Applied Pharmacodynamics

Pharmacodynamics

Study of biochemical and physiological effects of drugs and their mechanisms of action

Receptor

Protein that binds ligands (endogenous or drugs) and triggers cellular response

Endogenous ligand

Natural molecule (NT, hormone) binding receptor to produce physiological effect

Agonist

Drug with affinity + maximal intrinsic activity (efficacy) that stimulates receptor

Antagonist

Drug with affinity but no efficacy, blocks agonist action

Partial agonist

Drug with affinity + submaximal efficacy, weak agonist alone, antagonist in presence of full agonist

Inverse agonist

Drug with affinity + negative intrinsic activity, produces opposite effect of agonist

Affinity (Kd)

Strength of drug‑receptor binding, lower Kd

Spare receptors

Excess receptors not needed for max effect, increase tissue sensitivity (e.g. myocardium to epinephrine)

ED50

Effective dose producing 50% of maximal effect or response in 50% population

TD50

Toxic dose producing toxicity in 50% population

LD50

Lethal dose producing death in 50% population

Potency

Amount of drug needed to produce effect, lower ED50

Efficacy

Ability of drug to produce maximal response regardless of dose

Therapeutic index (TI)

TD50/ED50, larger TI

Therapeutic window

Range between MEC and MTC where drug is effective but not toxic

Receptor downregulation

Prolonged agonist exposure → receptor internalization/endocytosis → reduced sensitivity → tolerance

Receptor upregulation

Prolonged antagonist exposure → increased receptor expression → hypersensitivity on withdrawal

Mechanisms of drug action

Receptors, carriers/transporters, ion channels, enzymes, physical action, chemical reaction

GPCR (metabotropic)

Receptor linked to G‑protein → second messengers (cAMP, IP3, DAG) → cellular response

Ionotropic receptor

Ligand‑gated ion channel, fast response, e.g. nicotinic receptor → Na⁺ influx → depolarization

Enzyme‑linked receptor

Receptor dimerization → kinase activation → transcription factors → cellular response (e.g. insulin receptor)

Nuclear receptor

Intracellular receptor → gene transcription → long‑term effects (e.g. steroids)

Carrier/Transporter target

Digitalis inhibits Na⁺/K⁺ ATPase → ↑ intracellular Na⁺ → ↓ Na⁺/Ca²⁺ exchange → ↑ Ca²⁺ → ↑ contraction

Ion channel target

Local anesthetics block Na⁺ channels → prevent impulse transmission → anesthesia

Enzyme target

Neostigmine inhibits acetylcholinesterase → ↑ ACh → improved neuromuscular transmission

Drug physical action

Osmotic diuretics increase urine output by osmotic effect in renal tubules

Drug chemical reaction

Antacids neutralize gastric HCl (CaCO₃ + 2HCl → CaCl₂ + H₂O + CO₂)

Normal dose‑response curve

Hyperbolic, initial rapid response, plateau at maximal effect (ceiling dose)

Graded dose‑response curve

Dose vs intensity of effect in one subject/tissue, relates dose to effect magnitude

Graded log dose‑response curve

Sigmoid curve, compresses dose scale, easier mathematical analysis

Quantal dose‑response curve

Dose vs % population showing all‑or‑none effect (awake/asleep, convulsion/no convulsion)

Quantal ED50

Dose producing specified effect in 50% of population

Quantal TD50

Dose producing toxicity in 50% of population

Quantal LD50

Dose producing death in 50% of population

Clinical significance of ED50

Benchmark for potency, lower ED50

Clinical significance of TD50

Indicates toxicity threshold, used to calculate TI

Clinical significance of LD50

Used in toxicology studies, safety evaluation

Competitive antagonist

Structurally similar to agonist, competes for same receptor, reversible binding

Competitive antagonism surmountable

Increasing agonist dose overcomes antagonist, restores maximal effect

Competitive antagonist effect on DRC

Parallel right shift, potency reduced, efficacy unchanged

Non‑competitive antagonist

Structurally different or covalent binding, irreversible, allosteric site binding

Non‑competitive antagonist effect on DRC

Right shift + reduced maximal efficacy, curve height lowered

Agonist vs antagonist on DRC

Agonist increases response, competitive antagonist shifts curve right, non‑competitive reduces height

Partial agonist on DRC

Produces submaximal response even at full receptor occupancy, antagonizes full agonist when present

Spare receptors significance

More spare receptors → higher sensitivity, small agonist dose produces full effect

Myocardium sensitivity example

Extremely sensitive to epinephrine due to spare receptors

Kd importance

Drug concentration equal to Kd occupies 50% receptors, indicates affinity and receptor occupancy

Law of mass action

At equilibrium k1[D][R]

Clinical correlation potency vs efficacy

Drug A and B equally efficacious, Drug A more potent if lower ED50

Therapeutic index example

Drug A TI

Therapeutic window example

Warfarin narrow window, penicillin wide window

Additive drug interaction

Effect of two drugs equal to sum of individual effects (aspirin + paracetamol)

Synergistic drug interaction

Effect greater than sum of individual effects (sulfamethoxazole + trimethoprim)

Antagonistic drug interaction

Effect less than sum of individual effects (drug A + drug B reduce each other’s effect)

Cumulative drug effect

Repeated administration produces stronger effect (aspirin antiplatelet)

Clinical scenario competitive antagonism

Atropine competes with ACh at muscarinic receptors, surmountable with ↑ ACh

Clinical scenario non‑competitive antagonism

Phenoxybenzamine irreversibly blocks α‑receptors, not surmountable

Clinical scenario partial agonist

Buprenorphine produces submaximal opioid effect, antagonizes morphine when co‑administered

Clinical scenario inverse agonist

Flumazenil produces opposite effect of benzodiazepine agonists

GPCR clinical example

Salbutamol (β₂ agonist) → ↑ cAMP → ↓ Ca²⁺ → bronchodilation → relieves breathlessness

Ionotropic receptor clinical example

Nicotinic receptor activation → Na⁺ influx → depolarization → muscle contraction

Enzyme‑linked receptor clinical example

Insulin receptor activation → kinase cascade → glucose uptake

Nuclear receptor clinical example

Corticosteroids bind intracellular receptor → gene transcription → anti‑inflammatory effect

Carrier clinical example

Digitalis inhibits Na⁺/K⁺ ATPase → ↑ Ca²⁺ → ↑ myocardial contractility

Ion channel clinical example

Local anesthetics block Na⁺ channels → prevent nerve impulse → anesthesia

Enzyme clinical example

Neostigmine inhibits acetylcholinesterase → ↑ ACh → improved neuromuscular transmission

Affinity vs efficacy

Affinity is binding strength, efficacy is ability to produce maximal effect

Potency vs efficacy

Potency is dose required, efficacy is maximal effect achievable

Clinical importance of spare receptors

Explains tissue sensitivity and drug effectiveness despite receptor blockade

Receptor regulation clinical importance

Tolerance with agonists, rebound hypersensitivity with antagonist withdrawal

Therapeutic index clinical importance

Guides drug safety comparison, larger TI preferred

Therapeutic window clinical importance

Defines safe plasma concentration range for therapy

Dose‑response curve clinical importance

Predicts efficacy, potency, toxicity, and drug interactions