Pharmacodynamic:

It is a branch of pharmacology that deals with the mechanism of action and pharmacological effects of a drug.

  Four targets of drug action (target proteins):

•  Receptors (cholinergic and adrenergic receptors)
•  Ion Channels (Ca⁺ channel, K⁺ channel)
•  Enzymes (cholinesterase, cyclo-oxygenase)
•  Carriers (transporters in renal tubular cells)

Types

• According to location

Membrane receptor: cholinergic receptors

Cytoplasmic receptor: steroid receptors

Nuclear receptor: thyroid receptors

• According to activity

Active receptor: adrenoceptors (1-2%)

Silent receptor: plasma protein

Spare receptor: (98%)

Receptor mediated mechanism:

Type 1 (Direct ligand gated ion channel): Drug binds directly with ligand gated ion channel, regulation of ions across cell membrane occurs (fast synaptic transmission) e.g:

Benzodiazepine receptor: Chloride channel opens, hyperpolarisation occurs, producing an inhibitory  effect

Nicotinic receptor: Sodium channel opens, depolarisation occurs, producing an excitatory effect

Type 2 (G-protein coupled receptor system):

Receptors are linked to enzyme/ion channels by G-protein. Ligands bind to the receptor, G-protein is activated, which changes the activity of   effector enzymes/ion channels, then via the second messenger, cellular effects are produced 

• Adrenoceptors

• Muscarinic receptors

Second messenger: Chemical substances produced when a ligand binds with G-protein coupled receptor, via which cellular effect is produced. E.g: cAMP, IP₃, DAG

Type 3 (Enzymatic receptors): drug binds with

     Transmembrane receptor (bound to protein tyrosine kinase), confirmational change occurs, activated tyrosine kinase produces phosphorylation of other cellular proteins to produce effect of drug.

• tyrosine kinase receptor

Type 4 (Intracellular receptors): drug binds with receptor in cytosol, enters nucleus and regulate gene expression for protein synthesis to produce effect of drug

• steroid receptors

Non-specific mechanisms:

• Enzyme mediated_  enzyme inhibition by
•    physostigmine, neostigmine, OPC, NSAID, ACEi
• Alteration of metabolic process of cell_ penicillin
• Alteration of ion transport_ diuretics
• Chemical interaction_ neutralisation, chelation
• Alteration of physiochemical property of cells_
•    laxatives 

Dose-Response Relationship

• Affinity_ Tendency of a drug to bind with a receptor
• Efficacy_ Ability of a drug to bind to a receptor and produce a pharmacological effect
• Potency_ The dose of drug required to produce 50% of its maximal effect
• Agonist_ A drug that binds with receptor & activates it to produce a pharmacological effect. Eg: salbutamol (β receptor agonist), adrenaline (α and β receptor agonist)
• Partial agonist_ A drug that has affinity for receptor but with weak activity. Eg: pindolol (β receptor agonist)
• Inverse agonist_ A drug that has affinity for receptor  but produces opposite effect to that of an agonist.

Eg: ß carboline (benzodiazepine receptor)

• Antagonist_ A drug that has affinity for receptor but blocks the receptor and produces no effect.

                                             Eg: propranolol (β receptor antagonist)

• Effective dose_ dose which produces desired pharmacological effect
• ED50 (median effective dose): dose which produces desired pharmacological effect in 50% of experimental animals or individuals
•  EDmax: dose of drug which produces maximum pharmacological effect
• Toxic dose: Excess amount of drug that produce toxic effect
• TD50 (median toxic dose): Amount of drug that produces toxic effect in 50% of individuals
• Lethal dose: Amount of drug that produces death in certain number of experimental animals
• Fatal dose: Amount of drug that produces death in 100% experimental animals

Therapeutic index: Ratio between median toxic dose and median effective dose

                                             TI =   TD50/ED50

                                             Importance of TI

• Reflects the safety margin of drug_ high TI, more safe
• For safe application of drug TI must be > 1

Drugs with low TI : barbiturates, anticancer drugs

Drugs with high TI _ diazepam, antacid

Therapeutic window_ Dose of a drug between minimum effective concentration and minimum toxic concentration, where treatment is safest & most effective.

Dose & response relationship curves:

• Graded dose response relationship curve_
•  Graph which shows the relation between dose of a drug with the magnitude of drug response sigmoid curve (log graph)
• As dose increases, increase in drug response is continuous and gradual
•  Ceiling effect: maximum effect of drug
•  Potency and efficacy can be compared
• Quantal dose response curve: all or none response (anaesthetics)

QUANTAL DOSE-RESPONSE CURVE

Efficacy:

1.  determines clinical effectiveness of drug
2.  helps to select among drugs of same potency

Potency:

1.  determines the dose of the chosen drug
2.  affected by affinity and efficacy of drug

Pharmacodynamic Interaction

1. Synergism

• Summation / Addition
• Potentiation

Drug Synergism:

Synergism is when the action of one drug is facilitated or increased by another drug.

a) Addition:

Effect of drugs (A + B) = Effect of drug A + Effect of drug B

Example: 2 + 2 = 4
Beta-blocker + Thiazide diuretic → More antihypertensive effect

b) Potentiation:

Combined effect is greater than the individual effects of the drugs.
Effect of drug (A + B) > Effect of drug A + Effect of drug B

Example: 2 + 2 > 4
Trimethoprim + Sulfonamide → Cotrimoxazole

2. Antagonism

• Chemical antagonism
• Physiological antagonism
• Pharmacological antagonism

Drug Antagonism:

When the effect of one drug is reduced or blocked by the effect of another drug.

1. Chemical Antagonism

Two drugs react by chemical reaction.

Gastric HCl + Antacid → Chemical neutralization of gastric acid
Heparin + Protamine sulfate → Chemical neutralization of heparin

2. Physiological Antagonism

When one drug antagonizes the action of another by acting on a different receptor of the same physiological system.

Histamine (causes bronchoconstriction via histamine receptor) in bronchus
vs.
Adrenaline (causes bronchodilation via β₂ receptor) in bronchus

3. Pharmacological Antagonism

When one drug blocks the action of another by acting on the same receptor.

Types:

• Competitive Antagonism
  • Binds to the same receptor
  • Chemically resembles the agonist
  • Produces a parallel right shift of the Dose-Response Curve (DRC) with increasing dose of agonist
  • Intensity depends on the concentration of both agonist and antagonist
  • Examples: Acetylcholine and Atropine, Morphine and Naloxone
• Non-Competitive Antagonism
  • Binds to a different site
  • No chemical resemblance
  • Suppresses the maximum response
  • Intensity depends only on the concentration of the antagonist
  • Examples: Diazepam and Bicuculline

Understand key concepts of pharmacodynamic interactions such as synergism, potentiation, and antagonism — including competitive and non-competitive mechanisms. Learn more from NCBI’s Pharmacology Reference.

You may also like the Pharmacokinetics topic: