General Pharmacology

Pharmacodynamics
Prof. Gayani Liyanage
Department of Pharmacology
Faculty of Medicine
Galle

Amiru Rathnayake | 43rd | FoM UoR

At the end of this lecture students should be able to
• define the term pharmacodynamics
• list the types of receptors
• compare and contrast receptor types in relation to
onset, mechanism and location of action
• describe enzymes in relation to pharmacodynamics
• define the terms “tolerance” and “dependence”
• describe the mechanisms of tolerance
• define the terms potency and efficacy

• define antagonism

• describe the types of antagonists

• define an agonist

• describe the types of agonists

• apply knowledge of drug synergism in clinical practice

• list the quantitative aspects of pharmacodynamics

• define the dose response curves

• explain ED50 and LD50

• discuss the importance of dose response curve

• describe the therapeutic index

“Objective of pharmacology is to provide a
scientific foundation for therapeutics”
“Rational drug therapy ”

“Drug”
Any substance or mixture of substances
used in diagnosis, treatment or
prevention of diseases in man or animal
• Pharmacodynamics
what the drug does to the body
(mechanism of action of drug)

• Pharmacokinetics
What the body does to drugs
Absorption, distribution metabolism
and excretion of drug
 Mechanisms of drug action

On the cell membrane

Within the cell
Outside the cell
 Mechanisms of drug action
On the cell membrane

Action on specific receptors

H2 receptor blockers, Ach receptor agonists

Blocking passage of ions across membranes

Ca channel blockers - nifedipine
Na+ channel blockers - lignocaine

Inhibit membrane bound enzymes and pumps

Na+ / K+ ATPase - digoxin
Block the pump (amines) - tricyclic antidepressants
Within the cell

Enzyme inhibition
reversible - ACE inhibitors
irreversible - Platelet cyclo-oxygenase-
aspirin

Incorporation into larger molecules

Incorporated into mRNA - 5 flurouracil

Altering metabolic processes unique to microbes

Penicillin
Outside the cell

Drugs Act by Chemical Action:

Antacids neutralize gastric acid secretion

Protamine (alkaline & +ve charge) antagonizes

heparin (acid & -ve charge)

Drugs Act by Physical Means:

Osmosis e.g. mannitol

Lubricant e.g. liquid paraffin
Adsorbent e.g. kaolin and charcoal
 Receptor
Receptor is a special molecular component
of the cell
(protein macro-molecule or DNA)

which is capable of selectively recognizing

and binding a drug, hormone, mediator or
neurotransmitter, thereby eliciting a
cellular response
 Specific receptors on the cell
membrane and interior

1. Ligand gated ion channels

2. G-protein-coupled receptor systems
3. Protein kinase receptors
4. Cytosolic / nuclear receptors
1. Ligand gated ion channels
• Receptors are coupled directly to
membrane ion channels
• Response within miliseconds

• Example
neurotransmitters - postsynaptic
membrane on nerve/muscle
2. G-protein-coupled receptor systems
• Receptors on the cell membrane and coupled to
intracellular effector systems by G protein
• G-protein (Gs , Gi , Gq , …) involved in stimulation
or inhibition of a second messenger
• Response – seconds R

Second
messenger
Examples
• Stimulation of β1 & β 2 adrenergic receptors
stimulate Gs  increase cAMP
• Stimulation of α1 adrenergic receptors  Gq
 increase IP3
• Stimulation α2 adrenergic receptors Gi
decrease cAMP
3. Protein kinase receptors
• Contains protein kinase
• Response - hours
• Eg: peptide hormones involved in
control of cell growth and
differentiation
Platelet derived growth factor (PDGF)

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
4. Cytosolic/nuclear receptors
• Regulate DNA transcription and protein
synthesis
• Response - hours/days
• Eg: steroid and thyroid hormones
These hormones can easily pass the cell
membrane and bind with cytoplasmic mobile
receptors

The drug-receptor complex enters the

nucleus

Bind to DNA response element, which in turn

regulates RNA transcription with production
of unique protein concerned with the cell
response
 Factors influence drug action
• Dose
• Age
• Sex
Additive effect a+b = a+b
• Disease
Synergistic effect a+b = a+b+c
• Other drugs
Antagonistic
Biological
• Individual variation
Hereditary

• Acquired tolerance
• Drug potency
Strength expressed in terms of weight
A 2mg …….. B 30mg
• Dosage
How much of drug that you prescribe
• Formulation
How does it appear (oral/injectable
preparation)
Agonist
Chemical or drug that activates
receptors & produce a response

Antagonist
Chemical or drug that binds to are
receptors but do not activate them. So
prevents the agonist combine with the
receptors
Partial agonist
Blocking the access of the natural
agonist + low degree of receptor
activation

Inverse agonist
Activate receptors but produce effects
opposite to those of agonist
 Receptor binding
Affinity - measure of how strongly a drug binds to it’s
receptor

Competitive antagonist

Bind reversibly with

receptors
Response can be obtained by ↑ dose of agonist

Irreversible antagonist

effect can not be reversed by ↑ concentration

of agonist
• When tissues receptors are exposed to an agonist
continuously number of receptors
Down regulation
++

• When tissues are exposed to an antagonist

continuously number of receptors

Up regulation
 Dose - Response Curves
Response
A
Wanted
effect Un wanted
effect

Wanted
effect

Un wanted
effect
B
Dose
 Therapeutic index
Therapeutic index = maximum tolerated dose
minimum curative dose

Therapeutic index = LD 50 (dose that kills 50% animals

ED 50 (pharmacologically
effective in
50%)
20

Therapeutic index = ED 50 ( toxic dose)

100
ED 50 (therapeutic dose)
2 10
Ration between the dose required to produce a desired 10
effect and dose producing toxic effect
 Potency

• Amount of drug in relation to its effect

• 1 mg of drug A effect = 10 mg drug B
effect
• Clinically not useful
 Therapeutic efficacy

= effectiveness
Eg. Amiloride - low efficacy
Bendroflumethiazide - moderate
efficacy
Furosemide - high efficacy
 Tolerance
Gradual loss of the effect of a drug with its
continuous/repeated administration
• Natural
• Acquired
 Mechanisms of tolerance

• Down regulation of receptor

• Enzyme inducing activity
• Oxygen free radicals
 Dependence

If withdrawal symptoms and signs occur

upon cessation of a drug during
repeated drug administration