17/03/2021

GENERAL PRINCIPLES OF
PHARMACODYNAMICS

Dr A.C. Kalungia, PhD

Lecturer & Researcher

Learning Objectives
At the end of this session, YOU should be able
to:
1. Explain the scientific basis of drug action
2. Describe drug-receptor interactions and their
quantitative outcomes at the site of action
3. Describe different types of receptors and their
properties
4. Explain mechanisms of action of ligands on
different receptor types
5. Apply fundamental concepts of
pharmacodynamics to therapeutics
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Pharmacodynamics
Deals with the study of the biochemical,
molecular and physiological effects of drugs
and their mechanisms of action

Provides scientific basis of drug action and

rational therapeutic use of a drug

Founded on receptor theory by Paul Ehrlich

(1909)
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Pharmacodynamics
Considers interactions of drugs with cellular proteins, such as
receptors and enzymes, to control changes in physiological
function of particular organs
i.e. “what the drug does to the body”

• Drug-Receptor Interactions
– Binding & Activation/Inactivation of receptor
• Signal Transduction
– Signalling Pathways, Mechanism of action
• Dose-Response
– Biological Effect

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Mechanism of action of a drug

Refers to receptor interactions that alter the function

of the pertinent cellular component, thereby
initiating biochemical and physiological changes that
characterise the pharmacological response to the
drug

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Drug Targets: Receptors

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Receptors
The sensing elements in the system of biochemical
communications that coordinate physiological
functions of all diverse cells in the body

Bind mediator substances (Ligands) and

transduce this binding into an effect (i.e. signal
transduction);
Ligand

Receptor
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Classification of Receptors
1) Physiological
Bind chemical mediators (e.g. NE, ACh, Epi, Dopamine,
etc.)
2) Biochemical and Biophysical
2nd messenger systems (e.g. cAMP, PKA, DAG, IP3, etc),
Enzymes, etc.
3) Molecular or Structural
Subunit compositions (e.g. 5-HT1A)
4) Anatomical
Tissue (e.g. muscle & ganglionic nAChRs)
Cellular (i.e. membrane-bound & intracellular organelles)

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Drug-Receptor Interactions
1. Ligand binds to receptor via physicochemical &
steric Interaction  Stimulus
e.g. lipophilic/hydrophilic, Ionic, Hydrogen bonding, Steric
(stereospecific), Electronic or pK effects, etc)

2. Signal transduction or Signaling pathway: cascade

of cellular events  Activation

3. Effector mechanism  Transduction

4. Response  Effect (Quantifiable)

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Drug-Receptor Interactions
•Drug-receptor interactions serve as signals to trigger a cascade of
cellular events/signaling pathway (a collection of many cellular
responses which serve to amplify the signal and produce a final
effect).

•Effectors are thus the molecules that translate the drug-receptor

interaction into changes in cellular activity  effect

  +         EFFECT

DRUG DRUG + RECEPTOR DRUG + RECEPTOR EFFECTOR EFFECTOR
INTERACTION COMPLEX SYSTEM

STIMULUS BINDING ACTIVATION TRANSDUCTION AMPLIFICATION RESPONSE

SIGNALLING PATHWAY

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Examples of target receptors for drugs:

 Receptors for neurotransmitters, hormones,
autacoids, growth factors, transcription factors,
and other endogenous chemicals;

morphonix.com

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Examples of target receptors for drugs:

Enzymes of crucial metabolic or regulatory
pathways (e.g., dihydrofolate reductase,
acetylcholinesterase, phosphodiesterases, etc)
Transport proteins
(e.g. ATPases, etc)

 Ion channels (e.g. Ca2+, Na+)

 Glycoproteins
 Structural proteins
(e.g. tubulin, myosin, etc)
morphonix.com
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Types of Receptors

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Receptor Types
I. Guanyl-Protein Coupled
Receptors (GPCR)
• Most prevalent receptor type (~80%) in human
body
• Membrane-bound; Consist 7 α-helical
transmembrane-spanning loop of amino acid
chains with extramembranal sugar residues at
different N-glycosylation sites
• Binding of ligand molecule induces
conformational change of receptor protein
• This enables interaction with a Guanyl
nucleotide-binding protein (G-protein) in the
inner plasmalemma;
• Activity of G-protein depends on type of G-
alpha subunit (i.e. Gαs Gαi Gαq and/or Gα11/12).
Luellmann, 2010
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Receptor Types
II. Ligand-gated ion channels
• Receptor complex consists amino acid
loops of transmembrane subunits

• Typical examples: nACh receptors,

GABAA receptors, NMDA receptors, etc

• Receptor activation by ligand brings

about conformational change that
modifies the gating of ion channel

• In Figure: Binding of 2 Ach molecules to 2 α-

subunits of nicotinic receptor causes opening
of the ion channel allowing influx of Na+ and
efflux of K+ ions  Depolarization  AP firing Luellmann, 2010

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Receptor Types
III. Ligand-regulated enzyme
receptors
• They are catalytic receptors

• Examples: Growth hormone receptor;

Insulin receptor protein, etc.

• Ligand binding (e.g. Insulin) to

extracellular site activates tyrosine
kinase (a protein phosphorylating
enzyme)  Protein phosphorylation 
moderation of cell function (e.g.
glycogenesis)
Luellmann, 2010

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Receptor Types
IV. Protein synthesis
regulating receptors
• Nucleus and Cytosolic receptors;
• Examples: Steroid hormone receptors;
Thyroid hormone receptors, etc;
• Hormone-receptor complex
initiates/enhances or acts as DNA
transcription regulating factor;
• Hormone-receptor complex interact
with DNA in dimeric (pair) form;
Luellmann, 2010

• Cytosolic receptors e.g. Glucocorticoid,

mineralocorticoid, androgen receptors, etc;

• Nucleus receptors e.g. Estrogen, Thyroid

hormone receptors, etc
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Receptor Agonist & Antagonists

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Agonist
A drug/chemical substance that binds with affinity to
the receptor and activates the receptor to mimic the
regulatory effects of the endogenous ligand (i.e. has
positive intrinsic activity)

Antagonist (Inhibitor)
A drug/chemical substance that binds with affinity to
the receptor but does not activate the receptor; its
binding to receptor inhibits (blocks) the binding of
agonist or endogenous ligand (i.e. has zero intrinsic activity)

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Classes of Agonists
Agonist Class Action
Full Agonist Activates receptor with maximal efficacy
Partial Agonist Activates receptor but not with maximal efficacy
Inverse Agonist Inactivates constitutively active receptor (negative intrinsic activity)

Classes of Antagonists
Antagonist Class Action Effects on Effects on
Agonist Agonist
Potency Efficacy
Competitive Binds reversibly to active site of receptor, Yes No
Antagonist competes with agonist binding to this site
Non-competitive Binds irreversibly to active site of receptor, No Yes
active site Antagonist prevents agonist binding to this site
Non-competitive Binds reversibly or irreversibly to site other No Yes
allosteric Antagonist than active site of receptor, prevents
conformational change required for
receptor activation

Non-competitive Act via different receptors that affect same No No

physiologic variable but opposite effects
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Antagonist

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Mediators of Receptor Signaling

Pathways
SECOND
EFFECTORS MESSENGERS
Adenyl cyclase (AC) cAMP
Guanyl cyclase (GC) cGMP
Phospholipase-C (PLC) DAG and IP3
Phospholipase-A2 (PLA2) Arachidonic acid
Nitric Oxide Synthase (NOS) Nitric Oxide (NO)
Ion-linked Na+, Ca2+, K+, Cl-

Receptor Signaling Pathways

R R R R

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Receptor Agonist Signaling Pathways

Theoretical assumptions of drug-

receptor interactions
 Law of mass action: Drug-Receptor interaction follows
simple mass-action relationships, (i.e. one drug molecule binds
a receptor binding site – but theory has exceptions!!)

 Magnitude of the response proportional to fraction of

total receptor sites occupied by drug molecules
 Threshold agonist-receptor binding signals cellular
event which leads to a biological response
 Response to a drug is graded (dose-dependent
response)

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Law of Mass Action

When a drug (D) binds to a receptor (R), it does so at
a rate (k) which is dependent on the concentration
of the drug and the concentration (amount) of the
receptor expressed:
k1
[D] + [R]  [DR]
k2
D = drug
R = receptor
k2 = KD = [D][R]
DR = drug-receptor complex
k1 = rate for association k1 [DR]
k2 = rate for dissociation
KD = Dissociation Constant 1 = KA = k1 = [DR]
KA = Affinity Constant KD k2 [D] [R]

Quantifying Effects of Drugs

on Receptors

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Classification of Drug Effects

1. Action on Organ System i.e. Direct or Indirect Action
e.g. NE constricts BV  BP  HR
2. Effect on Cell functions
Excitation = function; Inhibition = function
(e.g. Amphetamines) (e.g. Barbiturates)

3. Selectivity of Effects e.g. Benzodiazepine effects on CNS,

Cardiac glycosides stimulate myocardium

4. Therapeutic effect: affecting functions &

pathophysiologic processes leading to treatment of disease
(i.e. Etiological or Symptomatic treatment)

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Classification of Drug Effects

5. Adverse Effect
A noxious, unintended & undesirable response, often
unrelated to primary mechanism of action of the drug
 Side effect
An undesirable effect, produced by therapeutic dose of drug,
often non-deleterious, may be related (or unrelated) to
mechanism of action of the drug
6. Toxic effect
A noxious effect produced by excessively large dosage of the
drug (acute or chronic exposure), often deleterious without
treatment
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Causes of drug adverse effects:

a) Overdose

Color Atlas of Pharmacology, Lullmann, 2005

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Causes of drug adverse effects:

b) Increased selectivity of the drug
e.g. due to hyperactivity of target body function, etc

Color Atlas of Pharmacology, Lullmann, 2005

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Causes of drug adverse effects:

c) Lack of selectivity e.g. drug does not specifically act
on the targeted tissue or organ

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Color Atlas of Pharmacology, Lullmann, 2005

DOSE-RESPONSE RELATIONSHIPS

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Dose-Response Relationships
1. Graded dose-response curve
Response to drug proportional to dose (drug concentration)

2. Quantal dose-response curve

Describes the concentrations of a drug that produce a given
effect in a population
 Useful for predicting effects of drug when administered to a
population

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1. Graded Dose-Response Curve

Emax Emax
Response

Response

EC50 EC50

Dose (log scale)

Dose (linear scale)

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Drug Potency vs. Efficacy

• Potency
The concentration at which the drug elicits 50% of its
maximal response (EC50)

• Efficacy
The maximal response produced by the drug (Emax) -
also called Intrinsic Activity

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Potent drugs are those which elicit a response by binding to a critical

number of a particular receptor type at low concentrations (high affinity)
compared with other drugs acting on the same system and having lower
affinity and thus requiring more drug to bind to the same number of
receptors.
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Efficacy assumption: the state at which

receptor-mediated signalling is maximal
(100%)

PARADOX: If this assumption is true for drug efficacy,

how is it that some drugs are capable of eliciting a
maximal response even when fewer than 100% of
receptors are occupied?

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2. Quantal Dose-Response Curves

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• ED50 Median effective dose at which 50% of

subjects in a population exhibit a
therapeutic response to a drug

• TD50 Median toxic dose at which 50% of

subjects in a population experience a toxic
response to a drug

• LD50 Median lethal dose at which 50% of

subjects in a population die
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Therapeutic Index & Therapeutic Window

• Therapeutic Index (TI) = TD50/ED50
• TI estimates margin of relative safety of a drug (in
animal models)

• Safe drug is expected to have very large TD50 range

and smaller ED50
• Therapeutic window (TW): dosage range between
minimum effective therapeutic dose (ED50) and the
minimum toxic dose (TD50)
• TW is clinically useful index for dose titration

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Therapeutic Index & Therapeutic Window

Hypnosis Toxicity

Adapted from: Goodman and Gilman’s The Pharmacological Basis of Therapeutics

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1. Determine the Therapeutic Index (TI) of Drug A and Drug B using the
Quantal Dose-Response curves below
2. Describe the difference between the two drugs in terms of relative
safety profile.

100 Drug A Drug B

Hypnosis Toxicity H T

50

0 100 250 180

100
ED50 TD50 TD50
ED50
Dose (mg) Dose (mg)

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For Further Reading:

• Katzung B.G. et al, Basic & Clinical
Pharmacology, Ch.2.

• Golan D.E. et al, Principles of

Pharmacology: the pathophysiologic
basis of drug therapy, 2nd ed. Ch.2

• Pratt W.B, et al (eds). Principles of

drug action: the basis of
pharmacology, 3rd ed. (contains in-
depth discussion of pharmacodynamics)

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