PHARMACODYNAMICS

LEARNING OBJECTIVES
 At the end of this topic the students will be able to:

 Define pharmacodynamic.

 Explain mechanism of drug actions (receptor & non receptor

mechanism)

 Understand dose-response relationships and factors that affect

the pharmacological response.

 know about structural activity relationships of drug

 INTRODUCTION
 Pharmacodynamics:

 Is the study of the action and effect of drugs on the body (tissue, cellular
& sub-cellular level).

 The actions of a drug on the body, including receptor interactions, dose-

response phenomena and mechanism of therapeutic & toxic actions.

 It deal with biochemical and physiological effects of drugs & their

mechanism of action.

 The study of biological and therapeutic effects of drugs.

 What the drugs does to the body.

  Pharmacodynamic effects of drug
 May be desirable therapeutic or undesirable adverse effect

 The adverse effects can be quantitative or qualitative effect.

 Quantitative adverse effects are expected effects of drug as side

effects or toxicity.

 Qualitative adverse effects are unexpected (hypersensitivity or

idiosyncrasy).
  Pharmacodynamic action of drug
 Stimulation – adrenaline on heart or pilocarpine on salivary
gland

 Depression – diazepam on CNS.

 Replacement – Hormone as insulin, thyroxin or levodopa in

parkinsonism.

 Cytotoxic action – anticancer drugs, antibiotics.

 Irritation – counterirritant or excitation of organs or part of the

body
  Mechanism of drug action
 Major target of drugs action:
- receptors
- ion channels
- enzymes
- carrier or transport proteins

 Receptors and Non-receptors mechanism of drug action

 Receptors:
- it is a binding site located on the surface (e.g cell
membrane) or inside (e.g cytoplasm, nucleus) of the effector
cell that serves to recognise the signal molecule or drug and
initiate the response.
 RECEPTOR OCCUPATION AND RATE THEORIES

Theories of drug-receptor complex:

 The receptor occupation theory observes that the level of response
which is produced from the drug-receptor complex is due to the
number of receptors which are occupied by the drugs. This means
that the level of the response will increase with increasing
concentration of the drug.

 The rate theory observes that response is not dependent on the

number of receptors occupied but on the rate at which the
complexes are formed i.e stimulus provided by drug is
proportional to the rate of combination between the drug
molecules and the receptors. This means that each association
between a drug molecule and a receptor produces a quantum of
stimulation/response.
 Receptor families

Ligand-gated ion channels

G-protein couple receptors

Nuclear (gene) receptors

Intracellular or transmembrane receptors

Spare receptors

Desensitization or silent receptors

 Channels-linked receptors: e.g. nicotinic receptor & GABA receptors.
When acetylcholine (on nicotinic receptor), or GABA (on GABA
receptor), bind their receptors, a conformational change occurs in the
channel resulting in altering of ion distribution across the cell membrane
and a unique cellular function produced.
 Ach on nicotinic receptors. • GABA on GABAA receptors
open sodium channels open chloride channels
entry of sodium entry of chloride.
depolarization hyperpolarization.
 Nuclear Receptors = Gene active receptors:
 The steroid hormones.
 Thyroid hormones.
 vitamin D and vitamin A
 These hormones can easily pass the cell membrane and bind with
cytoplasmic mobile receptors. The drug-receptor complex enters the
nucleus and bind to DNA response element, which in turn regulates
RNA transcription with production of unique protein concerned with the
cell response.
 G-protein coupled receptors: The receptors for catecholamines,
prostaglandines and many peptide hormones are linked to G-protein
(Gs, Gi, Gq, …) evolving in stimulation or inhibition of a second
messenger,
 e.g
 Stimulation of β1 & β2 adrenergic receptors stimulate Gs increase
cAMP.
 Stimulation of α1 adrenergic receptors Gq increase DAG, IP 3.
 Stimulation α2 adrenergic receptors Gi decrease cAMP

 Kinase-linked receptors:
 e.g. When insulin, epidermal growth factor (EGF) and platelet
derived growth factor (PDGF) bind their surface receptors, a
tyrosine-kinase (on the inner part of the receptor) is activated. This
leads to phosphorylation of certain protein on its tyrosine residue
producing the specific cellular function.
 Action of drug on receptor:

 Agonists, partial agonists or inverse agonist

 Antagonists, reversible (competitive or non-competitive) or

irreversible antagonist

 ligand – that binds selectively to a specific receptor

 Affinity – ability of the drug to bind to a receptor
 Intrinsic activity – ability of the drug to elicit a response after binding
with the receptor

 The forces that attract the drug to its receptor are termed
chemical bonds and they are (a) hydrogen bond (b) ionic bond
(c) covalent bond (d) Vander waals force. Covalent bond is the
strongest bond and the drug-receptor complex is usually
 K1 K3
D+R DR Biological effect
K2
•Where D = Drug, R= receptor DR= Drug receptor complex (affinity)
K1 = association constant
K2 = dissociation constant
K3 = intrinsic activity
• When first messengers like neurotransmitters, hormones, autacoids and
most of drugs bind with their specific receptors, the drug receptor
complex is formed which subsequently causes the synthesis and release
of another intracellular regulatory molecule termed as second
messengers e.g. cyclic AMP, calcium, cyclic GMP, inositol triphosphate
(IP3), diacylglycerol and calmodulin which in turn produce subcellular
or molecular mechanism of drug action.
 Agonist
- An agent which activates the receptor to produce an effect
similar to that of physiological signal molecule
- or can act as stimulate or to potentiate effects
- has significant receptor affinity and full intrinsic activity (IA =
1)
- drugs able to generate a maximal responses from a
receptor
- the potency of the drug is determined by its dissociation
constant (Kd), for many drugs the lower the Kd the higher potency.
However, ED50 corresponded to Kd.

-E.g adrenalin – α and β receptors, morphine – opioid receptors

 Partial agonist
- have affinity and submaximal intrinsic activity (IA =
between 0 and +1)
- They failed to achieve a maximal effect, even in very
high dose (with full receptor occupancy)
- They may act as either agonists or antagonists
depending on circumstances
- If used alone, they are agonists
- If used with low dose of full agonist, they produce
additive effects, but switches to competitive
antagonism as the dose increases.
- E.g nalorphine, pentazocin on opioid receptors
 Inverse agonist
- these drugs have affinity but produces actions
opposite to those produced by agonist (IA = between 0
and -1)
- Inverse agonists bind to these receptors and greatly
reduce the incidence of the active conformation
responsible for this constitutive activity, as a result inverse
agonists appear to exert an opposite effect to the
agonist.
- Inverse agonist will favour a shift of equilibrium
toward inactive receptors whereas a competitive antagonist
binds equally to active and inactive receptors and simply
prevents the agonist from binding
- Eg. β- carboline on benzodiazepine receptor
 Antagonists
- Agent which prevents the action of an agonist on a
receptor and subsequent response
- Does not have any effect of its own
- Antagonists have affinity but no intrinsic activity (IA = 0)
- oppose the action of agonist
Eg. propranolol – β- blocker, atropine – M-receptor
- Their binding may be reversible (competitive or
non-competitive) or irreversible
 Competitive antagonists
- The effect of the antagonist may be overcome by increasing
the concentration of the agonist – the two molecules are
competing for the same receptor and the
relative amounts of each (combined with affinity)
determine the ratios of receptor occupation
 - for reversible; both antagonists and agonists drugs
compete for the same receptor but antagonistic effect completely
revers.

- Eg. morphine and naloxone on opioid receptor

adrenaline and prazosin on alpha receptor

- for irreversible; both drugs act on the same receptor but

antagonistic effect is not reversible

Eg. adrenaline and phenoxybenzamin on α-receptor

 Non – competitive antagonists

- the drugs act at different sites of the same receptor or pathway

Eg. adrenaline and verpamil
 Receptor – down regulation

- continued use and stimulation of receptors by agonist

drugs may decrease the number and sensitivity of the receptors

- Eg. constant use of β2-agonist (salbutamol) reduce

therapeutic response in asthma.
 Receptor – up regulation

continued use and inhibition of receptors by antagonist

drugs may increase the number and sensitivity of the receptors

- Eg. sudden withdrawal of anti-anginal drug (propranolol)

may precipitate angina.
 Non-receptors mechanism of drug action
 Drugs act on enzymes:
 Pyrodoxine acts as co-factor for dopa-decarboxylase activity
(stimulation), aspirin inhibits cyclooxygenase (inhibition).
 Inducers e.g anticonvulsants CYP3A
 Inhibitors
- Nonspecific e.g heavy metals
- Specific
• Competitive
- Reversible e.g methyldopa and dopa decaboxylase
- Irreversible e.g methotrexate and DHFR
•Noncompetitive e.g ASA and COX

 Drugs Act on Plasma Membrane:

 Polymixins and amphotricin B increase the permeability of bacterial
plasma membrane.
 Drugs Act on Subcellular Structures:
 Erythromycin and chloramphenicol inhibit protein synthesis in bacteria
by binding to 50 S ribosomal subunit. Tetracyclines and
aminoglycosides bind 30 S ribosomal subunit.

 Drug altering metabolic processes: Interfere with folic acid synthesis

e.g. sulfonamides.

 Drugs Act by Chemical Action:

 Antacids neutralize gastric acid secretion.
 Protamine (alkaline & +ve charge) antagonizes heparin (acid & -ve
charge).

 Drugs Act by Physical Means:

 Mass of drug, adsorptive property e.g. kaolin & charcoal, osmotic
activity e.g. magnesium sulfate & mannitol, radio activity, oxidising
property (KMnO4), Lubricant e.g. liquid paraffin.
 Dose – Response Curve (DRC)

• It give dose-response relationship of drugs

• Use to compare the efficacy and potency of drugs
• Use to distinguish between competitive and non-competitive
antagonism of drugs
• Use for calculating the therapeutic index or safety margin of drugs
• Graded or Simple and Log or Log dose DRC
 simple DRC: - large dose variation can not be plot,
- comparison between other drug responses is not possible.
Log dose DRC: - large dose variation can be plot,

-can be use for comparison between different drug responses

 GRADED (QUANTITATIVE) DRC

 Plots of dose or log dose verse response for drug (agonist) that
activate receptors revealed; affinity, potency and efficacy of the drug.
Affinity: ability of drug to bind to receptor, shown by the
proximity of the curve to the y- axis (if the curves are parallel). The
nearer the y-axis, the greater the affinity.
Potency: shows relative doses of two or more drugs (agonists) to
produce the same magnitude of effect. It shown by the proximity of
the respective curves to the y- axis (if the curves do not cross).
Efficacy: a measure of how higher a drug produces a response. It
shown by the maximal height reached by the curve.
 Parallel and non-parallel DRC

 DRC: parallel slops when two drugs interact at the same

receptor. Hence, drug A and B have the same mechanism.
 Affinity can be compared only when two drugs bind to the
same receptor. Drug A has a greater affinity than B.
 Potency: drug A has greater potency than B and C

 Efficacy: drug A and B are equivalent and they have greater

efficacy than C.
(% Response)
 Full and Partial Agonist DRC

 Full agonists produce a maximal response and a maximal

efficacy
 Partial agonists are incapable of eliciting a maximal response

 Potency: drug A is more potent than drug B, and drug B is more

potent than drug C. However, no general comparisons can
be made between drugs A, B and C in terms of efficacy
because drug C is a partial agonist while drug A and B are
full agonist. But at low response, drug A and B are more
potent and more efficacy than drug C and vice vase at
higher responses.
 Graded DRC also provide information about antagonist
 Antagonists and potentiators

• Competitive antagonists cause a parallel shift to the right which appear to

decrease the potency of agonist drug
e.g. atropine block - acetylcholine (ACH) at M-receptor
propranolol block - norepinephrine (NE) at β- receptor
• Non-competitive antagonists cause a non-parallel shift to the right which
appear to decrease both the potency and efficacy of agonists.
e.g. phenoxybenzamine is irriversibly block the effect of NE at α- receptors
by formation of a covalent bond.
• Potentiation of agonist action lead to displacement of DRC to the left.

e.g. benzodiazepines to enhance the activity of GABA. Amphetamine to

enhance the activity of NE.
% Response

% Response
 QUANTAL (CUMULATIVE) DRC

 Plots of percentage of a population responding to a specific drug effect versus

dose or log dose.
 It is all or none response

 Use in estimations of the median effective dose or effective dose in 50% of a

population (ED50).

 Reveal the range of inter subject variability in response

 TOXICITY AND THERAPEUTIC INDEX (TI)

 Comparison between ED 50 and TD50 values permit evaluation of the relative

safety of a drug (therapeutic index)

TI = TD50 or LD50
ED50 ED50
 Therapeutic index / Safety margin

 The gap b/w therapeutic effect DRC and adverse effect DRC
defines the safety margin or therapeutic index (TI)

 It can be calculated as ratio b/w LD50 and ED50

TI = median lethal dose LD50

median effective dose ED50

NB: the greater the TI, the safety of the drug

LD50 = 50% of test population showing lethal effect

ED50 = 50% of test population showing therapeutic effect

% Responding Population
 Therapeutic Range

 Is the dose range of drug bounded by the dose which produce

minimal therapeutic effect and the dose which produce maximal
acceptable adverse effect (also known as therapeutic window).
 Factors modifying effect of drugs

 due to individual difference in the degree and characters of

response to drug.
 The optimum dose of drug that produces therapeutic effect may
varies from person to another.
 The variation in drug response may result in:

• Body weight size

• Age and sex

• Species and race

• Genetics – pharmacogenetics
• Condition of health

• Placebo effect

• Route of drug administration

• Drug interactions

• Environmental factors
 STRUCTURAL ACTIVITY RELATIONSHIP

• The activity of a drug is intimately related to its chemical

structure
• It is useful for:
 synthetic of new drugs with more specific action & fewer
adverse reaction
 synthesis of competitive antagonist

 understanding the mechanism of drug action

• Hence, slight modification of structure of drug can change its

effect completely.
 TETRACYCLINES

Core of TCNs
6

Chlortetracycline - Cl - CH3 -H
Oxytetracycline -H - CH3 - OH
Tetracycline -H - CH3 -H
Demeclocycline - Cl -H -H
Methacycline -H =CH2* - OH
Doxycycline -H -CH3* - OH
Minocycline -N(CH3)2 - H -H
* No – OH at position 6
41
Penicillins are susceptible to
bacterial metabolism,
inactivation by amidases and
lactamases (penicillinases) at
the points shown

Carbapenems have a
different stereochemical
configuration in the lactam
ring that apparently imparts
resistance to β-lactamases

42
 (PABA)

PABA Sulfanilamide

Inhibition of tetrahydrofolate synthesis by sulfonamide and trimethoprim

43