Receptor Theory & Pharmacodynamics

Pharmacodynamics is the study of what a drug does to the body — how it produces its effects at the molecular and cellular level. Understanding receptor theory is the bedrock of rational pharmacology.

DRUG-RECEPTOR INTERACTIONS

Drugs bind to their receptors through non-covalent bonds: ionic interactions (electrostatic attraction between oppositely charged groups), hydrogen bonds (between electronegative atoms), van der Waals forces (transient dipole attractions), and hydrophobic interactions. These reversible forces allow drugs to bind selectively yet still dissociate. A notable exception is covalent bonding, which produces irreversible binding: aspirin acetylates a serine residue in the active channel of cyclooxygenase (COX-1 and COX-2), permanently blocking prostaglandin synthesis for the lifespan of the enzyme — about ten days in platelets. Organophosphates similarly form an irreversible covalent bond with the serine at the active site of acetylcholinesterase (AChE), preventing ACh breakdown.

RECEPTOR SUPERFAMILIES

Four major receptor superfamilies mediate drug action. Type 1 receptors are ligand-gated ion channels — the fastest: binding opens an intrinsic ion channel within milliseconds. Examples include the nicotinic acetylcholine receptor (Na+/K+ influx), GABA-A (Cl− influx, hyperpolarisation), and the NMDA receptor (Na+/Ca2+ influx). Type 2 receptors are G-protein-coupled receptors (GPCRs) — the largest receptor family. They activate heterotrimeric G-proteins over seconds. Gs activates adenylyl cyclase → ↑cAMP; Gi inhibits adenylyl cyclase → ↓cAMP; Gq activates phospholipase C → IP3 + DAG → ↑intracellular Ca2+. Type 3 receptors are enzyme-linked (receptor tyrosine kinases, RTKs) — ligand binding (e.g., insulin, EGF) causes receptor dimerisation and autophosphorylation, initiating signalling cascades over minutes. Type 4 receptors are nuclear receptors (intracellular): steroid hormones and thyroid hormones cross the plasma membrane, bind nuclear receptors, and act as transcription factors — effects develop over hours to days.

AGONISTS AND ANTAGONISTS

A full agonist activates its receptor to produce the maximum possible response (Emax) for that receptor system. A partial agonist produces a submaximal Emax even at full receptor occupancy, because it has lower intrinsic efficacy. Partial agonists are clinically valuable because they produce a ceiling effect — buprenorphine (opioid partial agonist used in opioid dependence and pain) and buspirone (5-HT1A partial agonist used for generalised anxiety) are key examples.

Antagonists block agonist effects without activating the receptor. Competitive antagonists bind reversibly to the same site as the agonist: they produce a parallel rightward shift in the dose-response curve with the same Emax — the effect is surmountable by increasing agonist concentration. Naloxone (opioid antagonist) is the paradigm. Non-competitive antagonists bind irreversibly or at an allosteric site, depressing the Emax regardless of agonist concentration. Phenoxybenzamine (irreversible α-adrenoceptor blocker) is the classic example.

DOSE-RESPONSE CURVES AND KEY PARAMETERS

The graded dose-response curve describes the relationship between drug concentration and effect. Emax is the maximum effect achievable. EC50 is the concentration producing 50% of Emax and is the standard measure of potency — a lower EC50 means a more potent drug. The Hill coefficient (slope factor) reflects receptor cooperativity. Potency and efficacy are distinct: fentanyl is more potent than morphine (lower EC50) but morphine is more efficacious than codeine (higher Emax). Spare receptors (receptor reserve) allow Emax to be achieved at concentrations far below those needed to occupy all receptors, amplifying sensitivity.

The therapeutic index (TI = LD50/ED50) quantifies the safety margin between lethal and effective doses. Drugs with a narrow TI — digoxin, lithium, warfarin, aminoglycosides — require therapeutic drug monitoring. Receptor desensitisation following prolonged agonist exposure may be homologous (receptor-specific, e.g., GPCR phosphorylation and internalisation) or heterologous (broad desensitisation of multiple receptor types). Chronic antagonist therapy causes receptor up-regulation — important clinically with beta-blockers, which should not be stopped abruptly.