PharmacodynamicsFor BPH 1st Year

Dr. Pravin Prasad

2nd Year Resident, MD Clinical Pharmacology

Maharajgunj Medical Campus, Institute of Medicine

22nd December, 2016 (Poush 7, 2073), Thursday

Introduction

“Pharmacodynamics is the study of the biochemical and physiological effects of drugs and

their mechanisms of action”- Bluementhal DK, Garrison JC. Pharmacodynamics: Molecular Mechanisms of Drug Action. In:

Bruton LL, Chabner BA, Knollmann BC, editors. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. China: Mc Graw Hill Education; 2011. p 41-72

Pharmacodynamics is the study of drug effects• What & How

Introduction

Action-Effect sequence

Dose-Effect relationship

Pharmacodynamics

Modification of action of one drug

by another drug

Principles of Drug Action

Stimulation:• Selective enhancement of the

level of activity of specialized cells

Replacement:• Use of natural metabolites, hormones, or their congeners in

deficiency states

Irritation:• Non-selective, often noxious

effect on less specialized cells

Depression:• Selective diminution of the level

of activity of specialized cells

Cytotoxic Action:• Selective cytotoxic action on

invading microbes or cancer cells

• Physical interaction

• Chemical interaction

• Binding to proteins

• Binding to Nucleic acids

• Drug Targets

• Receptors

• Ion channels

• Carriers (transporters)

• Enzymes

Mechanism of Drug Action

RICE

Drug Target- Enzymes

• Enzyme stimulation• Pyridoxine

decarboxylase

• Enzyme inhibition• Competitive (equilibrium

type)• Competitive (non-

equilibrium type)• Non-competitive

Non-competitive

Drug Target- Enzymes

Enzyme Endogenoussubstrate

Inhibitor Type

Bacterial folate synthase

Para-amino benzoic acid

SulfadiazineCompetitive (equilibrium)

Cholinesterase Acetylcholine Physostigmine

Malathion, OPs Competitive (non-

equilibrium)Dihydrofolate reductase

DHF Methotrexate

Drug Target- Enzymes

Enzyme Endogenoussubstrate

Inhibitor Type

Carbonicanhydrase

H2O and CO2 Acetazolamide

Non-competitive

H+-K+ ATPase H+ and K+ Omeprazole

Cyclooxygenase

Arachidonic acid

Aspirin

Drug Targets- Ion Channels

•Types:• Ligand gated

• Nicotinic receptors

•G-protein regulated channels• β1 adrenergic receptor activated Ca++ channels

•Voltage operated• Local anaesthetics, phenytoin, Nifedipine

• Stretch sensitive

Drug Targets- Ion Channels

Drug Targets- Transporters (Carriers)

Drug Targets- Transporters (Carriers)

Carrier Transports Blockers

Norepinephrine transporters

Noradrenaline (Norepinephrine)

Desipramine, Cocaine

Gamma butyric acid transporter (GAT1)

GABA Tiagabine

Na+ - K+ - 2Cl- co-transporter

Na+, K+, Cl- Furosemide

Serotonin Transporter

Serotonin Fluoxetine

PharmacodynamicsFor BPH 1st Year

Dr. Pravin Prasad

2nd Year Resident, MD Clinical Pharmacology

Maharajgunj Medical Campus, Institute of Medicine

9th February, 2017 (Magh 27, 2073), Thursday

Drug Targets- Receptors

• Are the macromolecule or binding site located on the surface or inside the effector cell that serves to recognise the signal molecule/drug and initiate a response to it, but itself has no other function-Tripathi KD. Pharmacodynamics: Mechanism of Drug Action; Receptor Pharmacology. In: Essential

of Medical Pharmacology. 7th ed. India: Jaypee Brothers Medical Publishers (P) Ltd; 2014. p 40.

Receptors

Recognise

Response Drug Action

Drug Effect

Drug Targets- Receptors

Receptor Type Examples

G-protein coupled receptors Muscarinic receptors, adrenergic receptors

Ion channels receptors Nicotinic cholinergic, GABAA, glycine

Enzyme-linked Insulin, Epidermal Growth factor, Nerve Growth Factor

Transmembrane JAK-STAT binding receptors

Cytokines, growth hormone, prolactin,interferons

Receptors regulating gene expression Steroids, Vitamin A/D

Drug-Receptor Interaction

• Agonist:• Agent which activates a receptor to

produce an effect similar to that of the physiological signal molecule

• Partial agonist:• Agent which activates a receptor to

produce submaximal effect

• Inverse agonist:• Agent which activates a receptor to

produce an effect in the opposite direction to that of the agonist

Drug-Receptor Interaction

•Antagonist:• Agent which prevents the

action of an agonist on a receptor or the subsequent response, but does not have any effect on its own

Dose Response Curve

Dose Response Curve: Drug Potency

•Amount of drug needed to produce a certain response

•Position of DRC on the dose axis

•Dictates dose of drug

Drug Response Curve: Drug Efficacy

•Maximal response that can be elicited by the drug

•Upper limit of DRC

•Dictates choice of drug

Therapeutic Efficacy/Clinical Effectiveness

Drug Potency Drug Efficacy

Pharmacokinetic variables

Pathophysiological variables

Therapeutic Efficacy / Clinical Effectiveness

Therapeutic Efficacy/Clinical Effectiveness

• Expressed in terms of:

• Degree of benefit/relief afforded by the drug (in the recommended dose range)

OR• Success rate in achieving a defined therapeutic end point

Therapeutic window

Combined Effect of Drugs

Synergism

•Additive• Metformin +

Glibenclamide

• Supra-additive• Sulfamethoxazole +

trimethoprim

Antagonism• Physical antagonism

• Charcoal + alkaloids

• Chemical antagonism• KMnO4 + alkaloids

• Physiological antagonism• Glucagon & insulin on blood

sugar level

• Receptor antagonism

Combined Effects of Drugs- Receptor Antagonism

• Competitive equilibrium:• Acetylcholine & Atropine

• Competitive non-equilibrium:• Phenoxybenzamine +

adrenaline (α receptors)

• Diazepam & Bicuculline