Lecture 1 - Pharmacokinetics

Pharmacology: the study of how drugs affect a biological system, divided into…
-​ Pharmacokinetics: what the body does to the drug, how the drug moves in, through, out of the body.
-​ Pharmacodynamics: what the drug does to the body.

Process of Pharmacokinetics (ADME)

Absorption: movement of drugs from the site of administration to blood circulation.

-​ Bioavailability: the amount of the dose given that reaches systemic circulation in its active form,
affected by the rate and extent of drug absorption.
-​ IV administration = 100% Bioavailability
-​ Amoxicillin shows very good oral bioavailability.
-​ Routes of Administration: different routes of administration will affect the mechanism of absorption,
and include: IV, Oral, Transdermal, Inhaled, Topical, Rectal, SC, IM.

Factors affecting Absorption (Oral Route) or Bioavailability

-​ Mechanism of Transport: some drugs require active transport (ATP dependent).
-​ Ionization: Non–Polar (Lipophilic) drugs can pass via passive diffusion and are well absorbed.
-​ Molecular Weight: Light Molecules (less than 250 dalton) are more quickly absorbed.

Other Factors Affecting Absorption

Physicochemical Properties Stability in the GIT

Form of Drug (e.g. Syrup > Tablet) Sustained vs Quick Release Tablets

Changes in Gastric pH, Motility, Emptying Pathological Diarrhea or Vomiting

Distribution: the process by which a drug reversibly diffuses from intravascular → extravascular spaces and
target tissues, using the circulatory system as a transport mechanism.
-​ Drugs may distribute into Plasma, Interstitial Fluid, and lastly into Intracellular Fluid.
-​ Drugs in the plasma are inactive when they are bound to Albumin, and are active when they are
unbound and released into the interstitial and intracellular fluid.

Factors affecting Drug Distribution

1.​ Chemical Structure: Molecular Weight, Polarity, Lipid Solubility
2.​ Binding Levels to Blood Components
a.​ Albumin: binds to many acidic drugs, and a few basic drugs
b.​ β-Globulin and ɑ1 Acid Glycoprotein: bind to basic drugs
3.​ Body Composition: ↑ Fat → ↓ Distribution
4.​ Pregnancy: Diluted Albumin → Relatively Less Binding and Transport
5.​ Rate of Blood: different organs have different blood flow; ↑ blood flow → ↑ distribution
-​ Brain, Liver, and Kidneys have ↑ blood flow, Adipose Tissue has ↓ flow.
-​ Redistribution: e.g. Propofol → short anesthesia as it is distributed randomly.
6.​ Liver Disease: ↓ Albumin Levels → ↑ Active Drug → ↑ Distribution and Effect.
7.​ Capillary Permeability: Brain Capillaries are covered by Lipid Glial Cells, preventing many drugs from
passing, while general capillaries are non-selective.
Clinical Significance of Protein Binding: Protein Binding is a dynamic (reversible) process, and higher free
drug levels can be associated with disease states or competitive binding.
-​ Neonates have higher levels of free drugs that are normally bound highly to Albumin

Factors that Increase the amount of unbound (free, active) Drugs

-​ Renal Impairment (Uremia)
-​ Low Albumin Levels (<20–25g/L): e.g. Liver Disease and Malnutrition
-​ Late Pregnancy: diluted Albumin due to increased blood volume
-​ Displacement from binding site by other drugs: e.g. Phenytoin, Warfarin, Tolbutamide
-​ Saturation of Albumin binding Site: e.g. Valproic Acid

Metabolism: transformation of drugs into compounds which are easier to eliminate (usually a less toxic form).
-​ Function: Transformation of a drug from Lipid (Non–Polar) → Water Soluble (Polar) for excretion.
-​ Phase 1: Hydrolysis of Drugs into a Non–Polar Compound, involving Cytochrome P–450 System.
-​ Phase 2: Conjugation via Glucuronidation, making the drug polar (Very Water Soluble) for excretion.

First Pass Metabolism: the metabolism and excretion of a drug before it reaches the target site, occurring
primarily in the Liver and Gut Wall. It can render a drug less effective via PO, needing a higher dose for a
desired effect. Alternate Routes are used to avoid the First Pass Effect (e.g. sublingual nitroglycerin)

Factors Affecting Drug Metabolism

1.​ Genetic Factors: e.g. Acetylation Status of Drugs (e.g. INH)
2.​ Liver Disease: e.g. Advanced Liver Cirrhosis
3.​ Neonates and the Elderly have reduced clearance, metabolic capacity, and a longer half life of drugs.

Enzyme Induction: process where a drug induces the metabolizing capacity of a certain microsomal enzyme.
-​ Enzyme Inducers stimulate a specific CYP, and enhance the metabolism of that CYP’s substrates
-​ Enzyme Induction involves protein synthesis, and may take 3 weeks to reach full effect.
-​ Result: Lower Drug Level and Reduced Pharmacological Effect.
-​ Examples:
1.​ Anti–Epileptic Drugs (e.g. Phenytoin) and Saint John’s Wort induce CYP3A4
a.​ Carbamazepine (an Anti-Epileptic) is processed by CYP3A4 (Auto–Inducing)
2.​ Tobacco Smoking Induces CYP1A2, whose substrates are Clozapine and Olanzapine.

Enzyme Inhibition: decrease of the rate of metabolism of a drug by another drug, which may occur by
competitive inhibition of binding sites, which has a quick onset of inhibition (24 hours)
-​ Result: Increased Drug Level and Increased Toxicity

Excretion: the irreversible elimination of unchanged drug or its metabolite from the body via urine (usually),
bile, or the lungs (for volatile anesthetics).
-​ Renal Elimination is greatly affected by age and gender
-​ Some Drugs are Nephrotoxic and reduce elimination of other drugs.

Process of Renal Excretion

1.​ Filtration: a passive pressure-driven process that filters small molecules (not protein bound)
2.​ Active Secretion: requires energy and has separate mechanisms for acids and bases (saturable)
3.​ Reabsorption: depends on urine flow, urine pH, and states of ionization.
 Lecture 2 - Pharmacodynamics

Pharmacodynamics: the interactions between a drug’s dose and its effect on the body.

Drug Targets (Proteins)

Structural Targets: e.g. Tubulin → makes microtubules, which are

essential for cell division. Drugs that affect or inhibit Tubulin therefore
inhibit cell division, such as anti–cancer drugs.

Enzyme: many enzymes are targets for drugs, which behave as

substrates and work to competitively inhibit the enzyme (reversibly or
irreversibly bind to act as enzyme inhibitors or inducers).
-​ E.g. Neostigmine (an anti-cholinesterase) competes with ACh
-​ E.g. Aspirin irreversibly inhibits cyclooxygenase

Ion Channels: transmembrane proteins, working as pores to regulate

intracellular ion composition, and serve as direct targets for drug action
(e.g. local anesthetics which physically inhibit Na+ channels)
-​ Drugs can modulate opening/closing of these channels, working
through specific receptors (ligand-gated ion channels).

Carrier Molecules (Transporters): small organic molecules/ions are

transported across the cell membrane using carrier molecules as they
are too polar. Drugs can affect their transport ability.
-​ E.g. Carriers responsible for the transport of glucose and amino
acids into cells, sodium and calcium out of cells, and the
reuptake of neurotransmitters by nerve terminals.

Receptors: macromolecules present on the cell membrane or

intracellularly, responsible for selectively sensing and binding of a
stimulus (ligand), and its coupling to a response via a signal
transduction mechanism, which can be altered by drugs.
-​ Types of receptor-acting drugs: agonists, antagonists, or
partial agonists/antagonists.
Agonists: interact with receptors and initiate changes in cell function, producing effects. (e.g. Adrenaline, ACh)
-​ Agonists depend on…
-​ Affinity: tendency of a drug to bind to a receptor.
-​ Efficacy: ability of a drug to produce a desired
therapeutic effect.
-​ Full Agonist: agonists with high efficacy that can
produce a maximal effect.

Effects of Agonists
-​ Adrenaline Stimulation of β–Adrenergic Receptors
initiates the Gs Signal Transduction Pathway,
stimulating cAMP and increasing the function of Ca2+
Channels.
-​ ACh Stimulation of Muscarinic M2 Receptors initiates
the Gi Signal Transduction Pathway, inhibiting cAMP
and increasing the function K+ Channels.

Antagonists: bind to the receptor without initiating changes or producing

effects (Efficacy = 0). E.g. Atropine

Partial Agonists/Antagonists: have affinity, but incomplete intrinsic activity.

-​ Given alone, they act like agonists
-​ Given in combination, they may antagonize the action of a full agonist.

Graded Dose-Response Curve: charts the change in response as the administered dose increases. Both the
Potency (EC50) and Efficacy (Emax) of a drug can be demonstrated.

Importance of Graded Dose-Response Curves

1.​ Calculation and Comparison of EC50:
a.​ Comparison of different drugs on one animal allows
determination of Equiffective Doses (doses that
produce the same effect)
b.​ Comparison of the same drug in different patients
allows determination of Relative Sensitivity and Degree
of Variation in a population.
2.​ Calculation and Comparison of the Maximum Response of
Drugs (Intrinsic Activity)
3.​ Calculation and Comparison of the Steepness of the Dose Response (Steep = Potent = Easily Toxic)

Efficacy (Emax): refers to the maximal response that can be achieved by a drug.
-​ Efficacy is unrelated to Potency.

Potency: refers to the amount of drug needed to elicit a desired response (Compared using EC50).
-​ Potent drugs require a small amount to achieve the desired response.
-​ EC50: dose of the drug required to achieve 50% of the maximal response.
Therapeutic Index: a measure of the drug’s safety, comparing the median
dose needed to produce the desired effect (EC50) with the median dose
needed to produce toxicity (TD50).
-​ Therapeutic Window: refers to the doses of drugs that can be
given to produce the desired effect without producing toxicity.
-​ Small Therapeutic Window: Warfarin
-​ Large Therapeutic Window: Penicillin

Antagonism: the decrease/abolishment of the effect of one drug, in the

presence of another.
-​ Physiological (Functional) Antagonism: two drugs act on different
receptors to produce different physiological effects.
-​ E.g. Histamine (↓ Blood Pressure) & Adrenaline (↑ Blood Pressure)
-​ Chemical Antagonism: reaction between two compounds, resulting in loss of activity.
-​ Pharmacokinetic Antagonism: antagonist effectively reduces the concentration of the active drug at
its site of action.
-​ Pharmacological Antagonism: Competitive (Reversible or Irreversible) and Non–Competitive

Competitive Antagonists Non-Competitive Antagonist

Same Receptor as the Agonist (Active Site) Different Receptor (Allosteric Site)

Chemically Resembles the Agonist Does Not Resemble the Agonist

Intensity of the Response depends on the

Intensity depends only on conc. of Antagonist
Concentration of Both the Agonist and Antagonists

E.g. ACh + Atropine, Morphine + Naloxone E.g. Diazepam + Bicuculline

Drug–Drug Interactions

Synergism: when the action of one drug is increased by the other. Alone,
each may act in the same direction or one may be inactive but still
enhance the effects of the other when given together.
-​ E.g. Paracetamol + Caffeine

Additive: The effect of two drugs is in the same direction and simply adds
up (B + C = Effect of Both)
-​ E.g. Paracetamol + Aspirin, Nitrous Oxide + Halothane

Superadditive (Potentiation): the effect of combination is greater than

both effects combined.
-​ E.g. Adrenaline + Cocaine, ACh + Physostigmine

Tolerance: failure of responsiveness to the usual dose of drug, needing an increased dosage to maintain a
given therapeutic effect.
-​ Tachyphylaxis (Acute Acquired Tolerance): a type which occurs very rapidly (minutes)
 Lecture 3 - Adverse Drug Reactions

Different people may have different responses to the same drug, with possibilities including…
1.​ Drug Not Toxic and Beneficial (BEST)
2.​ Drug Toxic and Beneficial
3.​ Drug Not Toxic and Not Beneficial (No Effect)
4.​ Drug Toxic and Not Beneficial (Worst)

Intrinsic (Patient) Factors Affecting Drug Response

Age: Extremes of Age show extreme drug sensitivity, as their liver metabolism and kidney elimination is
degenerate in the elderly and immature in neonates, leading to drug accumulation and easy toxicity.
-​ Drugs commonly produce a greater effect with a more prolonged duration of action (↑ T½)
-​ Both the Elderly and Infants/Newborns require less drugs to produce a desired effect.

Genetic: there may exist two or more phenotypes in drug response within a population, as gene expression
can influence receptors and other proteins for drug binding → altered gene → altered effect.
-​ Pharmacogenetics: variation in drug responses due to genetic differences in drug metabolism.

Pathological Condition (Co–Existing Diseases): cause individual variation in drug response, including in…
-​ Liver Disease:
1.​ Liver Cirrhosis → ↓ Albumin → ↓ Plasma Protein–Drug Binding → ↑ Free Drug → ↑ Toxicity.
2.​ ↓ Hepatic Blood Flow → ↓ Clearance of the Drug → Drug Accumulation and Toxicity
3.​ Impaired Liver Enzymes → ↓ Drug Metabolism → Drug Accumulation and Toxicity
-​ Renal Impairment → ↓ Excretion of Drugs → Drug Accumulation and Toxicity
-​ Some Drugs only work in the presence of disease, such as…
-​ Aspirin only reduces body temp in the presence of Fever, but works as a painkiller otherwise.
-​ Uterus is more sensitive to Oxytocin during labor
-​ Thiazides induce Diuresis (increased urine) in edematous patients, but not for normal people.

Extrinsic (Drug) Factors Affecting Drug Response: Tolerance and Drug–Drug Interactions.

Adverse Drug Reactions (ADR): any noxious, unintended, undesired drug effect occurring at therapeutic
doses. It is not considered an overdose or side effect, and is one of the leading causes of morbidity/mortality.
-​ Second Purpose: A Drug can be used for its ADR properties, such as antihistamine use as a sedative.
-​ Serious ADRs cause death, disability, birth defects, are life–threatening, & require intervention
-​ Classification of ADRs based on Onset (not commonly used)
-​ Acute: within 60 minutes of drug administration
-​ Sub–Acute: 1–24 Hours after drug administration
-​ Latent: More than 2 Days after drug administration
 Types of ADRs

Type A (Augmented): common ADRs due to excess of normal, dose–related effects [low mortality].
-​ Management: These can be minimized by appropriate dosing.
-​ E.g. Insulin → Hypoglycemia, Beta Blockers → Hypotension, Warfarin → Bleeding.

Type B (Bizzare): rare ADR which occurs in some people due to unexpected patient–drug interaction, such as
genetic abnormalities (Idiosyncrasy) and Immunological processes (Allergy/Hypersensitivity) [High Mortality].
-​ Management: Withhold Medication and avoid it in the future.
-​ E.g. Penicillin Allergies (Immunologic Reaction) and Apnea from Anesthesia (Idiosyncratic Reaction)

Type C (Chronic): uncommon ADR due to continuous long term exposure, related to dose accumulation. It is
both time and dose dependent, and can be managed by dose reduction or withdrawal.
-​ E.g. NSAID → Peptic Ulcer, Corticosteroid → Cushing Syndrome (Obesity, Osteoporosis)

Type D (Delayed): rare ADR delayed effect after treatment has finished, making them more difficult to detect.
-​ E.g. Carcinogenesis and Teratogenesis (such as Fetal Hydantoin Syndrome from Phenytoin use).

Type E (Ending of Use): rare ADR from sudden withdrawal of a drug; should be reintroduced and tapered off.
-​ E.g. Beta–Blocker → Myocardial Ischemia, Corticosteroid → Adrenal Insufficiency

Type F (Failure of Efficacy): common dose–related ADR, when the expected response is not achieved often
due to drug interactions or error in dosage.
-​ Management: increase dosage or association with other drugs.
-​ E.g. Antimicrobial Resistance, Failure of Oral Contraceptives
 Lecture 4, 5 - Cholinergic System and Drugs

Cholinergic System: a biological system that uses

Acetylcholine (ACh) as a neurotransmitter and its receptors
[Muscarinic and Nicotinic Receptors].

Autonomic Cholinergic Nerves (that make ACh) include:

-​ All Preganglionic Neurons, both Sympathetic and
Parasympathetic.
-​ All Postganglionic Parasympathetic Neurons.
-​ Some Postganglionic Sympathetic Neurons
-​ Somatic Neurons at Neuromuscular Junctions.

Organs Supplied By the ANS

1.​ Cardiac/Smooth Muscles: Heart, Eye, Bronchi,
GIT, Blood Vessels, Urinary Bladder
2.​ Exocrine Glands: Lacrimal, Salivary, Sweat
3.​ Endocrine Glands: Adrenal Medulla
4.​ Metabolism: Liver, Adipose Tissue, Kidney

Steps of Cholinergic Transmission

1.​ Synthesis of ACh
2.​ Uptake into Storage Vesicles for protection
3.​ Release of ACh due to Action Potential
-​ Inhibited by Botulinum (Agonist)
-​ Induced by Spider Venom (Antag.)
4.​ Degradation of ACh by ACh–esterase [AChE]
5.​ Choline Reuptake

Types of Cholinesterase, the enzyme that breaks down ACh…

-​ True (Specific) Cholinesterase (Acetylcholinesterase): responsible for the hydrolysis of ACh and
released at the cholinergic sites and inside RBCs.
-​ Pseudo (Non-Specific) Cholinesterase: hydrolyzes drugs with structural similarity to ACh, which
plays an important role in the breakdown of Suxamethonium, a muscle relaxant given prior to surgery.
-​ Suxamethonium (Succinylcholine) Apnea: a rare condition when suxamethonium is given prior
to surgery, but the patient is incapable of metabolizing the drug.

Sympathetic Nervous System Parasympathetic Nervous System

Origin Thoracolumbar Craniosacral

Short Preganglionic Long Preganglionic

Length of Fibers
Long Postganglionic Short Postganglionic

Ganglia Location Close to the Spinal Cord Close to the Target

Pregang. Fiber Branching Extensive Minimal

Response Diffuse Discrete

 Cholinergic Receptors

Receptor Muscarinic Receptors Nicotinic Receptors

Location At Targets (Peripheral) At Ganglion (Central)

G-Protein Coupled Receptors Ligand-Gated Receptors

Function
(Metabotropic Receptor) (Ionotropic Receptor)

Work on Adrenal Medulla, Autonomic Ganglia,

Smooth Muscles and Glands
Skeletal Muscles

Affinity

Subtypes of Receptors

Effects of M1 Receptors (Excitatory)

-​ CNS: Arousal, Learning & Short Term Memory.
-​ Basal Ganglia: Balance between ACh and Dopamine is important for Fine Movement.
-​ Vestibular Pathway: Stimulate Vomiting
-​ GIT: Increased Gastric Acid Secretion

Effects of M2 Receptors (Inhibitory)

-​ CNS: Inhibit ACh at Presynaptic Neurons
-​ Heart: associated the parasympathetic tone (vagal tone) to atria, resulting in 60-80 BPM.
-​ Reduces SA Node Activity → Bradycardia
-​ Reduces Atrioventricular Conduction (AV Node)
-​ Reduces Atrial Force of Contraction

Effects of M3 Receptors (Excitatory)

-​ Smooth Muscles: stimulate wall contraction of the bronchi, GIT, bladder and relax sphincters
-​ Eye: Induce Miosis and Near Vision Accommodation by Pupil Constrictor and Ciliary Muscle contraction
-​ Exocrine Glands: Increase all secretions (except milk)
-​ Vascular Endothelium: stimulate NO release → Vasodilation → Decreased Blood Pressure

Nn Receptors: in Autonomic Ganglia, Presynaptic Motor Nerves, Adrenal Medulla → Catecholamine Release.

Nm Receptors: Induce Skeletal Muscle Depolarization → Induce Contraction (Blocked by Curare).

 Cholinomimetic (Cholinergic Agonist) Agents: drugs that cause effects similar to acetylcholine.

AcetylCholine: key features include a quaternary ammonium group and an ester group.
-​ It is non–specific and non–selective, binding equally to Muscarinic and Nicotinic Receptors and AChE.
-​ It is irregularly absorbed (as it is a 4ry drug) and is rapidly hydrolysed if given systematically.

Therapeutic Uses of Direct Acting Agonists

Mixed M & N Agonists Muscarinic Agonists (AChE Resistant)

-​ AcetylCholine: no uses due to its diffuse -​ Bethanechol: treat urinary retention, post-op
actions and rapid inactivation by AChE ileus by increasing GIT/Bladder contraction
-​ Carbachol (Eye Drops): Glaucoma via Ciliary -​ Pilocarpine: Emergent Glaucoma (Eye
and Muscle Contraction Drops) and Xerostomia (Dry Mouth)

Therapeutic Uses of Indirect Acting Agonists (AChE Inhibitors, working on both M/N Receptors)

Reversible Anti–AChE Drugs Irreversible Anti–AChE Drugs

-​ Edrophonium (aka Tensilon): short acting, -​ Echothiophate: irreversible, used for

used for Myasthenia Gravis Diagnosis Glaucoma only as eye drops (localized)
-​ Neostigmine: mid–acting, treats Myasthenia
Gravis and Post–operative Ileus (2nd choice) Side Effects of Cholinergic Agonist [DUMBBLE]
-​ Physostigmine: long acting, Atropine Overdose -​ Diarrhea, Urination,
-​ Pyridostigmine: long acting, best treatment for -​ Miosis, Bradycardia & Hypotension,
Myasthenia Gravis -​ Bronchial Constriction,
-​ Donepezil: pass the BBB to treat Alzheimer’s -​ Lacrimation (Tears),
and Dementia of Parkinson's Disease -​ Emesis (Vomiting)

Organophosphorus Compounds: highly lipid–soluble toxic compounds, which are

well absorbed and cross the BBB. They are present in insecticides (Parathion,
Malathion) or Nerve Gases (Sarin), and present as…
1.​ Excessive Muscarinic Effects (DUMBBLE)
2.​ Nicotinic Effects: Muscle Tremors/Fasciculations followed by Flaccid Paralysis
3.​ CNS Effects: Stimulation (i.e. seizures) followed by Depression (Coma,
Respiratory Failure)
4.​ Death occurs due to respiratory center depression → diaphragm paralysis →
excessive bronchial secretions with acute pulmonary edema.
-​ Malathion is less toxic, and results in delayed neuropathy and numbness.

Treatment of Organophosphorus Poisoning

1.​ Maintenance of Vital Signs: Intubation and Ventilation, IV Fluids, BP Monitoring
2.​ Decontamination to avoid further absorption: Removal of Clothes, Skin Wash, Gastric Lavage
3.​ Symptomatic Treatment: Large Doses of ATROPINE (2–5 mg within 5 mins → Full Atropinization)
4.​ Antidote: AChE reactivators (Pralidoxime or other –oxime drugs).
 Antimuscarinic Agents

Atropine: a muscarinic–specific cholinergic antagonist, it works specifically on muscarinic receptors of the

parasympathetically (and some sympathetically) innervated target organs.
-​ Lipophilic → well absorbed from the GIT, conjunctiva of the eye, and can cross the BBB.
-​ Mechanism: Atropine causes reversible competitive inhibition of the action of ACh at all muscarinic
receptors, with both central and peripheral effects. Its non–selective behavior results in side effects.
-​ Essentially, it inhibits parasympathetic activity at dually–innervated sites.
-​ Natural Source: Atropa Belladonna

Effects of Atropine on the CNS

-​ M1 of the Chemoreceptive Zone: Antiemetic (Anti–Vomiting)
-​ M2 of the Medullary Centers: Respiratory Center Stimulation
-​ M3 of the Basal Ganglia: Anti–Parkinsonian

Effects of Atropine on Cardiac Actions

-​ M1 of the CNS and Presynaptic Fibers: ↑ Vagal ACh release →
Cardiac Inhibition → Bradycardia
-​ M2 of the Cardiac Center: After 2–5 Minutes of IV Atropine,
Cardiac Blockade of Inhibitory Receptors → Dominant Cardiac
Stimulation → Tachycardia

Effects of Atropine on the Eye: effects last up to 7 days

1.​ Relaxation of the Constrictor Pupillae → Passive Mydriasis
2.​ Relaxation of the Ciliary Muscle → Cycloplegia, where the eye is
stuck in far vision accommodation
3.​ Increased Intra–Ocular Pressure → Glaucoma
4.​ Inhibits Lacrimation → Dry Eye

Other Effects of Atropine

-​ Bronchodilation: increasing the airway passage and decreasing secretions
-​ Relaxation of the Bladder and GIT Walls and Contraction of the Sphincter → Decreased Emptying
-​ Antispasmodic of the Ureter → Ureter Relaxation

Therapeutic Uses of Atropine

1.​ Preanesthetic Medication: inhibits secretions, antiemetic, simulated respiration, dilates bronchi.
2.​ Bradycardia: by blocking M2 Inhibitory Cardiac Receptors.
3.​ Organophosphate Poisoning (with PAM)
4.​ Cycloplegia in Children: stronger action over its substitutes.
5.​ Traveler’s Diarrhea: with Diphenoxylate to enhance its constipating effect and reduce its abuse.

Adverse Effects of Atropine Treatment of Atropine Overdose

-​ Confusion, Restlessness, Hallucinations, Mania 1.​ Gastric Lavage
-​ Dry Eye, Blurred Vision, Photophobia (+Glaucoma) 2.​ Physostigmine: antagonizes effects
-​ Dry Mouth and Skin 3.​ Diazepam: to control CNS excitement
-​ Hyperthermia, Vasodilation and Flushing 4.​ Cooling Blankets: to treat hyperthermia
-​ Urine Retention and Constipation
 Atropine Substitutes (More Selective)

Natural Substitutes: Scopolamine, which produces similar peripheral but greater CNS effects.
-​ Uses: Mydriatic, Prevention of Motion Sickness, induces CNS excitement and hallucination when used
as a preanesthetic in females, and may produce euphoria (potential for abuse).

Selective Substitutes
1.​ Mydriatic Cycloplegics: Cyclopentolate (24 hrs.), Tropicamide (6 hrs.), Homatropine are used for…
a.​ Iridocyclitis: edema and inflammation of the iris
b.​ Fundus Examination and measuring Refractive Errors
2.​ Antispasmodics Antisecretory: 4ry drugs, which are less absorbed and have less side effects.
a.​ Glycopyrrolate: anti–secretory in preanaesthetic medication
b.​ Buscopan (Hyoscine Butylbromide): anti–spasmodic in renal, biliary, intestinal colic and IBS.
c.​ Dicyclomine & Pirenzepine: 3ry drugs which decrease gastric HCl to treat ulcers.
3.​ Urinary Substitutes: Solifenacin, Darifenacin, and Oxybutynin induce urine retention, and are more
uroselective than atropine with fewer side effects. Uses: incontinence and nocturnal enuresis.
4.​ Bronchial Substitutes
a.​ Ipratropium: inhaled bronchodilator (M3 Blocker), used in asthma and COPD (tolerance).
b.​ Tiotropium: selective M3 Blocker with longer duration for maintenance in COPD (no tolerance).
5.​ Antiparkinsonians: Benztropine, Biperiden, and Benzhehon to prevent tremors and control salivation.

Neuromuscular Blockers: interfere with the action of ACh at Nm Receptors

-​ Competitive Agents (CNMBs): pure antagonists, such as curare
-​ Depolarizing Agents (DNMBs): produce depolarization and fail transmission, such as succinylcholine.
-​ They are useful as skeletal muscle relaxants to decrease anesthetic dose and enhance healing.

Competitive Agents: they are administered via IV due to their 4ry structure, and do not cross the BBB.
-​ Curare is a mixture of alkaloids with CNMB properties, of which Tubocurarine is the most important.
-​ Curare has been replaced by safer agents like pancuronium (excreted by the kidney),
rocuronium and vecuronium (excreted by the liver).
-​ Mechanism: at low doses, they block the Nm Receptor, which can be overcome by increasing ACh.
Higher Doses block the ion channel at the motor end plate, and cannot be reversed by Anti–AChEs.
-​ Paralysis of Muscles in Order: Eye Muscles, Face Muscles, Pharynx, Limbs, Respiratory Muscles.

CNMB drug interactions

-​ Cholinesterase Inhibitors: Antagonism
-​ Halogenated Hydrocarbon Anesthetics and Aminoglycoside Antibiotics: Synergism
-​ Calcium Channel Blockers: Enhancement

Depolarizing Agents: bi–quaternary ammonium compounds, like Suxamethonium (Succinylcholine, which is 2

ACh Molecules connected and has a shorter duration of action) and Decamethonium.
-​ Mechanism: produce short-lasting muscle tremors, followed by paralysis (respiratory muscles last)
-​ Uses: Useful when rapid intubation is required, also for electroconvulsive shock treatment.
-​ Adverse Effects:
-​ Prolonged paralysis/apnea due to genetic deficiency in Pseudocholinesterase
-​ Post–op Myalgia, especially in the Neck, Back, and Abdomen
-​ Malignant Hyperthermia when given with Halothane due to Synergism
-​ Hyperkalemia due to prolonged depolarization
 Lecture 6, 7 - Adrenergic System and Drugs

Direct Acting Agonists: act on ɑ and/or β receptors

Mixed ɑ and β Agonists

Epinephrine (Adrenaline): potent stimulator of both ɑ and β Adrenoceptors

-​ Effects on ɑ1–Adrenergic Receptors: Vasoconstriction, ↑ Blood Pressure, ↓ Mucosal Secretions
-​ Effects on β1–Adrenergic Receptors: ↑ Cardiac Contractile Force, ↑ Heart Rate
-​ Effects on β2–Adrenergic Receptors: Bronchodilation, ↓ Mediator Release

Therapeutic Uses of Epinephrine

1.​ Anaphylactic Shock: induces bronchodilation and vasoconstriction
2.​ Cardiac Arrest and Bronchial Asthma
3.​ Glaucoma: EP decreases aqueous humor production via vasoconstriction → ↓ IOP
4.​ Bloody Nose: Inhibits Bleeding when applied Topically
5.​ Added to Local Anesthetics to prolong their action (vasoconstriction → ↓ Absorption → Localization)

Administration of Epinephrine: It cannot be given orally due to its inactivation by MAO, and is only given as
IV for emergencies as it could cause ventricular fibrillation.
-​ It can be given SC (prolonged absorption), IM, Inhalation (Bronchial Asthma), Topically, or Eye Drops.

Adverse Effects of Epinephrine (HAT): Headache & cerebral Hemorrhage, Arrhythmias, Tolerance

Contraindications
1.​ Hypertension
2.​ Cardiovascular Issues (like Ischemic heart Disease)
3.​ Large Doses of Local Anesthesia + Epinephrine (may cause Necrosis due to Vasoconstriction)
4.​ Cardiac Outflow Obstruction
5.​ Hyperthyroidism (Epi will increase T3 and T4 Hormones)

Norepinephrine: potent stimulator of ɑ Adrenoceptors, weak stimulator of β Adrenoceptors

-​ Effects on ɑ1–Adrenergic Receptors: Intense Vasoconstriction, ↑ BP → Reflex Vagal Stimulation
which antagonizes Heart Rate → ↑ BP + Reflex Bradycardia
-​ Therapeutic Uses: Septic Shock and Pulmonary Embolism
-​ Administration: IV Infusion only, not IV Bolus
-​ Contraindication: Atropine use, or any drugs that increase BP

Dopamine: stimulator of Dopamine Receptors, ɑ and β Adrenoceptors

-​ At Low Concentrations: Stimulates Dopamine Receptors → Vasodilation
-​ At Intermediate Concentrations: Stimulates β1 Adrenoceptors → +ve effect on the Heart
-​ At High Low Concentrations: Stimulates ɑ1 Adrenoceptors → Vasoconstriction
-​ Therapeutic Doses of Dopamine: improve cardiac function in cardiogenic shock and failure
-​ Administration: IV use only, with a short T½ (3–5 minutes).
 β Agonists

Isoproterenol: potent, nonselective (β1 = β2) Agonist

-​ Effects of β1 Stimulation: ↑ Cardiac Contractility, ↑ Heart Rate, ↓ BP
-​ Effects of β2 Stimulation: Vasodilation of Skeletal Muscles Arterioles, Bronchodilation, ↓ BP
-​ Therapeutic Uses: stimulate HR in Bradycardic Patients, Bronchodilator (rarely used now)
-​ Adverse Effects: Palpitations, Tachycardia, Coronary Insufficiency

Dobutamine: selective β1 Agonist

-​ Effects of β1 Stimulation: +ve Inotropic and Chronotropic (to an extent) Effects, with minimal HR and
BP changes. Used for Cardiac Shock and Acute Heart Failure in there is normal BP and renal function.

Selective β2 Agonists: Albuterol, Terbutaline, Metaproternol, Salmeterol

-​ Effects of β2 Stimulation: Bronchodilation, Inhibits Uterine Contractions
-​ Advantages: no cardiac effect, longer duration, many methods of administration.
-​ Short Acting Members (SABA): Albuterol (Ventoline), Salbutamol, Terbutaline
-​ Long Acting Members (LABA): Salmeterol, Formoterol, Bambuterol
-​ Therapeutic Uses: Bronchial Asthma (Salmeterol, Salbutamol) and Premature labor (Terbutaline)

Adverse Effects of Selective β2 Agonists

1.​ Tachycardia and palpitations 3.​ Hypoxemia 5.​ Hypokalemia

2.​ Tremors 4.​ Tolerance 6.​ Hyperglycemia

ɑ Agonists

Oxymetazoline: nonselective (ɑ1 = ɑ2) Agonist, used for Vasoconstriction

-​ Administration and Uses: Local Eye/Nose Drops for Decongestion
-​ Adverse Effects: Rebound Congestion, Mucosal Burning, Headache, Sneezing

Selective ɑ1 Agonists: induce vasoconstriction and ↑ BP with reflex bradycardia

-​ Phenylephrine: used as a nasal decongestant, and for red eyes
-​ Methoxamine: used in hypotensive states
-​ Midodrine: used in postural hypotension
-​ Adverse Effects: Hypertension, Rebound Congestion and Atrophic Rhinitis.

Selective ɑ2 Agonists: Alpha–Methyldopa, Clonidine, Rilmenidine.

-​ Mechanism: inhibit Norepinephrine and inhibit central sympathetic outflow
-​ Therapeutic Uses: Hypertension, Alcohol/Opiate Withdrawal
-​ Precaution: sudden withdrawal → severe hypertension

Mixed–Acting Adrenergic Agonists: act on receptors and release catecholamines

Ephedrine & Pseudoephedrine: resistant to COMT and MAO, with a long duration of action.
-​ Mechanism: both directly act on adrenoreceptors and indirectly release stored catecholamines
-​ Therapeutic Uses: Spinal Shock and Topic Hemostatic (Ephedrine), Nasal Decongestant (Both)
-​ Adverse Effects: Urinary Retention, Minimal CNS/CVS Stimulation → Insomnia, Anxiety, Arrhythmia.
 Indirect–Acting Adrenergic Agonists: release catecholamines

Amphetamines: release stored Norepinephrine

-​ CNS Effects: Stimulation, Alertness, ↑ Mood, ↓ Fatigue and Appetite
-​ CVS Effects: ↑ Arterial BP → Reflex Bradycardia
-​ Therapeutic Uses: Appetite Suppressant, ADHD, and Narcolepsy
-​ Adverse Effects:
-​ CNS: Dependence and Schizophrenia, Anorexia, Insomnia, Tremors, Depression due to CA
depletion, Toxicity → Convulsions, Coma, Hemorrhage
-​ CVS: Palpitation, Arrhythmia, Anginal Pain, Hypertension

Tyramine: found in fermented food, it is metabolized by MAO in the liver and releases stored catecholamines,
with similar effects to Amphetamines. MAO inhibition could lead to Hypertensive Crisis (↑ BP and HR)

Cocaine: blocks Norepinephrine reuptake and sodium channels to act as a local anesthetic.
-​ Therapeutic Uses: potent CNS stimulant
-​ Adverse Effects: causes tachyarrhythmias and BP Elevation
 Lecture 7 - Adrenergic Antagonists

Adrenergic Antagonists (Blockers): Sympatholytic Agents that block adrenergic receptors (ɑ and β),
preventing stimulation of the Sympathetic Nervous System by catecholamines.
-​ Effects: blocking the SNS (fight–or–flight response) can result in lower blood pressure, reduced heart
rate, and vasodilation.

Blood Pressure Maintenance:

-​ Cardiac Output: blood released from the ventricles every minute, determining systolic blood pressure.
-​ Stroke Volume: the amount of blood ejected from the ventricles every heart beat.
-​ Total Peripheral Resistance (TPR): determines diastolic blood pressure
-​ Orthostatic (Postural) Hypotension: sudden change from supine to standing resulting from
blood pooling in the lower limb, minimized by reflex vasoconstriction in the legs.
-​ Sudden Rise in BP → cardiac brain centers → vagal nerve stimulation → reflex bradycardia
-​ Sudden Drop in BP → cardiac brain centers → sympathetic nerve stimulation → reflex tachycardia.

ɑ–Adrenergic Antagonists: these block ɑ–adrenergic receptors, which normally cause vasoconstriction.
-​ ɑ1 Blockers: in vessel smooth muscles → vasodilation → sudden drop in BP → reflex tachycardia
-​ ɑ2 Blockers: block pre–synaptic sympathetic nerves, resulting in ↑d norepinephrine release → β1
stimulation → ↑d heart rate and cardiac output → tachycardia

Non–Selective ɑ–Adrenergic Antagonists (ɑ1 + ɑ2): include Phenoxybenzamine & Phentolamine.

Phenoxybenzamine: non–selective (ɑ1 + ɑ2), non–competitive ɑ–adrenergic blocker. It treats…

-​ Pheochromocytoma: a catecholamine–secreting tumor from adrenal medulla cells. Epinephrine
interacts with both ɑ and β receptors → Phenoxybenzamine + β–blockers for treatment.
-​ Raynaud’s Disease: causes spasms in finger/toes blood vessels in response to cold temperatures or
stress → white and blue skin due to ischemia, relieved by
Phenoxybenzamine.
-​ Epinephrine Overdose
-​ Effect on Receptors: the body needs to form new
receptors over 24 hours.
-​ Adverse Effects: Reflex Tachycardia, Postural
Hypotension, Nasal Conjunction, and Inhibits Ejaculation

Phentolamine: non–selective (ɑ1 + ɑ2), competitive ɑ–Adrenergic blocker

-​ Effects: last for 4 hours after one injection, and are similar to those
of Phenoxybenzamine
-​ Therapeutic Uses: Pheochromocytoma Diagnosis and Short-Term
Management, Dermal Necrosis Antidote, Hypertensive Crisis (due
to withdrawal of clonidine or ingestion of tyramine in patients taking
monoamine oxidase inhibitors).

Side Effects of Non–Selective ɑ–Adrenergic Antagonists: Vasodilation Results in…

-​ Postural Hypotension and Reflex Tachycardia, Headache due to cranial vasodilation, ↓ Ejaculation due
to ↓ vasoconstriction, and Nasal Congestion.

Selective ɑ–Adrenergic Antagonists: Tamsulosin, Prazosin/Doxazosin, and Yohimbine (ɑ2 blocker).

Tamsulosin: ɑ1A selective, competitive antagonists in the prostate/bladder
-​ Effects: ↓ tone in smooth muscles of the bladder neck and prostate
→ ↑ Urine Flow, with less effects on blood pressure (↓ side effects).
-​ Use: Treatment of Benign Prostatic Hyperplasia (BPH)
-​ Side Effect: Floppy Iris Syndrome

Prazosin: ɑ1B selective, competitive blockers in blood vessels

-​ Effects: Vessel Relaxation → ↓ Peripheral Resistance → ↓ BP & ↓
Reflex Tachycardia
-​ Use: Treatment of Hypertension, but not as a monotherapy

Therapeutic Uses of ɑ1 Selective Antagonists

-​ First Dose Effect: the first dose of these drugs may result in orthostatic hypotension, minimized by
adjusting the first dose to ¼ dose at bedtime.
-​ Therapeutic Use: Hypertension, Lipid/Glucose Improvement

Adverse Effects of ɑ1 Selective Antagonists: First–Dose Orthostatic Syncope, Lack of Energy, Nasal
Congestion, Headache, Drowsiness, Sexual Dysfunction

Yohimbine: ɑ2 selective, competitive blockers which work in the CNS to ↑ sympathetic outflow.
-​ Use: Sexual Stimulant, and treating Erectile Dysfunction (not effective).

Competitive β–Adrenergic Antagonists (β–Blockers): block β–Adrenergic receptors, which are found in the
heart, lungs, and blood vessels. All β–Blockers lower blood pressure without inducing postural hypotension.
-​ β1 Blockers: in the heart, resulting in decreased inotropy, chronotropy, and overall depression.
-​ β2 Blockers: result in constriction of the bronchioles, GIT, bladder, uterus, and vascular muscles.
-​ β3 Blockers: in adipose tissue → decreased lipolysis.

Non–Selective β–Adrenergic Antagonists (β1 + β2): include Propranolol (short T1/2, cross BBB) and Timolol.
-​ Effects: block both heart (β1) and lung/vessel (β2) receptors,
resulting in overall cardiac depression, decreased blood pressure
without postural hypotension, bronchospasm (bronchial
constriction) due to parasympathetic overactivity, and overall
vasoconstriction from blocked sympathetic activity.
-​ Uses: Hypertension, Angina, Arrhythmias, Glaucoma and ↑ IOP
(Timolol), Migraine Prevention, Performance Anxiety, Tremors, MI.
-​ Contraindications: Diabetics (↑ risk of Hypoglycemic Coma due
to masked symptoms [tachycardia/tremors]), Asthma/COPD
patients (due to bronchospasm), Peripheral Vascular/Raynaud’s
Diseases (due to vasoconstriction → ischemia and intermittent
claudication [pain when walking due to ischemia] → use β1–selective blockers instead).

Selective β1–Adrenergic Antagonists: Atenolol, Metoprolol, and Esmolol (short T1/2) → Cardiac Depression.
-​ Uses: Chronic Heart Failure (Metoprolol), Arrhythmias (Esmolol; emergencies), Hypertension (safer).

β1 + β2 + ɑ1–Adrenergic Antagonists: have vasodilatory and cardiac depressor effects.

-​ Labetalol: used in hypertension in pregnancy (very safe)
-​ Carvedilol: used in heart failure (reduces heart workload) and has antioxidant protective properties.
 Lecture 8, 9 - Cell Wall Inhibitors

Bacterial Cell Wall Structure

-​ Gram Negative Cell Wall: a peptidoglycan layer, and an
outer membrane with highly selective porins.
-​ Gram Positive Cell Wall: a thick peptidoglycan layer.
-​ Both: contain a Periplasmic Space (where β–Lactamase
lies) in between the Peptidoglycan and Inner Cell
Membrane (with Penicillin Binding Peptide).

Resistance against Penicillins

-​ Natural (Innate) Resistance: where the organism lacks a peptidoglycan cell wall
(e.g. Fungi, Animal Cells, Mycoplasma, Mycobacteria, Chlamydia, Viruses).
-​ Acquired Resistance: where the bacteria was susceptible then became resistant.
1.​ β–Lactamase Production: inactivates penicillin by breaking a bond within
the Lactam Ring. It is mediated by plasmid DNA, which can be transferred.
2.​ Alteration of the Outer Membrane Porins, decreasing drug permeability
3.​ Increasing Efflux Pump Activity, which remove toxins from the cell
4.​ Alteration of the Penicillin–Binding Peptide, such as in MRSA and VRSA

Antibiotics acting on the cell wall of bacteria

-​ β Lactams: Penicillins, Cephalosporins, Carbapenems, Monobactams
-​ Glycopeptides: Vancomycin, Teicoplanin

Penicillins → Mechanism of Action:

1.​ Penicillins enter bacteria via the cell wall. Inside they bind to
Penicillin–Binding Protein (transpeptidase enzyme responsible for
peptidoglycan cross–linking) to disrupt normal cell wall synthesis.
2.​ Bacteria become hypoosmotic, swelling → burst.
-​ Penicillin is bactericidal, only active against actively proliferating bacteria.
-​ It is inactive against protozoa, mycobacteria, fungi, and viruses.

Penicillins
-​ Natural (Benzyle) Penicillins: Pen G (I.V.), Pen V (P.O.)
-​ Active against G+ Cocci, G+ Bacilli, G– Cocci (Gonococcus), and Spirochetes (T. Pallidum,
Syphilis). Penicillin G can also be combined with Procaine or Benzathine.
-​ Narrow Spectrum (Antistaphylococcal) Penicillins: Methicillin, (Di)Cloxacillin, Floxacillin, Oxacillin,
Naficillin. Anti–Staph Penicillins are not susceptible to β–Lactamase.
-​ Extended Spectrum (Amino) Penicillins: Ampicillin (I.V.), Amoxicillin (P.O.), Unasyn (Ampicillin +
Sulbactam), Augmentin (Amoxicillin + Clavulanic Acid).
-​ Active against G– Organisms (Except Pseudomonas), and weakly against G+ Organisms.
-​ Antipseudomonal Penicillins: Carbenicillin, Azlocillin, Timentin (Ticarcillin + Clavulanic Acid),
Zosyn/Tazocin (Piperacillin + Tazobactam).
-​ Active against P. Aeruginosa, and can be taken with an aminoglycoside for Pseudo. Septicemia.

Long–Acting Penicillins: some penicillins are given in depot forms (I.M slow release), such as Procaine Pen
G (which releases over 12–24 hours) and Benzathine Pen G (used to treat Rheumatic Fever; 3–4 Weeks).
-​ Use as Prophylaxis against Strep. Pyogenes (Rheumatic Fever), Artificial Valves (Endocarditis), and
after delivery for a newborn with Gonorrheal Conjunctivitis.
β–Lactamase Inhibitors: formulations with β–Lactamase Inhibitors protect Amoxicillin or Ampicillin from
enzymatic hydrolysis, extending their antimicrobial spectrum.
-​ Augmentin (P.O.): Amoxicillin + Clavulanic Acid
-​ Unasyn (I.V./I.M.): Ampicillin + Sulbactam

Pharmacokinetics of Penicillins

Absorption: most penicillins are poorly absorbed orally, except: Pen V, Amoxicillin, Augmentin, and Indanyl
Carbenicillin. They are given on an empty stomach (1 hour before/2 hours after food).
-​ Ampicillin is very poorly absorbed orally.

Distribution: penicillins are not lipid soluble, and so cannot cross the cell membrane or the blood brain barrier.
-​ Penicillins can only cross the BBB and Bone in inflammation (e.g. Meningitis, Osteomyelitis).
-​ If Penicillins cross the placenta, they are not teratogenic (very safe for pregnant women).

Metabolism & Excretion (very safe): excreted mainly unchanged in urine by active tubular secretion (except,
Nafcillin, Cloxacillin, Dicloxacillin, and Oxacillin, which are excreted through the liver).
-​ Half Life (T1/2) → 30–60 minutes, or 10 hours in Renal Failure
-​ Probenecid binds with the organic acid transport mechanism in the kidneys and inhibits Penicillins
tubular secretion, increasing the levels in their blood.
-​ Penicillins are also secreted in milk and in saliva.

Clinical Uses of Penicillins

1.​ Streptococcal Infections (Throat Infections,
Bacterial Endocarditis [Dental Surgery])
2.​ Staphylococcal Infections
3.​ Spirochetes (Syphilis) and Gonorrhoea
(Gram – Cocci)
4.​ Rheumatic Fever (Benzathine Penicillin G)
5.​ Diphtheria and Salmonella Infections
6.​ Prophylaxis in patients with Congenital Heart
Disease and Rheumatic Fever
-​ When Penicillin is given with
Aminoglycoside → Synergistic Effects

Penicillins – Adverse Effects

1.​ Type 1 Hypersensitivity Reactions (IgE–Immediate Reactions): any reactions that damage tissues,
occurring in 5–10% of all patients. Anaphylactic shock occurs in 1–3:10,000 of all patients.
-​ Antibiotic Skin Testing occurs intradermally on the forearm, with wheal and erythema acting as
the standard for a positive result due to degranulation of mast cells at the site of injection.
2.​ Diarrhea (Pseudomembranous colitis by C. Difficile due to Ampicillin): treated with Metronidazole or
Vancomycin orally.
3.​ Hypervitaminosis (Vitamin K)
4.​ Platelet Dysfunction: especially with Piperacillin, Nafcillin
5.​ May Cause Seizures if given intrathecally (spinally), and inhibit GABA (especially Procaine Pen G).

Patients with Penicillin Allergies are recommended to use…

-​ G + Organisms → Macrolides, Quinolones, or Vancomycin
-​ G – Organisms → Monobactams (Aztreonam)
Cephalosporins: β–Lactam antibiotics which bind to PBP to inhibit bacterial cell wall synthesis (Bactericidal).
-​ They are broad spectrum antibiotics which are more resistant to β–Lactamase.
-​ They are commonly used in surgical procedures to reduce the risk of post–operative infections.
-​ They are inactive against LAME + CD → Listeria Monocytogenes, Legionella, Atypical Bacteria
(Chlamydia, Mycoplasma), MRSA, Enterococci, and C. Difficile.

Cephalosporin Sub–Groups

First Generation Cephalosporins: Cefazolin, Cephalexin (P.O.), and Cephradine

-​ Active Against: G+ Organisms: S. Aureus, Pneumonia, Pyogenes, Epidermidis, and Streptococcal
Pharyngitis, with moderate activity against G– Organisms (E. Coli, K. Pneumoniae).
-​ They do not cross the BBB, and are used as surgical prophylaxis.

Second Generation Cephalosporins: Cefclor, Cefoxitin, Cefprozil, Cefuroxime

-​ Active Against: G– Organisms (H. Influenza, Moraxella Catarrhalis, S. Pneumonia) and Intestine
Anaerobes (Bacteroides Fragilis) with moderate activity against G+ Organisms.
-​ They are NOT active against P. Aeruginosa.
-​ Use: URTIs (Acute Otitis Media, Sinusitis, Laryngitis) and LRTIs (Chronic Bronchitis, COPD)

Third Generation Cephalosporins: Cefotaxime, Ceftriaxone, Ceftazidime, Cefixime (P.O.), Cefoperazone

-​ Active Against: G– Organisms (H. Influenza, N. Gonorrhoeae, E. Coli, N. Meningitidis, M. Catarrhalis,
Klebsiella Pneumoniae, and P. Aeruginosa) and are
less active against G+ Organisms.
-​ They cross the BBB, except Cefixime and
Cefoperazone.

Fourth Generation Cephalosporins: Cefepime (I.V.)

-​ Active Against: Wide Spectrum, including G+
Organisms G– Organisms, and P. Aeruginosa.
-​ They cross the BBB, and are resistant to most
β–Lactamases.

Pharmacokinetics of Cephalosporins
-​ Administration: mostly parenterally, but some are available for oral use.
-​ Blood–Brain Barrier: only the third and fourth generation cephalosporins can cross the BBB.
-​ Cephalosporins are relatively lipid–insoluble (like penicillins).
-​ Elimination: Renal Excretion
-​ Probenecid inhibits elimination, increasing its blood levels (except Ceftazidime, Cefoperazone).
-​ Half Life (T1/2) → 30–90 Minutes (Ceftriaxone T1/2 → 4–7 hours)

Clinical Uses (MOST URGENT)

-​ M: Meningitis -​ U: UTIs -​ N: iNtestinal Infections
-​ O: Osteomyelitis -​ R: RTIs -​ T: Topical
-​ S: Skin Infections -​ G: Gonorrhea
-​ T: Typhoid Fever -​ E: ENT Infections

Cephalosporins – Adverse Effects (Similar to Penicillins): About 5–10% of patients with penicillin allergies
show cross–sensitivity to cephalosporins. Therefore, patients with a history of anaphylaxis to penicillins cannot
be prescribed cephalosporins.
Carbapenems: β–Lactam antibiotics which bind to PBP to inhibit bacterial cell wall synthesis (Bactericidal).
-​ Members: Imipenem + Cilastatin (Gram + Cocci), Meropenem (Gram – Rods), Ertapenem
-​ Activity Against: Active against almost everything, and are used as a last resort.
-​ They can cross the BBB

Pharmacokinetics of Carbapenem:
-​ Absorption: they are not absorbed orally, and given only intravenously
-​ Metabolism: they are inactivated by the Renal Dehydropeptidase–I enzyme, which is why they are
given with Cilastatin, which inhibits the enzyme, to increase the plasma drug level.
-​ Excreted: Primarily by the Kidney
-​ Half Life (T1/2) → 1 hour

Clinical Uses: Carbapenems are used in Empiric Therapy, for infections that require multiple antibiotics
(nosocomial [hospital–induced] infections). MRSA is one microbe that is resistant.

Adverse Effects of Carbapenems:

-​ CNS Toxicity at High Plasma Levels (Confusion, Seizures).
-​ Meropenem is not metabolized by the Renal Dehydropeptidase–I enzyme, and is less likely to
cause seizures than Imipenem (Meropenem > Imipenem).
-​ Patients allergic to Penicillins/Cephalosporins may also be allergic to Carbapenems.

Monobactams (Aztreonam): similar to other β–Lactam antibiotics.

-​ Activity Against: G – Aerobic Rods (Klebsiella, Pseudomonas, H. Influenza, N. Gonorrhoeae, Serratia,
N. Meningitidis, and Enterobacteriaceae).
-​ They cannot cross the BBB, with very limited CSF penetration.
-​ Adverse Effects: Similar to other β–Lactam antibiotics.

Pharmacokinetics of Monobactams:
-​ Administration: IV, IM.
-​ Excretion: primarily by the Kidney
-​ Half Life (T1/2) → 2 hours

Clinical Uses: Alternative choice for Penicillin– and Cephalosporin–Allergic Patients for G– Infections.
-​ It can also be used as an alternative for aminoglycosides, in the elderly with renal impairments.

Glycopeptides: Vancomycin, Daptomycin, Bacitracin, Metronidazole, Linezolid

-​ Mechanism: they inhibit cell wall synthesis by inhibiting transglycosylation reactions (Bactericidal).
-​ Active Against: Aerobic and Anaerobic G+ Organisms (Staphylococci, MRSA, C. Difficile). They are
not effective against G– Organisms because they are too large to penetrate the outer membrane.

Pharmacokinetics of Glycopeptides:
-​ Absorption: given IV or Orally (in C. Difficile–associated colitis), and it is not absorbed from the GIT.
-​ Distribution: widely distributed, even in CSF during inflammation
-​ Elimination: Excreted unchanged in the urine.
-​ Half Life (T1/2) → 8 hours
Clinical Uses
1.​ Staphylococcal Infections caused be MRSA or MRSE
2.​ Prophylaxis for common procedures
3.​ Antibiotic–associated colitis (Metronidazole)
4.​ Daptomycin, Linezolid → Vancomycin–Resistant Staph Infections
5.​ Bacitracin → used for skin infections (topically) only due to its nephrotoxicity

Adverse Effects: Chills, Fever, Phlebitis at injection site, Ototoxicity, Nephrotoxicity, Red Man Syndrome due
to rapid I.V. infusion (Vancomycin → should be at least over 60 minutes), and Rhabdomyolysis (Daptomycin).

Linezolid: binds to 23S RNA of 50S ribosomal subunit, inhibiting the formation of the 70S initiation complex.
-​ Adverse Effects:
-​ Serotonin Syndrome is given with lots of tyramine–containing foods, Selective Serotonin
Reuptake Inhibitors (SSRIs), or Monoamine Oxidase Inhibitors
-​ Irreversible peripheral neuropathies and optic neuritis (→ Blindness) with over 28 days of use.

Metronidazole (Flagyl): it destroys bacterial or parasitic DNA

-​ Uses: Gram – Anaerobes
-​ Adverse Effects: Nausea, GI Upset, Metallic Taste.
 Lecture 10 - Protein Synthesis Inhibitors

Inhibitors of Protein Synthesis

1.​ Chloramphenicol: Binds to the 50S portion of
the ribosome to inhibit peptide bond formation.
2.​ Erythromycin (Macrolide): Binds to the 50S
portion of the ribosome, to prevent
translocation via inhibition of the ribosome
movement along mRNA.
3.​ Tetracycline: Interfere with attachment of
tRNA to mRNA–ribosome complex.
4.​ Streptomycin (Aminoglycoside): changes the
shape of the 30S portion of the ribosome,
causing incorrect codon reading of the mRNA.

Tetracyclines (Bacteriostatic): reversibly bind to 30S bacterial ribosomal subunits leading to the inhibition of
binding of tRNA to the mRNA complex → inhibiting bacterial protein synthesis.
-​ Members: Tetracycline, Doxycycline, Minocycline, Demeclocycline
-​ Tetracycline Uses: Broad–Spectrum; Gram + and –
-​ Gram – Rods → V. Cholerae [Cholera], H. Pylori [Peptic Ulcer
Disease], B. Burgdorferi [Lyme Disease], Mycoplasma
Pneumoniae, Chlamydia, Rickettsia [Rocky Mountain Spotted
Fever])
-​ Demeclocycline Uses: treats excess production of ADH (SIADH)

Pharmacokinetics of Tetracyclines:
-​ Absorption: incompletely orally absorbed, except for Minocycline and
Doxycycline which are almost completely absorbed. Absorption is
decreased by food due to non–absorbable chelate formation.
-​ Distribution: they penetrate the BBB in insufficient concentrations,
except Minocycline which is effective for meningococcal carrier states
only, and not for CNS infections.
-​ Bind to tissues that undergo calcifications → concentrated in teeth
and bones, causing deformities in children up to 8 years old
(Teratogenic, causing fetal bone deformities).
-​ Metabolism & Excretion: unchanged in urine, except Doxycycline which
is eliminated by bile.

Adverse Effects and Contraindications

-​ Gastric Discomfort due to gastric irritation, potentially causing non–compliance.
-​ Tooth Discoloration and Bone Hypoplasia (Stunting growth) → should be avoided in pregnancy and
must not be taken with Ca2+–rich foods.
-​ Fatal Hepatotoxicity in renal dysfunction or pregnant females receiving high doses
-​ Vestibular Dysfunction → Dizziness, Vertigo, and Tinnitus with Minocycline (accumulates in the ear).
-​ Phototoxicity, Superinfection, and Renal Dysfunction
Glycylcycline (Tigecycline): derivative of minocycline, it binds to the 30S subunit to inhibit protein synthesis.
-​ Tigecycline (I.V.) Uses: Broad Spectrum; Gram + (MRSA and Enterococci), Gram –, Anaerobes, and
Atypical Organisms. (No activity against the 3P’s → Pseudomonas, Proteus, and Providencia Species).
-​ Pharmacokinetics: Lipophilic and a High Volume of Distribution → Poor Serum Concentrations, and
should not be used for Endovascular Infections, such as Bacteremia or Endocarditis.
-​ Uses: Complicated Skin and Intra–Abdominal Infections (Abscesses, Burns, Appendicitis), and
Community–Acquired Bacterial Pneumonia (S. Pneumoniae, H. Influenzae, Legionella Pneumophila).
-​ Adverse Effects: Hepatotoxicity, Pancreatitis, Photosensitivity, Teeth Discoloration in Kids, Increase
Risk of Death (Last Resort), and increase the INR in patients taking Warfarin.

Aminoglycosides (Bactericidal): 2 amino sugars connected by glycosidic bonds to a central hexose nucleus.
-​ Members: Streptomycin, Gentamicin, Tobramycin, Amikacin, Neomycin.
-​ Mechanism: binds to the 30S subunit to inhibit protein synthesis by inhibiting initiation complex
formation, misreading of codons, and breakdown on polysomes.
-​ Characteristics: they have concentration–dependent killing, exponentially increasing the number of
killed bacteria at a more rapid rate. They also have a post–antibiotic effect, inhibiting bacterial growth
even after concentrations have fallen below the minimum–inhibitory conc., enabling once–daily dosing.
-​ Uses: Most Aerobic Gram – Organisms, TB and Plague (Streptomycin, IM), Tularemia (Gentamicin),
and for Empirical Treatment (Synergistic) with β–Lactam or Vancomycin.
-​ It is ineffective against Anaerobes and Meningitis.

Pharmacokinetics of Aminoglycosides:
-​ Absorption: not absorbed orally, and must be given parenterally to achieve adequate serum levels.
-​ Neomycin is not given due to severe nephrotoxicity (given topically or orally).
-​ Distribution: don't cross the BBB, but they do cross the placental barrier and are concentrated in fetal
plasma, renal cortex, perilymph & endolymph of the inner ear → Nephrotoxicity and Ototoxicity.
-​ Excretion: unchanged through the kidney, so dose must be adjusted in renal dysfunction.

Aminoglycosides – Adverse Effects:

-​ Ototoxicity (Irreversible): due to high plasma levels and duration due to accumulation in the ear.
-​ Nephrotoxicity (Reversible)
-​ Neuromuscular Paralysis: due to rapid increase in concentrations or administration with neuromuscular
blockers (Myasthenia Gravis → Increase Risk). Reversible by Calcium Gluconate or Neostigmine.
-​ Allergic Reactions: contact dermatitis is a common reaction to topically–applied Neomycin.

Macrolides (Bacteriostatic; Bactericidal at high doses): irreversibly binds to 50S

subunit to prevent translocation via inhibition of the ribosome movement along mRNA.
-​ Members: Erythromycin, Clarithromycin (methylated Erythromycin),
Azithromycin (larger lactone ring), Telithromycin (Semisynthetic Derivative of
Erythromycin).
-​ Erythromycin Uses: Drug of Choice for Penicillin–Allergic Patients, Gram +
Cocci/Bacilli alternatives to Penicillin/Cephalosporin/Tetracycline, Chlamydia
(pregnancy), Mycoplasma (kids), Spirochetes.
-​ Clarithromycin Uses: similar to Erythromycin, including H. Influenzae, with stronger activity against
intracellular pathogens, like Chlamydia, Legionella, Moraxella, and H. Pylori, than Erythromycin.
-​ Azithromycin Uses: more active against RTIs (H. Influenzae), Urogenital Chlamydia (Urethritis), and
Drug of Choice for Legionellosis.
Pharmacokinetics of Macrolides:
-​ Absorption: all are orally absorbed orally, except
Erythromycin (enteric/esterified forms used).
-​ Distribution: Erythromycin diffuses everywhere
except the CSF, accumulating in Macrophages
and Neutrophils. Azithromycin has the longest half
life (taken once daily).
-​ Metabolism & Excretion: mainly by the Liver (not
excreted in the kidney).

Macrolides – Adverse Effects

-​ Cholestatic Jaundice: especially with Erythromycin Estolate (not used in patients with liver dysfunction).
-​ Ototoxicity: Erythromycin → Deafness at High Doses; Azithromycin → Irreversible Hearing Loss.
-​ QT Interval Prolongation
-​ Inhibition of P450 Mechanism in the Liver → Drug Interactions.

Clindamycin (Bacteriostatic): similar to macrolides, using the same mechanism (binds to the 50S subunit).
-​ Active Against: most Gram + Bacteria, Anaerobes (Bacteroid Fragilis), Bone Infections (good
penetration into bone). Clindamycin is a leading cause of Clostridium Difficile Super–Infections.

Clostridium Difficile: when antibiotics kill normal healthy GI flora, Clostridium Difficile can proliferate causing
drug–resistant superinfections (such as Clostridioides), and produce toxins that inflame the GI mucosa.
-​ Symptoms can be mild (loose stool, abdominal cramping) to severe (pseudomembranous colitis).
-​ Recently, C. Diff infections have become more common, severe, and difficult to treat.
-​ Treatment: Vancomycin (oral), Fidaxomicin, and Metronidazole

Chloramphenicol: binds reversibly to the 50S subunit → inhibits translocation at peptidyl transferase reaction.
-​ Side Effects: Dose–Related Anemia, Hemolytic Anemia (in G6P DH deficiency), and Aplastic Anemia.
-​ Gray Baby Syndrome: Neonates have decreased ability to excrete Chloramphenicol as it is
metabolized by Glucuronyl Transferase in the liver, which is decreased in neonates → accumulating
levels → Bone Marrow Suppression and Cyanosis.
 Lecture 11 - Nucleic Acid Synthesis Inhibitors

Quinolones:
-​ First Generation: Nalidixic Acid
-​ Second Generation: Fluoroquinolones →
Ciprofloxacin, Norfloxacin, Ofloxacin, Pefloxacin
-​ Third Generation: Levofloxacin (Tavanic),
Gatifloxacin, Sparfloxacin
-​ Fourth Generation: Trovafloxacin, Moxifloxacin

Mechanism of Quinolone Action (Bactericidal):

Quinolones inhibit DNA gyrase (Topoisomerase II),
responsible for DNA unwinding before replication (more
important in Gram – Organisms) and Topoisomerase IV, required for cell division (Gram + Organisms).
-​ Cross–Resistance (altered target/decreased accumulation) exists among quinolones

Pharmacokinetics
-​ Absorption: not completely absorbed when orally administered (35–70% for Norfloxacin, 85–95% for
others). When Quinolones are given parenterally, the binding to plasma proteins → 10–40%.
-​ Levofloxacin and Moxifloxacin have the longest half lives → once daily dosing.
-​ Absorption is affected by Sucralfate, Antacids, or dietary supplements with Al, Mg, Fe, Zn, or Ca
-​ Distribution: well distributed into all tissues, while penetration into CSF is low (except for Ofloxacin).
-​ Excretion: via the renal route, while Moxifloxacin is excreted mainly by the liver.

Antibiotic Spectrum Treats

-​ Mainly Gram – Organisms: Pseudomonas, H. 1.​ Typhoid & Traveler’s Diarrhea.

Influenza, E. Coli, Moraxella, Chlamydia, Legionella. 2.​ UTIs via Gram – Bacilli.
-​ Effective against β–Lactamase producing 3.​ Prostatitis (Norfloxacin and
Gonococci, and is less effective against Gram + Levofloxacin).
Organisms. 4.​ Gonorrhea [NOT Syphilis] (Ofloxacin
-​ Second Generation: active against Gram – Aerobes, and Levofloxacin).
some Gram + Organisms, & atypical Mycoplasma. 5.​ RTIs via S. Pneumonia (Respiratory
-​ Third Generation: increased activity against Gram +, Fluoroquinolones → Levofloxacin,
Atypical, and some Anaerobic Organisms. Trovafloxacin, Moxifloxacin,
-​ Fourth Generation: active against Aerobic and Gatifloxacin, but NOT Ciprofloxacin).
Anaerobic Gram – and + Organisms 6.​ Bone and Soft Tissue Infections.

Ciprofloxacin: prophylaxis and treatment of anthrax. Levofloxacin

-​ Most potent for Pseudomonas Infections -​ Broad Spectrum Activity; Skin Infections,
-​ Effective against Traveler’s Diarrhea and TB Acute Sinusitis, Chronic Bronchitis
-​ Effective against Systemic Infections, not MRSA, -​ Treatment of Prostatitis, STDs
Enterococci, and Pneumococci. -​ Treatment of RTIs due to S. Pneumonia.

Norfloxacin Moxifloxacillin

-​ Effective against Gram – and + Organisms -​ Active Against Anaerobic and Gram +
-​ Effective against UTIs and Prostatitis Organisms
-​ Not Effective against systemic infections -​ Very poor activity against P. Aeruginosa.
Adverse Effects:
1.​ GIT Disturbances (most common)
2.​ CNS Symptoms → Headache, Dizziness
3.​ Phototoxicity
4.​ Ciprofloxacin → interferes with Theophylline absorption, and may evoke seizures.
5.​ Trovafloxacin → Nephrotoxicity & Hepatotoxicity, and so is reserved for serious infections.
6.​ Arthropathy (Cartilage Damage; Tendinitis) in children under 18, adults over 60, patients undergoing
steroid therapy, or those with Heart/Kidney/Lung Transplants.

Contraindications: in Pregnancy, Lactation, and patients less than 18 years old.

-​ Sparfloxacin, Gatifloxacin, Levofloxacin, Moxifloxacin → Prolong QT Intervals, so should not be used in
those with dysrhythmia predispositions.

Drug Interactions
-​ Absorption: affected by antacids and cations
-​ Metabolism: Ciprofloxacin inhibits Theophylline metabolism; 3rd/4th generations increase
concentrations of warfarin, caffeine, and cyclosporine.
-​ Elimination: interfered with by Cimetidine

Resistance
-​ Altered Targets: mutations in Bacterial DNA Gyrase/Topoisomerase IV → ↓ fluoroquinolone affinity.
-​ Decreased Intracellular Accumulation: decreased porin proteins in the outer membrane → ↓ access.

Folate Antagonists

Sulfonamides:
-​ Members: Sulfadiazine, Sulfamethoxazole, Sulfadoxine, Sulfacetamide, Sulfisoxazole, & Sulfasalazine.
-​ Mechanism (Bacteriostatic): a structural analog of PABA, they compete with it on the dihydropteroate
synthase enzyme, leading to Folate, DNA, and RNA synthesis inhibition.
-​ Human Cells utilize already formed Folic Acid → Sulfonamides do not affect them.

Pharmacokinetics
-​ Absorption: all are orally absorbed except sulfasalazine, which is why it is used in chronic IBDs.
-​ Distribution: Highly Plasma Protein Bound (depends on pKa), crossing the BBB and placental barrier.
-​ Metabolism: acetylated in the liver into metabolites that can cause crystalluria (pH = 0–7)
-​ Excretion: by glomerular filtration (affected by renal dysfunction).

Therapeutic Uses:
1.​ Eye Infections → Topical Sulfacetamide
2.​ Burns → Topical Silver Sulfadiazine
3.​ Ulcerative Colitis → Sulfasalazine linked to Sulfapyridine (not absorbed).
4.​ Toxoplasmosis → Sulfadiazine
5.​ Chloroquine–Resistant Malaria → Sulfadoxine + Pyrimethamine
6.​ Urinary Tract Infections → Enterbacteria + Nocardia, but Trimethoprim/Co–Trimoxazole are preferred.
Adverse Effects
-​ Crystalluria & Nephropathy: due to insoluble metabolite condensation, avoided by increasing fluid
intake, alkalinization of urine, or the use of more soluble agents like Sulfisoxazole.
-​ Hypersensitivity Reactions: Skin Rash, Erythema Multiforme, Steven–Johnson Syndrome (severe)
-​ Hematopoietic Disturbances: Granulocytopenia and Thrombocytopenia, Hemolytic Anemia (in G6PD).
-​ Kernicterus: Sulfonamides displace Bilirubin from Plasma Protein, which causes Bilirubin to cross the
BBB (immature in neonates) → CNS → contraindicated in neonates and pregnant women.
-​ Drug Interactions: increased plasma levels of oral hypoglycemic drugs and anticoagulants dye to
plasma protein displacement → ↑ Levels of Methotrexate.

Trimethoprim: 20–50x more potent than Sulfonamides

-​ Mechanism: inhibits Dihydrofolate Reductase, which converts Folic
Acid → Tetrahydro–Folic (Folinic) Acid, essential for DNA synthesis.
-​ It is 50,000x less efficient in Human Cells → barely affects it.
-​ Antibacterial Spectrum: same as Sulfamethoxazole.
-​ Used in: UTIs, Prostatitis, and Vaginitis.

Adverse Effects
1.​ Megaloblastic Anemia → due to folate deficiency
a.​ Reversed by administration of Folinic Acid
2.​ Granulocytopenia.
3.​ Leucopenia, especially in pregnant women and those with very poor
diets.

Co–Trimoxazole (Bacteriostatic): combination of Sulfamethoxazole (400 mg) + Trimethoprim (80 mg) [5:1].
-​ Mechanism: synergistic action, due to inhibition of two steps in Folinic Acid Synthesis.
-​ Advantages: More Potent, Synergistic,
Delayed Bacterial Resistance, Wider
Spectrum against U/RTIs.

Therapeutic Uses:
-​ Urinary Tract Infections, Gonococcal
Urethritis, Prostatitis, and Vaginitis.
-​ GIT infections → Salmonella and Shigella
-​ RTIs due to H. Influenza and S. Pneumonia
-​ Pneumocystis Jirovecii Pneumonia in AIDS
→ most effective therapy.

Adverse Effects: same as Sulfonamides and Trimethoprim

1.​ Dermatologic: very common, which may be serious in the elderly
2.​ Hematological: Megaloblastic Anemia, Granulocytopenia, Leucopenia, and Hemolytic Anemia
3.​ GIT Disturbances
4.​ In AIDS → Fever, Rashes, Diarrhea and/or Pancytopenia.
5.​ Interactions with Phenytoin, Methotrexate, and Warfarin.
 Lecture 12 - Antiviral Drugs

Treatment of Respiratory Virus Infections (e.g. Influenza A/B and Respiratory Syncytial Virus [RSV])

Neuraminidase Inhibitors: include Oseltamivir and Zanamivir (Sialic Acid analogues), sold as Tamiflu.
-​ Mechanism: decrease the duration and severity of the disease if administered early (24–48 hrs) after
infection, by inhibiting the neuraminidase enzyme → preventing the release of new virions.
-​ Use: effective against both influenza A and B (they don’t interfere with influenza A vaccines).
-​ Pharmacokinetics: Oseltamivir is active orally, while Zanamivir is taken inhaled or taken intranasally.
-​ Adverse Effects: GIT Upset (Oseltamivir), Respiratory Tract Irritation (Zanamivir), and Resistance.

Inhibitors of Viral Uncoating: include Amantadine and Rimantadine, given as supplements to vaccination.
-​ Mechanism: inhibits the uncoating or viral RNA and release of new virions into host cells.
-​ Use: effective against influenza A and in Parkinson’s (Amantadine).
-​ Pharmacokinetics: given orally, Amantadine crosses the BBB, while Rimantadine doesn’t (longer T1/2).
-​ Adverse Effects: Amantadine causes CNS symptoms (insomnia, ataxia, convulsions), while
Rimantadine doesn’t. Both cause CNS Upset and are Teratogenic.

Ribavirin: a guanosine analogue triphosphate by host cell kinases, inhibiting viral mRNA capping and RNA
polymerase, which inhibits replication of many RNA/DNA Viruses (Rhinoviruses/Enteroviruses are resistant).
-​ Uses: effective against influenza A and B, RSV in children, Viral Hepatitis C, and Lassa Virus.
-​ Pharmacokinetics: taken orally/IV/aerosol, doesn’t cross the BBB, and is excreted in urine.
-​ Adverse Effects: GIT Upset, Respiratory Irritation, Teratogenicity, Dose–Dependent Hemolytic Anemia.

Anti–Hepatitis Agents (e.g. against Hepatitis A/B/C/D/E Viruses)

Interferon: induces host enzymes that inhibit viral RNA translation → stops replication of the virus.
-​ Uses: Hepatitis C (with Ribavirin) and Genital Warts.
-​ Pharmacokinetics: Not active orally, metabolized by the liver, dosing is once a week.
-​ Adverse Effects: Severe, including Myalgia, Arthralgia, Bone Marrow Depression, Severe Fatigue,
Irreversible Nephrotoxicity, Hepatic Failure, CHF, Myelosuppression.

Lamivudine: Inhibits both Hepatitis B Virus (HBV) DNA Polymerase and HIV Reverse Transcriptase.
-​ Uses: Hepatitis B (alone, NOT with interferon) and HIB
-​ Pharmacokinetics: orally active, well distributed, excreted in urine (dose adjustment in renal failure).
-​ Chronic Treatment improves biochemical markers and reduces hepatic inflammation.

Adefovir and Entecavir: discontinued as they makes severe hepatitis worse after discontinuation of the
medication (25%), and are dangerous in renal failure, but they can also be used for Hepatitis B.

Treatment of Herpes Virus Infections (e.g. cold sores, viral encephalitis, genital infections).

Herpes Drugs: nucleotide analogues that inhibit DNA synthesis, except Foscarnet and Fomivirsen, only active
during the acute phase of viral infections.

Valacyclovir: rapidly converted into acyclovir after oral administration → 3-5x higher bioavailability, with similar
or slightly more efficacy than acyclovir. It may result in GIT Manifestations or Thrombocytopenic Purpura
Acyclovir (Zovirax): gold standard for herpes, which phosphorylated by host cell kinase into its active
triphosphate form → inhibits viral DNA polymerase and terminates DNA chain elongation.
-​ Uses: Varicella Zoster Infections , Herpes Simplex 1/2 Infections (HSV Encephalitis [DOC]).
-​ Pharmacokinetics: Well Distributed (Crosses the BBB), Partially Metabolized, and excreted in urine.
-​ Adverse Effects: GIT Upset (when given Orally), Local Inflammation due to Crystalluria (when given
IV), Stinging Sensation (when given Optically), Headache, CNS Effects, and Resistance.

Treatment of Cytomegalovirus Infections (Ganciclovir): phosphorylated by host cell kinase into its active
triphosphate form → inhibits viral DNA polymerase and terminates DNA chain elongation.
-​ Uses: DOC for life–threatening CMV pneumonia or retinitis (ocular implants in immunocompromised).
-​ Pharmacokinetics: IV Administered, Well Distributed (Crosses the BBB), and Excreted in Urine.
-​ Adverse Effects: Myelosuppression, Neutropenia (when given with zidovudine or azathioprine),
potential carcinogenicity and teratogenicity, vitreous hemorrhage and retinal detachment.

Treatment of AIDS: the most effective combinations (highly active anti–retroviral therapy [HAART]) of two
nucleoside reverse transcriptase inhibitors (NRTIs) with either a non–nucleoside reverse transcriptase inhibitor
(NNRTI) or a protease inhibitor (PI) → very effective suppression of viral replication and immune restoration.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs): phosphorylated by host cell kinase into their active
triphosphate forms → competitive inhibition of HIV–1 Reverse Transcriptase, incorporated into the growing
viral DNA chain to cause its termination, and causing fatal hepatic toxicity (Lactic Acidosis and Hepatomegaly).
1.​ Zidovudine: well distributed, it is used in pregnancy to prevent prenatal infection.
-​ Adverse Effects: Myelosuppression, Neurotoxicity, Megaloblastic Anemia, Myopathy,
Neurotoxicity which increases with drugs metabolized in the liver (avoid Ribavirin/Stavudine).
2.​ Didanosine: should be given 2 hours after drugs that require acidity to be absorbed
-​ Adverse Effects: Dose–Dependant Pancreatitis, Neuropathy, Hepatitis, Hyperuricemia, CNS.

Non–Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): bind directly to a site on HIV–1 Reverse
Transcriptase → blockade of RNA–dependent DNA polymerases (not competitive or phosphorylated).
1.​ Nevirapine: prevents vertical transmission of HIV (Zidovudine substitute).
-​ Adverse Effects: Stevens–Johnson Syndrome, Toxic Epidermal Necrolysis (Life–Threatening
Dermatological Effects), Fatal Hepatotoxicity.
2.​ Efavirenz: mainly CNS adverse effects
3.​ Etravirine: Second Generation NNRTI, active against many strains resistant to the first generation.

Protease Inhibitors (PIs; e.g. –navirs): disrupt the virus–specific proteases (HIV–aspartyl protease) which
cleave viral polypeptides into mature structural and functional viral proteins.
1.​ Ritonavir: used as a pharmacokinetic enhancer (‘booster’) of other protease inhibitors → higher levels
of boosted protease inhibitors, preventing resistance.
-​ Adverse Effect: inhibits CYP3A, increases the bioavailability of the boosted protease inhibitor.
2.​ Cobicistat: boosts HIV–1 Protease Inhibitors (e.g. Darunavir), inhibits CYP3A enzymes.
-​ Adverse Effects: GIT Disturbances, Increased Triglycerides/LDL, Glucose Intolerance, Enzyme
Inhibition and Serious Drug Interactions, Cushingoid Fat Distribution, Kidney Stones (Indinavir).

Viral Fusion (Entry) Inhibitors → Enfuvirtide Intergrase Inhibitors → Raltegravir

 Lecture 13 - Antifungal Drugs

Superficial Fungal Infections: Include Dermatomycosis (Cutaneous Mycoses) and Candidiasis.

Deep Fungal Infections: include Aspergillus, Cryptococcus,
Candida, Blastomyces, Histoplasma.

Deep Fungal Infections

Amphotericin B: binds to ergosterol in fungal cell membranes →

form amphotericin pores → disturb cell membrane permeability →
leakage of intracellular ions and enzymes → cell death (fungicidal).
-​ Use: DOC in Cryptococcal Meningitis, Mycotic Corneal
Ulcers and Keratitis, Fungal Arthritis
-​ Resistance: due to decreased ergosterol content.
-​ Pharmacokinetics: Given by Slow IV Infusion of Intrathecally in Meningitis, 90% is plasma protein
bound, Widely distributed (Crosses Placenta, not BBB), Metabolized in the Liver (T1/2 → 2 weeks).
-​ Adverse Effects: Rigors and Fever (prevented by Corticosteroids and
NSAIDs), Hypersensitivity, Anaphylaxis, Hypotension w/ Hypokalemia,
Delayed Nephrotoxicity w/ sodium depletion, Delayed Thrombophlebitis,
CNS Stimulation.

Flucytosine → 5–FU → 5F–dUMP, which inhibits thymidylate synthase →

5F–dTMP, inhibiting DNA/RNA Synthesis (Synergistic w/ Amphotericin B,
combined w/ Itraconazole for Chromoblastomycosis).
-​ Use: narrow spectrum antifungal drug, working on Candida Albicans,
Cryptococcus Neoformans, and Molds causing Chromoblastomycosis.
-​ Pharmacokinetics: given orally, well distributed (crosses BBB).
-​ Adverse Effects: Bone Marrow Depression, Alopecia (reversible),
Hepatic Dysfunction. GIT Upset.

Azoles:
-​ Imidazoles: Ketoconazole (Systemic and Topical), Miconazole (Topical → Athlete’s Foot), Clotrimazole
(Topical → Vaginal Yest, Oral Thrush, Ringworm) → less selective, more adverse effects/interactions.
-​ Triazoles: Fluconazole, Itraconazole (Aspergillus), and Voriconazole (Invasive Aspergillosis) → broad
spectrum fungistatic drugs (less toxic than amphotericin B).
-​ Mechanism: inhibit fungal cell membrane synthesis through inhibition of Cytochrome P450
dependent C14–ɑ demethylase enzyme, essential for conversion of lanosterol → ergosterol.

Ketoconazole: first broad spectrum oral antifungal drug, active against superficial/systemic fungal infections
such as candida, histoplasma, blastomyces, coccidioides, but NOT aspergillus and fungal meningitis (cannot
cross the BBB), and is used in androgen–dependent cancer (inhibits gonadal/adrenal steroid synthesis).
-​ Pharmacokinetics: given orally, requiring gastric acidity for absorption (doesn’t cross the BBB),
metabolized in the liver, and excreted via vile, with low therapeutic index [toxic].
-​ Adverse Effects: dose–dependent GIT Upset, Hepatotoxicity, inhibits gonadal/adrenal steroid
synthesis resulting in gynecomastia, decreased libido, and fertility, pruritus and skin rash, teratogenic.
-​ Drug Interactions: H2 Blockers, Antacids, and Proton Pump Inhibitors decrease its absorption.
-​ Enzyme Inhibition → Increase Levels and Toxicity of Phenytoin and Warfarin.
-​ Serious Cardiac Effects when given with Antihistamines (e.g. Astemizole).
-​ Cannot be given with Amphotericin B as it makes A.B. less effective.
Echinocandins Caspofungin: active against Aspergillus and most Candida species (even resistant ones),
and should be administered by slow IV infusion over 1 hour (don’t give with cyclosporine).

Fluconazole: broad spectrum, DOC in Cryptococcus Neoformans, Sandidemia, and Coccidiomycosis,

Esophageal/Oropharyngeal/Vaginal Candidiasis, and prophylactic in bone marrow transplants or AIDS.
-​ Adverse Effects: GIT Upset, Hepatitis (Rare),
Enzyme Inhibition, Teratogenic
-​ Differs from Ketoconazole: absorption doesn’t
depend on acidity, good bioavailability and BBB
penetration, No endocrine adverse effects, kidney
excretion, least effect of azoles on drug metabolism.

Voriconazole: broad spectrum, DOC in Invasive

Aspergillosis (not Amphotericin B), given IV or Orally
-​ Adverse Effects: Visual and Auditory Hallucinations

Superficial Fungal Infections

Terbinafine: DOC for treating Dermatophytes (especially of nails

[Onychomycosis]) and Candida Albicans. It is better tolerated, shorter duration
of action (3 months), and more effective than Griseofulvin and Itraconazole.
-​ Mechanism: inhibits fungal squaline epoxidase, which converts
squalene to ergosterol → accumulation of toxic squalene → cell death.
-​ Pharmacokinetics: orally acid, deposited in skin, nails, fat, and breast
milk (not for lactating mothers), and metabolized in the liver before
excretion via urine (no drug interactions).
-​ Adverse Effects: GIT Disturbances are most common, Headache,
Pruritus, Rash, Joint/Muscle Pain, Hepatitis (rare), Visual and Taste
Hallucinations.

Nystatin: similar to Amphotericin B, used topically for Oral Thrush (Candida Infection) due to systemic toxicity.
-​ It is not absorbed systemically → acts locally after oral administration to treat oral candidiasis.

Miconazole, Clotrimazole: rarely used due to systemic toxicity → Oral Thrush, Vuvlovaginal Candidiasis,
Tinea Cruris/Corporis/Pedis (Athlete’s Foot).
-​ Miconazole is a potent enzyme inhibitor → accumulation of warfarin → bleeding, even if given topically.

Ketoconazole: effective in Seborrheic Dermatitis.

Tolnaftate: not effective against Candida, used for Tinea Cruris/Corporis/Pedis (Athlete’s Foot).
 Lecture 14, 15 - Anticancer Drugs

Cancer: disease with uncontrolled multiplication and metastasis of abnormal forms of the body’s own cells.
-​ Approaches to Treating Cancer: Surgical Excision (Ideal), Irradiation, Chemotherapy (Indicated for
Disseminated Tumors and as a Supplement after Surgical Excision and Irradiation).

Cell Cycle Specificity of Drugs: rapidly dividing tumors are usually more sensitive
to anti–cancer drugs, while non–proliferating cells (G0 Phase) are more resistant.
-​ Cell Cycle Specific (CCS): Agents that are only effective against
high–growth fraction malignancies (replicating cells) (e.g. Antimetabolites,
Bleomycin, Vinca Alkaloids, Etoposide).
-​ Cell Cycle Non–Specific (CCNS): affect both low–growth and high–growth
fraction malignancies (e.g. Alkylating Agents, Cisplatin, Nitrosurias).

Treatment Regimens: usually according to body surface area, and are specific to
each patient. (First–order kinetics → constant number of cells destroyed by a dose).
-​ Combination Therapy: have the advantages of maximal killing effect, affect
broader ranges of cell lines, with delayed or prevented resistance.

Problems associated with Chemotherapy:

1.​ Development of Resistance.
2.​ Multiple Drug Resistance (MDR).
3.​ Toxicity: affect rapidly growing normal cells (e.g. GIT Mucosa, Hair, Bone Marrow, Buccal Mucosa)
4.​ Treatment–Induced Tumors: most agents are mutagens, especially alkylating agents.

Drugs used in Cancer Therapy

Antimetabolites (CCS): analogues of normal metabolites, interfering with purine or pyrimidine precursors.
1.​ Folate Antagonists (Methotrexate [MTX]): essential coenzyme for DNA Synthesis and Cell Division,
needing conversion to FH4 by Dihydrofolate Reductase (DHFR). Methotrexate becomes polyglutamated
which inhibits DHFR. inhibiting DNA/RNA/Protein Synthesis → Cell Death.
-​ Antidote: Administration of Leucovorin or Folinic Acid (Leucovorin Rescue) when a fatal dose of
MTX is given → bypass the blocked enzyme and replenish the folate pool.
-​ Adverse Effects: vomiting, diarrhea, stomatitis, myelosuppression, alopecia (low-dose).
Renal Damage, Hepatic Toxicity, Pulmonary Toxicity, Neurologic Toxicity (high-dose).
-​ Uses: Acute Lymphocytic Leukemia, Breast Caner, Rheumatoid Arthritis/Psoriasis (low-dose).
-​ Resistance: associated with increased production of dihydrofolate reductase.
-​ Contraindicated in pregnancy (abortifacient and mutagenic).
2.​ Purine Analogues (6–mercaptopurine): metabolized to 6–MMP/Thiouric Acid by
Xanthine Oxidase, which is inhibited by allopurinol → accumulation and toxicity.
-​ Treatment: 6–MMP should be decreased in patients taking Allopurinol,
Salicylates, NSAIDs, Sulphonamides, and Sulphonylureas.
-​ Adverse Effects: Myelosuppression, GIT Upset, Hepatotoxicity.
3.​ Pyrimidine Analogues (5–Fluorouracil): converted to FdUMP which competes
with dUMP for Thymidylate Synthetase → complex formation with FdUMP, Thymidylate Synthetase,
and Leucovorin → decreased thymidine and DNA synthesis → Cell Death.
-​ Adverse Effects: GIT Upset, Severe oral and Mucosal Ulceration, Alopecia, Myelosuppression,
Hand Foot Syndrome (erythematous desquamation of hands and soles).
-​ Uses: slow–growing solid tumors, allopurinol mouth wash is be given to decrease oral toxicity.
Antibiotics (CSS): direct action on DNA, causing description of DNA Function
1.​ Bleomycin: Dose–Dependent Pulmonary Toxicity, Hypertrophic Skin Changes, Hyperpigmentation.
2.​ Doxorubicin, Daunorubicin: used with other agents to treat sarcomas/carcinomas (Wilms Tumor).
-​ Mechanism: intercalation into DNA stands, Inhibits Topoisomerase II–Catalyzed Breakage
Reunions → Irreparable DNA Strand Breaks → Free Radicals → ssDNA breakage
-​ Adverse Effects: Cardiotoxicity (increased by Thorax Irradiation, Trastuzumab), Red Urine.
-​ Iron–Chelator Dexrazone protects against Cardiac Toxicity.
-​ Liposomal Encapsulated Formulation causes less Cardiotoxicity.

Alkylating Agents (CCNS): mutagenic and carcinogenic, leading to a second malignancy like acute leukemia.
1.​ Mechlorethamine (works via Nitrogen Mustard): transfers alkyl groups to the N7 position of guanine
in DNA → DNA Strand Breakage, Cross (Intrastrand) Linking → prevent normal synthesis.
-​ Adverse Effects: severe nausea and vomiting (treated with Ondonsetron and
Dexamethasone), Bone Marrow Depression, Extravasation (treated with Sodium Thiosulfate).
2.​ Cyclophosphamide: can cause nausea and vomiting, Hemorrhagic Cystitis (due to acrolein; treated
with MESNA → non–toxic compound), neurotoxicity, amenorrhea, testicular atrophy and sterility.
3.​ Nitrosoureas: cross–link DNA through alkylation → inhibiting DNA, RNA, and Protein synthesis.
-​ Drugs: Lomustine and Carmustine (cross the BBB, used for Brain Tumors), Streptozotocin
(toxic to β–cells of the islets of Langerhans; used in Insulinomas).
-​ Adverse Effects: aplastic anemia, renal/pulmonary toxicity, diabetogenicity (Streptozotocin).

Microtubule Inhibitors (CCS; Phase Specific): part of the cytoskeleton and mitotic spindle, these drugs
affect the equilibrium between polymerized and depolarized forms of microtubules → cell can’t divide.
1.​ Vincristine (VX), Vinblastin (VBL) [aka Vinca Alkaloids]: VX is used for treatment of leukemias
(POMP)/Wilms Tumor, while VBL is used for testicular carcinomas with Bleomycin and Cisplatin.
-​ Adverse Effects: Myelosuppression (VBL), Autonomic Neuropathy, Areflexia, and Muscle
Weakness (VX) causing constipation, GIT Upset, Alopecia.
2.​ Paclitaxel, Docetaxel: causes Neutropenia (prevented by Granulocyte Colony–Stimulating Factor
[G–CSF → Filgrastim]), Hypersensitivity Reactions, Peripheral Sensory Neuropathy, Alopecia.

Steroid Hormones and Antagonists (CCNS):

-​ Hormone Responsive Tumors: tumor regresses after treating with the specific hormone (palliative).
-​ Hormone Dependent (Sensitive) Tumors: tumor regresses after removal of the hormonal stimulus.
1.​ Corticosteroids (Prednisone): reduce inflammatory/allergic/immune responses → reduce sickness.
-​ Adverse Effects: Hyperglycemia, Hypertension, Cushing Syndromes, Cataract, Glaucoma.
-​ Uses: for Lymphomas and Leukemias.
2.​ B–Sex Hormones (Estrogen, Progestins): can cause MI, Thromboemobli, Strokes, Impotence, etc.
3.​ Sex Hormone Antagonists (Tamoxifen): anti–estrogen drug, with weak estrogenic activity, used in
treating estrogen–receptor positive breast cancer.

Monoclonal Antibodies: directed at specifically targeted cancer cells, with fewer adverse effects, via DNA
recombinant technology → replacing mouse gene sequences with human genetic material.

Platinum Coordination Complexes (Cisplatin, Carboplatin) [CCNS]: similar to alkylating agents.

-​ Adverse Effects: Nephrotoxicity, Proximal Tubular Toxicity, Ototoxicity, Neurotoxicity, Alopecia.

Interferons (IFN): antineoplastic, antiviral, and immunosuppressive → classified into ɑ, β, and γ.

-​ Adverse Effects: Depression (ɑ–IFN), Leukopenia and Thrombocytopenia, Nephrotoxicity and
Elevation of Liver Enzymes, Loss of Weight, Hair, and Fatigue, Neuropathy and Myopathy.