Pharmacodynamics & Dose-Response
Pharmacology · General Pharmacology · lean revision notes
Pharmacodynamics & Dose-Response
Pharmacodynamics is what the drug does to the body — receptor binding, signal transduction, and the quantitative relationship between dose and effect. This chapter distils receptor theory, agonist/antagonist classification, the efficacy-versus-potency discrimination, and the high-yield numerical concepts (ED50, LD50, therapeutic index) that NEET PG repeatedly tests.
High-yield: Pharmacokinetics = what the body does to the drug (ADME). Pharmacodynamics = what the drug does to the body (receptor + dose-response). One-word swap is a favourite distractor.
Receptor theory & drug-receptor interaction
A receptor is a macromolecule (usually protein) to which a drug (ligand) binds to produce an effect. The interaction is governed by affinity (tendency to bind) and intrinsic activity / efficacy (ability to activate the receptor once bound).
Two key derived terms:
- Affinity → reflected by Kd (dissociation constant) = concentration of drug occupying 50% of receptors. Lower Kd = higher affinity.
- Intrinsic activity (α) → ranges 0 to 1; quantifies the maximal response a ligand can evoke relative to a full agonist.
Receptor families (transduction speed)
| Receptor type | Example | Signal | Time scale |
|---|---|---|---|
| Ligand-gated ion channel (ionotropic) | Nicotinic ACh, GABA-A, NMDA | Ion flux | Milliseconds |
| G-protein coupled (GPCR, 7-TM) | β-adrenergic, muscarinic, opioid | 2nd messengers (cAMP, IP3/DAG) | Seconds |
| Enzyme-linked (receptor tyrosine kinase / JAK-STAT) | Insulin, EGF, growth hormone | Phosphorylation cascade | Minutes–hours |
| Intracellular / nuclear | Steroids, thyroxine, vitamin D | Gene transcription | Hours–days |
High-yield: Fastest signalling = ion channels (ms). Slowest = nuclear receptors → effect even after drug cleared (e.g., steroids). Insulin acts via receptor tyrosine kinase; steroid hormones via cytoplasmic/nuclear receptors with a heat-shock-protein chaperone.
Classification of drugs by intrinsic activity
The cleanest way to organise pharmacodynamic agents is by affinity and intrinsic activity:
| Class | Affinity | Intrinsic activity (α) | Net effect |
|---|---|---|---|
| Full agonist | Yes | = 1 | Maximal response |
| Partial agonist | Yes | 0 < α < 1 | Sub-maximal response (ceiling) |
| Antagonist | Yes | 0 | No effect alone; blocks agonist |
| Inverse agonist | Yes | −1 (negative) | Opposite of agonist; reduces constitutive activity |
Agonist → binds + activates (full intrinsic activity). Partial agonist → binds + sub-maximally activates; acts as an agonist when alone but as an antagonist in the presence of a full agonist (because it competes for the receptor yet produces a smaller maximal effect). Classic examples: buprenorphine (partial μ-opioid agonist), pindolol and acebutolol (β-blockers with intrinsic sympathomimetic activity), aripiprazole (D2 partial agonist), buspirone (5-HT1A partial agonist), varenicline (nicotinic α4β2 partial agonist).
Inverse agonist → requires a receptor with constitutive (baseline) activity; produces the opposite effect. Examples: β-carbolines at GABA-A benzodiazepine site, and the classic statement that some antihistamines (H1 inverse agonists) and propranolol (β inverse agonist) behave this way.
High-yield: A partial agonist given with a full agonist lowers the full agonist's maximal effect — it behaves like a competitive antagonist with intrinsic activity. This is the mechanism by which buprenorphine precipitates withdrawal in a heroin-dependent patient.
Antagonism — the most tested discrimination
An antagonist has affinity but zero intrinsic activity. The crucial NEET PG split is pharmacological (receptor-level) versus physiological/chemical, and within receptor antagonism, competitive (reversible) versus non-competitive (irreversible/allosteric).
Competitive vs non-competitive antagonism
| Feature | Competitive (reversible) | Non-competitive (irreversible/allosteric) |
|---|---|---|
| Binding site | Same as agonist (orthosteric) | Different site OR irreversible covalent bond |
| Effect on dose-response curve | Parallel right shift | Curve flattened, lowered Emax |
| Emax (max effect) | Unchanged (surmountable) | Reduced (insurmountable) |
| Potency (EC50) of agonist | Decreased (apparent) | Often unchanged early |
| Overcome by ↑ agonist dose? | Yes | No |
| Example | Naloxone vs morphine; propranolol vs adrenaline; atropine vs ACh | Phenoxybenzamine vs noradrenaline (α); aspirin vs COX |
High-yield: Competitive antagonism → parallel shift right, Emax preserved (surmountable). Non-competitive → Emax depressed (insurmountable). This single table answers a large fraction of pharmacodynamics questions.
Curve-reading flow: Add competitive antagonist → curve shifts right → add more agonist → response fully restored → Emax unchanged. Add non-competitive antagonist → curve shifts right + downward → add more agonist → response NOT fully restored → Emax falls.
Other antagonism types
- Physiological (functional) antagonism → two drugs, different receptors, opposite effects on same physiological system. Example: histamine (bronchoconstriction via H1) vs adrenaline (bronchodilation via β2) — basis of adrenaline in anaphylaxis. Also glucagon vs insulin on blood glucose.
- Chemical antagonism → drugs combine chemically and inactivate each other. Examples: chelators (dimercaprol–arsenic, EDTA–lead, deferoxamine–iron), protamine–heparin.
- Pharmacokinetic antagonism → one drug alters ADME of another (e.g., enzyme induction by rifampicin reducing warfarin levels).
High-yield (anaphylaxis): Adrenaline reverses histamine effects by physiological antagonism, not receptor blockade — that is why antihistamines (true H1 antagonists) cannot rescue anaphylaxis.
Potency vs efficacy
This is a perennial single-best-answer trap.
- Potency = amount of drug needed to produce a given effect → quantified by EC50 / ED50. A more potent drug works at lower dose. Determined by affinity + access to receptor. Potency shifts the curve left/right on the X-axis.
- Efficacy (Emax) = the maximal effect a drug can produce regardless of dose → the ceiling/height of the curve. Determined by intrinsic activity.
| Concept | Synonym | Curve parameter | Clinical meaning |
|---|---|---|---|
| Potency | ED50/EC50 | Horizontal position | Dose required |
| Efficacy | Emax | Plateau height | Maximum benefit achievable |
High-yield: Efficacy >> potency clinically. Furosemide is less potent but has higher efficacy (ceiling natriuresis) than thiazides — so it is the loop diuretic of choice in renal failure. A high-potency drug is NOT necessarily a better drug.
Memory hook: "Potency = Position (left/right); Efficacy = Elevation (height)."
Spare receptors
A spare (reserve) receptor system is one where the maximal response is achieved when only a fraction of receptors are occupied — i.e., EC50 (concentration for 50% response) is less than Kd (concentration for 50% occupancy).
- Mechanism: amplification in signal transduction or temporal (catalytic) — agonist–receptor complex acts catalytically and dissociates to activate further receptors.
- Functional consequence: increases sensitivity of the tissue without changing Emax; the system can respond to low agonist concentrations.
- Classic example: catecholamines on cardiac/smooth muscle; insulin receptors (maximal glucose uptake at ~10% occupancy).
High-yield: Spare receptors present ⇒ EC50 < Kd. With spare receptors, an irreversible antagonist will initially shift the curve right (Emax preserved) until the spare reserve is exhausted, then depress Emax. This nuance distinguishes a sharp candidate.
Quantal dose-response & the therapeutic index
A graded dose-response curve plots the intensity of effect in one individual/tissue. A quantal dose-response curve plots the fraction of a population showing an all-or-none (yes/no) effect against dose — used to derive ED50, TD50, LD50.
- ED50 = dose producing the therapeutic effect in 50% of population.
- TD50 = dose producing toxic effect in 50%.
- LD50 = dose lethal in 50% (animal data).
Therapeutic Index (TI)
$$ TI = \frac{LD_{50}}{ED_{50}} \quad (\text{or } TD_{50}/ED_{50} \text{ in humans}) $$
- Higher TI = safer/wider margin. Penicillin (very high TI) vs narrow-TI drugs that need monitoring: digoxin, lithium, warfarin, theophylline, phenytoin, aminoglycosides, ciclosporin, oral anticoagulants.
- Standard Safety Margin (SSM) is a more rigorous index using the curve extremes:
$$ SSM = \frac{LD_1 - ED_{99}}{ED_{99}} \times 100 $$
High-yield: TI is a population statistic and ignores curve overlap; the Certain Safety Factor / SSM (LD1/ED99) is a better real-world safety measure. Drugs with low TI (digoxin, lithium, warfarin, phenytoin, theophylline, aminoglycosides) require therapeutic drug monitoring (TDM).
Mnemonic for narrow-TI / TDM drugs: "Digital LiThium Watches Phone Theatres And Cinemas" → Digoxin, Lithium, Theophylline, Warfarin, Phenytoin, Aminoglycosides, Ciclosporin.
Receptor regulation: tolerance, tachyphylaxis, supersensitivity
- Tolerance → gradual loss of response on repeated dosing (e.g., opioids, nitrates over weeks).
- Tachyphylaxis → rapid tolerance over minutes–hours, often due to depletion of mediator or receptor desensitisation (e.g., ephedrine, tyramine, nicotine, GTN if continuous). Mechanism for indirect sympathomimetics = noradrenaline store depletion.
- Down-regulation → ↓ receptor number with chronic agonist exposure.
- Up-regulation / denervation supersensitivity → ↑ receptor number after chronic antagonist or denervation → rebound on withdrawal. Explains β-blocker withdrawal rebound tachycardia/angina, clonidine rebound hypertension.
High-yield: Tachyphylaxis = rapid, often mediator depletion (ephedrine, GTN infusion). Abrupt β-blocker stoppage → up-regulated β-receptors → rebound hypertension/MI; always taper.
Dose-response curve interpretation flow
A typical NEET PG image-based item gives a sigmoid curve (log dose on X-axis) and modifies it. Decode using:
- Curve shifted right, same height → competitive antagonist (or lower potency agonist) — surmountable.
- Curve shifted right + lower plateau → non-competitive/irreversible antagonist — insurmountable; OR a partial agonist added to full agonist.
- Same potency, lower plateau alone → partial agonist vs full agonist comparison.
- Left shift → higher potency agonist OR presence of spare receptors / positive allosteric modulator (e.g., benzodiazepine on GABA-A enhances effect of GABA).
High-yield: Benzodiazepines and barbiturates are allosteric (modulatory) agents on GABA-A: benzodiazepines ↑ frequency of Cl⁻ channel opening (need GABA — ceiling effect, safer), barbiturates ↑ duration of opening (can act without GABA at high dose — no ceiling, lethal). This frequency-vs-duration line is heavily examined.
Recently asked / exam angle
- "Parallel right shift with preserved Emax" → competitive antagonist (surmountable). Counterpart "depressed Emax" → non-competitive.
- Partial agonist behaving as antagonist in presence of full agonist — buprenorphine precipitating opioid withdrawal.
- Furosemide vs thiazide to test efficacy ≠ potency.
- EC50 < Kd ⇒ spare receptors.
- Therapeutic index = LD50/ED50; higher = safer; identify narrow-TI drug from a list (lithium/digoxin/warfarin).
- Adrenaline–histamine = physiological antagonism; protamine–heparin and chelators = chemical antagonism.
- Benzodiazepine = frequency, barbiturate = duration of GABA-A Cl⁻ channel opening.
- Inverse agonist needs constitutive activity (distinguish from simple antagonist that gives no effect alone).
- Insulin → receptor tyrosine kinase; steroids → nuclear receptor; nicotinic ACh → ligand-gated ion channel (receptor–transduction matching).
- Tachyphylaxis vs tolerance — ephedrine/GTN as the tachyphylaxis examples.
- Standard safety margin (LD1/ED99) as better than TI.
Key differentials / commonly confused pairs
- Affinity (Kd) vs intrinsic activity (α) — binding tendency vs activating ability.
- Potency (ED50) vs efficacy (Emax) — dose needed vs ceiling effect.
- Competitive (surmountable, Emax kept) vs non-competitive (insurmountable, Emax fallen).
- Pharmacological vs physiological vs chemical antagonism.
- Partial agonist vs antagonist — partial agonist does produce a sub-maximal effect alone.
- Tolerance vs tachyphylaxis vs supersensitivity.
- Quantal (population, all-or-none) vs graded (individual, intensity) curve.
Rapid revision
- Lower Kd = higher affinity; Kd = concentration occupying 50% of receptors.
- Full agonist α = 1; partial agonist 0 < α < 1; antagonist α = 0; inverse agonist α negative (needs constitutive activity).
- Partial agonist + full agonist ⇒ net antagonism (lowers full agonist's Emax) — buprenorphine.
- Competitive antagonist → parallel right shift, Emax preserved, surmountable (naloxone, atropine, propranolol).
- Non-competitive/irreversible → depressed Emax, insurmountable (phenoxybenzamine, aspirin–COX).
- Potency = position (ED50), efficacy = elevation (Emax); efficacy matters more clinically — furosemide > thiazide.
- Spare receptors ⇒ EC50 < Kd; maximal effect at sub-maximal occupancy (catecholamines, insulin).
- Therapeutic Index = LD50/ED50; higher = safer; SSM (LD1/ED99) is more rigorous.
- Narrow-TI / TDM drugs: digoxin, lithium, warfarin, phenytoin, theophylline, aminoglycosides, ciclosporin.
- Physiological antagonism = adrenaline vs histamine; chemical = protamine–heparin, chelators.
- Tachyphylaxis = rapid tolerance via mediator depletion (ephedrine, tyramine, continuous GTN).
- Benzodiazepine ↑ frequency, barbiturate ↑ duration of GABA-A Cl⁻ channel opening; β-blocker abrupt stop → rebound (up-regulation).