or as a retention enema. clothes.

2. OSMOTIC LAXATIVES:
They are salts of magnesium, sodium or potassium.
Those having magnesium or phosphate are known as saline laxatives.

Osmotic purgatives
are given orally, Act on the small and
early morning on
empty stomach
large intestine
(within 1-3 hours)
* Not absorbed in the gut
with plenty of water
Draw fluid into the
lumen by osmotic activity

Evacuation of watery
. , .. . ... . ... .
Stimulate peristalsis < Distend the bowel
.
stools in 1-3 hours * r
3.LACTULOSE:
Lactulose is a disaccharide of fructose and galactose.
Lactulose is available as liquid and powder
On oral administration -> it is not absorbed through SI mucosa.
Colonic bacteria convert it into acidic products, which exert osmotic effect - draw
fluid into lumen and distend it, thus useful in constipation.
It produces soft to loose stools.
It can be used to -> treat constipation in children and pregnant women.
Lactulose is used in hepatic coma to -> reduce blood ammonia levels
The side effects include abdominal discomfort and flatulence.
DRUGS FOR PEPTIC ULCER
DRUGS FOR PEPTIC ULCER

]
Anti H. pylori
drugs
Amoxicillin
Clarithromycin
Metronidazole
Hntdaznlc
Tetracycline
CBS

DRUGS THAT INHIBIT GASTRIC ACID SECRETION:

1.PROTON-PUMP INHIBITORS (PPIS):
Proton pump (H , K-ATPase) is a membrane- bound enzyme that plays an important
role in final step of gastric acid secretion

Omeprazole is -> prototype drug.

The other PPIs are lansoprazole, pantoprazole and rabeprazole.
 PPIs (prodrugs)

Absorbed in small intestine

1
blood
1
diffuse into parietal cells
i
canaliculi of the cell (acidic pH)
I
converted to sulphenamide
(active, charged form).
Activated form (sulphenamide) binds covalently with SH group of proton pump
and irreversibly inactivates it.
PPIs ore most powerful inhibitors of gastric acid secretion
As PPIs act in final step of acid secretion, they are effective in inhibiting acid
production following any stimulation.

PPIs are administered orally about 30 minutes before food because food stimulates
secretion of acid (in the canaliculi of parietal cell), which is necessary for
activation of PPIs.

THERAPEUTIC USES:
Peptic ulcer: PPIs can be Zollinger-Ellison (Z-E) Gastroesophageal reflux
->PPIs are most powerful acid used syndrome: disease:
suppressive agents. preoperatively
->They inhibit all phases of to reduce the Z-E syndrome is In GERD, the goal of
gastric acid secretion. risk of characterized by therapy is to produce
aspiration hypergastrinaemia with symptom relief, heal
PPIs are superior to H2- pneumonia multiple peptic ulcers. erosive oesophagitis and
blockers as their onset of prevent complications.
action is rapid and cause PPIs are the preferred PPIs are the preferred
faster ulcer healing. agents for Z-E syndrome. agents for the treatment
Higher doses of PPIs are of GERD and are usually
The standard dose of needed for healing of given once daily.
omeprazole is 20 mg, ulcers. Surgery is the
lansoprazole 30 mg and definitive treatment
pantoprazole 40 mg once daily.
2.H2 -RECEPTOR ANTAGONISTS (H2-BLOCKERS):
• Ranitidine
Parietal cell Famotidine
Histamine
(Agonist)
Hj-receptors • Nizatidine
• Cimetidine
(Antagonists)
 MECHANISM OF ACTION:
H2- receptor antagonists competitively block H2- receptors on parietal cell and
inhibit gastric acid production.
They suppress all phases (basal, cephalic and gastric) af acid secretion.
Cimetidine Ranitidine
t Hz-blocker (competilive blocker) FL blocker (competitive blacker)
2. Less patent More potent
3. Has shorter duration of action (6-8 hours) Has longer duration of action (24 hours)
4. Cimetidine is an enzyme inhibitor, hence Has less affinity for hepatic cytochrome
increases the plasma concentration of P450 enzymes, hence drug interac¬
many co administered drugs, such as tions are rare
phenytoin, digox»n+ theophylline^ warfarin
and propranolol
5. Increases pfasma prolactin level; can cause Has no antiandrogenc effect; does not
menslruai irregularities and galactorrhoea in increase prolactin secretion
women; gynaecomastia, ofigospermia and
impotence in men
6. Crosses BBS and produces CNS side Poorly crosses BBB, CNS side effects
effects like confusion, headache and are rare
hallucinations

THERAPEUTIC USES;
Peptic ulcer: Gastroesophageal Zollinger-Ellison H2-blockers
H2 -blockers are one of the commonly used drugs reflux disease: syndrome: are used
in peptic ulcer. In GERD, H2- In Z-E syndrome, preopenatively
blockers are surgery is the to reduce the
H2 -blockers produce symptomatic relief within effective and definitive risk of
days and ulcer healing within weeks. The produce therapy. PPIs or aspiration
duration of treatment far duodenal ulcer is 4-6 symptomatic H2-blockers are pneumonia
weeks. relief. PPIs are used to control
more effective the
H. pylori- associated ulcers: H2- blockers can be than H2- hypersecretion of
used along with antimicrobial agents to treat H. blockers. acid. PPIs are
pylori infection. the preferred
Stress ulcers are commonly seen in critically ill agents in Z-E
patients with severe medical or surgical illness. syndrome.

3. ULCER PROTECTIVES SUCRALFATE:

It is a complex of aluminium hydroxide ond sulphated sucrose.

In acidic environment of stomach (pH 4), sucralfate undergoes polymerization to

farm a sticky polymer that adheres to -> ulcer base and protects it.

It also precipitates proteins at ulcer base - forms a barrier against acid-pepsin.

It stimulates release of PGs and epidermal growth factor locally, thus produces
cytoprotective effect.
Sucralfate is given orally on on empty stomach at least 1 hour before meals.
Constipation is a common side effect.
Nausea may occur.
 Aluminium toxicity can occur in patients with renal failure.
Sucralfate is effective for prevention of bleeding from stress ulcers and to reduce
risk of aspiration pneumonia.
It is also useful in GERD with oesophagitis, as it is a mucosal protector.
Other uses are oral mucositis, radiation proctitis, rectal ulcer, bums, bed sores,
etc
4.DRUGS THAT NEUTRALIZE GASTRIC ACID (ANTACIDS):
NON-SYSTEMIC: 2. SYSTEMIC:
Magnesium hydroxide, magnesium trisilicate, aluminium Sodium bicarbonate and sodium citrate.
hydroxide gel and calcium carbonate.
Sodium bicarbonate (NaHCO3):
When this reaches intestine, chloride salt reacts with It rapidly neutralizes gastric acid, but the
bicarbonate, duration of action is short.
so HCO3- is not available for absorption;
hence, there is no systemic alkalosis. The disadvantages of NaHCO3 are that
(i) it is highly water soluble and rapidly
Combination of antacids produces various beneficial absorbed from the gut;
effects: (ii) it releases CO2 that can cause abdominal
1. Aluminium salts cause constipation and magnesium distension
salts cause diarrhoea, so combination of these two can (iii) it may cause metabolic alkalosis;
counteract the adverse effects of each other. (iv) it produces rebound acidity.
2 . Magnesium hydroxide has a rapid onset of action,
but aluminium hydroxide acts slowly - the combined Sodium bicarbonate is also used to alkalinize
product produces rapid and sustained effect. urine and to treat acidosis.
3. Dose of individual antacid is reduced; hence, It should be avoided in patients with
systemic toxicity is minimized. Calcium may be hypertension and congestive cardiac failure
absorbed from its salts resulting in hypercalc aemia (CCF), as it causes sodium retention.
and hypercalciuria
5. Anti- H. pylori Agents
H. pylori. Gram-negative, rod -shaped bacterium, is associated with gastritis,
duodenal ulcer, gastric ulcer and gastric carcinoma
Ammonia produced by urease activity may directly damage cells

The antimicrobials used in H. pylori infection are amoxicillin, tetracycline,

clarithromycin, metronidazole and tinidazole. Resistance develops rapidly to
metronidazole and clarithromycin but not to amoxicillin.
Amoxicillin should be avoided in patients with history of penicillin allergy.
Other anti-H. pylori drugs are PPIs, H2 -blockers and CBS.
SOME OF RECOMMENDED REGIMENS ARE LISTED BELOW:
Triple Therapy X 14 Days (2 Weeks) Quadruple Therapy X 14 Days (2 Weeks)
Lansoprazole 30 nig b.d + Omeprazole 20 mg b.d. +
Clarithromycin 500 mg b.d, 4- CBS 120 mg q.i.d. +
Amoxicillin 1 gb.d. Tetracycline 500 mg q.i.d.+
Metronidazole 400 mg t.i.d.
 DRUGS AFFECTING COAGULATION AND BLOOD FORMATION

ANTICOAGULANTS
Anticoagulants are drugs that prevent or reduce coagulability of blood.
[ Anticoagulants
I 1
Oral Parenteral

I
Vlt K inhibitors Direct thrombin
I-
Indirect thrombin inhibitors
—I
Direct thrombin
• Warfarin Inhibitors inhibitors
• Dicumarol Ximoiagatran • Hirudin
- Acenocoumann - Datugatran L epirudin
- Phenmidione etcxiialc - Bivalinidin
- Argatroban
Unfractionated L^W heparin Fondaparinux
Factor Xa inhibitor heparin Enoxaparin idrapannux - Melagatran
- Rivaroxaban Dalteparin
- Aoixaban Tinzapann

1.Parenteral anticoagulants:
Indirect thrombin inhibitors Direct thrombin inhibitors:
Heparin (Unfractionated Heparin): Hirudin
Low molecular weight heparin Lepirudin
Fondaparinux Bivalirudin
Intrinsic system Extrinsic system

xnia

Fibrin (stable)
Fig. 8.1 The coagulation cascade. Heparin inactivates factors Xlla. Xia. IXa, Xa, Ila and Xllla
through antithrombin. Low-molecular- weight heparins (LMWHs) inhibit Xa through antithrombin.
Heparin Low molecular weight heparin Fondaprinux
(unfractioned heparin)
ooooo-***-**-** ocooo Ooooo
pentasaccharide* GAG pentasaccharide* short chain of GAG Only polysaccharide
No GAG chain
MOA: LMWHs and are obtained from
Anti-thrombin III is synthesised by standard heparin by fractionation.
liver.
Heparin binds to anti-thrombin III LMWHs produce anticoagulant effect
and accelerates it activity. mainly by inactivation of factor Xa
(anti-thrombin HI inhibits factor through antithrombin.
II and factor X) 1
— -0— 0
Heparin binds to anti-thrombin III
As they are notof sufficient length to
bind to both thrombin and antithrombin
simultaneously, they have little effect
Heparin binds to plasma on thrombin inhibition.
antithrombin III (AT III) and
activates it. LMWH has less effect on aPTT as
compared to UFH.
For binding to AT III, five ACTIVATED PARTIAL THROMBOPLASTIN
saccharides (pentasaccharide) of TIME (aPTT) IS A BLOOD TEST THAT
heparin is essential. MEASURES HOW WELL A PERSON’S
The heparin-antithrombin III BLOOD CLOTS
complex enhances the rate of
The following are the advantages of
inactivation of activated clotting
factors Xa, Ila. IXa, XIa, XHa LMWHs:
and XlHa. 1. They have a higher s.c.
bioavailability as compared to UFH.
At low concentration, heparin 2. They have a longer ti/z ; can be
selectively inhibits the conversion of administered once a day.
prothrombin to thrombin. 3. They do not routinely require aPTT
Heparin thus prevents further monitoring.
thrombus formation. 4. There is a lower incidence of
thrombocytopaenia and osteoporosis as
Heparin, in high doses, has
antiplatelet action and prolongs the compared to UFH.
bleeding time.

PHARMACOKINETICS:
Heparin is not absorbed after oral
administration because of its high
negative charge and large molecular
size.

It must be given parenterally -

intravenously or subcutaneously.
On i.v. administration, the
anticoagulant effect starts
immediately, whereas through s.c.
route, it takes 1-2 hours.
Heparin is highly protein bound.
It does not cross blood-brain
barrier or placental barrier and is
safe for use during pregnancy.

It is rapidly inactivated in liver by

heparinase and the metabolites are
excreted in urine

ADVERSE EFFECTS;
Bleeding
Heparin induced thrombocytopenia
Hypersensitivity reactions
Osteoporosis
Alopecia

PARENTERAL DIRECT THROMBIN INHIBITORS:

They bind directly to thrombin and inactivate it.
They do not bind to AT XU.
Lepirudin, obtained by Argatroban and Bivalirudin are synthetic, reversible direct thrombin
recombinant ONA technology, inhibitors with rapid onset of action.
inhibits thrombin irreversibly.
They are short acting and administered as i.v. infusion.
It is secreted in bile and can be used in patients with renal failure.

WARFARIN
ORAL ANTICOAGULANTS:
Among oral anticoagulants, WARFARIN are commonly used.
THEY ARE VITAMIN K ANTAGONISTS
I
Clotting factors II, VII, IX and X are synthesized in liver as inactive proteins.
These factors are rich in glutamic acid residues and are carboxylated in liver
where vitamin K acts as a cofactor.
Vitamin K is converted to inactive epoxide form by oxidation and is regenerated to
its active form by vitamin K epoxide reductase (VKOR) enzyme.
I
Warfarin is a coumarin derivative and has a structure similar to that of vitamin K.
It competitively inhibits epoxide reductase, prevents regeneration of active form
of vitamin K resulting in inhibition of synthesis of factors II, VII, IX and X.
 Fig. 8,2 The role of vitamin K in ciottrg and mechanism of action of warfarin.

PHARMACOKINETICS:
Warfarin is almost completely absorbed after oral administration.
It is highly bound to plasma proteins, freely crosses placental barrier, is
metabolized in liver and the inactive metabolites are excreted in urine and stool.
Heparin Warfarin
1. Naturally occurring anticoagulant: Synthetic anticoagulant
animal source - ox lung, pig intestine
2. Active in vivo and in vitro Active only in vivo
3. Administered parenterally (Lv., s.cj Administered orally
< Acts by activating antilhrombm III and It inhibits synthems of vitamin K
inactivates Xa. Ila, IXa( Xia, Xlla and dependent clotting factors IL VIL
Xllla IXandX
5. Has a rapid onset, but short duration Has a delayed onset, but tong duration of
of action (3-6 hours) action (3-6 days)
6. Therapy is monitored by measuring Therapy is monitored by measuring
aPTT INR
7. Overdosage is treated with Overdosage is treated with fresh frozen
protamine sulphate (antagonist) plasma and vitamin K,
8. Does not cross the placental barrier Crosses placental barrier and has
and is safe during pregnancy teratogenic potential
9, Hepam is used manly to initiate therapy For maintenance therapy
TO, Expensive Not expensive

ADVERSE EFFECTS
.
1 Bleeding:
Bleeding is most important and common side effect of warfarin. Bleeding can occur
-
anywhere skin, pulmonary, gastrointestinal and urinary tract, etc.
2. Teratogenic effect:
Warfarin is contraindicated during pregnancy as it may cause nasal hypoplasia,
CNS abnormalities, fetal haemorrhage, abortion or intrauterine death.
3. Skin necrosis:
It is a rare complication that occurs within the first week of therapy The skin
lesions are commonly seen on breast, buttocks, abdomen and thighs.
4. Other rare side effects:
These include diarrhoea, alopecia, urticaria, dermatitis, abdominal cramps and
anorexia.
 THERAPEUTIC USES OF ANTICOAGULANTS:
The main aim of anticoagulant therapy is to prevent formation of intravascular
thrombus or further extension of already formed clot.
They do not break the clot or thrombus once it is formed.
An oral anticoagulant, warfarin, is used for maintenance therapy but is usually
started simultaneously as it has a delayed onset of action.
Venous thromboembolism (VTE): 2. Atrial 3. Myocardial 4. Anticoagulants,
Anticoagulants are used for the fibrillation: infarction (MI): e.g. vitamin K
treatment and prevention of Oral Antiplatelets are antagonists (along
thromboembolism. anticoagulants, the primary agents with low-dose
Treatment is initiated with parenteral e.g. warfarin, used in MI. aspirin) are useful
anticoagulants, e.g. are used to in patients with
LMWH/UFH/(because of their rapid reduce the risk In patients prosthetic valves
action). of systemic undergoing to prevent
LMWH are preferred over UFH as they embolization and stenting, a short thrombosis.
are administered subcutaneously, have stroke in patients course of
better bioavailability, are longer acting with atrial parenteral
and usually do not require laboratory fibrillation. anticoagulants is
monitoring. administered.
Warfarin is also started simultaneously
with parenteral anticoagulant.

FIBRINOLYTICS (THRIMBOLYTICS)

Fibrinolytics: Antifibrinolytics
streptokinase Epsilon amino-caproic acid
Urokinase Tranexamic-acid
Alteplase
Reteplase
Tenecteplase
Plasminogen Plasmin Degrades fibrin Lysis of clot

Promote / \ Inhibit

Fibrinolytics Antifibrinolytics
Fig. 8.3 Mechanism of action of fibrinolytics and antifibrinolytics.
USES OF FIBRINOLYTICS
1. Acute MI: DVT: Pulmonary embolism:
The main aim of fibrinolytic therapy Thrombolytic therapy Fibrinolytics ore used to lyse the
is to restore coronary artery patency. helps to provide symptom clot - improve pulmonary
These drugs dissolve the clot by relief, improve limb perfusion and right ventricular
promoting conversion of plasminogen to perfusion and prevent function.
plasmin. pulmonary embolism.
They should be administered as early
as possible once diagnosis is made.
Early administration will help to
decrease infarct size, improve left
ventricular function and decrease
mortality.

Table 8.2 Pharmacological properties of fibrinolytics

Streptokinase Urokinase Alteplase (rtPA)
1. It is a protein derived It is an enzyme obtained It is derived from recombinant
from p-haemolytic from human fetal DNA technology
streptococci kidney cell culture
2. It binds with plasminogen It directly activates It has more effect on plasmin¬
to form a complex that plasminogen to ogen that is bound to fibrin
activates plasminogen to plasmin than circulating plasmino¬
plasmin: both circulating gen
and fibrin-bound plasmino¬
gen are activated
3. Streptokinase is Urokinase is Alteplase is
• antigenic • nonantigenic • nonantigenic
• pyrogenic • nonpyrogenic • not destroyed by antibodies
• destroyed by circulating • rapid acting,
antistreptococcal anti¬ • short half-life, so hepann
bodies, hence not suit¬ has to be administered
able for repeated use along with it to prevent
• less expensive rethrombosis
• expensive
4. Administered by Administered initially as Administered initially as
i.v. infusion i.v. bolus, followed i.v. bolus, followed by
by i.v. infusion i.v. infusion
5. Adverse effects: Bleeding can occur: Lower risk of bleeding and
Bleeding, hypotension, hypotension and allergic reactions
allergic reactions like allergic reactions are
fever, chills, skin rashes rare
and rarely anaphylac¬
toid reaction
 HEMATINICS
HAEMATINICS

Iron Maturation factors

“I
Adjuvant
Vitamin Bi:: haematinics
C y anocobalamin c,Tf*T
Oral iron Parenteral iron Hydroxocubalamin Pyridoxine
Methykobalamin Ribofl.n in
Ferrous sulfate Iron-dextran
Folic acid:
Ferrous fumarate Iron-sorbitob
Fol true acid
Ferrous gluconate citric acid
(leucovorin,
Fernius nmviiiaIe Ferrous sucrose
citrovorum factor)
Ferrous aminoalv Ferric carboxy* I
Ferric ammonium maltose
citrate
PREPARATIONS OF IRON:
Oral Preparations : Parenteral Preparations:
Oral administration of iron is convenient for the patient. 1. Iron sorbitol citric acid complex:
Various preparations are as follows: It is given intramuscularly, but never
1. Ferrous sulphate contains 20% (hydrated salt) and 32% intravenously.
(dried salt) elemental iron.
It is the oldest and cheapest iron preparation. 2. Iron dextran:
2. Ferrous fumarate contains 33% elemental iron. 3. Ferrous It can be administered intravenously
gluconate contains 12% elemental iron. or intramuscularly.

Other oral preparations are ferrous succinate, iron choline 3. Newer formulations like ferrous
citrate, ferric ammonium citrate, colloidal ferric hydroxide sucrose, ferric carboxymaltose, iron
(50% elemental iron), carbonyl iron (highly purified metallic isomaltoside and ferumoxytol are
iron), etc. administered intravenously.
ADVERSE EFFECTS of oral iron are nausea, vomiting, Hypersensitivity reactions are less
epigastric discomfort, dyspepsia, metallic taste, constipation or frequent as compared to older
diarrhoea and staining of teeth (with liquid preparation). formulations of parenteral iron

INDICATIONS FOR PARENTERAL IRON THERAPY:

1. Intolerance to oral iron
2. Malabsorption of iron
3. Severe iron deficiency
4. Patients with renal disease receiving erythropoietin

The total dose of iron (including amount required to replenish the stores) is
calculated using the formula:
Iron requirement (mg) = 4.4 X body weight (kg) X Hb deficit (g/dL)
(Normal Hb: in men = 14-16 g%; women = 12-14 g%)
Intramuscular therapy: Intravenous therapy:
The preparations used are Iron dextran complex Iron dextran (low molecular weight): It can be
Iron sorbitol-citric acid complex administered as a total dose infusion.
The recommended adult dose is 100 mg daily The total dose required is diluted in 500 mL of
(2 mL) normal saline and infused slowly intravenously
To prevent staining of skin, injections are over 6-8 hours, after administering a test dose,
given deep intramuscularly into but tock using under constant supervision.
'Z- track' technique (pull the skin and underlying It can also be given intravenously slowly in small
subcutaneous tissue at the site of injection to doses of 2 mL daily
one side before injecting the drug).

ADVERSE EFFECTS:
The i.m. injections are painful, may cause abscess and discolouration of skin at
the site of injection.
The systemic side effects following administration by i.m./ i.v. routes are
headache, pyrexia, nausea, vomiting, arthralgia, lymphadenopathy, urticaria and
circulatory collapse. Anaphylactoid reaction can occur

ACUTE IRON POISONING

It is seen frequently in young children.
The manifestations are nausea, vomiting, epigastric pain, bloody diarrhoea,
dehydration, cyanosis, drowsiness, hyperventilation, metabolic acidosis, convulsions,
coma and death.
Treatment
1. General measures
2. Specific therapy General Measures.
Airway, breathing, circulation, fluid and electrolyte balance should be
maintained.
-» Gastric
Vomiting can be induced to remove iron from the stomach.
-> lavage with sodium bicarbonate precipitates iron and reduces its
absorption.
-> Diazepam i.v. slowly to control convulsions.
Specific Therapy;
Desferrioxamine (deferoxamine), a potent iron chelating agent, is administered by
i.v. infusion or intramuscularly depending on severity of poisoning.
It binds with iron in -> blood and facilitates its excretion.
Deferiprone, an oral iron chelator, is less effective than desferrioxamine in acute
poisoning.
Calcium edetate is also useful in iron poisoning.
 ANTIPLATELET drugs

ANTIPLATELET DRUGS
(Antithrombotic drugs)

Thromboxane Platelet
“I
P2Y1Z
I-
receptor
L_
GP Ht/IHg
synthesis cAMP blockers antagonists
inhibitor enhancer
Tidopidine Abciximab
Aspirin Dipyridamole Clopidogrel Eptifibatide
Prasugnel Iirofiban
Tieagrelor

1.TXA2 Synthesis Inhibitor:

Low-dose aspirin (50-325 mg/day) irreversibly acetylates platelet COX-1 and
reduces the production of TXA2.
platelets cannot synthesize new enzymes, the antiplatelet effect lasts for the
lifetime of the platelets, i.e. 7-10 days.
In higher doses, aspirin inhibits both TXA2 and PGI2, hence antiplatelet efficacy
is reduced.
Common adverse effects are gastric irritation and bleeding

2 .P2Y12 Receptor Antagonists:

Adenosine diphosphate (AbP) released from platelets promotes their aggregation
Tidopidine, clopidogrel and prasugrel are prodrugs and structurally related.
They inhibit AbP-mediated platelet aggregation by irreversibly blocking purinergic
(P2V12) receptors on the platelets.

The antiplatelet effect persists even after discontinuation of the drugs.

They produce synergistic effect when combined with aspirin or GP Ilb/IIIa
antagonists.
They are administered orally

Bleeding is an important adverse effect; risk is more with prasugrel.

The other adverse effect of ticlopidine and clopidogrel is diarrhoea.
Neutropenia and thrombocytopenia are serious adverse effects of ticlopidine but
rare with clopidogrel.
ADP release from platelets — Acts on P2Y12 receptor on platelets
* — Conformational change in GP lib/
Illa receptor on platelets

I
Promotes binding of fibrinogen
to GP llb/llla receptor on platelets

I
Platelet aggregation
3 .Glycoprotein Ub/IHo Receptor Antagonists:
Activation of GP Ilb/HIa receptors on platelets favours binding of fibrinogen to
receptors resulting in platelet aggregation

9
 Abciximab, eptifibatide and tirofiban block GP Ub/HIa receptors on platelet
surface to inhibit final step of platelet aggregation.

Abciximab is a monoclonal antibody that binds to GP Hb/IHa receptor.

Eptifibatide is a synthetic drug, which is more specific for GP Ilb/HIa receptor.
Tirofiban is a nonpeptide GP lib /Illa receptor antagonist.
The main side effects of these drugs are bleeding and thrombocytopenia

USES OF ANTIPLATELET AGENTS:

Acute coronary Coronary artery Prosthetic heart Peripheral artery Transient
syndrome: disease: valves: disease: ischaemic
It includes acute Studies have Valve thrombosis and Aspirin/clopidogrel attack (TIA);
MI and unstable shown that low- thromboembolism are may prevent Early initiation
angina. Dual dose aspirin problems associated thromboembolism. of aspirin in
antiplatelet reduces the with prosthetic valves. patients with
therapy is used- occurrence of Aspirin with warfarin TIA reduces
incidence of MI, subsequent MI, reduces these risks. risk of
stroke and stroke and death Dipyridamole may be recurrent
mortality is in post- MI used with warfarin to attacks.
reduced. patients . prevent
Clopidogrel can be thromboembolism in
used as an patients with
alternative if prosthetic heart
aspirin cannot be valves.
used.
 DRUGS ACTING ON CENTRAL NERVOUS SYSTEM
NEUROTRANSMITTERS IN CNS:
I. Inhibitory neurotransmitters

•GABA
•Glycine
•Dopamine

2. Excitatory neurotransmitters

•Glutamate F

•Aspartate
Stimulatory effect on CNS
•Acetylcholine Mediate both inhibitory
•Noradrenaline and excitatory effects
•Serotonin (5-HT)

SEDATIVES AND HYPNOTICS

Sedative is a drug that reduces excitement and calms -> person.
Hypnotic is a drug that produces sleep- resembling normal sleep
SEDATIVE-HYPNOTIC DRUGS

1
I
Anticonvulsant
Diazepam
IAMazrpam
Clnna/cfMm
Clnbj/am

Barbiturate*

Long acting
Phrnobarbitonv IhiopenUMU*
MrihohCMkUM'

Hypnotics: Long acting barbiturates Non - benzodiazepines

LO DIA F A N PHONE BARBI Z EE TV
Anti-anxiety: Short acting
LO DIA CAL OX KA BP
Anti-convulsant: Ultra short acting
LO DIA CLONA CLOBA TIME
 1.Benzodiazepines :
Sites of Action Midbrain (ascending reticular formation), limbic system, brain
stem, etc.
MECHANISM OF ACTION
BZDs facilitate action of GABA - they potentiate inhibitory effects of GABA

PHARMACOLOGICAL ACTIONS AND THERAPEUTIC USES;

AC Di A (Z E)P A M (Uses of BZDs: Mnemonic) Benzodiazepines
I
Bind to specific site on GABAa receptor
(different from GABA- binding site )

I
Increase in frequency of opening of Cl channels
I
Increase in GABA-mediated chloride current
I
Membrane hypcrpolarization

Conscious sedation
Alcohol withdrawal symptoms
i
CNS depression

1.Sedation and hypnosis; 2. Anticonvulsant; 3 . Diagnostic (endoscopies)

BZDs decrease time required to Diazepam, lorazepam, and minor operative
fall asleep (sleep latency). clonazepam, clobazam, etc. have procedures: i.v. BZDs are
The total sleep time is increased. anti convulsant effect. used because of their
They shorten all stages of NREM Intravenous (i.v.) sedative-amnesic- analgesic
sleep except stage 2, which is diazepam/lorazepam is used to and muscle relaxant
prolonged control life-threatening seizures properties .
The duration of REM sleep is in status epilepticus, tetanus,
usually decreased. drug- induced convulsions, febrile
BZDs reduce night awakenings and convulsions, etc.
produce refreshing sleep.
4. To treat alcohol-withdrawal 5.Muscle relaxant (centrally 6. Antianxiety (anxiolytic)
symptoms; acting): effect:
Long -acting BZDs, such as They reduce skeletal muscle tone Some of the BZDs
chlordiazepoxide and diazepam are by inhibiting polysynaptic (diazepam, oxazepam, alpra
used reflexes in the spinal cord. zalam, lorazepam,
The relaxant effect of BZDs is chlordiazepoxide, etc.) have
useful in spinal injuries, tetanus, selective antianxiety action
cerebral palsy and to reduce at low doses. The anxiolytic
spasm due to joint injury or effect is due to their action
sprain. on limbic system
(Q) Why BZDs are preferred to barbiturates for treatment of short-term
insomnia?
BZDs are preferred to barbiturates for treatment of short-term insomnia
because:
->They have a wide therapeutic index.
->They produce minimal hangover effects (headache and residual drowsiness on
waking) .
->They cause minimal respiratory depression.
->They are less likely to cause tolerance and dependence when used for short
period.
->They have no enzyme -inducing property; hence, drug interactions ore less.
^They have a specific BZD -receptor antagonist, flumazenil, for the treatment of
overdosage .

PHARMACOKINETICS:
->BZDs are usually given orally or intravenously and occasionally by rectal route
(diazepam) in children.
->They have a large volume of distribution.
->They have a short duration of action on occasional use because of rapid
redistribution
->BZDs are metabolized in liver.
Some undergo enterohepatic recycling.
Some of them produce active metabolites which have long half-life; hence,
cumulative effects may be seen.
->The metabolites are excreted in urine.
->BZDs cross placental barrier.

Adverse Effects
BZDs have a wide margin of safety.
They are generally well tolerated.
The common side effects are drowsiness, confusion, blurred vision, amnesia,
disorientation, tolerance and drug dependence.
BZD agonists /'‘’""'X
BZDR « Flumazenil (antagonist)

BZD inverse agonists /

Fig. 5.4 Competitive antagonism. BZDR. Benzodiazepine receptor.
2.BARBITURATES
All barbiturates are derivatives of barbituric acid.
They are non -selective CNS depressants and act at many sites, ascending
reticular activating system (ARAS) being main site.
MECHANISM OF ACTION:
Barbiturates have GABA facilitatory action - they potentiate inhibitory effects of
GABA.
 Barbiturates
l
Bind to ( jABAa retcptor
(different from BZD- binding site)

l
The duration of Cl" channel k^pr open is increased

Increase in GABA* medialed chloride current

!
Membrane hyperpolarination

I
CNS depression

At high concentrations, barbiturates have GABA -mimetic effect (i.e. barbiturates

can directly increase Cl conductance into the neuron).
PHARMACOLOGICAL ACTIONS AND USES:
Sedation and General anaesthesia Anticonvulsant: Neonatal jaundice of
hypnosis: (GA); Ultrashort¬ Phenobarbitone has nonhaemolytic type;
Barbiturates acting barbiturates anticonvulsant effect and Phenobarbitone may be used to
were used in (thiopentone and is used in the treatment reduce serum bilirubin levels.
the treatment methohexitone) may of status epilepticus and It induces glucuronyl
of insomnia. be used for induction generalized tonic-clonic transferase enzyme and
of GA (GTCS, grand seizures (GTCS, grand hastens the metabolism of
mal epilepsy). mal epilepsy). bilirubin
ADVERSE EFFECTS
1. The common side effects are drowsiness, confusion, headache, ataxia,
hypotension and respiratory depression.
2. Hypersensitivity reactions like skin rashes, itching and swelling of face may
occur.
3. Tolerance develops to their sedative and hypnotic actions on repeated use.
4. Physical and psychological dependence develops on repeated use.
5. Prolonged use of phenobarbitone may cause megaloblastic anaemia by interfering
with absorption of folic acid from gut.

ACUTE BARBITURATE POISONING

The signs and symptoms are drowsiness, restlessness, hallucinations, hypotension,
respiratory depression, convulsions, coma and death,
TREATMENT OF ACUTE BARBITURATE POISONING
-> Maintain airway, breathing and circulation.
-> Maintain electrolyte balance.
-> Gastric lavage - after stomach wash, administer activated charcoal that may
enhance the elimination of phenobarbitone.
Endotracheal intubation is performed before gastric lavage to protect the
airway in unconscious patients.
-> Alkaline diuresis - there is no specific antidote for barbiturates; main
treatment is alkaline diuresis, i.v. NaHCO3 alkalinizes urine.
 ALCOHOLS (ETHANOL AND METHANOL)

ACTIONS OF ALCOHOL:

•Diuresis due to •Dose-dependent CNS depression •TAppetite

inhibition of
ADH reEease
•Initially apparent stimulation and
later depression
.tGastnc acid secretion
•Gastritis
Aggravation of peptic ulcer
. |—CNS—|
Fatty degeneration
I Kidney |
*I Evaporates and

and cirrhosis
Fall in body
temperature
— > cools the skin
Increased sweating

Respiratory
centre
_ „ . . •Astringent
Cutaneous vasodilation and .
- .
_

„ .. Antiseptic
Depression flushing
• Large doses - myocardial and
VMC depression
THERAPEUTIC USES OF ALCOHOL:
Antiseptic: 2. Trigeminal and 3. Prevent 4. Methanol poisoning: 5. Fever:
70% ethyl other neuralgias; bedsores: Ethanol competes with Alcoholic
alcohol is used as Injection of Alcohol is used methanol for metabolic sponges are
an antiseptic on alcohol directly locally to enzymes and saturates them. useful to
skin before giving into nerve trunk prevent Hence, it prevents the reduce body
injection and relieves pain by bedsores in formation of toxic temperature.
surgical destroying them. bedridden metabolites of methanol
procedure. patients . (formaldehyde and formic
acid

ACUTE ETHANOL OVERDOSAGE (ACUTE ALCOHOL INTOXICATION)

The signs and symptoms of acute alcohol intoxication are drowsiness, nausea,
vomiting, ataxia, hypotension, respiratory depression, hypoglycaemia, etc.
Treatment (Note A-G).
It is a medical emergency.
The main aim of therapy is to prevent severe respiratory depression and aspiration
of vomitus.
1. Maintain Airway, Breathing, Circulation, Fluid and Electrolyte balance, and
Gastric lavage if necessary.
2. Intravenous glucose to correct hypoglycaemia.
3. Thiamine is administered as i.v. infusion in glucose solution.
4. Haemodialysis helps to hasten the recovery.

METHANOL POISONING (METHYL ALCOHOL POISONING)

This occurs when methylated spirit is consumed or when liquor is adulterated with
methyl alcohol.
Methanol is a mild CNS depressant.
It is metabolized to formaldehyde and formic acid which, in turn, cause metabolic
acidosis and injury to retina.
 b—
Methanal Ethanol
Alcohol dehydrogenase
Formaldehyde Acetaldehyde

F- Aldehyde dehydrogenase
Acetic acid

r^r 1
Respiratory
depression
Acidosis Retinal
damage
SIGNS AND SYMPTOMS OF METHANOL POISONING
Nausea, vomiting, abdominal pain, headache, vertigo, confusion, hypotension,
convulsions and coma.
Metabolic acidosis is due to formic acid which also causes dimness of vision, retinal
damage and blindness.

TREATMENT
1. Patient is kept in a dark room to protect eyes from light.
2. Maintain airway, breathing and circulation.
3. Gastric lavage is done after endotracheal intubation.
4. Intravenous sodium bicarbonate is given to correct acidosis and to prevent
retinal damage.
5. Ethanol (10%) is administered via nasogastric tube.
Ethanol competes with methanol for metabolic enzymes and saturates them, thus
prevents formation of toxic metabolites (formaldehyde and formic acid).
Methanol is excreted unchanged in urine and breath.

6. Calcium leucovorin is administered intravenously (folate adjuvant therapy) to

enhance metabolism of formate, thereby decreasing its levels.
7.Haemodialysis is done to promote excretion of methanol and its toxic metabolites

ANTIEPILEPTIC DRUGS

Epilepsy is a Greek word that means convulsions.

Epilepsy is a disorder of brain function characterized by paroxysmal cerebral
dysrhythmia.
Epilepsy
1
Generalized seizures Partial seizures
1. Generalized tonic-clonic seizures 1. Simple partial seizures
2. Absence seizures 2. Complex partial seizures
3. Myoclonic seizures
 ANTIEPILEPTIC DRUGS

Barbiturate Hydantoin Succinimide Benzodiazepines Newer drugs

Phrnobarbitonc Phenytoin Ethosuximide Clonazepam Topiramate
Fosphenytoin Diazepam Zonisamide
Lorazepam Levetiracetam
Clobazam Vigabatrin
Tiagabine
Lacosamide
Deoxy barbiturate iminostilbene Aliphatic
Primidone I Carbamazepine carboxylic acid
Phenyltriazine Cyclic GABA
I Oxcarbaxepine Valproate sod analogues
(Valproic acid) Iximotriginc
Gabapentin
Divalproex Pregabalin

Hydantoin-phenytoin
Hide and seek jeetoge toh pepsi milega

Iminostillbene -carbamazepine
Im not still into bin-I have my car,Im an amazing person

succimide - > sab sexy hai ethosuximide

carboxylic acid- sodium valproate
Wall ke upr pepsy ki aisi add ki maza aagaya

Phenyltriagine -> pyar lamda

MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS
1.PHENYTOIN
Is one of most commonly used antiepileptic drugs.
It has a selective antiepileptic effect and does not produce significant drowsiness.

MECHANISM OF ACTION
Phenytoin acts by stabilizing neuronal membrane and prevents spread of seizure
discharges.
The sodium channels exist in three forms; resting, activated and inactivated
states .
Phenytoin delays recovery of Na channels from inactivated state, thereby reduces
neuronal excitability and inhibits high-frequency firing.
At high concentrations, phenytoin inhibits CaZ influx into neuron, reduces
glutamate levels and increases responses to GABA
 Reduces intraneuronal
Na concentration
(membrane-stabilizing effect)

Inhibits the generation of

repetitive action potentials

Therefore, prevents or
reduces the spread of
seizure discharges; it inhibits
the high-frequency firing
prevents further entry of
Na ions into the neuron
Fig. 5.9 Mechanism of action of phenytoin.

• Phenytoin
* Fosphenytoin
Bind to voltage- dependent Na* channels
• Carbamazepine
(prolong the inactivated state) and
• Oxcarbazepine
prevent further entry of
Sodium valproate
‘ Na+ ions into neurons
* Lamotrigine (stabilize neuronal membrane)
• Topiramate
* Zonisamide
• Lacosamide j
Inhibit generation of
repetitive action potentials

Therefore, prevent or reduce the

spread of seizure discharges
Fig* 5*8 (A) Mechanism of action of antiepileptic drugs: effect on sodium channels.

GAD, (J GABA T
Sodium valpro

Facilitate GABA
Benzodiazepines 1 (-) GABA-T
activity Vigabatrin

Facilitates GABA activity GABA

Phenobarbitone activity
has GABA mimetic Promotes GABA release
Gabapentin
action

Blocks uptake of GABA

Tiagabine
into neurons

TCI conductance into the neuron (IPSP)

Hyperpolarization

Reduced neuronal excitability

Antiepileptic effect
PMARMACOKINETICS:
Phenytoin is absorbed slowly through GI tract, widely distributed and highly
(about 90%) bound to plasma proteins.
It is almost completely metabolized in liver by hydroxylation and glucuronide
conjugation.

USES
Phenytoin is used for treatment of:
1. Generalized tonic-clonic seizures (grand mat epilepsy).
2. Partial seizures.
3. Trigeminal and other neuralgias.
4. Status epilepticus: Phenytoin is administered intravenously in normal saline
(it precipitates in glucose solution).

ADVERSE EFFECTS
(Note the 'H's). Phenytoin has dose -dependent toxicity.
The adverse effects are as follows:
1. Hypertrophy and Hyperplasia of gums (due to defect in collagen catabolism) -
seen on chronic therapy and can be minimized by proper oral hygiene.
2. Hypersensitivity reactions include skin rashes, neutropenia and rarely Hepatic
necrosis .
3. Hirsutism - due to increased androgen secretion.
4. Hyperglycaemia - due to decreased insulin release.
5. Megaloblastic anaemia - due to folate deficiency.
-
6. Osteomalacia due to increased metabolism of vitamin D.
7. Hypocalcaemia - due to decreased absorption of Ca2 from the gut.
8. Fetal Hydantoin syndrome - cleft lip, cleft palate, digital Hypoplasia, etc. due
to use of phenytoin during pregnancy.

2. VALPROIC ACID (SODIUM VALPROATE):

Carboxylic Acid Derivative Sodium valproate is a broad -spectrum antiepileptic
drug.

Adverse Effects (Note the Mnemonic VALPROATE)

1. The common side effects related to GI tract are nausea. Vomiting, Anorexia
and abdominal discomfort.
2. CNS side effects include sedation, ataxia and tremor.
3. A rare but serious complication is fulminant hepatitis (Liver), hence avoided in
children younger than 3 years. Monitoring of hepatic function is essential during
valproate therapy; Elevation of liver enzymes occurs.
4. Teratogenicity: Orofacial and digital abnormalities; neural tube defects with
increased incidence of spina bifida, so it should not be given during pregnancy.
5. The other adverse effects include skin Rashes, Alopecia and curling of hair;
acute Pancreatitis may occur rarely.
 USES
Sodium volproate is highly effective in absence, myoclonic, partial (SPS and CPS)
and generalized tonic-clonic seizures.
Other uses of valproate are mania, bipolar disorder and migraine prophylaxis.

STATUS EPILEPTICUS

It is a medical emergency and should be treated immediately.

It is characterized by recurrent attacks of tonic-clonic seizures without the
recovery of consciousness in between or a single episode lasts longer than 30
minutes .

TREATMENT
1. Hospitalize -> patient.
2. Maintain airway and establish a proper i.v. line.
3. Administer oxygen.
4. Collect blood for estimation of glucose, calcium, electrolytes and urea.
5. Maintain fluid and electrolyte balance.

Watch for hypotension

and respiratory
depression

Monitor cardiac
rhythm and BP

Watch for
respiratory depression

Maintain airway
and BP

10
 opioid analgesics

OPIOID ANALGESICS AND ANTAGONISTS

OPIOID RECEPTORS
The three main types of opioid receptors are receptor -mediated effects are given
below-
fi: Analgesia (spinal + supraspinal level), respiratory depression, dependence,
sedation, euphoria, miosis, decrease in GI motility.
k: Analgesia (spinal + supraspinal level), respiratory depression, dependence,
dysphoria, psychotomimetic effect.
& Analgesia (spinal + supraspinal*level), respiratory depression, proconvulsant
action.

OPIOID AGONISTS
MECHANISM OF ACTION:
Morphine is prototype drug.
PHARMACOLOGICAL ACTIONS OF MORPHINE:
MARPHINE CVS«
Miosis
Analgesia
Respiratory depression
Physical and psychological
dependence
Histamine release,
hypotension, hypothermia
Itching
Nausea and vomiting
Euphoria
Cough suppression,
constipation
Vagal stimulation
(bradycardia)
Sedation and hypnosis
1. CNS
(A) THE DEPRESSANT EFFECTS:
1.Analgesic effect:
Mediated mainly through p- receptors at spinal and supraspinal sites
(central action), it is most important action of morphine.
It causes sedation, drowsiness, euphoria, makes person calm and raises the pain
threshold.
Perception of pain and reaction to it (fear, anxiety and apprehension) are altered
by these drugs.
Moderate doses of morphine relieve dull and continuous pain, whereas sharp,
severe intermittent pain such as traumatic or visceral pain requires larger doses of
morphine.
2 .Euphoria (feeling of well-being):
It is an important component of anal gesic effect. Anxiety, fear, apprehension
associated with painful illness or injury are reduced by opioids.
3 . Sedation:
Morphine, in therapeutic doses, causes drowsiness and de creases physical
activity .
4.Respiratory depression:
It depresses respiration by a direct effect on the respiratory centre in the
medulla; both rate and depth are reduced because it reduces sensitivity of
respiratory centre to CO2.
Respiratory de pression is the commonest cause of death in acute opioid poisoning.

(B) THE STIMULANT EFFECTS:

1. Miosis; Morphine produces constriction of pupils due to stimulation of III
cranial nerve nucleus.
Some tolerance develops to this action.
Pin point pupils are an important feature in acute morphine poisoning.
Miosis is not seen on topical application of morphine to the eye.

(ii) Nausea and vomiting: It is due to direct stimulation of the CTZ in medulla. 5-
HT3 antagonists are the drugs of choice to control opioid induced nausea and
vomiting.
Hl -blockers, such as cyclizine or prochlorperazine may also be used.

(iii) Vagal centre: It stimulates vagal centre in the medulla and can cause
bradycardia.

2. CVS: Morphine produces vasodilatation and fall of BP

Depression of VMC

Morphine Histamine release ' Hypotension

causes
Direct action on
blood vessel
 3 . GIT : It causes constipation by direct action on GI tract and CNS - decreases
GI motility and increases tone of the sphincters.
4. Urinary bladder: It may cause urinary retention by increasing tone of urethral
sphincter.
5. Histamine release: Morphine is a histamine liberator and causes itching, skin
rashes, urticaria, vasodilatation, bronchoconstriction, etc.

ADVERSE EFFECTS
1. Nausea, vomiting and constipation.
2. Respiratory depression.
3, Hypotension due to vasodilatation,
4. Drowsiness, confusion and mental clouding.
5. Itching (due to histamine release) and skin rashes.
6. Difficulty in micturition.
7. Respiratory depression in newborn due to administration of morphine to mother
during labour.
8. Drug tolerance develops to most of effects of morphine (some tolerance
develops to miotic effect). There is cross -tolerance among the opioids.

ACUTE MORPHINE POISONING

The characteristic triad of symptoms are respiratory depression, pinpoint pupils
and coma.
The other signs and symptoms are cyanosis, hypotension, shock and convulsions.
Death is usually due to respiratory depression.
Treatment of acute morphine poisoning:
1. Hospitalization.
2. Maintain airway, breathing and circulation.
3. Ventilatory support (positive pressure respiration).
4. Gastric lavage with potassium permanganate
5. Specific antidote:
Naloxone 0.4-0.8 mg intravenously; dose is repeated till respiration becomes
normal
The duration of action of naloxone is short; hence, repeated administration is
needed .
THERAPEUTIC USES OF OPIOIDS:
As analgesic : Preanaesthetic Acute pulmonary Postanaesthetic shivering -
Morphine and other apioids medication: oedema (cardiac pethidine is effective.
are potent and efficacious Opioids like asthma): i.v. Cough: Codeine and
analgesics, hence used for morphine and morphine relieves dextromethorphan are used
moderate to severe painful pethidine are used breathlessness
conditions, such as acute about half an hour associated with Synthetic apioids such as
myocardial infarction (MI), before acute left loperamide and
bums, pulmonary embolism anaesthesia ventricular failure diphenoxylate are used for
symptomatic treatment of
diarrhoea.
 ANTIPARKINSONIAN DRUGS

PARKINSON'S: It is characterized by tremor, rigidity, bradykinesia (slowness of

movements) and loss of postural reflexes.
The balance between inhibitory dopaminergic neurons and excitatory cholinergic
neurons is disturbed resulting in relative cholinergic overactivity.

DA 1
*
ACh da
__ A ACh
DA- influencing drugs
I
1
J
Anticholinergic drugs

1
J

(A) (B) (a
Fig. 5.12 (A Normally, there is a balance between DA and ACh in the striatum: (B) parkinsonism -
deficiency of DA leads to a relative increase in ACh activity; (C) balance between DA and ACh
is restored with the use of antiparkinsonian drugs.

ANTIPARKINSONIAN DRUGS

Drugs affecting brain Drugs

dopaminergic system cholinergic system

J
Dopamine Dopaminergic COMT Central Antihistamlnlcs
precursor agonists inhibitors anticholinergics
Levodopa Bromocriptine Ent>K«ipone Trihexyphenidyl Orphcnadrine
Ropinirole Tokaponc Procyclidine Promethazine
Pramipexole Biperiden

Peripheral MAO-B Glutamate (NMDA receptor)

decarboxylase Inhibitors agonist (Dopamine facilitator)
Inhibitors Selegiline Amantadine
Carbidopa Rasagiline
Bensera/ide

Lelo Car Rupali Salt rasgula leke aman ko diya ent ne dekha
Bhage -> cycle se

DOPAMINE
Precursor: Levodopa L-Dopa is main drug for treatment of idiopathic parkinsonism.
Dopamine does not cross BBB; hence, its immediate precursor L-Dopa (prodrug) is
used.
1
It is converted to dopamine by decarboxylase enzyme in the dopaminergic neurons
of the striatum.
Dopamine produced then interacts with D2- receptors in basal ganglia to produce
antiparkinsonian effect.

All clinical symptoms (rigidity, bradykinesia and tremor) of parkinsonism improve,

but progression of the disease is not stopped.
A large amount of the drug is converted to dopamine in the peripheral tissues by
peripheral decarboxylase enzyme.
Only a small amount (2%-3%) of L-Dopa enters the brain.
Therefore, L-bopa is used in combination with carbidopa/benserazide (peripheral
decarboxylase inhibitor) which does not cross the BBB: the peripheral metabolism
of L-bopa is reduced, thus increasing its bioavailability in the basal ganglia
In the basal ganglia
Dopa Interacts with Relieves symptoms
Levodopa
decarboxylase * Dopamine Q2,receptors * Of parkinsonism

/ CTZ BBB
7 • Nausea
© • Vomiting
Levodopa
Peripheral
Oopa.decarboXytese *
•

pamme
.• Tachycardia
Palpitation

• Postural
Blood hypotension
vessel
Carbidopa/benserazide In the periphery

PHARMACOKINETICS
On oral administration, L-bopa is rapidly absorbed from small intestine by an
active transport system
Amino acids present in food may interfere with absorption of L-bapa; hence, it
should be given 30-60 minutes before meal.
Active transport of L-bopa into brain may be inhibited by competition from
dietary amino acids.
The metabolites are excreted in urine.

Peripheral Decarboxylase Inhibitors:

Carbidopa and Benserazide

These drugs do not cross BBB.

L-bopa is always given in combination with carbidopa/benserazide.

The currently used combinations are as follows:

L-bopa carbidopa (4:1 or 10:1 ratio). L-bopa benserazide (4:1 ratio).
The advantages of these fixed -dose combinations are as follows:

1. Increased bioavailability of dopamine in basal ganglia

2. Prolongation of plasma half-life of L-bopa.
3. Reduction in incidence of 61 side effects like nausea and vomiting.
4.Cardiovascular side effects like tachycardia, hypotension and cardiac
arrhythmias are minimized.
5. Better patient compliance.
6. Sustained release preparation of L-bopa -carbidopa helps to reduce on/off
phenomenon .
 ANTIPSYCHOTIC
ANTIPSYCHOTIC DRUGS
(Neuroleptic drugs)

Fekte hoi sabkuch -phenothiazines

Batiyaate hai khud se- butyrophenones
Thokhre khate hai-thioxanthenes
Auro ke sth-other
Asamaanya se rehte hai yeh or yeh hai pagla ke Iaxhan- atypical
Phenothiazines: Butyrophenones: Thioxanthenes Others Atypical
CFT3 batiyate hai apni Thokre khate Auro ke sth CLOSE
doll se hai pee Io RUPA
Foolo pe ni OLA ME
Hello Priya QUITE
tere fal m no ARHI HAI
bird flu hai
MECHANISM OF ACTION:
Chlorpromazine (Phenothiazines) Chlorpromazine is -> prototype drug.
PH ARMACOKINETICS:
Phenothiazines are effective orally and parenterally.
Chlorpromazine is highly bound to plasma proteins - reaches high concentration in
the brain.
It is metabolized in liver and excreted in urine.

ay Adrenergic Postural hypotension,

receptors tachycardia, palpitation

H -receptors — Sedation, antipruritic effect

Dryness of mouth, blurred

Muscarinic receptors
(atropine-like actions) — vision, constipation, urinary
retention
 ADVERSE EFFECTS OF ANTIPSYCHOTICS:
Important side effects of these drugs are dose -dependent EPS.
1. Parkinsonism: They are tremors, rigidity, hypokinesia, etc.

2. Acute dystonias: Sudden onset of muscle spasms resulting in uncontrolled

muscular movements involving the face, tongue, neck, etc. It responds to centrally
acting anticholinergics, e.g. benz hexol.

3. Akathisia: Feeling of restlessness - the person cannot sit at a place and has a
desire to move about. It is treated with a BZD (e.g. clonazepam) or -blocker (eg.
propranolol) or centrally acting anticholinergic.

4. Neuroleptic malignant syndrome: It is a rare but serious complication,

characterized by muscular rigidity, hyperpyrexia, mental confusion and coma. It is
treated with i.v. dantrolene.

5 Tardive dyskinesia (Tardive - late occurring): It is characterized by involuntary

.
movements of the mouth, tongue and the upper limbs.

6. Weight gain is common with clozapine and olanzapine.

7.Endocrine side effects are due to increased prolactin level resulting in

amenorrhoea, galactorrhoea and infertility in females: gynaecomastia in males.
Hyperglycaemia and precipitation of diabetes can occur with chlorpromazine.

8. Hypersensitivity reactions can occur - skin rashes, itching, dermatitis,

leucopenia and rarely obstructive jaundice.

THERAPEUTIC USES:
1 Schizophrenia: . 2 Mania: 3. As antiemetic: 4. Intractable hiccough
The neuroleptics are the Acute mania can be These drugs has been treated with
only efficacious drugs treated with a Phenothiazine, such as chlorpromazine.
available for the neuroleptic prochlorperazine, is
treatment of (chlorpromazine or useful for prevention
schizophrenia haloperidol); lithium is and treatment of
used for maintenance nausea and vomiting
therapy. associated with
migraine or emesis due
to anticancer drugs.
 ANTIDEPRESSANTS
ANTIDEPRESSANTS

Selective serotonin Atypical

reuptake Inhibitors (SSRIs) antidepressants
Fluoxetine Trazodone
Mianserin
Fluvoxamine
Paroxetine Mirtazapine
^ertrahne Bupropion
Citalopram Tianeptine
E^italopram Amineptine
Atomoxctinc
Dapoxctine

Serotonin and noradrenaline

reuptake inhibitors (SNRIs)
Venlafaxine
Duloxedne

-
ATYPICAL ANTIDEPRESSANTS TARZAN KI AMI
SNRIS - VELA DUD WALA
SSRI - PYARA DIL CUTE SIR KA KYO KI FAST OX HAI
MAO INHIBATOR - M.C
TCA -
V TRICYCLIC ANTIDEPRESSANTS
MECHANISM OF ACTION

TCAs inhibit norepinephrine transporter (NET) — block

reuptake of NE into neuron, and enhance the
availability of NE at the receptors in the CNS

TCAs inhibit serotonin transporter (SERT) block

*
reuptake of 5-HT into neuron and enhance the availability
of 5-HT at the receptors in the CNS

Muscarinic blockade - of mouth, blurring

(atropine-like actions) * Dryness
of vision, constipation, may
precipitate glaucoma

a1 Adrenergic Postural hypotension,

blockade tachycardia, cardiac
arrhythmias
H( -blockade Sedation, confusion

Lowers seizure threshold and may

precipitate convulsions (thetelare,
contraindicated in epileptics)
PHARMACOKINETICS:
TCAs ore well absorbed through the SI tract and are highly bound to plasma
proteins.
They are widely distributed in tissues including CNS.
They are metabolized in liver.
These drugs are excreted mainly in urine as inactive metabolites.
ADVERSE EFFECTS AND CONTRAINDICATIONS
1. 'Atropine-like* side effects:
Dryness of mouth, blurring of vision, constipation, urinary retention, etc.
2. al -Adrenergic blocking effects:
Postural hypotension, tachycardia, cardiac arrhythmias, etc.
3. Hl -blocking effects: Sedation and confusion.
4. Other effects: Increased appetite, weight gain and may precipitate convulsions
(seizure threshold is lowered).

2. MAO INHIBITORS
MAO is a mitochondrial enzyme involved in the metabolism of biogenic amines.
There are two isoforms of MAO.
MAO- A is responsible mainly for the metabolism of NA, 5-HT and tyramine.
MAO-B is more selective for dopamine metabolism.
CHEESE REACTION
Normally, tyramine in food is metabolized by MAO present in the gut and liver.
So, very little tyramine reaches systemic circulation.
When a patient on MAO inhibitor consumes food stuff rich in tyramine, it may
result in fatal hypertensive crisis and cerebrovascular accidents.
The reaction can be treated with i.v. phentolamine
MAO inhibitors x cheese, fish, meat, beef, wine, yeast

Rich in tyramine

fff BP leading to
Hypertensive crisis
Cerebrovascular accident
Fig. 5.17 Cheese reaction MAO. Monoamine oxidase; BP. blood pressure.
USES OF ANTIDEPRESSANTS
1. Depression;
Antidepressants are used in the treatment of endogenous depression (major
depression) and during the phase of depression in bipolar illness.
(a) Better tolerability.
(b) Less side effects (do not cause hypotension and sedation; do not have
anticholinergic effects and no precipitation of convulsions, do not cause cardiac
arrhythmias).
(c) Longer duration of action.

2. Anxiety disorders;
SSRIs (selective serotonin reuptake inhibitor) are used for the treatment of
generalized anxiety disorder.
Onset of action is slow; hence, BZDs are co -administered for a short period to
control anxiety during this period.

3. Obsessive compulsive disorder (OCD);

Clomipramine (TCA) and fluvoxamine (SSRI) are highly effective.

5. Nocturnal enuresis: Imipramine is effective.

6. Prophylaxis of migraine; Amitriptyline is effective.

7. Chronic pain including neuralgias; TCAs are effective in trigeminal, herpetic and
postherpetic neuralgias. Venlafaxine and duloxetine (SNRIs) are used in the
treatment of fibromyalgia.

8. Atopic dermatitis; Topical doxepin is useful; it has antipruritic action.

9 . Premature ejaculation; SSRIs like paroxetine, fluoxetine, sertraline citalopram

and dapoxetine are effective.
Dapoxetine is taken 1 hour before intercourse as it acts rapidly.
If SSRIs are not tolerated, TCA like clomipramine can be used.
 THYROID HORMONES
The hormones secreted by thyroid gland are thyroxine (T4), triiodothyronine (T3)

SYNTHESIS OF THYROID HORMONES

1 . Iodide trapping:
Active transport of iodide ions into follicular cells of thyroid gland is known as
iodide trapping and takes place by a basement membrane protein called
sodium/iodide symporter.
2. Oxidation and iodination:
The iodide ion is oxidized to iodine by peroxidase enzyme.
Iodine combines with tyrosine residues of thyroglobulin molecule and forms
monoiodotyrosine (MIT) and diiodotyrosine (DIT).
3. Coupling:
This is the final step in the synthesis of thyroid hormones and is catalysed by
thyroid peroxidase.
Two molecules of DIT couple to form thyroxine (T4) and one molecule of MIT with
one molecule of DIT forms triiodothyronine (T3).
MIT +DIT -> T3; DIT+ DIT ->T4
4. Hormone release:
Release of thyroid hormones takes place under control of TSH.
The process involves endocytosis and proteolysis of iodinated thyroglobulin and
results in release of T4, T3, MIT and DIT.
5. Peripheral conversion of T4 to T3:
Most of -> hormone released from thyroid is T4, which is less potent than T3.
Conversion of T4 to T3 occurs mainly in liver and kidney.
Differences between T3 and T4
Tj (Triiodothyronine) T4 (Thyroxine)
Formed by DIT + MIT = T3 Formed by DIT + DIT = Tj
Relatively rapid onset of action Slower onset ot action
Short duration of action (half-life: 1 day) Long duration of action (hall iife: 7 days)
More potent than Tj Less potent
Useful to treat myxoedema coma Used to treat myxoedema coma and
for regular treatment of myxoedema

ANTITHYROID DRUGS

PYARA PATT MTHI LENE CAR SE GY A HAI -> PLANT KE PASS 4 INTO
RADIATION ME

ANTITHYROID DRUGS
These drugs reduce -> level of thyroid hormones by reducing thyroid hormone
synthesis or release or both.
These drugs play an important role in management of hyperthyroidism caused by
both benign and malignant conditions of thyroid gland.

1 THIOAMIDES
Thioamides by inhibiting-
act
1. Thyroid peroxidase enzyme, which converts iodide to iodine
2. Iodination of tyrosine residues in thyroglobulin
3. Coupling of iodotyrosines (MIT and DIT)

PHARMACOKINETICS:
Thiaamides are well absorbed orally.
Propylthiouracil is most rap idly absorbed.
Carbimazole is converted to methimazole after absorption.
They are widely distributed but get accumulated in thyroid gland

ADVERSE EFFECTS:
Skin rashes are most common.
The other side effects are joint pain, fever, hepatitis, nephritis, etc.
 Fig. 9.5 Synthesis, storage and secretion of thyroid hormones and drugs affecting them,
Site 1: Thiocyanates, perchlorates, excess iodides
Sites 2 and 3: Iodides, thioamides
Site 4: fodtdes
Site 5: Propylthiouracil, propranolol, iopanoic acid, ipodate, glucocorticoids
Site 6: Radioactive iodine (destruction of thyroid tissue)

Important feature* of Propylthiouracil and Carbimazole

Propylthiouracil Carbimazole
Less potent More potent
Highly bound to plasma proteins Less protein bound
Has short duration of action (4-8 hours) Has longer duration of action (12-24 hours)
Inhibits peripheral conversion Negligible action
of T4 to T3
No active metabobte Gets converted to methmazole which is
active
Passage across placenta is low Passage across placenta is low
Levels in breast milk are low Levels in breast milk are low

USES:
1. For long-term treatment of 2. Preoperatively in 3. 4 long with 4. For treatment of
hyperthyroidism due to Graves thyrotoxic patients radioactive iodine: thyrotoxic crisis,
disease/toxic nodular goitre before subtotal Radioactive iodine has a propylthiouracil is
where surgery is not indicated thyroidectomy - slow onset of action. used along with
or not feasible and radioactive carbimazole is used Hence, carbimazole is iodide and
iodine is contraindicated. to achieve also administered for propranolol.
euthyroidism initial control of
Carbimazole/methimazole is hyperthyroidism in
preferred for long-term those patients treated
treatment as it is long acting with radioactive iodine.
and is not hepatotoxic
 2 IODINE AND IODIDES
Iodides are -> oldest agents used to treat hyperthyroidism.
They are ->most rapid acting antithyroid drugs.

PREPARATIONS AND USES

1. Lugol's iodine (5% iodine in 10% solution of KI).
2. Ipodate sodium and iopanoic acid
The above preparations of iodine are used orally preoperativeIy before
thyroidectomy and in thyroid storm.
They render -> gland firm, less vascular and decrease its size, which makes
surgery convenient with less bleeding and complications.

OTHER USE :•
1 As an expectorant: Potassium iodide (KI) acts as a mucolytic agent that
enhances expectoration.
2. As an antiseptic: Tincture of iodine (iodine in alcohol).
3. Prophylaxis of endemic goitre: Iodized salt is used.

ADVERSE EFFECTS
Angioedemo, laryngeal oedema, arthralgia, fever, eosinophilia and lymphadenopathy
may occur acutely (type III hypersensitivity)

3.RADIOACTIVE IODINE
Therapeutically used radioactive iodine is 131I (half -life: 8 days).
Sodium iodide 123I (half-life: 13 hours) is used for diagnostic scan.

USES AND CONTRAINDICATIONS:

Radioactive iodine is used for treatment of hyperthyroid is due to toxic nodular
goitre/Graves disease specially in elderly and patients with coexisting cardiac
disease.
It is also useful in hyperthyroidism due to adenoma or carcinoma when surgery is
not feasible or contraindicated.
It is contraindicated in pregnancy, children and nursing mothers.

ADVANTAGES: DISADVANTAGES:
1. Treatment is simple; does not require It is slow acting and causes local soreness in the
hospitalization - can be done in outpatient neck.
department Incidence of hypothyroidism is high.
2. Low cost It is not suitable for pregnant women, children
3. No risk of surgery and scar and young patients.
4. Permanently cures hyperthyroidism
 THYROTOXIC CRISIS (THYROID STORM)
This is a manifestation of severe hypermetabalic state due to very high levels of
circulating thyroid hormones.
Besides the usual features of hyperthyroidism, this is characterized by
hyperpyrexia, cardiac arrhythmias (eg. atrial fibrillation), nausea, vomiting,
diarrhoea and mental confusion.
It is usually precipitated by infection, trauma, surgery (thyroid or nonthyroid),
diabetic ketoacidosis, myocardial infarction, etc.

TREATMENT
1. Hospitalization.
2. Supportive core: Cooling blankets, hydration, sedation and antibiotics to treat
infection.
3. Propranolol, 1-2 mg i.v. slowly every 4 hours; then, oral propranolol 40-80 mg
every 6 hours. It controls palpitations, tremors, tachycardia and inhibits
peripheral conversion of T4 to T3.
4. Propylthiouracil is administered via nasogastric tube.
5. Sodium ipodate, 0.5 g orally, is administered orally. It inhibits release of
thyroid hormones and peripheral conversion of T4 to T3.
6. Diltiazem can be used if propranolol is contraindicated.
7. Intravenous hydrocortisone 100 mg i.v. every 8 hours - inhibits peripheral
conversion of T4 to T3; also corrects adrenal insufficiency, if present.

INSULIN AND ORAL ANTIDIABETIC AGENTS

INSULIN
Insulin is synthesized by beta cells of pancreatic islets from a single -chain
polypeptide precursor called preproinsulin, which is converted to proinsulin.
Insulin is formed by removal of C-peptide from proinsulin by proteolysis.
Insulin consists of two peptide chains called A and B
These two chains are connected by two disulphide bridges
ACTIONS OF INSULIN:
Hepatic glycogenolysis

Fig. 9.19 Structure of proinsulin.

Lipogenesis
Fig. 9.22 Actions of insulin. @. stimulation; e. inhibition
 MECHANISM OF ACTION OF INSULIN:
Insulin binds to specific receptors (tyrosine kinase receptor) present on the cell
mem brane.

The receptor consists of two and two subunits

The subunits are entirely extracellular, whereas the subunits are transmembrane
proteins with tyrosine kinase activity.

Binding of insulin to the subunit activates tyrosine kinase activity of the subunits
resulting in phosphorylation of tyrosine residues of the receptor.

This results in a complex series of phosphorylation-dephosphorylation reactions,

which promotes entry of glucose into the cell and mediates various actions of
insulin.

PHARMACOKINETICS
Insulin is destroyed by proteolytic enzymes in the gut, hence, not effective orally.
Insulin is administered usually by subcutaneous (s c.) route, but in emergencies,
regular (soluble) insulin is given by i.v. route.
After i.v. injection, soluble insulin is rapidly metabolized by the liver and kidney
with a half-life of about 6 minutes.

INSULIN PREPARATIONS;
Conventional Insulin Preparations Monocomponent Insulins: Human Insulins
1. Bovine (beef) insulin; Conventional porcine They are produced by recombinant
It differs from human insulin by insulin are purified to DMA technology
three amino acid residues and is form monocomponent They have the same amino acid
antigenic to man. insulins. sequence os endogenous insulin, e.g.
2. Porcine (pig) insulin: human regular insulin and human NPH
It differs from human insulin by insulin. Purified human insulins are
only one amino acid residue and is the commonly used insulin
less immunogenic than bovine insulin preparations.
Rapid - lag, short - soluble, long - goal
Table 9.7 Insulin preparations based on onset and duration of action
Peak Duration
effect of action
Class Type Onset (hours) (hours)
1. Rapid-acting 1. Insulin lispro 0.25 hour (15 minules) 1-1.5 3-4
insulins 2. Insulin aspart 0.25 hour (15 minutes) 1-1.5 3-4
3. Insulin 0.25 hour (15 minutes) 1-2 3-4
giulisine
II. Short-acting Regular soluble 0.5-1 hour 2-4 6-8
insulin insulin
(crystalline)
III. Intermediate- NPH’ (isophane) 1-2 hours &-10 10-20
acting insulin
IV, _b
Long-acting 1. Insulin glargine 2-4 hours 20-24
_o
insulins 2. Insulin detemir 1-4 hours 20-24
 INSULIN THERAPY
Insulin is the main drug far all patients with type 1 DM, and for patients with
type 2 DM who are not controlled by diet and oral antidiabetic drugs.
The main goal of insulin therapy is to maintain fasting blood glucose
concentration between 90 and 120 mg/ dL and postprandial glucose level below 150
mg/dL.

CONCENTRATION OF INSULIN:
Insulin preparations are available in a concentration of 100 U/mL or 40 U/mL.
Regular insulin is also available in 500 U/mL.

INSULIN ADMINISTRATION:
Insulin syringes and needles.
Pen devices: They are convenient to carry; a preset amount is delivered
subcutaneously .
Insulin pumps are available for continuous s.c. insulin infusion.
Short- acting insulin, eg. regular insulin is used.

INDICATIONS FOR INSULIN :

1. Type 1 DM
2. Diabetic ketoacidosis
3. Non-ketotic hyperglycaemic coma
4. Diabetes during pregnancy
5. Stress of surgery, infections and trauma (temporarily to tide over trauma,
infection, surgery, etc.) in diabetics
6. Patients with type 2 DM in addition to oral antidiabetic drugs Site of

ADMINISTRATION
Insulin is usually administered subcutaneously in -> abdomen, buttock, anterior
thigh or dorsal arm.

COMPLICATIONS OF INSULIN THERAPY:

Hypoglycaemia is the most Allergic reactions Lipodystrophy 4. Oedema due to
common and dangerous are rare (either atrophy or salt and water
complication. Prolonged They may cause hypertrophy) may occur at retention.
hypoglycaemia may cause local skin reactions the site of injection.
permanent brain damage. (swelling, redness)
at the site of It may be avoided by using
injection and may purified insulin preparations
be due to minor and changing the injection
contaminants. . site by rotation
 INSULIN THERAPY
Insulin is the main drug far all patients with type 1 DM, and for patients with
type 2 DM who are not controlled by diet and oral antidiabetic drugs.
The main goal of insulin therapy is to maintain fasting blood glucose
concentration between 90 and 120 mg/ dL and postprandial glucose level below 150
mg/dL.

CONCENTRATION OF INSULIN:
Insulin preparations are available in a concentration of 100 U/mL or 40 U/mL.
Regular insulin is also available in 500 U/mL.

INSULIN ADMINISTRATION:
Insulin syringes and needles.
Pen devices: They are convenient to carry; a preset amount is delivered
subcutaneously .
Insulin pumps are available for continuous s.c. insulin infusion.
Short- acting insulin, eg. regular insulin is used.

INDICATIONS FOR INSULIN :

1. Type 1 DM
2. Diabetic ketoacidosis
3. Non-ketotic hyperglycaemic coma
4. Diabetes during pregnancy
5. Stress of surgery, infections and trauma (temporarily to tide over trauma,
infection, surgery, etc.) in diabetics
6. Patients with type 2 DM in addition to oral antidiabetic drugs Site of

ADMINISTRATION
Insulin is usually administered subcutaneously in -> abdomen, buttock, anterior
thigh or dorsal arm.

COMPLICATIONS OF INSULIN THERAPY:

Hypoglycaemia is the most Allergic reactions Lipodystrophy 4. Oedema due to
common and dangerous are rare (either atrophy or salt and water
complication. Prolonged They may cause hypertrophy) may occur at retention.
hypoglycaemia may cause local skin reactions the site of injection.
permanent brain damage. (swelling, redness)
at the site of It may be avoided by using
injection and may purified insulin preparations
be due to minor and changing the injection
contaminants. . site by rotation
 DIABETIC KETOACIDOSIS

Diabetic ketoacidosis is a complication of type 1 DM

It is rare in type 2 DM.
The common precipitating factors are infection, trauma, severe stress, etc.
The clinical features are anorexia, nausea, vomiting, polyuria, abdominal pain,
hypotension, tachycardia, hyperventilation, altered consciousness or coma in
untreated cases.
Diabetic ketoacidosis is a medical emergency

MANAGEMENT OF DIABETIC KETOACIDOSIS

1.Insulin replacement:
Regular insulin is administered as intravenous bolus in a dose of 0.2-0. 3 U/kg
followed by 0.1 U/kg/hour i.v. infusion.
Blood glucose levels should decrease by 10% in first hour.
Monitoring of blood glucose levels should be done for optimal insulin replacement.
Once patient becomes conscious, insulin can be administered subcutaneously.

2.Fluid replacement:
Initially, normal saline is infused intravenously at 1 L/h; then rate of infusion is
gradually decreased depending on -> requirement of patient.
Once blood glucose levels fall to about 250 mg/dL, 5% glucose in N saline is
administered to prevent development of hypoglycaemia and cerebral oedema.

3.Potassium:
Following insulin therapy and correction of acidosis, potassium shifts into cells
resulting in hypokalaemia.
Potassium chloride 10-20 mEq/h is in fused after 4 hours of initiation af insulin
therapy.
Serum potassium and ECG should be monitored to determine potassium
replacement.

4. Sodium bicarbonate i.v. is administered if required.

5.Phosphate; Patients with severe hypophosphataemia require phosphate

replacement.

6. Antibiotics to treat associated infection

 ORAL ANTIDIABETICS DRUGS

ORAL ANTIDIABETIC DRUGS

Dapagliflozin

KATP - SURAJ GADHA PCMB MUJHE FEEL KRWAVA PRIDE

MEHENGA - RAP GAAYA NETA NE
DPP -4 INHIBITORS - SITA, ALOK, LINA KO MILI VILD(WILD) SUCCESS
BIGUANIDE - BMW PEEGYA
MISCELLANEOUS - CAR BRO PRAM KI

1 SULPHONYLUREAS:
MECHANISM OF ACTION:
Sulphonylureos stimulate -> insulin secretion from 0 -cells of pancreas.
It is an insulin secretogogue .

Sulfon^lureas
Bind to specific receptors on 0- cells of islets of pancreas

Block ATP* sensitive potassium channels

;
Depolarization and influx of Ca2+ ions into p- cells

Degranulation and increased release of stored insulin from B- cells

PHARMACOKINETICS:
Sulphonylureas are well absorbed after oral administration, highly bound to plasma
proteins and have law volume of distribution.
They are metabolized in liver and excreted mainly in urine.
ADVERSE EFFECTS
1. Hypoglycaemia is common, particularly with glibenclamide and chlorpropamide
due to their lang duration of action. Glibenclamide is best avoided in elderly
patients because of the high risk of hypoglycaemia.
2. 61 disturbances like nausea, vomiting, diarrhoea and flatulence.
3. Weight gain is due to stimulation of appetite.
4. Allergic reactions: Skin rashes, itching and photosensitivity.
5. Teratogenicity Sulphonylureas are not safe during pregnancy.

USE. Sulphonylureas are useful in patients with type 2 DM.

2BI6UANIDES Metformin is the only biguanide used clinically.

MECHANISM OF ACTION:
Hepatk glycogenolysis

Fig. 9.24 Mechanism of action of blguenldes ®+ stimulation: O, mhijition

METFORMIN
1. It activates enzyme AMP-dependent protein kinase (AMPK).
This results in
a. Decreased hepatic gluconeogenesis (major action).
b. Increased peripheral utilization of glucose in skeletal muscle and fat resulting in
glycogen storage in the skeletal muscle, increased fatty acid oxidation and
decreased lipogenesis.
2. Inhibition of alimentary absorption of glucose. Biguanides do not affect insulin
release; they improve tissue sensitivity to insulin

PHARMACOKINETICS:
Metformin is taken orally, well absorbed through 61 tract and is excreted mostly
unchanged in urine.
ADVERSE EFFECTS:
Metallic taste, anorexia, nausea, vomiting, diarrhoea, loss of weight and skin
rashes .
Lactic acidosis is most serious complication but is rare with metformin.
Prolonged use can cause vitamin 812 deficiency due to malabsorption.
Metformin usually does not cause hypoglycaemia even in large doses.
USE:
Metformin is used in patients with type 2 DM either alone or in combination with
other antidiabetic agents.
Hypoglycaemia is rare
It protects against vascular com plications of diabetes.

3 . Thiazolidinediones :
They increase sensitivity of peripheral tissues to insulin.
PiogEUzonc 1 Selective agonists of PPAR-7
and | ( peroxisome proliferator activated receptor 7)
roiigUtazone J
I
Bind * nuclear
to PPAR-*y

*
Activate insulin-responsive genes that regulate
carbohydrate and lipid inrtabolhm

1
Sensitize the peripheral tissues to insulin

I
Reduce blood glucose by:
- increasing glucose transport into muscle and adipose tissue
- inhibiting hepatic gluconeogenesis
- promoting lipogencsis
PHARMACOKINETICS:
Pioglitazone is almost completely absorbed from 61 tract, highly bound to plasma
proteins (95%) and metabolized in the liver.

ADVERSE EFFECTS:
Nausea, vomiting, anaemia, oedema, weight gain, and precipitation of heart failure
in patients with low cardiac reserve; rarely hepatotoxicity and bladder cancer may
occur.

4. A -GLUCOSIDASE INHIBITORS.
These drugs should be given just before food.
Acarbose. Miglitol and Voglibose.
They reduce intestinal absorption of carbohydrates by inhibiting enzyme -
glucosidase in -> brush border of the small intestine and reduce postprandial
hyperglycaemia.
They are mainly used in obese patients with type 2 DM.
Side effects are mainly on GI tract: flatulence, fullness and diarrhoea.
 CORTICOSTERIODS
CORTICOSTEROIDS

Fig. 9.17 Regulation of synthesis arid secretion of corticosteroids. CRF. corticolropiti releasog
factor; ACTH. adrenocorticotropic hormone; ®. stimulation; 0. mhibrtion,

PHARMACOLOGICAL ACTIONS:

1 CARBOHYDRATE MRTABOLISM
Carbohydrate Metabolism
Stimulate glycogen deposition in liver
and gluconeogenesis ( formation of
glucose from amino acids)
Glucocorticoid*

Decrease peripheral utilization of glucose

2 .Lipid Metabolism
Prolonged use of glucocorticoids causes redistribution of body fat that is deposited
over the neck, face, shoulder, etc., resulting in moon face', 'buffalo hump* and
'fish mouth’ with thin limb.

3 . PROTEIN METABOLISM
Protein Metabolism

Glucocorticoids (catabolic)
l
Protein breakdown and mobilization of amino acids from
lymphoid tissue nni'ide, skin, bone, etc.
1
Muscle wasting, lympholysis, thinning of loss of bone matrix (osteoporosis]
skin,
and growth retardation; wound healing and fibrosis are also inhibited
4.Electrolyte and Water Metabolism :
Glucocorticoids have weak mineralocorticoid action, cause sodium and water
retention; promote potassium excretion.
prolonged use of these drugs may cause oedema and hypertension.
Some of the synthetic glucocorticoids (dexamethasone, betamethasone and
triamcinolone) have no sodium- and water-retaining property.

5 .Calcium Metabolism (Anti- Vitamin D Action) :

Prolonged use of these drugs may lead to osteoporosis and pathological fracture of
vertebral bodies

Bone

Osteoblasts (bone forming cells)

Osteoclasts (bone resorption cells)

6 .Cardiovascular system:
Glucocorticoids have sodium and water retaining property; exert a permissive
effect on pressor action of adrenaline and angiotensin.
On chronic administration, these drugs may cause hypertension and worsening of
CCF (congestive cardiac failure).

7. Skeletal muscle:
Corticosteroids are required for -> normal function of skeletal muscles
Weakness occurs in both hypocorticism and hypercorticism

——— Hypocorticism: due to inadequate circulation

Muscle weakness
and fatigue
Hypercorticism: due to hypokalaemia

8.Gastrointestinal tract:
Inhibit PGs— acid and pepsin secretion;
may aggravate peptic ulcer

XX Local immune response against Helicobacter pylori

9. Anti -inflammatory effect:

They have powerful anti-inflammatory and immunosuppressant effects.
They prevent or suppress -> clinical features of inflammation such as redness,
heat, pain and swelling.
 [ Glucocorticoids |
Membrane phospholipids
I Phospholipase Ai <9 *
Lipocortin

Arachidonic acid

Cyclooj^genase Lipoxygenase

PGs LTs

ADVERSE REACTIONS :
Most of adverse effects are extension of their pharmacological actions,
1. Metabolic effects :
Hyperglycaemia, or aggravation of pre-existing diabetes.
2, Cushing's habitus:
Abnormal fat distribution causes peculiar features with moon face, buffalo hump
and thin limbs.
3. GIT .
Peptic ulceration, sometimes with haemorrhage or perforation.
4. Salt and water retention:
Mineralocorticoid effect may cause oedema, hypertension and even precipitation of
CCF, particularly in patients with primary hyper aldosteronism.
5. Muscle:
Steroid treatment can cause hypokalaemia leading to muscle weakness and
fatigability. Long-term steroid therapy leads to steroid myopathy
6. Bone:
Osteoporosis with pathological fractures of vertebral bodies is common. Ischaemic
necrosis of femoral head can also occur.
7. Growth retardation
Children is more common with dexamethasone and betamethasone.
8. Eye;
Glaucoma and cataract may occur on prolonged therapy.
9. CNS;
Behavioural disturbances like nervousness, insomnia, mood changes and even
psychosis may be precipitated.
10. Long-term therapy with steroids leads to immunosuppression, which makes the
patient vulnerable to opportunistic infections like fungal (candidiasis,
cryptococcosis), viral (herpes, viral hepatitis) and bacterial (reactivation of latent
tuberculosis).

THERAPEUTIC USES OF GLUCOCORTICOIDS:

1. Rheumatoid arthritis:
They produce an immediate and dramatic symptomatic relief in rheumatoid
arthritis, but they do not halt progression of disease.
By their anti-inflammatory effects, they decrease the swelling, redness, pain and
improve mobility of joints.
2. Osteoarthritis:
They are rarely used in osteoarthritis. Intra-articular injection is recommended
for acute episodes involving one or two joints.
3. Rheumatic fever:
Glucocorticoids produce more rapid symptomatic relief than aspirin and are
indicated in cases with carditis and CCF.
4. Gout: They are reserve anti-inflammatory drugs in acute gout not responding to
NSAIDs.
5. Allergic diseases: The manifestations of allergic diseases, such as hay fever,
reactions to drugs, urticaria, contact dermatitis, angioneurotic oedema and
anaphylaxis, can be suppressed by glucocorticoids, but they have slow onset of
action.
6. Bronchial asthma: Glucocorticoids have anti-inflammatory and antiallergic
effects; hence, they reduce mucosal oedema and bronchial hyperreactivity.
In acute severe asthma, i.v. hydrocortisone is given along with nebulized 2 -agonist
and ipratropium bromide.
If a chronic asthmatic needs steroid, it is better to give inhalational preparations
like beclomethasone, budesonide or fluticasone because they cause minimal
systemic adverse effects.
7. Collagen diseases: Collagen diseases such as polymyositis, polyarteritis nodosa,
polymyalgia rheumatica and dermatomyositis can be controlled with large doses of
glucocorticoids.
8. Renal disease Glucocorticoids are the first-line drugs in nephrotic syndrome.
9. Ocular diseases: They are frequently used to suppress inflammation in the eye,
thus prevent damage to vision. Agents may be administered topically, sub
canjunctivally, systemically or by retrobulbar injection, depending upon the
condition.
10. Skin diseases: Glucocorticoids dramatically relieve itching, pain and
inflammation in allergic and other dermatoses. To minimize systemic effects,
topical steroids are preferred.
11 Haematological disorders : Autoimmune haemolytic anaemias usually respond to
glucocorticoids. Because of their lympholytic action, glucocorticoids are used to
treat certain malignancies, leukaemia, lymphomas, Hodgkin disease, multiple
myeloma, etc.,
12. Cerebral oedema: The effectiveness of glucocorticoids in cerebral oedema
depends upon the underlying cause. They are very effective when the oedema is
caused by brain tumours, metastatic lesions and tubercular meningitis. They are
least effective when the cerebral oedema is due to head injury.
13. Intestinal diseases: They are used in ulcerative colitis when the patient is not
responding to other forms of treatment. Methylprednisolone can be administered
as retention enema during acute episodes
14. Shock: Prompt intensive treatment with i.v. glucocorticoids may be life saving
in septic shock.
 HORMONAL CONTRACEPTIVES

Hormonal contraception is one of most effective contraceptive methods available

today .
Progestin (norethynodrel) was used in -> first contraceptive trial
HORMONAL CONTRACEPTIVES

Hormonal contraceptives

i
Oral
J
Parenteral
I
Intrauterine devices
।
I 1
v
- Levonorgestrel
Progesterone (Progestasert)

Injection Implants
DMPAJ - Norplant
NET-ENb - Implanon

Combined oestrogen and

progestin preparations* (minipill)
—
Progestin only pill Postcoital contraceptives
(emergency contraception)
-- Monophasic • Norethindrone •Levonorgestrel
•Ulipristal
Biphasic • Norgestrel
- Triphasic * Mifepristone

Menstrual cycle

Repeat the
1st day - 1 tablet orally 21st day 28th day course
(day 1 of bleeding) daily tor 21
consecutive days
Cap ot
7 days
—
* till required
Efficacy: 98%-99.9% f *ori 1 st day
Fig. 9.14 Schedule for use of combined pill.

Menstrual cycle

I st day
* 1 tablet daily orally without a break 28th day Continue the
course without a
Efficacy: 96% gap till required
Fig. 9.15 Schedule for use of minipill.
 MECHANISM OF ACTION OF COMBINED CONTRACEPTIVE PUL:
The numerals 1, 2, 3 and 4 shown in figure are described in the following ways:
1. Both oestrogen and progestin act synergistically on hypothalamic-pituitary axis
by negative feedback mechanism and inhibit the release of FSH and LH, which
leads to inhibition of ovulation.
2. Cause tubal and uterine contractions that may interfere with fertilization.
3. Make the endometrium less suitable for implantation.
4. Thick, viscid cervical mucus secretion prevents sperm penetration (progestins).

Fig. 9.13 Mechanism of action of contraceptives.

POSTCOITAL PILL (EMERGENCY CONTRACEPTION)

It interferes with implantation and also has anti -ovulatory affect.

Drugs that can be used for postcoital contraception are levonorgestrel, ulipristal
and mifepristone.
They are mainly used following rape, unprotected intercourse or accidental rupture
of condom during coitus.

Levonorgestrel tablet 0.75 mg (two doses,) Mifepristone (antiprogestin) 600

Oral administration of levonorgestrel is effective, if taken mg as a single dose can be used
within 72 hours of unprotected intercourse (morning after pill). as postcoital pill
Levonorgestrel (0.75 mg) Levonorgestrel (0.75 mg)
One pill 12 hours later One pill
(as early as possible within
72 hours)
Fig. 9.16 Schedule for the use of postcoital contraceptive.

BENEFICIAL EFFECTS OF CONTRACEPTIVES:

Unwanted pregnancy is avoided.
NONCONTRACEPTIVE BENEFICIAL EFFECTS
*> Relieve dysmenorrhoea and premenstrual tension.

> Prevent iron- deficiency anaemia by reducing menstrual loss.

-> Reduce incidence of pelvic inflammatory disease and endometriosis.
-> Protect against ovarian and endometrial carcinoma
 PARENTERAL CONTRACEPTIVES
PARENTERAL CONTRACEPTIVES
INJECTABLE CONTRACEPTIVES
1. Depot medroxyprogesterone acetate (DMPA): 150 mg deep i.m. once in 3
months .
2. Norethindrone enanthate (NET-EN) ZOO mg i.m. once in 2 months.
ADVANTAGES DISADVANTAGES:
1. Regular oral medication is avoided, so Injectable contraceptives cause menstrual irregularities,
patient compliance is better. headache, mood changes, weight gain, osteoporosis.
2. Can be used safely during lactation decrease in HDL and increase in LDL levels.
3 . Decreased risk of endometrial cancer Return of fertility after stoppage is usually delayed for
on prolonged administration several months (6-8 months).
ADVERSE EFFECTS OF HORMONAL CONTRACEPTIVES :
The current low- dose preparations have minimal side effects:
1. Nausea, vomiting, headache, breakthrough bleeding, which occurs initially during
therapy but subside following continuous use.
2. Weight gain, fluid retention, acne and pigmentation of skin occur later.
3. Impaired glucose tolerance and alteration in lipid profile was observed with high
dose contraceptives and is rare with low dose, newer preparations.
4. Blood pressure may increase following long-term use.
It is less common with low dose preparations.
5. Long-term adverse effects include increased incidence of venous
thromboembolic disease especially in women with risk factors far thromboembolism
like smoking; risk of myocardial infarction and stroke in women with coexisting
diabetes or hypertension.
6 . Increased risk of gallstones, benign liver tumours and breast cancer on
prolonged use.

UTERINE RELAXANTS

UTERINE RELAXANTS
(Tocolytics)

USES OF TOCOLYTICS
1. To delay preterm labour
2. Threatened abortion
3. Dysmenorrhoea
I p -adrenergic agonists
The selective 2 -agonists used as uterine relaxants are isoxsuprine, salbutamol,
terbutaline and ritodrine.
They can cause -> tachycardia, palpitations, arrhythmias, pulmonary oedema,
hyperglycaemia and hypokalaemia.
They should be avoided in pregnant women with diabetes or heart disease.

2.Prostaglandin synthesis inhibitors

NSAIbs, like indomethacin, produce tocolytic effect by inhibiting prostaglandin
synthesis.
But they are not used because of adverse effects, such as premature closure of
ductus arteriosus with subsequent development of pulmonary hypertension.
These drugs can be used for relief of dysmenorrhoea, but not to delay labour.
Both beneficial and adverse effects of these drugs are due to inhibition of PG
synthesis.

UTERINE STIMULANTS (OXYTOCICS, ECBOLICS)

UTERINE STIMULANTS
(Oxytocics)

OXYTOCIN:
It is a hormone synthesized in the hypothalamus along with antidiuretic hormone
(AbH) and stored in neurohypophysis.
PHARMACOLOGICAL ACTIONS:

Supraoptic and paraventricular nuclei

Synthesis of the hypothalamus along with ADH

Contraction of the Contraction of myoepithelial cells of the

pregnant uterus female breast (milk ejection occurs)
 Uterus: Breast; Kidney; Cardiovascular system;
Oxytocin stimulates contraction of the Oxytocin Oxytocin (high Oxytocin (high doses)
pregnant uterus. contracts doses) -> ADH-like ^vasodilatation and
Uterine sensitivity to oxytocin is myoepithelial action -> decreased transient hypotension
increased by oestrogens and decreased cells of the urine output.
by progestins breast and -> reflex tachycardia
causes milk Water intoxication and flushing
Oestrogens increase oxytocin receptors. ejection. may occur if large
Mechanism of action; amount of fluids is
Oxytocin binds to specific G-proietn-coupied administered along
receptors on myometrium with oxytocin.
1

i
This leads to:
• Generation of IPi (inositol triphosphate)
• Release of CaJ k from intracellular stores
• Increased production of PGs by endometrium
l
Contraction of the pregnant uterus

USES;
Induction of labour: Postpartum haemorrhage Oxytocin (i.v. Intranasal oxytocin
Oxytocin is drug of choice for (PPH): Oxytocin is used infusion) is also used may be useful in
induction of labour. for prevention (i.m. or to increase intensity, breast
i.v. infusion) and frequency and engorgement.
It is administered by i.v. treatment (i.v. infusion) duration of uterine
infusion. of PPH. It contracts contractions, if they Oxytocin stimulates
The starting dose should be uterine smooth muscle are not adequate the myoepithelial
low and the rate of infusion is resulting in compression (uterine inertia), cells resulting in
monitored and adjusted of the blood vessels as during labour. milk let down.
according to response. they pass through the
myometrium - bleeding is It should not be used
During oxytocin infusion, arrested, to enhance uterine
uterine contractions, maternal has fewer side effects contractions, if
blood pressure (BP), fetal and than ergot derivatives labour is progressing
maternal heart rate should be and is preferred to them satisfactorily.
monitored . for prevention and
treatment of PPH.
 CHEMOTHERAPY

CLASSIFICATION OF ANTIMICROBIAL AGENTS

According to their type of action According to their spectrum of According to their

Bactericidal Bacteriostatic activity mechanism of action:
agents: agents Norrow- Brood - 1.Drugs that inhibit cell
spectrum spectrum wall synthesis
Penicillins Clindamycin Antibiotics antibiotics 2. Drugs that affect cell
Cephalosporins Chloramphenicol membrane function
Fluoroquinolones Dapsone Penicillin G Tetracyclines 3. Drugs that inhibit
Aminoglycosides Erythromycin Aminoglycosides Chloramphenicol protein synthesis
Rifampin Sulphonamides 4. Drugs that alter protein
Metronidazole Tetracyclines synthesis
NALI ME - BROAD - TC 5. Drugs that inhibit viral
PC -FARM CLOSE AAYE PEEVE DNA synthesis
DESD ( DEAD) 6. Drugs that affect DNA
function
7. Drugs that inhibit DNA
gyrase
8. Antimetabolites

Fig. 11.1 Classification of antimicrobials based on their mechanism at acton. PABA.

para-aminobenzoic add; DHFA. dihydrofdic acid; THFA, tetrahydrofdic add.

1.Inhibit cell wall syntesis 2. Affect cell 3.Inhibits protein 4 Drugs that alter protein
B lactam antibiotics - membrane function synthesis: synthesis by misreading of
Penicillins, cephalosporins, mRNA code ond premature
carbapenems, monobactams Polymyxins Tetracyclines termination of mRNA
Vancomycin Amphotericin -B Macrolides translation
Fosfomycin azoles Chloramphenicol
Bacitracin Clindamycin Aminoglycosides
Cycloserine Linezolid
aminoglycosides
5. Drugs that inhibit viral DNA 6.Drugs that 7. Antimetabolites 8.Drugs that inhibit DNA
synthesis affect DNA gyrase
function Sulphonamides
Acyclovir dapsone Fluoroquinolones (FQs)
Zidovudine Rifampin trimethoprim
rifabutin pyrimethamine
 B-LACTAM ANTIBIOTICS

P-Lactam antibiotics include penicillins, cephalosporins, carb openems and

monobactams.
All of them have a p- lactam ring in their chemical structure , hence the name -
lactam antibiotics.
0 c
II z\ CH,
1
R— C—NH— CH— CH
I B |
C<
A | CH,,
O=C — N— CH— COOH

A: Thiazolidine ring
Site of action of pencillinase B: |l-Lactam ring
Fig. 11.5 Structure Of penicillins.

PENICILLIN
Penicillin was the first antibiotic developed and used clinically.
It was discovered accidentally by Alexander Fleming.
PENICILLINS

f
Natural penicillin
Benzyl penicillin
(Penicillin C)

Acid-resistant
alternative to
penicillin G
I’henoxymcihyl
penicillin
(Penicillin V>

MECHANISM OF ACTION
p- Lactam antibiotics produce bactericidal effect by inhibiting cell wall synthesis in
susceptible bacteria.

Bacterial cell wall is composed of peptidoglycan which contains amino sugars, N-

acetylmuramic acid (NAM) and N- acetylglucosamine (NAG).
I
The enzyme, transpeptidase removes terminal alanine of one strand resulting in
its linkage with glycine of adjacent strand.
Cross -Iinking makes the cell wall rigid and stable.
0-Lactams, the structural analogues of d -alanine, inhibit transpeptidase, thus
inhibiting cross -linking of peptidoglycans and cell wall synthesis.
I
Cell wall-deficient farms are produced which undergo lysis (bactericidal action). -
there is an outer lipopolysaccharide layer.
Hence, gram negative organisms are less susceptible to penicillin than gram¬
positive organisms.

PHARMACOKINETICS :
Most of orally administered penicillin & is destroyed by gastric acid (acid labile);
hence, penicillin & is usually given by i.v. route.
It can also be administered by i.m. route but is painful.
Penicillin G is widely distributed in body tissues, but poorly crosses BBB, although
during meningitis, adequate amount reaches CSF.

Table 11.5 Characteristic features of preparations of penicillin G

Duration
Penicillin Route and dose of action Special features
1. Penicillin G i.v.. I.m. 4-6 hours Rapid onset of action, reaches
(benzyl penicillin, 20-24 million units high plasma concentration:
crystalline (MU) daily mainly used in severe
penicillin) -
infections meningitis,
endocarditis, pneumonia, etc.
2. Repository
penicillins
(depot penicillins)

• Procaine 600.000- 12-24 hours Moderate plasma concentration,

penicillin G 1.200,000 units used n mild- to- moderate
(0.6-1.2 MU) infections; less painful
i.m. daily because of procaine
component

• Benzathine 600.000- 3-4 weeks Slow onset but has longest

penicillin G 2.400.000 units duration of action among
(0.6-2.4 MU), penicillins. Used in syphilis,
i.m. once rheumatic fever prophylaxis,
a month etc.
• Fortified 300.000 units 12-24 hours Rapid onset with high plasma
procaine procaine concentration and longer
penicillin G penicillin G + duration of action; used in
100.000 units mild-to-moderate infections
penicillin G i.m. by sensitive organisms
Fig. 11.7 Preparations of pentcdltn G with their duration of action and plasma concentration.

adverse reactions:
Penicillins are relatively safe.
They may cause hypersensitivity reactions, such as skin rashes, urticaria, fever,
dermatitis, bronchospasm, angioedema, joint pain, serum sickness or anaphylactic
reaction.
The major manifestations of anaphylactic shock are severe hypotension, broncho
spasm and laryngeal oedema.

Treatment of Anaphylactic Shock

1. Inj. adrenaline 0.3-0. 5 mL of 1:1000 solution intramuscularly
2. Inj. hydrocortisone 200 mg intravenously
3. Inj. diphenhydramine 50-100 mg intravenously or intramuscularly

OTHER ADVERSE EFFECTS OF PENICILLINS are pain and sterile abscess at the
site of i.m. injection.
Prolonged use of i.v. penicillin 6 may cause thrombophlebitis.

JARISCH-HERXHEIMER REACTION:
It is an acute exacerbation of signs and symptoms of syphilis during penicillin
therapy due to release of endotoxins from 4 dead organisms.
The manifestations are fever, chills, myalgia, hypotension, circulatory collapse,
etc.
It is treated with aspirin and corticosteroids.

THERAPEUTIC USES OF PENICILLINS

1. Streptoccocal Infections.
Ampicillin and amoxicillin are effective for pharyngitis, sinusitis, otitis media,
bronchitis, etc., caused by S. pyogenes, S. pneu moniae and H. influenzae.
Among oral -lactams, amoxicillin is the most effective agent against penicillin -
sensitive and penicillin -resistant S. pneumoniae.

2. Urinary tract infection (UTI):

Fluoroquinolones are -> preferred Antimicrobial agents (AMA) for UTTs.
3 . Meningitis:
At present, third -generation cephalosporins along with vancomycin are drugs of
choice for treatment of meningitis caused by 5. pneumoniae or N. meningitidis, as
the organisms have developed resistance to ampicillin.

4. Bacillary dysentery:
FQs are drugs of choice.
Some cases may respond to ampicillin, but many strains have developed resistance
to it
5. Typhoid fever:
A FQ or ceftriaxone is drug of choice for typhoid.
Ampicillin, cotrimoxazole or ciprofloxacin is useful for eradicating carrier state.
6 Syphilis:
Penicillin G is the drug of choice for syphilis.
T. pallidum is very sensitive to penicillin and is killed at very low concentration of
the drug.

7.Diphtheria:
It is an acute infection of upper respiratory tract caused by C. diphtheriae.
It is treated mainly with the specific antitoxin. Penicillin G helps to eliminate
carrier state.

8. Clostridial infections (tetanus and gas gangrene):

The main treatment is neutralization of the toxin by using human tetanus
immunoglobulin. For gas gangrene, penicillin G is used as an adjunct to antitoxin.

9 . Gonococcal infections:
Penicillin was drug of choice for gonococcal infections.
10. Other infections:
Leptospirosis, anthrax, Lyme disease, actinomycosis, rat-bite fever, etc., are
effectively treated with penicillin G.

p- LACTAMASE INHIBITORS
They are clavulanic acid, sulbactam and tazobactam.
They structurally resemble p- lactam molecules.
(J -Lactamase inhibitors bind to P- lactamases and inactivate them.
Coadministration of these drugs with p-lactams increases -> activity of p-lactams
by preventing them from enzymatic destruction.
Clavulanic Acid -> It is isolated from Streptomyces clavuligerus .

It competitively and irreversibly inhibits p- lactamases produced by a wide range of

gram-positive and gram-negative bacteria.
After binding to the enzyme, clavulanic acid itself gets inactivated, hence called a
'suicide* inhibitor
 CEPHALOSPORINS
PH ARMACOKINETICS
Cephalosporins are administered either orally or parenterally.
These drugs are excreted mainly unchanged through kidney by either glomerular
filtration or tubular secretion.
Some cephalosporins are metabolized in body before their excretion.
Cefotaxime is deacetylated in -> body before its excretion.
Cef operazone is mainly excreted through bile.
CEPHALOSPORINS

Third generation Fourth generation

Oral Parenteral
Cefaclor Ccfuroxinw
Ccfuroximc Cefoxitin

CeffW/il |

Parenteral lrt generation:

Bhat hi jolly nature- cef azolin
Oral lw generation: delhi shift hue aulad ko hua droxy bimari -cefodroxil
Aulad ko leke hospital gye- cephalexin
India se ab daosri jagah gye
Parenteral 2nd gen:
india se bahar Europe gye- cefuroxime
Vha unka khan ani jama thin hogye -cefoxitin
Paisa ni kama paate the bas ten rupee milta tha-cefotetan
Oral 2"d generation: aulad bhi khush ni the ghumte ghumte paaji mile-cefprozil
3rd generation:
Parenteral-parents ne baccho ko peer chuna sikhaya: cefuperazone
Pr bacche ziddi the jokim uthake try kiya taxi m bithane ka- ceftazidime, ceftizoxime,
ceftriaxone, cefotaxime
Paste m beautiful ladki mili fix kiya dinner hotel podoximc m or baccho ki death hogai-
ceftibuten.cefdinir.cefpodoxime
A*1" generation
Parents udas hogye bacche gye unka pi pi khtm hogya ar shift hogye romc m:
cef ipine , cefpirome
5th generation:
Rome m naya role mila medicine dene ka:
Ceftaroline.ceftopirole medaoaril
 Table 11 9 । Antibacterial spectrum, pharmacokinetics and uses of cepfuta spoons
Cephalosporins First generation Second generation Third genera bon Fourth generation
1 Drugs • Ccphataxrt (O) * Cefaclor (Oj • Oeftxsnc(Cn • Cetopimo (i.v)
Ofadroiul (O| * Ceti jroxtme axelit (Of * Cetpodpxwne proveH tO) • Cefoirome
• Ofazdr li m i vj • CfHuroximoOjn , l v.) • CoftfHMOTGti.m I «1
I .
fi m iv)
• Cepbradiho (0, im„ i.vj • MnAti ILm., I v.) • Cefouwmo (i m , iv.)
• Oipiiatothin p m.) • Cofotetar (i m j • Cofopero^OfW(j ff Tn i v)
• Cdprazi (Of • Cefowdirnti m „ LvJ
(i m . LvJ
* Cefti2oxime
• Gelder O}
1 CefttUien (0)
2. Anttbact&nal
speclrun
• Agwst 4 ++ ++ + 4
gram positive
organrams (except
onttirococa
and MRSA)
• Agari&t + (E co*. K prMufTKrividtf} + 4 if K prXNsmOfMO. + ++ +++
gram negutive Proteus. H riflbonzw)
organtsnia
* Ai’iriHftXxri EFfudM} ornl cavity Effective agatrut anat-vobes E ifoct Ive agamst anaerobes deluding Noi dfoclne agamst
anaoroooj; uMCfltii nclud^g £ frugdrs B, (cofoponuCTie. H. frogti^
0JKT<y<Xtei' fragfa (evtetetsn, cefoxitin) ceftizosurne)
• Aganst Not effective Not effective Efface Ecefoperazone. cettazicbmei EHucirva (cetopmei
Pseuabmtxw
Agamst Not effective Not effective Effective (cettrtaxone. cefoperwone)
SaJmonefe
3. Among ihe fast generalion Cefoxitin and ceforojtima are Most of ihem are resistant to most of Same as ihrd
^ Lactamase
ervyme agents , cdazotai ta begNy nrastant to p fectamases the lactsmasps (excepl eoiopora generation
SUSCt^ifciC to StapiTyfo produced by gram zonal produced by gram rxfga^
coccai |i lactamases negative organisms orgardsrns
Cephalosporins First generation Second generation Third generation Fourth generation
4 Blood-brain bamer — Sonia of the second
genaratron drugs
Cefotaxime, ce^axorie emss 8B8 and Cross 8BB
Teach high concGHirLUion <1 CSF
(cekxoxime) cross B8B
& Uses 1. Skn and soft tissue 1 Hesptraiory tract ntsc TFwd- generation copnat<ispan-i£i atone Same aS Hurd
lilfecttonsi tkuj to lions Otitis media nnd cr with jinunD^ycosxteSi am used n generation
Strapicxwx* and -
SinuSltifi Orel cokxoxkno suvwh gram negalrve idled tons They am tosOrvfi
Sr^jyfococcus eunous iixtfm can be used 1 Pyakinepteflis caused by gran dfugh tor hosprlal
J Surgicai prophylaxis 2 Celontin and cfHOteiar negative organisms: Cottria^one acqurnd rasslant
Cetookn Isproferrsd .ve Dn?leni3d lor mixad 2 CoTTrnunity acqured pneumonia intocbona
because of its longer ^ram- negative bactena Cetlnaxone, cefoUxwrie
durabon of action and anaefcbes; nva- 3 . Gonorrhoea Cefttiuuis s the drug of
abdOTiinai and pehne chocs. 250 mg Lm. as a Mkje dose
nfectwns 4 T>pho-j fovw Gehriaxttoe and
coloparaions am vwy uffloctMi fcx
tne imaunent of m.Midrug-n>Sf slant
Saknono^r 'rrfocbons
& Memngilis caused by monngo^
coca and Maorwpivkjs rtfkjanzaa
lh. cafotaxkno and cefinaxono am
the iMdurrod ckugs
6 Mwtl phobic and antwobtc rtuc
tmi wr npdmtu wrtn
7 Septicaemia caused by (ram
nog^iwe rtoctocia

ADVERSE EFFECTS
1. Hypersensitivity:
The most common adverse effects are allergic reactions.
They are skin rashes, urticaria and rarely anaphylaxis.
Cross-reactivity to penicillin is seen in few patients.
2. 61 disturbances mainly diarrhoea, vomiting and anorexia can also occur.
3. Pain at site of i.m. injection mainly with cephalothin.
Intravenous cephalosporins can cause thrombophlebitis.
4. Nephrotoxicity is also seen, particularly with cephaloridine, because of which it
has been withdrawn. Coadministration of cephalothin and gentamicin increases the
risk of nephrotoxicity.
5. Severe bleeding can occur due to either hypoprothrombinaemia (which responds
to vitamin K therapy) or thrombocytopenia and/or platelet dysfunction, especially
in patients with renal failure.
 AMINOGLYCOSIDES
They include streptomycin, gentamicin, tobramycin, amikacin, kanamycin, sisomicin,
neomycin, framycetin, netilmicin and paromomycin.
SYSTEMIC TOPICAL
Streptomycin Neomycin
Gentamycin Framycetin
Kanamycin
Amikacin
tobramycin

MECHANISM OF ACTION
Aminoglycosides are bactericidal agents - inhibit protein synthesis.
Entry of aminoglycosides into bacterial cell (Ch is required)

Bind to 3OS ribosomal subunit

1
Inhibit initiation Cause misreading of codon
of protein synthesis |_

Premature termination of Insertion of wrong amino acid

protein synthesis into the growing peptide chains

Formation of defective proteins

Incorporation of defective proteins into bacterial cell membrane

Altered permeability and disruption of cell membrane (bactericidal effect)

THERAPEUTIC USES OF GENTAMICIN AND OTHER AMINOGLYCOSIDES;

Among aminoglycosides, gentamicin is most commonly used because it is cheap and
-
effective against most of aerobic gram negative bacilli.

1. Severe aerobic gram-negative bacillary infections

Urinary tract infection with pyelonephritis, Pneumonia, Meningitis, Osteomyelitis
Due to Pseudomonas, Klebsiella, Septicaemia E. coli, Proteus, etc.
Peritonitis Infected burns Gentamicin, tobramycin, amikacin ond netilmicin are
effective against P. aeruginosa.

2. Bacterial endocarditis due to S. viridans and Enterococcus :

Gentamicin is used in combination with a penicillin or vancomycin
Combination broadens -> spectrum of activity, produces synergistic effect and
decreases emergence of resistance.
3. TB: Streptomycin, kanamycin and amikacin are used in the treatment of TB.
4. Other gram-negative infections Plague:
Streptomycin/gentamicin is used intramuscularly.
Brucellosis; Streptomycin/gentamicin is used in combination with doxycycline.
 AMINOGLYCOSIDES
They include streptomycin, gentamicin, tobramycin, amikacin, kanamycin, sisomicin,
neomycin, framycetin, netilmicin and paromomycin.
SYSTEMIC TOPICAL
Streptomycin Neomycin
Gentamycin Framycetin
Kanamycin
Amikacin
tobramycin

MECHANISM OF ACTION
Aminoglycosides are bactericidal agents - inhibit protein synthesis.
Entry of aminoglycosides into bacterial cell (Ch is required)

Bind to 3OS ribosomal subunit

1
Inhibit initiation Cause misreading of codon
of protein synthesis |_

Premature termination of Insertion of wrong amino acid

protein synthesis into the growing peptide chains

Formation of defective proteins

Incorporation of defective proteins into bacterial cell membrane

Altered permeability and disruption of cell membrane (bactericidal effect)

THERAPEUTIC USES OF GENTAMICIN AND OTHER AMINOGLYCOSIDES;

Among aminoglycosides, gentamicin is most commonly used because it is cheap and
-
effective against most of aerobic gram negative bacilli.

1. Severe aerobic gram-negative bacillary infections

Urinary tract infection with pyelonephritis, Pneumonia, Meningitis, Osteomyelitis
Due to Pseudomonas, Klebsiella, Septicaemia E. coli, Proteus, etc.
Peritonitis Infected burns Gentamicin, tobramycin, amikacin ond netilmicin are
effective against P. aeruginosa.

2. Bacterial endocarditis due to S. viridans and Enterococcus :

Gentamicin is used in combination with a penicillin or vancomycin
Combination broadens -> spectrum of activity, produces synergistic effect and
decreases emergence of resistance.
3. TB: Streptomycin, kanamycin and amikacin are used in the treatment of TB.
4. Other gram-negative infections Plague:
Streptomycin/gentamicin is used intramuscularly.
Brucellosis; Streptomycin/gentamicin is used in combination with doxycycline.
ADVERSE EFFECTS:
1 . Ototoxicity;
Vestibular and cochlear dysfunctions can occur due to VIII cranial nerve damage.
Aminoglycosides get concentrated in the perilymph and endolymph of the inner ear
which can lead to progressive damage to vestibular and cochlear hair cells.
Streptomycin and gentamicin mainly affect vestibular function.
2. Nephrotoxicity:
Aminoglycosides get concentrated in renal cortex and produce nephrotoxicity,
which is usually reversible on discontinuation of drug.
The incidence of nephrotoxicity is highest with neomycin and least with
streptomycin.
3 . Neuromuscular blocking effect:
Apnoea and muscular paralysis have been reported.
It may be reversed by administration of calcium salt.
Aminoglycosides inhibit release of acetylcholine from -> motor nerve.
Myasthenic patients are more susceptible to neuromuscular blocking effect of
these drugs; hence, they should be avoided.
4. Hypersensitivity reactions are rare: occasionally skin rashes, drug fever and
eosinophilia can occur. Cross-sensitivity between aminoglycosides may occur.

5. Use of aminoglycosides during pregnancy may cause ototoxicity in fetus.

TETRACYCLINES

Tetracyclines

1“ GENERATION 2nd GENERATION

3'd GENERATION
l)Tetracydine 1) Doxycycline 1) Tigecycline
2)Oxytetracycline 2) Minocycline 2) Oniadacycline
3) Chlortetracycline 3) Lymecycline 3) Sarecydine
4) Eravacycline
4)Demeclocydine

Mechanism of Action
Actively taken up by Bind reversibly to
Tetracyclines —
susceptible bacteria SOS ribosomal subunit

Prevent
I
binding of aminoacyl tRNA to
mRNA-ribosome complex

Inhibit bacterial protein

I
Prevent the addition of amino acid
synthesis (bacteriostatic) to the growing peptide chain
PHARMACOKINETICS!
The absorption of tetracyclines is reduced by simultaneous administration with
dairy products, antacids, iron, sucralfate and zinc salts.
Tetracyclines are widely distributed throughout -> body, and get concentrated in
liver, spleen, bone, dentine, enamel of unerupted teeth but concentration in CSF is
relatively low.
They cross placental barrier, and are metabolized in liver and excreted in urine.
Doxycycline is excreted mainly in faeces via bile.
Therefore, doxycycline is safe for use in patients with renal insufficiency.
Doxycycline undergoes enterohepatic cycling.

THERAPEUTIC USES
1. Rickettsial infections:
Tetracyclines are first-choice drugs far treatment of rickettsial infections -
epidemic typhus. Rocky Mountain spotted fever, scrub typhus, rickettsial pox and
Q fever.

2. Mycoplasma pneumoniae infections:

Doxycycline has good activity against Mycoplasma - used ta shorten the duration
of illness. It is a first choice drug in atypical pneumonia due to M. pneumoniae

3. Chlamydial infections Lymphogranuloma venereum:

It is a sexually transmitted infection caused by C. trachomatis.
Doxycycline is drug of choice.
In complicated cases (i.c. pelvic inflammatory disease), doxycycline 100 mg b.d.
should be continued for 21 days.

4. Cholera:
Fluid and electrolyte replacement is mainstay of therapy.
Single dose of tetracycline 2 g or doxycycline 300 mg is effective in adults.
It reduces -> stool volume.

5. Brucellosis:
Treatment of choice is a combination of doxycycline with rifampin/
gentamicin/streptomycin.

6. Plague:
Doxycycline is highly effective for treatment of plague.

7. As an alternative drug:
For treatment of leptospirosis (doxycycline is an alternative to penicillins),
pneumonia due to Chlamydia pneumoniae (doxycycline alternative to azithromycin),
tularaemia (alternative to streptomycin, gentamicin), etc.
8. Acne:
Low doses of tetracyclines are used.
ADVERSE EFFECTS:
1. GI:
On oral administration, they can cause GI irritation manifested as nausea,
vomiting, epigastric distress, abdominal discomfort and diarrhoea.
Diarrhoea is more common with tetracycline and oxytetracycline as they are
incompletely absorbed n cause alteration of normal flora.

2. Phototoxicity:
It is particularly seen with demeclocycline and doxycycline
They may also produce sunburn-like reaction in -> skin on exposure to sunlight.
They may also produce pigmentation of nails.

3. Hepatotoxicity:
Acute hepatic necrosis with fatty changes is common in patients receiving high
doses ( 2 g/day) intravenously. It is more likely to occur in pregnant women.

4. Renal toxicity:
Demeclocycline may produce nephrogenic diabetes insipidus by blocking action of
antidiuretic hormone (ADH) on collecting duct.
FANCONI SYNDROME Use of outdated tetracyclines may damage proximal renal
tubules - the patient may present with nausea, vomiting, polyuria, proteinuria,
acidosis, etc.

5. Effects on bones and teeth:

Tetracyclines have calcium chelating property and form tetracycline-calcium
orthophosphate complex which is deposited in growing bone and teeth.
Use of tetracyclines in children and during pregnancy can cause permanent
brownish discolouration of deciduous teeth due to deposition of chelate in the
teeth.

6.They may cause increased intracranial pressure (pseudotumour cerebri) in

infants.

/.Hypersensitivity reactions: Skin rashes, fever, urticaria, exfoliative dermatitis,

etc., may occur rarely. Cross -sensitivity among tetracyclines is common.
 CHLORAMPHENICOL

Chloramphenicol, a broad -spectrum antibiotic

Mechanism of Action

r
u i
Chloramphenicol *=>
Binds
r„_ ., . .
reversibly to
.
50S ribosomal subunit =
_
=>
Prevents the Inhibits
formation of «=> protein
peptide bond synthesis

PHARMACOKINETICS:
Chloramphenicol is commonly given by oral route and is rapidly absorbed from gut.
It is also available for parenteral and topical administration.
It has a bitter taste; to improve the taste, chloramphenicol palmitate suspension
has been developed for paediatric use.
It gets activated in intestine by pancreatic lipase
Chloramphenicol is widely distributed to all tissues including CSF and brain.
It also crosses placental barrier and is secreted in milk.
It gets metabolized in liver by glucuronide conjugation and metabolite is excreted
mainly in urine

THERAPEUTIC USES
1. Typhoid fever:
Chloramphenicol was the first-choice drug for typhoid.
Antibiotics useful in typhoid are third-generation cephalosporins.

2. Bacterial meningitis:
Third -generation cephalosporins are the preferred drugs for the treatment of
bacterial meningitis caused by H. influenzae, N. meningitidis and S. pneumoniae.
However, chloramphenicol can be used alone or in combination with ampicillin.

3. Anaerobic infections:
Chloramphenicol is effective against most anaerobic bacteria including B. fragilis.
It is often used in combination with metronidazole for the treatment of brain,
lung, intra -abdominal ar pelvic abscesses.

4. Rickettsial infections:
Tetracyclines are -> drugs of choice for the treatment of rickettsial diseases.

5. Eye and ear infections:

Chloramphenicol is used topically for eye and ear infections due to susceptible
organisms.

6. Brucellosis:
Chloramphenicol can be used when tetracyclines are contraindicated.

ADVERSE EFFECTS:
1. Hypersensitivity reactions:
Skin rashes, drug fever and angioedema may occur rarely.
2. Bone marrow suppression:
The most serious adverse effect of chloramphenicol is on bone marrow.
It can occur in two ways:
(a) Dose -dependent reversible suppression of bone marrow, which manifests as
anaemia, leucopenia and thrombocytopenia
(b) Idiosyncratic non -dose -related irreversible aplastic anaemia, which is often

3. 61 effects:
These include nausea, vomiting and diarrhoea.
Prolonged use may cause superinfection -> due to suppression of gut flora.

4. Gray baby syndrome:

In neonates, especially in premature babies, chloramphenicol can cause a dose-
related gray baby syndrome due to reduced degradation and detoxification of the
drug in liver because of the deficiency of glucuronyl transferase enzyme

The manifestations are nausea, vomiting, abdominal distension, diarrhoea, refusal

to suck, cyanosis, irritability and circulatory collapse.
The skin appears ashen gray colour, hence the name 'gray baby' syndrome.
Mortality is high. Therefore, chloramphenicol should be avoided in neonates
 MACROLIDES

| Clnwificution of Macrolides

Older Macrolides Newer Macrolides

1.9 AMAs inhibit proIein synlhesis by binding to alter SOS or SOS ribosomal subunit.
> Erythromycin •Roxithromycin
•Clarithromycin Penidflins Bacitracin
Azithromycin
Cephalosporins Celt wall Vancomycin
•Spiramycin synthesis
inhibitors
Carbapenerm (bactericidal) Teicoplantn

Monobacrams
Fig. 11.10 AMAs that inhibit bacterial cel waB synthesis.

MECHANISM OF ACTION
Erythromycin and other macrolides bind to bacterial 50S ribosomal subunit and
inhibit protein synthesis.
They are bacteriostatic, but at high concentrations, they can act as bactericidal
agents.
They are more active at alkaline pH.

PHARMACOKINETICS
Erythromycin is adequately absorbed from -> upper GI tract.
It is destroyed by gastric acid (acid labile), hence must be administered as
Enteric -coated tablets to protect it from gastric acid.
Food may delay -> absorption of erythromycin
It is widely distributed inbody and reaches therapeutic concentration in prostatic
secretions but does not cross BBB.
It is partly metabolized in liver and excreted in bile.

ADVERSE EFFECTS
1. The common side effects are related to GI tract (Enteral toxicity):
Nausea, vomiting, epigastric pain and diarrhoea.
Erythromycin increases GI motility by stimulating motilin receptors in gut.

2 . Hypersensitivity reactions :
Skin rashes, drug fever, eosinophilia and hepatitis with cholestatic jaundice,
particularly with erythromycin estolate.
Incidence of hepatotoxicity is more in pregnant women.
 SULFONAMIDES
SULFONAMIDES

Sulphonamides

I
Systemic-acting agents Local-acting agents
J
Others
• Sulphacctamidc Sulphasalazinc
• Silver sulphadiazine (acts both locally and
• Mafcnide systemically)

Short-acting Intermediate-acting Long-

Iacting
(4-8 h) (8-12 h) (>7 days)
Sulphadiazine Sulphamethoxazole Sulphadoxine

MECHANISM OF ACTION
Prmi-aminobenzoic acid

Sulphonamides -—— Folate synthetase

Dihydrofolic acid

Folate reductase

Tetrahydrofolic acid
para- Aminobenzoic acid (PABA) is a precursor of folic acid which is essential for
growth and multiplication of many bacteria.
Sulphonamides, being structurally similar to PABA, competitively inhibit folate
synthase enzyme and prevent the formation of folic acid, thereby producing
bacteriostatic effect.
PHARMACOKINETICS:
All systemic -acting sulphonamides are well absorbed from -> gut
They are bound to plasma proteins, particularly albumin.
Sulphonamides are distributed in almost all tissues of the body including CSF.
They cross placental barrier and reach fetal circulation; they are metabolized in
liver mainly by acetylation.
The acetylated products have no antibacterial activity but retain the toxic
potential of the parent compound.
Sulphonamides are excreted partly unchanged and partly as metabolic products.
ADVERSE EFFECTS:
1. The acetylated products of sulphonamides are poorly soluble in acidic urine and
may cause crystalluria, haematuria or even obstruction to urinary tract.
This may be avoided by taking plenty of water and alkalinizing -> urine.

2. Hypersensitivity reactions include skin rashes, itching, drug fever and

exfoliative dermatitis.
Stevens-Johnson syndrome is the most severe type of hypersensitivity reaction
characterized by fever, erythema multiforme and ulceration of mucous membranes

3. In patients with glucose-6- phosphate dehydrogenase deficiency, sulphonamides

may cause acute haemolytic anaemia.

4. Rarely cause hepatitis and suppression of bone marrow.

5. Use of sulphonamides in neonates, especially in premature babies, may cause

displacement of bilirubin from plasma proteins.
The free bilirubin can cross BBB and get deposited in the basal ganglia resulting in
kernieterus .

THERAPEUTIC USES:
1. Sulphadaxine and pyrimethamine are used in combination with artesunate in the
treatment of chloroquine- resistant Plasmodium falciparum malaria.

2. Sulphadiazine and pyrimethamine combination is the drug of choice for

toxoplasmosis.

3. Nocardiosis: Sulphamethoxazole in combination with trimethoprim is used

4. Sulphamethoxazole in combination with trimethoprim is used in the treatment of

P. jiroveci infection in patients with AIDS.

5.Sulphasalazine is useful in treatment of inflammatory bowel disease and

rheumatoid arthritis.

6.Rheumatic fever: Sulphadiazine can be used for prophylaxis of rheumatic fever

 COTRIMOXAZOLE
Mechanism of Action

Rnni-aminobenzoic acid (PABA)

| Folate synthetase <- Q Sulphamethoxazole

Dihydrofolic acid (DHFA)

| Dihydrofolate reductase

Tetrahydrofolic acid (THFA)

G Trimethoprim

Cotrimoxazole (sulphamethoxazole and trimethoprim in a dose ratio of 5:1)

produces sequential blockade, i.e. two drugs interfere with two successive steps in
the same metabolic pathway, hence, their combination produces supra -additive
effect.

Sulphamethoxazole inhibits folate synthetase, whereas trimethoprim inhibits folate

reductase enzyme.
The pharmacokinetic properties of these two drugs match each other almost
closely, hence are selected for combination.
They have similar half -lives.

The advantages of this combination are the following;

1. Individually, both are bacteriostatic but the combination has cidol effect.
2. Chances of development of bacterial resistance is greatly reduced.

PHARMACOKINETICS:
Cotrimoxazole is well absorbed after oral administration and is also available for
parenteral use, widely distributed to venous tissues including CSF and sputum,
metabolized in liver and excreted mainly in urine; hence, dose reduction is needed
in patients with renal insufficiency.

ADVERSE EFFECTS:
Cotrimoxazole is well tolerated in most patients.
Most of adverse effects are same as those of sulphonamides.
The common adverse effects are skin rashes A gastrointestinal (GI) disturbances.
Exfoliative dermatitis, erythema multiforme and Stevens Johnson syndrome are
rare.

GI symptoms include nausea, vomiting, glossitis and stomatitis.

Megaloblastic anaemia due to folate deficiency may occur rarely, especially in
alcoholics and malnourished persons.
Bone marrow suppression with leucopenia, neutropenia and thrombocytopenia occurs
rarely .
Cotrimoxazole is contraindicated in pregnancy.
Table 11.3 Preparations of cotrimoxazole
Strength of cotrimoxazole Preparations
Sulphamethoxazole 400 mg + trimethoprim 80 mg Oral. i.v.
Sulphamethoxazole 800 mg + trimethoprim 160 mg Double strength (DS); oral. i.m.
Sulphamethoxazole 200 mg + trimethoprim 40 mg Oral suspension
Sulphamethoxazole 100 mg + trimethoprim 20 mg Paediatric tablet

THERAPEUTIC USES
1 Urinary tract infection (UTI):
.
Cotrimoxazole is effective for treatment of acute uncomplicated lower UTIs due
to gram-negative organisms such as E coli, Proteus and Enterobacter spp.
The usual dose is 800 mg sulphamethoxazole plus 160 mg of trimethoprim
(cotrimoxazole daub Ie -strength tablet) b.d. for 3 days.

2. Respiratory tract infections:

Cotrimoxazole is useful for acute and chronic bronchitis due to H. influenzae and
Moraxella catarrhalis.
It is also useful for acute maxillary sinusitis and otitis media

3. Bacterial diarrhoeas:
Cotrimoxazole may be used for infections due to Shigella, E. coli and
Salmonella spp. But FQs are the preferred agents.

4 . Pneumocystis jiroveci infection:

High doses of cotrimoxazole are used for treatment of infection due to P. jiroveci
in immunocompromised patients.

5. Nocardiosis:
Cotrimoxazole has been used in treatment of infection due to Nocardia

6 . Chancroid:
The drug of choice is azithromycin. Cotrimoxazole is equally effective.
The alternative drugs are ceftriaxone and ciprofloxacin.

7. Typhoid fever :
Fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin, etc.) or third -generation
cephalosporins (ceftriaxone and cefoperazone) are the treatment of choice for
typhoid fever. Cotrimoxazole may also be effective.
 QUINOLONES AND FLUOROQUINOLONES
The first quinolone, nalidixic acid, is a urinary antiseptic.
It is effective against gram- negative bacteria including E. coli, Proteus,
Klebsiella, Enterobacter, Salmonella and Shigella, but not Pseudomonas.

It is useful in treatment of uncomplicated UTT due to gram- negative bacteria and

diarrhoea due to Shigella or Salmonella.
The most common adverse effects are related to &I tract, central nervous system
(CNS) and skin.
Fluoroquinolones (FQs) are synthetic, fluorinated analogues of nalidixic acid.
Mechanism of Action

DNA gyrase (topoisomerase II) in Topoisomerase IV in

gram-negative bacteria gram-positive bacteria

Nicking, formation Nicking and separation of daughtei

of negative supercoils and DNA strands following
resealing of strands of DNA DNA replication
FQs inhibit bacterial DNA synthesis (bactericidal).
They inhibit DNA gyrase, thus blocking DNA replication in gram-negative bacteria
Inhibition of topoisomerase IV in gram-positive bacteria prevents separation of
replicated DNA

PHARMACOKINETICS;
Ciprofloxacin is administered by oral. i.v. or topical routes.
It is well absorbed from the gut, but food delays its absorption.
It is widely distributed in the body, and reaches high concentration in kidney,
lung, prostatic tissue, bile, macrophages, etc.
It is excreted mainly in urine.

ADVERSE EFFECTS:
The common adverse effects are related to &I tract, e.g. nausea, vomiting and
abdominal discomfort.
CNS effects include headache, dizziness, insomnia, confusion, hallucinations and
convulsions.
Hypersensitivity reactions include skin rashes, urticaria, itching, eosinophilia and
photosensitivity.
FQs have caused cartilage damage in immature animals - hence, they should be
avoided in young children.

USES OF FLUOROQUINOLONES :
1. UTT:
FQs ore one of most commonly used AM As for UTT.
They are effective against gram -negative bacilli, such as E. coli, Proteus and
Enterobacter.
2. Prostatitis; FQs are used in prostatitis as an alternative to cotrimoxazole

3. Bacterial diarrhoeas:
FQs are effective for a variety of 61 infections caused by E. coli, Shigella,
Salmonella, etc.
For traveller's diarrhoea (due to E. coli), FQs are as effective as cotrimaxazoie .

4. Typhoid fever:
Ciprofloxacin (750 mg orally b.d. for 10 days) is -> preferred drug for treatment
of typhoid.
It is bactericidal and causes rapid resolution of symptoms.
Levofloxacin or ofloxacin con also be used.

5. Sexually transmitted diseases Gonococcal infections:

FQs were effective for treatment of cervicitis and urethritis caused by N.
gonorrhoea® but their use has declined because of high rates of resistance.

6. Skin, soft- tissue and bone infections

due to S. aureus and gram -negative bacilli require prolonged antimicrobial therapy.
FQs can be used in combination with an agent effective against anaerobes
especially in diabetic foot infections.

7. Ciprofloxacin can be used to eradicate meningococci from nasopharynx, thus

eliminating the carrier state, but the preferred drug is rifampin.

8. Mycobacterial infections:
In MDR-TB, atypical mycobacterial infections, MAC infection in AIDS patients and
leprosy, FQs are used in combination with other AM As.

9 . Prophylaxis and treatment of infections in neutropenic patients:

10. Ciprofloxacin, levofloxacin, moxifloxacin and ofloxacin are used topically for
conjunctivitis due to susceptible organisms.

11. Respiratory infections:

Newer FQs (levofloxacin and moxifloxacin) are highly effective for community -
acquired pneumonia and chronic bronchitis.

12. Anthrax:
Ciprofloxacin is preferred drug for treatment and prophylaxis of anthrax.
 ANTTTUBERCULOSIS DRUGS
ANTITUBERCULAR DRUGS

First line drugs Second line drugs

Isoniazid 1
Rifampin
Pyrazinamide Fluoroquinolones | Other Ori drugs Injectable drugs
Ethambutul Ofloxacin Ethionamide Kanamycin
Streptomycin Iz’v ofloxacin Prolhionamide Amikacin
Muxifloxacin Cycloserine Capreomycin
Ciprofloxacin Terizidone
Paraamino*
salicylic acid (PAS)
Rifabutin
Thiacctazune

Table 11.15 i First line antituberculosis drugs and their daily doses WHO 2010 guidelines)
Drug Daily dose (mg/kg)
Isoniazid (H) 5 (4-6)
Rifampin (R) 10 (8-12)
PyraztnEHnide (Z) 25 (20-30)
Ethambutol (E) 15(15-20)
Streptomycin (S) 15(12-18)

1.ISONIAZID (Isonicotinic Acid Hydrazide [INH])

MECHANISM OF ACTION:
Isoniazid inhibits biosynthesis of mycolie acids, which are essential constituents of
the mycobacterial cell wall.
Inhibits the
Inside , . f
Isoniazid mycobactcna^ converted to , mycolic acids , s bactern
(Prodrug) active form (components of ;TubercUlneidal)
mycobacterial
cell wall)

PHARMACOKINETICS:
INH is readily absorbed from the gut, distributed well all over the body,
tubercular cavities and body fluids like CSF, and also crosses placental barrier.
It is metabolized by acetylation and the metabolites are excreted in urine.

USES:
Isoniazid (INH) is a first- line drug for the treatment of TB.
It is also used for chemoprophylaxis of tuberculosis.
ADVERSE EFFECTS
1.Hepatotoxicity:
The risk of hepatic damage is more in chronic alcoholics, elderly patients and rapid
acetylators.
It is reversible on discontinuation of drug.
Patients receiving INH should be monitored for symptoms like anorexia, nausea,
vomiting and jaundice.

2. Peripheral neuritis:
It is a dose-related toxicity.
Isoniazid is structurally similar to pyridoxine; hence, INH competitively interferes
with utilization of pyridoxine.

3. Other side effects are fever, skin rashes, arthralgia, anaemia, 61

disturbances, psychosis and rarely convulsions.

2 RIF AMPIN (RIFAMPICIN)

Rifampin is a derivative of rifamycin and is a first -line antitubercular drug.
It rapidly kills intracellular and extracellular bacilli including spurters
(those residing in caseous lesion).
MECHANISM OF ACTION:
Rifampin binds to bacterial DNA -dependent RNA polymerase and inhibits RNA
synthesis.
It has bactericidal effect against mycobacteria, N. meningitidis, H. influenzae, S.
aureus, E. coli, Pseudomonas, etc. Pharmacokinetics.

It is given orally and is rapidly absorbed from the 61 tract but presence of food
reduces its absorption; it is distributed widely throughout the body and gets
metabolized in liver.

USES:
1. Tuberculosis:
Rifampin is used along with INH and other antitubercular drugs for the treatment
of TB.
It is also used for chemoprophylaxis of tuberculosis.
2. Leprosy
3. Prophylaxis of meningococcal and H. influenzae meningitis:
Rifampin reaches high concentration in the nasopharynx and eradicates the carrier
state in case of meningococcal and H. influenzae infections.

4. Rifampin, in combination with 0- lactam antibiotics, may be useful in

staphylococcal infections, such as endocarditis and osteomyelitis.

5. Rifampin is used with doxycycline for the treatment of brucellosis.

ADVERSE EFFECTS
1 . Hepatitis is main adverse effect - the risk of hepatotoxicity is more in
alcoholics and elderly patients.
2. Flu -like syndrome with fever, chills, headache, muscle and joint pain.
3. 61 disturbances, such as nausea, vomiting and abdominal discomfort.
4. Skin rashes, itching and flushing.

3.PVRAZINAMIDE
Pyrazinamide is a synthetic analogue of nicotinamide.
It is active in acidic pH - effective against intracellular bacilli (has sterilizing
activity).
It has tuberculocidal activity.
pyrazinamide inhibits mycobacterial mycolic acid biosynthesis but by a different
mechanism.
It is given orally, absorbed well from the 61 tract and distributed widely
throughout the body including CSF.
It is metabolized in liver and excreted in urine.

ADVERSE EFFECT of pyrazinamide is dose -dependent hepatotoxicity

The other side effects are anorexia, nausea, vomiting, fever and skin rashes.

4.ETHAMBUTOL
It is a first-line antitubercular drug.
It inhibits arabinosyl transferases that are involved in mycobacterial cell wall
synthesis.
It is a bacteriostatic drug.
It is used in combination with other antitubercular drugs to prevent emergence of
resistance and for faster sputum conversion.
Ethambutol is well absorbed after oral administration, is distributed widely in the
body, is metabolized in liver, crosses BBB in meningitis and is excreted in urine.

ADVERSE EFFECT
Optic neuritis is the main adverse effect seen with ethambutol, which is
characterized by decreased visual acuity and colour vision defects (red-green).
Other side effects are nausea, vomiting, abdominal pain, skin rashes, itching and
joint pain.

5. Streptomycin:
Streptomycin is on aminoglycoside antibiotic.
It is a bactericidal drug. It is active against extracellular bacilli in alkaline pH.
Streptomycin is not effective orally; it must be injected intramuscularly.
The adverse effects are ototoxicity, nephrotoxicity and neuromuscular blockade.
TREATMENT OF TUBERCULOSIS:
WHO recommends -> use of MDT for alt cases of TB.
The objectives of MDT are as follows:
1. To make the patient non- infectious as early as possible and decrease
transmission of disease
2. To prevent the development of drug -resistant bacilli
3. To prevent relapse
4. To reduce total duration of effective therapy

RNTCP 2016 GUIDELINES FOR TREATMENT REGIMENS IN DRUG-SENSITIVE

TUBERCULOSIS
Type of patient Intensive phase (IP) Continuation phase (CP)
New patients 2 HRZE 4 HRE
Previously treated patients 2 HRZES + 1 HRZE 5 HRE

Tlie prefix number before a regimen indicates the number of months of treatment H. isoniazid: R.
rifampin: Z. pyrazinamide: E, ethambulol: S. streptomycin: RNTCP, Revised National Tuberculosis
Control Programme.

Dose of fixed dose combinations (FDCs) of first-line antituberculosis drugs and

streptomycin for adults
Number of FDCs Number of FDCs
Body weight (kg) of HRZE“ of HREb Streptomycin (g)
25-39 2 2 0.5
40-54 3 3 0.75
55-69 4 4 1
≥70 5 5 1

Drug Resistance
Monoresistance The bacilli are resistant to only one first-line anti-TB drug
Polydrug resistance The bacilli are resistant to more than one first -line anti-TB drug
but not both INH and rifampin
MDR The bacilli are resistant to both isoniazid and rifampin with or
without resistance to any other first-line aiti-TB drugs
XDR A MDR-TB case with bacilli being additionally resistant to
a fluoroquinolone or second line injectable anti-TB drug
(amikacin, kanamycin/capreomycin)

MULTIDRUG-RESISTANT TUBERCULOSIS
MDR-TB can be treated by either standard or individualized regimens.
Drug sensitivity testing should be done for all patients.
Patients with or highly likely to have MDR-TB should be treated with regimens
containing at least four drugs to which organisms are known or presumed to be
susceptible.
Pyridoxine should also be administered to patients with MDR-TB to prevent
neurotoxicity due to ethionamide, cycloserine, etc,
Standard treatment regimen for MDR-TB
Intensive phase (6-9 months) Continuation phase (18 months)
Kanamycin, levofloxacin, ethionamide, Levofloxacin, ethionamide, ethambutol,
cycloserine, pyrazinamide, ethambutol cycloserine + pyridoxine 100 mg/day
+ pyridoxine 100 mg/day

CHEMOPROPHYLAXIS OF TUBERCULOSIS
It is prophylactic use of antitubercular drugs to prevent the development of active
TB in patients who are at risk.
INH 300 mg (10 mg/kg in children) is administered daily for 6 months.
INDICATIONS FOR CHEMOPROPHYLAXIS
1. Newborn of a mother with active TB
2. Young children (younger than 6 years) with positive tuberculin test
3 Household contacts of patients with TB
4. Patients with positive tuberculin test with additional risk factors, such as
diabetes mellitus, malignancy, silicosis and AIDS

ANTILEPROTIC DRUG
Leprosy is a chronic infectious disease caused by M. leprae, which is an acid -fast
bacillus.
DAPSONE a sulphone, is oldest, cheapest and most widely used agent for the
treatment of leprosy even today.
ANTILEPROTIC DRUGS

MECHANISM OF ACTION:
Sulphones are chemically related to sulphonamides and have same mechanism of
action.
Lepra bacilli utilize PABA for -> synthesis of folic acid, which, in turn, is
necessary for its growth and multiplication.
Dapsone is structurally similar to PABA, hence competitively inhibits folate
synthetase enzyme and prevents the formation of TUFA. Thus, dapsone produces
leprostatic effect.

Punpaminobenzoic acid

Dapsone ———* Folate synthetase

Dihydrofolic acid

Dihydrofolale reductase

Tetrahydro folic acid

 PMARMACOKINETICS:
Dapsone is given orally and is almost completely absorbed from the gut; it is bound
to plasma proteins, widely distributed in the body and concentrated mainly in the
infected skin, muscle, liver, kidney, etc.
It is partly secreted in bile and undergoes enterohepatic cycling.
Dapsone is metabolized by acetylation and metabolites are excreted in urine.

ADVERSE EFFECTS:
The common adverse effects are dose-related haemolytic anaemia particularly in
patients with G6PD deficiency.
Other side effects are anorexia, nausea, vomiting, fever, headache, allergic
dermatitis, itching and peripheral neuropathy.
Methaemoglobinaemia can also occur.

CHEMOTHERAPY OF LEPROSY :
The WHO recommends the use of MOT for all leprosy cases.
The National Leprosy Eradication Programme (NLEP) has implemented the guidelines
for treatment.

The objectives and need for MOT are as follows:

1 . To make patient noncontagious as early as possible by killing the dividing bacilli
2. To prevent -> development of drug- resistant bacilli
3. To prevent relapse
4. To shorten the duration of effective therapy

TREATMENT SCHEDULES OF LEPROSY

All drugs ore administered orally.
For MBL (LL, BL and BB) For PBL (TT, BT and I) Alternative regimens
Rifampin 600 mg once monthly Rifampin 600 mg once monthly Clofazimine any two newer
(supervised) (supervised) drugs (minocycline, ofloxacin,
Dapsone 100 mg daily (self- Dapsone 100 mg daily (self¬ clarithromycin, etc.) daily for 6
administered) administered) months followed by clofazimine
ofloxacin/minocycline daily for
Clofazimine 300 mg once monthly The duration of treatment is another 18 months
(supervised) 6 months
Clofazimine 50 mg daily (self¬
administered)

The duration of treatment is 1

year.
 ANTIMALARIAL DRUGS
Malaria is a protozoal infection caused by genus Plasmodium and transmitted to
humans by -> infected female Anopheles mosquito
The species of malarial parasites are Plasmodium vivax, Plasmodium ovale,
Plasmodium malariae, P. falciparum and Plasmodium knowlesi.

LIFE CYCLE WITH DRUG ACTION

Fig. 11.15 The life cycle of malarial parasite and the site of action of antimalarial drugs.

CLINICAL CLASSIFICATION:
| This classification is based on stage of parasite they affect ] Based on clinical indication for use
(a) This classification is based on stage of parasite they affect:

1.Tissue schizontocidal agents:

These act on primary (pre-erythrocytic) and latent (hypnozoites) tissue forms in
the liver, e.g. primaquine

2 .Blood schizontocidal agents:

These act on erythrocytic stage of Plasmodium and, thereby, terminate the clinical
attack.
RAPID ACTING AND HIGH-EFFICACY AGENTS, e.g. chloroquine, artemisinin
derivatives, quinine, mefloquine, atovaquone, amodiaquine and lumefantrine.
SLOW- ACTING AND LOW -EFFICACY AGENTS, eg. praguanil. pyrimethamine
sulphadoxine and clindamycin; used always in combination with rapid -acting agents.
3 6ametocidal agents:
These kill gametocytes of plasmodia in blood,
eg artemisinin and primaquine (active against all species); chloroquine and quinine
(vivax). They reduce transmission to mosquitoes.

(b) Based on clinical indication for use:

(i) Drugs used for causal prophylaxis

Pre -erythrocytic stage of Plasmodium in liver, e.g. proguaniI and primaquine.
Primaquine is effective against all species but not used due to its toxic potential.
Proguanil is effective mainly for P. falciparum.

(ii) Drugs for suppressive prophylaxis:

Suppress erythrocytic phase, thus clinical attack af malaria is prevented - clinical
disease is not manifested, eg. chloroquine, mefloquine and doxycycline.

(iii) Drugs used for clinical cure:

These agents act on erythrocytic stages of malarial parasite to terminate the
clinical attack.
They are rapid-acting and slow-acting blood schizontocidal agents.

(iv) Drugs used to prevent relapse:

These drugs act on latent tissue forms (hypnozoites) of P. vivax and P. ovale which
cause relapse, eg. prima quine and tafenoquine

Table 1 1.21 Antimalarial drugs effective against various stages of life cycle of malarial
parasite
Hepatic stages Blood stages
Stages of Primary tissue Latent tissue Asexual forms Sexual forms
malarial forms forms
parasite (hypnozoites)
Drugs • Sutfadoxine • Primaquine • Chloroquine • Chloroquine
t • Tafenoquine • Mefloquine • Quinine
Pyrimethamine • Quinine • Pnm.iquine
• Proguanil/ • Artemisinins • Artemisinins
atovaquone
• Sutfadoxne + • Quinghaosu
• Primaquine pyrimethamine
• Proguanil/
atovaquone
• Antibiotics
• Tafenoquine
Note: Points to remember
1. None of the agents available are effective against sporozoites.
2. Mos! of the antimalarials are effective against asexual blood stages except primaquine
3. Only primaquine and tafenoquine are affective against hypnozortes (latent tissue forms!.
4. Ail agents with quine (pnm.iquine chk>f quine and qulninei are effective against gametocytes
except mefloquine and tafenoquine.
5. Pnmaquine. proguaml and pyrimethamine are effective against hepatic primary tissue forms
 CHLOROQUINE
Chloroquine is a 4- aminoquinoline.
It is very effective and rapidly acting blood schizontocide against P. vivax, P.
ovale, P. malariae, chloroquine- sensitive strains of P. falciparum and P. knowlesi.

MECHANISM OF ACTION
Chloroquine is a basic drug, which is taken up by acidic food vacuoles of
susceptible plasmodia and inhibits -> conversion of haeme to haemozoin.
The 'drug-haeme' complex is toxic and kills the parasite.
Resistance to chloroquine is common with P. falciparum.
Haemoglobin => Haemc (toxic) <=o Hacmozoin (nontoxic)
Chloroquine
Chloroquine (weak base) *=> Concentrated in acidic —> binds to haeme
vacuole of parasite | Enters
RBCs
Damages plasmodial membrane <= Drug-haeme complex
(prevents formation of haemozoin) I
Acidic food vacuole of the parasite

l
Inhibits heme polymerase

I
Accumulation of toxic heme

l
Parasite membrane lysis

Death of the parasite |

PHARMACOKINETICS:
Chloroquine is commonly administered by oral route
It is well absorbed after oral and parenteral administration.
It has strong affinity for melanin -containing tissues.
It gets concentrated in liver, spleen, kidney, lungs, skin, etc.
Chloroquine is metabolized in liver and slowly excreted in urine.

Adverse Effects
Chloroquine in antimalarial doses may cause nausea, vomiting, skin rashes, itching,
headache and visual disturbances.
Parenteral administration con cause hypotension, confusion, cardiac arrhythmias,
convulsions and even cardiac arrest.
Prolonged administration in large doses, as in rheumatoid arthritis, may cause
irreversible retinopathy and ototoxicity.
It can also cause myopathy, cardiomyopathy, neuropathy and rarely psychiatric
disturbances.
Long-term therapy requires ophthalmological examination once in 3-6 months.
It should be avoided in patients with epilepsy
It is safe for use in pregnancy.
USES:
1. Malaria
(a) Chloroquine is drug of choice for treatment of acute attack of malaria caused
by P. vivax, P. ovale, P. malariae, chloroquine -sensitive P. falciparum and P.
knowlesi .
(b) For malaria due to P. vivax and P, ovale, primaquine is also administered in
addition to chloroquine (for radical cure).
(c) Chloroquine is a very effective chemoprophylactic agent for all types of malaria

2. Other uses are the following:

Amoebiasis
Rheumatoid arthritis
Infectious mononucleosis.
Autoimmune disorder - discoid lupus erythematosus.

Table 11.22 Regimens for treatment of malaria HUE

1. Treatment of uncomplicated malaria
(a) For acute attack of malaria due to P. vivax, P. ovale, P. malariae
Oral chloroquine is the drug of choice.
Chloroquine 600 mg base (10 mg/kg) stat, fallowed by
600 mg base (10 mg/kg) - second day
-
300 mg base {5 mg/kg) third day
(b) For radical cure of P. vivax and P ovale
Chloroquine (as above)
+
Primaquine 15 mg base orally, from day 4 daily for 14 days
Primaquine destroys the hypnozoites in liver and prevents relapse in P vivax and
P ovale infections)
(c) For acute attack of malaria due to P. falciparum
(0 ACT regimen + Primaquine (on Day 2), single dose 0.75 mg/kg body weight
(for gametocidal action)
ACT regimens
Artesunate (4 mg/kg) 100 mg BD x 3 days
+
Sulphadoxine and Pyrimethamine (S/P) 1500 mg/75 mg as a single dose - day 1
(recommended in India except north eastern states)
Artemether + Lumefantrlne (AL) - (FDC - 20 mg + 120 mg ) 4 tablets BD
x 3 days (for those with body weight > 35 kg) -preferably administered
with fatty meal to increase absorption
(recommended in north eastern states)

Artesunate 100 mg BD x 3 days

+
Mefloquine 750 mg (15 mg/kg) - 2nd day
-
and 500 mg (10 mg/kg) 3rd day
(Mefloquine is given in divided doses to minimize nausea and vomiting)
Artesunate 4 mg/kg/day + Amodiaqutne 10 mg/kg/day OD x 3 days
(ii) Alternative to ACT regimens
Quinine sulphate 8 mg base/kg orally TDS for 7 days with either
Doxycycline or clindamycin
 2 For severe or complicated P falciparum malaria (cerebral malaria)
Parenteral antimalarials should be administered for at least 24 hours once started
Then complete the treatment with full course of oral ACT once the patient is able to
take orally
Artesunate:
Dose: 2.4 mg/kg at 0 hour (i.v./i.m.); repeat at 12 and 24 hours
Then, once a day till patient is able to take oral medication
If patient is able to take orally after 24 hours, switch over to full course of 3 -day
oral ACT
Alternatives
• Quinine dihydro chloride 600 mg (20 mg/kg) is diluted in 500 mL of 5%
dextrose and infused intravenously slowly over 3-4 hours; 10 mg/kg is
repeated as i.v. infusion over 4 hours every 8 hours till the patient can take
orally. Then oral quinine sulphate 600 mg t.d.s. should be substituted to
complete 1 -week therapy along with doxycycline 100 mg o.d. x 7 days.
Stood pressure, blood glucose and electrocardiogram (ECG) should be
monitored during quinine therapy. Infusion rate should not exceed 5 mg
salt/kg/h
• Artemether
On admission - 3.2 mg/kg i.m.
Then once a day - 1.6 mg/kg i.m. till patient can take orally - then switch over to full
course of 3-day oral ACT
• a/3 Arteether
150 mg i.m. daily for 3 days; then switch over to 3-day oral ACT when the patient
can take orally
Oral ACT : see treatment of uncomplicated falciparum malaria. ACT containing me¬
floquine should be avoided in cerebral malana because of risk of neuropsychiatric
complications.
Supportive measures
• Tepid sponging for fever
• Sodium bicarbonate to correct acidosis
• Intravenous diazepam to control convulsions
• 10% dextrose to combat hypoglycaemia
• Blood transfusion to correct anaemia

Table 11.23 Regimens for chemoprophylaxis of malaria

(a) For travel to areas with chloroquine -sensitive P. falciparum, P. vivax, P. malariae
and P. ovale malaria
Chloroquine phosphate is given orally. Chloroquine phosphate 500 mg (chloroquine
300 mg base) once weekly; start 1 week before entering the endemic area; continue
during the stay there, and tor 4 weeks after leaving that area
(b) In areas with chloroquine-resistant P. falciparum malaria
Mefloquine 250 mg salt (228 mg base) orally, once weekly; start 1 week before entering
the endemic area; continue once weekly there, and for 4 weeks after leaving that
area
Or
Doxycycline 100 mg orally daily, start 1 day before entering the endemic area; continue
daily during the stay there, and daily for 4 weeks after leaving that area. Doxycycline
is contraindicated in pregnancy and in children
Or
Atovaquone 250 mg + proguanil 100 mg, fixed-dose combination tablet is available
for oral administration. One tablet of FDC daily; start 1 day before entering the en¬
demic area: continue daily during the stay there and daily for 1 week after leaving
that area
(c) For terminal prophylaxis (for P. vivax and P. ovale malaria - to prevent relapse)
Primaquine 30 mg daily is started shortly before or after the person leaves the endemic
area, and continued for 2 weeks
 ARTEMISININ

Artemisinin is derived from -»

plant Artemisia annua.
The semisynthetic derivatives of artemisinin are dihydroartemisinin, artemether
and artesunate.
They are highly effective against erythrocytic stages of all plasmodia.
They also have gametocidal action - reduce transmission of malarial parasite.
They have no effect on hepatic stages of the parasite.

MECHANISM OF ACTION
In the acid vacuole of parasite, cleavage of endoperoxide
bridge of artemisinin compounds by haeme iron

I
Free radicals generated

Damage to
I
proteins and lipid peroxidation

II
Death of parasite
Artesunate and artemether are metabolized to active metabolite,
dihydroartemisinin.
The half-life of dihydroartemisinin is about 2 hours.

ADVERSE EFFECTS:
They are generally well tolerated.
Artemisinins can cause mild 61 disturbances, neutropenia and prolongation of QT
interval.
 ANTIFUNGAL AGENTS
Most of fungal infections are opportunistic, hence they are common in diabetes
mellitus, cancer, AIDS and pregnancy, and in patients on broad - spectrum AMAs
and on immunosuppressant therapy such as prolonged course of corticosteroids and
anticancer drugs.

ANTIFUNGAL DRUGS

T
Antibiotics Topical aQants

Tdtufutv

—1 ,
HiH'ytoMnt*
Undecyk-nk Add
Bcn/xHt ACld
C sdopiroM uUminr
Polyenes
Amphotericin B
Nv»Utin
Heterocyclic
benzofuren
Ghstofulvin
1
r-
imidazole*
Butm.ihnc
Qumiodtx'hlur
Sod thiusulUtr
Hjmicin

Echinocandins
< .Vipotungin
Mkifungin
1
Topical \ ^1 Systemic
Amdulatungin Clotrimazole I Kctoconazolr
Lidfuui’k I
MKmazolc
Ouitnwitlr
Amphotericin B-
AMB is a broad -spectrum antifungal antibiotic.
It is effective against Cryptococcus, Coccidioides, Candida, Aspergillus,
Blastomyces, Histoplasma, Sporothrix, fungi causing mucormycosis, etc.

PHARMACOKINETICS
AMB is not absorbed from gut, hence is not suitable orally for systemic infections.
It is highly bound to plasma proteins and sterols in tissues, and widely distributed
to various tissues but does not cross BBB.
It is metabolized in liver and excreted slowly in urine and bile.

MECHANISM OF ACTION:
Fungal cell membrane contains a sterol which resembles cholesterol and is called
'ergosterol'.

•Amphotericin B Form 'pores’ and

Bind tightly to ergosterol in 'channels’ in
• Nystatin fungal cell membrane
• Hamycin the membrane

Permeability of the
membrane increases

Death of the fungi Leakage of

(fungicidal) intracellular contents
ADVERSE EFFECTS;
The acute reactions are fever, chills, headache, dyspnoea, 61 disturbances,
phlebitis at the site of injection, etc.

USES:
AMB is highly efficacious but highly toxic too; hence, azoles (fluconazole and
itraconazole) have replaced AMB in the treatment of many fungal diseases.
1. It is effective in almost all systemic mycoses, eg. mucormycosis, aspergillosis,
cryptococcosis, sporotrichosis, histoplasmosis and blastomycosis.
2. It is useful topically for oral and cutaneous candidiasis
3. Other uses: L-AMB is useful in leishmaniasis (as the drug reaches the
reticuloendothelial cells) and febrile neutropenia.

AZOLES:
Azole antifungals are broadly divided into imidazoles and triazoles.
Both of them are structurally related compounds, and have similar mechanism of
action and antifungal spectrum
Terbinafine Azoles

e O

Squalene 2,3-epoxidase 14a-Demethylase

Squalene Lanosterol Ergosterol
Fig. 11.12 Mechanism of action of azoles and terbinafine. 0, inhibition.
 ANTI- AMOEBIC DRUGS

Amoebiasis is a protozoal infection caused by E. histolytica, which is transmitted

through faeco-oral route.
AN TIA MOEBIC DRUGS

Tiuue amaebicklM Lumtn*l AmoMMctdM

METRONIDAZOLE:
Metronidazole is a nitroimidazole derivative which is highly effective against most
anaerobic bacteria and several protozoa, such as E. histolytica, Gtardia lamblia
and Trichomonas vaginalis.

MECHANISM OF ACTION:
enters
Metronidazole (prodrug) * Microorganism ‘Nitro’ group of the drug
accepts electrons from
ferredoxins

Death of the Generation of

organism highly reactive
(tidal effect) * nitro radical

PHARMACOKINETICS:
Metronidazole is available for oral, i.v. and topical administration.
It is usually well absorbed in small intestine after oral administration and poorly
bound to plasma proteins.
It diffuses well into tissues including brain
Metronidazole is metabolized in liver and the metabolites are excreted mainly in
urine.
USES
1 . Amoebiasis:
Metronidazole (400-800 mg t.d.s. for 7-10 days) is the first-line agent for the
treatment of both intestinal and extraintestinal amoebiasis except in asymptomatic
carriers
2. Trichomonas vaginitis:
Metronidazole (400 mg t.d.s. orally for 7 days) is the drug of choice. Both sexual
partners should be treated simultaneously.

3 . Giardiasis:
Metronidazole is very effective and is given orally (200 mg t.d.s. for 7 days).

4. Anaerobic infections:
Metronidazole is highly effective in most of the anaerobic infections - pelvic
inflammatory disease, lung abscess, intra -abdominal infection, etc., caused by B
fragilis, Clostridium and other anaerobic organisms. (

5. Others:
It is used for treatment of bacterial vaginosis, extraction of guinea worm and
Crohn's disease.

Table 11.24 Treatment of amoebiasis

For asymptomatic carriers (luminal amoebicide is used)
Diloxanide furoate or paromomycin or iodoquinol
Tab. diloxanide furoate 500 mg t.d.s. for 10 days
11. For intestinal amoebiasis (amoebic dysentery or diarrhoea)
Metronidazole/tinidazole * luminal agent
Tab. metronidazole 400 mg t.d.s.
+ for 7-10 days
Tab. diloxanide furoate 500 mg t.d.s.
III. For severe amoebic dysentery and extraintestinal amoebiasis
Similar to intestinal amoebiasis (metronidazole + luminal agent) or metronidazole
500 mg i.v. infusion q6h till patient can take oral therapy (total duration is 10 days)
IV. Hepatic amoebiasis
Similar to severe amoebic dysentery (metronidazole * luminal agent). Chloroquine may
be used if patient is not responding to above therapy (Tab. chloroquine phosphate
500 mg b.d. for 2 days, later 500 mg o.d. for 3 weeks)

ADVERSE EFFECTS:
1. GIT; Anorexia, nausea, metallic taste, dry mouth, epigastric distress,
abdominal cramps and occasionally vomiting.
2. Allergic reactions: These include skin rashes, urticaria, itching and flushing.
3. CNS: Dizziness, vertigo, confusion, irritability, headache, rarely convulsions
and ataxia may occur. Polyneuropathy may occur on prolonged therapy.
4 . (nausea, vomiting, abdominal cramps, headache, flushing, etc.) may occur if
taken with alcohol; hence, the patient should be warned to avoid alcohol during
treatment with metronidazole
 ANTHELMINTICS
Anthelmintics are drugs used in treatment of infestation with helminths in the
intestinal tract or tissues of the body.
Helminths
1
Roundworms Flatworms
(nematodes)

Flukes Tapeworms
(trematodes) (cestodes)

DRUGS:
Mebendazole, Albendazole, Niclosamide, Ivermectin, Pyrantel pamoate,
Albendazolea, Levami sole
MEBENDAZOLE ALBENDAZOLE
It has a broad spectrum of anthelmintic activity. It has a broad spectrum of anthelmintic activity.
It binds to (5* tubulin and inhibits microtubule The mechanism of action is similar to that of
polymerization mebendazole.
It also blocks glucose transport into the parasite.
As a result, intestinal parasites are immobilized or PHARMACOKINETICS:
die slowly Albendazole is given orally.
It is erratically absorbed - fatty food increases
PHARMACOKINETICS: its absorption; it is metabolized in liver.
Mebendazole is administered orally, poorly It produces an active metabolite, albendazole
absorbed from the GI tract, highly bound to sulphoxide, which is widely distributed into various
plasma proteins and metabolized in liver. tissues including hydatid cyst,
Most of oral dose is excreted in faeces. albendazole is preferred to mebendazole in the
treatment of hydatid disease.
ADVERSE EFFECTS:
Systemic toxicity of mebendazole is low because of ADVERSE EFFECTS:
its poor absorption. Albendazole is very well tolerated.
It is well tolerated and rarely causes GI side The side effects are rare, but can cause nausea,
effects - anorexia, nausea, vomiting, diarrhoea vomiting, diarrhoea and epigastric distress.
and abdominal discomfort. During long-term therapy, it may cause hepatic
It is contraindicated in pregnancy and children dysfunction, headache, dizziness, fever,
younger than 1 year. weakness, loss of hair and neutropenia.
USES: DOSE AND ADMINISTRATION:
Mebendazole is highly effective against intestinal It can be taken as a single oral dose of 400 mg
nematodes - roundworm, hookworm, whipworm, for adults and children older than 2 years, and as
pinworm and mixed worm infestations. 200 mg single dose for children between 1 and 2
It is more effective than albendazole in years of age.
trichuriasis. It is taken at any time of the day, does not
DOSE AND ADMINISTRATION: require fasting or purging and side effects are
Mebendazole 100 mg orally b.d. for 3 days. rare.
It does not require fasting or purging, is well
tolerated and is relatively cheap
 USES:
1 . Nematodes:
Albendazole is highly effective against intestinal nematodes - roundworm,
hookworm, whipworm, pinworm and threadworm - and also in mixed worm
infestations. It is more effective than mebendazole in trichinosis.

2. Neurocysticercosis:
Both albendazole and praziquantel are highly effective in neurocysticercosis.

3. Hydatid disease:
In hydatid cyst, surgical resection is the treatment of choice, but albendazole is
the drug of choice for medical therapy.

4. Filariasis:
Single dose of (400 mg) albendazole is given with diethylcarb amazine citrate (DEC)
or ivermectin in the treatment of lymphatic filariasis.
ANTICANCER DRUGS

TOXICITY OF ANTICANCER DRUGS (CYTOTOXIC DRUGS)

While destroying cancer cells, anticancer drugs also affect rapidly proliferating
normal cells.
Bone marrow, skin, hair, GI mucosa, reticuloendothelial system, gonads, fetus,
etc., are most severely affected
1. General toxicity 1 2. Specific toxicity
(a) Bone marrow suppression: It manifests as leucopenia, (a) Haemorrhagic cystitis with
agranulocytosis, thrombocytopenia and aplastic anaemia. In cyclophosphamide: Ameliorated by
such patients, infection and bleeding are common. It is administering mesna systemically and
ameliorated/reduced by: acetylcysteine locally.
(i) Platelet transfusion
(ii) Granulocyte colony -stimulating factor (G-CSF) (iii) (b) Megaloblastic anaemia with
Erythropoietin methotrexate; Ameliorated by folinic
(iv) Bone marrow transplantation acid/ leucovorin/citrovorum factor.
(v) Using bone marrow- sparing drugs if possible (eg. 1-
asparaginase, bleomycin, cisplatin and vincristine) (c) Nephrotoxicity with cisplatin: Saline
infusion and mannitol reduce the
(b) Immunosuppression: incidence of nephrotoxicity.
Decreased lymphocytes result in immunosuppression.
Such patients are prone to opportunistic infections with (d) Neuropathy with vincristine and
fungi, bacteria, viruses and parasites (P. jiroveci, Candida, paclitaxel.
cytomegalovirus, etc ).
(e) Pulmonary fibrosis and pigmentation
(C) GIT: of skin with busulphan and bleomycin.
Nausea and vomiting are due to central action (stimulation
of CTZ) and peripheral action in the GI tract. Most of the (f) Cardiotoxicity with doxorubicin and
cytotoxic drugs cause vomiting. Cisplatin has the most daunorubicin. An iron chelating agent.
emetogenic potential. 5-HT3 antagonists, such as dexrazoxane, is useful in reducing the
ondansetron and granisetron, are the commonly used toxicity.
antiemetics. The other antiemetics are metoclopramide and
dexamethasone .

(d) Skin and hair:

Alopecia (toss of hair) is due to the damage to hair follicles.
It is usually reversible on stoppage of therapy. Dermatitis
and skin rashes too can occur.

(e) Gonads:
Cytotoxic drugs also affect gonadal cells and cause
oligozoospermia and infertility in males, ond amenorrhoea
and infertility in females.

(f) Fetus:
Administration of cytotoxic drugs during pregnancy usually
causes abortion or teratogenic effects.
(g) Hyperuricaemia :
Gout and urate stones in the urinary tract are due to
excessive cell destruction. They are prevented by good
hydration, allopurinol and corticosteroids .

(h) Hypercalcaemia:
It may be due to either the malignancy or certain
anticancer drugs. It is treated with adequate hydration,
bisphosphonates, corticosteroids, etc.

(i) Carcinogenicity (secondary malignancy):

These drugs may rorely cause secondary cancers in some
patients, e.g. development of leukaemia in patients with
prolonged use of alkylating agents.

HORMONES ANO HORMONE ANTAGONISTS

1. Glucocorticoids:
Because of their marked lympholytic action, they are used in acute leukaemias and
lymphomas.
Apart from this effect, glucocorticoids:
(a) Have anti-inflammatory effect, decrease oedema associated with the tumour
(b) Produce feeling of well-being
(c) Suppress hypersensitivity reaction due to certain anticancer drugs
(d) Control hypercalcaemia
(e) Increase the antiemetic effect of ondansetron/gr anisetron/metoclopramide
Because of the above effects, glucocorticoids are useful in the treatment of
various cancers.
2. Oestrogens:
The oestrogens are physiological antagonists of androgens. Hence, they are used
to antagonize the effects of androgens in androgen -dependent prostatic tumours.
Fosfestrol is a prodrug which is activated to stilboestrol in prostatic tissue. It
achieves high concentration in prostatic tissue, therefore is preferred in carcinoma
of prostate.
3. Tamoxifen:
This is an antioestrogen mainly used in the palliative treatment of hormone-
dependent breast carcinoma.

4. Progestins: The progestins are useful in endometrial carcinoma.

5 . Antiandrogens:
Flutamide is a nonsteroidal agent that blocks the action of androgen at the
receptor level.
6. Finasteride:
This blocks the conversion of testosterone to dihydrotestosterone by inhibiting 5-
reductase. Both flutamide and finasteride are useful for the palliative treatment
of advanced carcinoma of prostate. Finasteride is also effective in BPH.
7. Aromatase inhibitors:
They are used in hormone-dependent breast cancer in postmenopausal women.
8. GnRH agonists:
The pulsatile administration of these agents (buserelin, goserelin, leuprolide, etc.)
produces a rise in follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
Continuous administration, however, suppresses the pituitary gonadotropins by
downregulating GnRH receptors. These agents produce palliative effects in
advanced prostatic and breast cancers.

ANTICANCER DRUGS (1)

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