PHCL 204

PHARMACODYNAMICS
2019/2020 SESSION
OLORUKOOBA A.B. PhD
DEPARTMENT OF PHARMACOLOGY AND
THERAPEUTICS
ABU, ZARIA

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 Course outline
• Pharmacology
• Definition of Pharmacology, Pharmacokinetics
and Pharmacodynamics and the relationship
between them
• Drugs and Receptors
• Agonism and Antagonism
• Dose Response Relationship
• Adverse Drug Reactions
• Bioassay
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 Introduction
• Pharmacology is the study of drug action on
living cells or organisms
• A drug is any substance or mixture of
substances designed for the administration to
man or animals
• For use in the diagnosis, treatment,
investigation and prevention of disease or for
the modification of physiological function

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 Pharmacology

Pharmacokinetics Pharmacodynamics

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 Pharmacodynamics
• From the greek word “pharmacon” – drug and
“dynamics” - power
• Briefly defined as the study of the actions and
the effects of chemicals (drugs) upon cells,
tissues or organs in living systems
• Encompasses the science and study of
biochemical and physiological effects of
drugs and their mechanisms of action

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 Relationship between drug administration and
production of effects
Drug Administration

Disintegration of dosage form

Pharmaceutical Phase
Dissolution of drug
Drug available for absorption
(Pharmaceutical availability)

Absorption, Distribution, Pharmacokinetic Phase

Metabolism, Excretion
Drug available for action
(Pharmacological availability)

Drug-receptor interaction Pharmacodynamic Phase

Effect/Response
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 Action of drugs on living systems
• The action of a drug is the process by which a
drug brings about a change in the pre-existing
function or biochemical process of a living
organism
• Drugs may increase or decrease the normal
function of cells, tissues or organs such as
excitability, contractility, rhythmicity or
secretion
• But they do not impact any new function on
them
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 Contd…
• The effects of drugs are therefore quantitative
never qualitative and may be:
i) Specific – aimed directly at the agent
responsible for the disease
ii) Non-specific – ameliorating a symptom of
the disease

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 Types of drug action
• Stimulation: Enhancement of the level of a
specific biological activity (usually already
ongoing physiological process). E.g. adrenaline
stimulates heart rate, pilocarpine stimulates the
salivary glands
• Depression: Diminution of the level of a specific
biological activity (usually already ongoing
physiological process). E.g. barbiturate depress
the CNS, omeprazole depresses gastric acid
secretion
• Replacement: Replacement of the natural
hormones or enzymes (any substance) which are
deficient in our body. E.g. insulin for treating
diabetes, iron in anemia
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 Types of drug action contd…
• Cytotoxic action: Toxic effects on invading
micro organisms or cancer cells.
• Irritation: Non-selective noxious effect
particularly applied to less specialized cells.
Eg. Bitters increase salivary and gastric
secretions
• Stabilizing action: Drug seems to act neither as
a stimulant or as a depressant Eg. Some drugs
possess receptor activity that allows them to
stabilize general receptor activation,
like buprenorphine in opioid dependent
individuals
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 Site of drug action
• The part of the cell, tissue or organ where a
drug acts to initiate a chain of events leading
to an effect is known as the site of action of
the drug
• Site of drug action could be at
- The surface of a cell (Cellular)
- Within the cell itself (Intracellular)
- Outside the cell (Extracellular)

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 Targets of drug action
• Enzymes

• Ion channels

• Transporters

• Receptors

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Factors affecting the pharmacodynamic
properties of a drug
• Disease - including genetic mutations, malnutrition,
myasthenia gravis, Parkinson disease, and some forms of
insulin-resistant diabetes mellitus can change receptor
binding, alter the level of binding proteins, or decrease
receptor sensitivity
• Age - Aging tends to affect pharmacodynamic responses
through alterations in receptor binding or in post
receptor response sensitivity, in the newborn the liver
and kidney are not fully mature to handle some drugs
• Drug interactions - Drug–drug interactions result in
competition for receptor binding sites or alteration in
post receptor response
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 Factors contd…
• Genetics - Determinants of drug responses –
transporter, enzymes, ion channels, receptors and
couplers are controlled genetically and this may lead
to individual variation of responses to drugs

• Chronic exposure to drugs (Up and down regulation

of drugs)

• Gender - Females generally have a smaller body size,

thus they would require lower doses. Also the
hormonal status of females may influence drug
response
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 Factors contd…
• Species - Strains of rabbits are resistant to atropine,
Rat and mice are resistant to digitalis
• Race – racial differences have been observed Blacks
require higher doses of atropine and ephedrine,
while Mongols require lower doses In Africans – beta
blockers are less effective
• Body weight - recommended daily doses of drugs
are usually calculated for mediumly built individuals.
Thus for obese and underweight persons
• Diet – food interferes with the absorption of drugs
for eg tetracyclines forms complexes with calcium
present in food
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 Concept of receptor site for drug action
• Drugs show selectivity and specificity in their
actions
• They act at particular sites to produce their
characteristic biological effect
• These sites also called tissue elements which drugs
act to produce their characteristic biological effects
are called receptors
• These receptors may be extracellular or
intracellular as mentioned earlier
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 Drug Receptor Complex

DRUG

RECEPTOR

Drug + Receptor Drug-Receptor Complex

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 Drugs and Receptors
• Drugs do not bind directly with enzymes, channels,
transporters or structural proteins, but act through
specific macromolecules called receptors
• Receptors are macromolecules or binding sites
located on the cell surface or inside the effector
cell that serves to recognize the signal molecules
and initiate response to it but it itself has no
function
• Characteristics of receptors: “Specificity, Selectivity
and Sensitivity”

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 How drugs bind to produce effect
• Drugs are postulated to combine reversibly with
receptors by a concerted operation of
- Ionic bonds
- Hydrogen bonds
- Van der Waals forces
- Covalent bonds
• Formation of a number of these different bonds
gives the drug-receptor complex sufficient
stability to initiate the events that ultimately
lead to a pharmacological activity
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 Definition of some terms
• Affinity - ability of a drug to get bound to the
receptor or the measure of the propensity of a
drug to bind to the receptor
• Intrinsic activity – ability of a drug to produce a
pharmacological effect after making a drug-
receptor complex (response)
• Efficacy – maximal response that can be elicited
by a drug
• Potency – amount of drug needed to produce
an effect or response
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 Potency

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 Efficacy

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 Agonist and Antagonists

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 Agonist
• An agonist is a drug whose interaction with a
receptor becomes a stimulus for a biologic response

• An agonist has both affinity and efficacy and will thus

produce a response

• Affinity + Intrinsic Activity

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 Partial agonist
• Has affinity but less intrinsic activity than the full
agonist on the receptor
• Continous increase in the concentration of a partial
agonist can never produce the full effect of the tissue
is capable of producing

• Affinity + < Intrinsic Activity

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 Inverse agonist
• Has full affinity towards the receptor but intrinsic
activity is - 1
• It binds to the same receptors as an agonist but
induces a pharmacological response opposite to that
of the agonist
• Eg. Chlorpheniramine of histamine H1 receptors

• Affinity + Intrinsic Activity is – 1

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 Graphical representation of the effect of
an agonist, partial agonist, antagonist and
inverse agonist

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 Types of agonism
• Additive
• Synergism
• Potentiation

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 Additive Effect-
It occurs when two drugs with the same effect
given together produce an effect that is equal
in magnitude to the sum of the drugs taken
individually
EAB= EA+EB (1+1= 2)
Effect of drugs A + B = Effect of drug A + Effect
of drug B
e.g ephedrine +aminophylline , ASA + PCM,
glibenclamide+metformin

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 Synergism/Synergistic Effect
 It occurs when two drugs with the same effect
given together produce an effect that is greater in
magnitude than the sum of the effect of the two
drugs taken individually
 EAB= EA+EB (1+ 1> 2)
Effect of drugs A + B > Effect of drug A + Effect of
drug B
e.g procaine +adrenaline, the latter prolongs the
action of the former.
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 Potentiation
 It occurs when a drug lacking an effect of its
own increases the effect of a second active
drug.

EAB= EA+EB (0+1= 2)

e. g Ach+physostigmine,
levodopa+carbidopa,
sulfamethoxazole+trimethoprim e.t.c
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 Drug antagonism
• This is the term applied when the effect of a drug is
diminished or abolished by another

• Or when the effect of two drugs is less than the sum

effects of the individual drugs

• Affinity + Intrinsic Activity is 0

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 Chemical antagonism
• This is simply the reaction between an agonist and an
antagonist to form an inactive product
• Two drugs react chemically to form an inactive
product
• An example is dimercapol and mercury
• Protamine sulphate and heparin

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 Physical antagonism
• Based on the physical property of the drug

• E.g. Charcoal adsorbs alkaloids and can

prevent their absorption

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Physiological or functional antagonism
• Is observed when two agonists acting at different
sites or receptors counterbalance each other by
producing opposite effects on physiological
function
• Example - histamine binds to a receptor site and
produce vasodilation while epinephrine binds to
a separate receptor to produce vasoconstriction.
• Glucagon and insulin on blood glucose levels
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 Pharmacological antagonism
• Is observed when a drug (antagonist) reduces the
effect of another drug (agonist) by preventing the
latter from combining to its receptor.
• Drugs which bind to the receptors but lack
intrinsic activity
• Produce their effects by competitively or non
competitively inhibiting the action of endogenous
molecules at the receptors

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1. Competitive antagonism –
• An antagonist combines reversibly with the
same active site as the agonist (compete for the
same receptors)
• Agonist and antagonist are chemically similar
• Antagonist can be displaced from the these sites
by excess of the agonist
Example: atropine and acetylcholine, histamine
and antihistamine; nalorphine and morphine
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2. Non-competitive antagonism –
• The antagonist is chemically unrelated to the
agonist
• The effect of an antagonist cannot be overcome
by increasing the concentration of an agonist
• A non-competitive antagonist may produce its
effects by combining either with the same sites as
the active drug (agonist) or with different sites in a
manner that alters the agonist’s capacity to
combine with its own receptors

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 Non-competitive
Antagonism

Reversible where the Irreversible where the

removal of the receptor is destroyed
antagonist returns the and has to be re-
system to full activity synthesized

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 Importance of Drug antagonism
1. Correct adverse effects of drugs
2. Treat drug poisoning
3. Predict drug combinations that can reduce
drug efficacy or cause toxicity

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 Non Receptor Mediated Actions
These reactions are not mediated through
receptors and include:
• Formation of antibodies (vaccines)
• Chemical reactions (chelation)
• Binding of alkylating agents to nucleic acid
(cytotoxicity)
• Osmotic action (Magnesium sulphate)
• Targeting specific genetic changes

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 Types of receptors

Receptors

Ligand gated
ion channels Enzymatic
G-protein
(sodium, receptors Receptor for
coupled
potassium (Tyrosine steroids
receptors
and chloride kinases)
channels)
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 Ligand gated ion channels
• Drugs bind with these receptors to open a
transmembrane channel that permits ions to
cross the membrane phospholipid area
• The nicotinic, acetylcholine (Ach) receptors
permits sodium and potassium ions to cross the
membrane and cause depolarization of the cell
membrane
• The gamma-aminobutyric acid (gaba) receptor
channel allows chloride ions to permeate
causing hyperpolarization of the cell membrane
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 G-proteins (Guanosine diphosphate or
triphosphate) coupled receptors
• These are a specific class of proteins linked to certain
receptors and are involved in the regulation of
secondary messengers

• They are found on all cell types and are especially

abundant in the brain and the gut

• They are either stimulatory (Gs) or inhibitory (Gi) in

action

• ACh and GABA can activate receptor ion channels as

well as G-protein coupled receptors
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• A ligand binding to G-protein coupled receptors
causes G-protein activation, which leads to
intracellular chemical events through complex
processes
• Distinct secondary messengers have been
identified which mediate the effects of the
activated G-proteins and include;
1. Calcium ions
2. Cyclic AMP
3. Inositol 1, 3, 5-triphosphate (IP3)
4. Diacylglycerol (DAG)
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• A classical example of a G-protein coupled receptor is
the adrenergic receptor with noradrenaline binds
and produces its action

• Drugs such as opiates act via this receptor

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 Tyrosine kinases
• A classical example are the insulin receptors

• Tyrosine kinase activate themselves by

autophosphorylation after the hormone binds to
them

• The autophosphorylated tyrosine kinase then

phosphorylates intracellular proteins on the tyrosine
residues

• Many cells possess this kind of receptors

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 Receptor for steroids
• Steroidal or Nuclear receptors are present in the
cytoplasm

• These receptors can interact directly with DNA to

regulate gene trancription

• These receptors after activation by hormone binding

act on the genetic material in the nucleus to initiate
or inhibit the process of transcription

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 Characteristics of Receptors
Receptor type Coupling Location Effector Examples
mechanism
Ligand gated Direct Membrane Ion channel Nicotinic
Entry/exit of acetylcholine
ions γ-
Depolarization aminobutyric
or acid
hyperpolarizati
on

G-protein Receptor Membrane Ion Muscarinic

coupled protein channel/Enzyme acetylcholine
associated Dopamine
with a G- Serotonin
protein

Enzymatic Direct Membrane Enzyme Atrial

Initiate protein natriuretic
phosphorylatio peptide
n insulin

Intracellular Stimulate Intracellular Gene Steroid

receptors mRNA hormones
synthesis
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Receptor Up and Down Regulation
• Receptor Down Regulation • Receptor Up Regulation
• Prolonged exposure to a high • Prolonged occupation of
concentration of an agonist
receptors by antagonist leads
causes a reduction in the number
of receptors available for
to increase in the number of
activation receptors with increase in
• This results in masking or receptor sensitivity
internalization of receptors from • Due to unmasking or
the cell surface externalization of receptors
• Eg. Asthmatics taking beta from inside the cell surface
adrenergic agonists results in • Prolonged use of propranolol
decreased number of receptors
thus decreasing the effect of the causes an increase in blood
drug pressure
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 Dose Response Relationship
• The magnitude of the effect of a drug is a
function of the dose administered
• Two basic types of dose effect relationship have
been observed
I. Graded or quantitative dose-response
relationship
II. Quantal or all or none dose-response
relationship

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 Graded or quantitative dose-response
relationship
• This relationship relates the size of the response
in a single biological unit to the dose of the drug
• As the dose administered to an organ or tissue is
increased the pharmacological response also
increases in graded fashion
• Maximum response obtained corresponds to the
point at which receptor occupancy is approaching
100%
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• As thus the graded dose response relation is
partially a reflection of the extent of occupancy
of the receptors by the drug
• The degree of response produced by increasing
doses of a drug eventually reaches a steady level
and this phenomenon is is termed a as the ceiling
response
• The dose at which the with which the ceiling
response is obtained is the ceiling dose
• If the dose of a drug exceeds the ceiling dose,
there is no further increase in therapeutic effect
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• The dose-response curve is usually a hyperbola
when plotted on an arithmetic scale

• However the graph plotted with the drug

response against the logarithm of the dose has a
sigmoid shape

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 Quantal or all or none dose-response
relationship
• Many pharmacological effects occur which cannot be
measured as graded response on a continuous scale

• For example if one were determining the relationship

between the dose of a barbiturate and its propensity
to induce sleep, the effect will be measured only as
an all or none response: either sleep was induced by
the drug or the animal remained awake
• In the case of lethal toxicity experiments, each
animal is classified as dead or alive at a specific time
after drug administration
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• Thus for a given drug, if the log dose is plotted on the
horizontal axis and the percentage responding to the
various dose levels is plotted on the vertical axis a
gaussian or normal distribution curve is obtained

• Although there are some extraneous effects in some

dose ranges which can modify the curve

• For example the drug may have other actions apart

from the desired effect and experimental limitations
may influence the quantal-response curve

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 Some terms derived from the dose-
response curve
• Median Lethal Dose (LD50) = this is the dose which would
be expected to kill half of a population of the same species
an strain

• Median Effective Dose (ED50) = this is the dose which

produces a desired response in 50% of the test population

• Therapeutic Index = it is an approximate assesment of the

safety of a drug

• It is expressed as the ratio of the median lethal dose to the

median effective dose
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Therapeutic Index =

• The therapeutic index varies from species to species

• The larger the therapeutic index the safer the drug is
• For safe therapeutic application of a compound, its
therapeutic index must be more than 1
• Thus penicillin has a very high therapeutic index
while digoxin has a very low therapeutic index
• The margin of safety is the difference between the
therapeutic index and the lethal dose of a drug
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 Importance of Dose Response Curve
• The potency and efficacy of drugs can be compared
• Comparison of the actions of agonists and
antagonists is easier
• Stimuli can be graded by fractional change in
intensity
• Therapeutic index and margin of safety of a drug can
be calculated
• Possible to distinguish between competitive and non
competitive drug antagonism
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 Limitations of the DRC
• Large variation in doses cannot be plotted on a
single graph
• Not possible to compare with other drug
responses

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 Spare Receptors
• When only a fraction of the total population of
receptors in a system are needed to produce
maximal effect then the system is said to have
spare receptors

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 Desensitization
• Chronic loss of response over a longer period
of exposure to a drug and may be caused by
structural change in receptor morphology or
by an absolute loss in receptor numbers
• Eg. Loss of beta adrenergic receptors from the
heart in the continued presence of adrenaline

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 Tolerance
• Phenomenon where an unusually larger dose
of a drug is required to produce an effect
ordinarily produced by the normal therapeutic
dose of a drug
• Diminished response to a drug as the body
adapts to the continued presence of drug so a
higher dose is required to achieve the same
response

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 Tolerance contd…
• Occurs in chronic opioid use or abuse
• May be as a result of a reduction in receptor
density or a reduction in receptor affinity
• Two types
- True/Natural tolerance
- Acquired tolerance

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 True/Natural vs Acquired Tolerance
True/Natural tolerance Acquired tolerance
• Observed in various • Usually develops after the
repeated administration of a
animal specials and drug in an individual who was
human races initially responsive
• The specie or human is • Eg. Tolerance to opioid
inherently less sensitive analgesics and antidepressant
to a drug drugs
• Types include: Tissue tolerance
Eg. Rabbits are tolerant to
and Cross tolerance
atropine (development of tolerance to
Types include: Species pharmacologically related
tolerance and Racial groups (morphine and
pethidine)
tolerance
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 Tachyphylaxis
• Rapid decrease in pharmacological response
to repeated doses of a drug
• Presumed to be as a result of diminished
receptor sensitivity in response to consistent
stimulation by a drug agonist
• Eg. – diminishing response to repeated doses
of ephedrine

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 Adverse Drug Reactions (ADR)

• An ADR is any response to a drug that is noxious and

unintended and that occurs at doses used in man for
prophylaxis, diagnosis and therapy

Adverse Drug Event (ADE)

. An untoward event that may be present during

treatment with a drug but which does not necessarily
have causal relationship with the drug

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 Classification of ADR’s
ADR’s can be classified based on
1. Onset of event
2. Type of reaction
3. Severity

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 Onset of Event
• Acute - 60 mins
• Sub- acute – 1 to 24 hours
• Latent - > 2 days

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 Types of Reaction
• Type A – Augmented – reaction that can be
predicted from the pharmacology of the drug. Dose
dependent. Can be elevated by dose reduction.
Eg. Anticoagulants causing bleeding
• Type B – Bizarre – Cannot be predicted from the
pharmacology of the drug. Not dose dependent.
Eg. Penicillins causing anaphylactic reactions
• Type C – Chemical – Biological activity can be
predicted from chemical nature of the drug
Eg. Paracetamol leading to hepatoxicity
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 Types of Reaction contd..
• Type D – Delayed – Occurs after many years of
treatment. May be due to accumulation of the drug
Eg. Analgesics causing nephropathy
• Type E – End of treatment – Occurs on withdrawal
when drug treatment stops abruptly
Eg. Phenytoin withdrawal causes seizures
• Type F – Familial – Occurs only in the genetically
predisposed individual
Eg. Hemolytic anemia with primaquine observed in
G6PD deficient individuals
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 Types of Reaction contd..
• Type G – Genotoxicity – Causes irreversible genetic
damage
Eg. Teratogenic agents like thalidomide
• Type H – Hypersensitivity - Requires activation of the
immune system. Improves if the medicine is
withdrawn.
Eg. anaphylaxis with penicillin
• Type U – Unclassified – Requires activation of the
immune system. Improves if the medicine is withdrawn
Eg. Anaphylaxis with penicillin

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 Severity
• Minor – No therapy, antidote or hospitalization
required
• Moderate – Requires drug therapy and or
hospital stay for at least 1 day
• Severe – Potentially life threatening, causing
permanent damage or requiring intensive
medical treatment
• Lethal – Directly or indirectly leads to pateint
death
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 Assay
• This is the estimation of the potency of an
active principle in a unit quantity of
preparation
• Assay can be
i. Chemical
ii. Biological
iii. Immunological

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 Chemical Assay
• The concentration of the active principle is
estimated by means of a chemical method
• Techniques used
- Spectrophotometry
- Fluorometry
- Gas chromatography

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 Biological Assay
• Determination or estimation of the
amount/concentration/potency of an active
principle in a unit quantity of a preparation
• Detection and measurement of the concentration
of a substance in a preparation using biological
methods
• Can be performed on whole animals (in vivo) or an
isolated tissues (in vitro)
• Also called bioassay, biometrics, biological
standardization
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Characteristics of a Good Bioassay
 Highly sensitive
 Specific
 Reproducible
 Accurate
 Stable
 Precise

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 Principle of Bioassay
• Active principle to be assayed should show some
measured response in all animal species
• The activity assayed should be the activity of interest
• The standard and the test sample should have
similar pharmacological effects and mode of action
• Specified pharmacological techniques should be
used for comparison
• Degree of pharmacological response should be
reproducible

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 Principle of Bioassay contd..
• Method selected should be reliable, sensitive,
reproducible and accurate
• Experimental conditions should be kept
constant, animals should be of same species,
sex and weight, number used should be large
enough to minimize error

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