Anaes · Applied cardiovascular & respiratory physiology
Pharmacodynamics: receptors and the dose-response relationship
Also known as Pharmacodynamics · Receptor theory · Dose-response curve · Agonist and antagonist · Affinity efficacy potency · Biased agonism
Pharmacodynamics is what the drug does to the body — the study of the molecular events, almost always at a receptor, that produce a clinical effect, and how that effect scales with dose. The framework rests on seven exam-critical ideas. First, drugs act chiefly through four receptor superfamilies in teaching: ligand-gated ion channels (millisecond signalling), GPCRs (seconds, the largest family), kinase-linked receptors (minutes), and intracellular nuclear receptors (hours). Second, a drug's action is described in teaching by affinity (how tightly it binds), efficacy (how big a response it can generate once bound) and potency (the concentration at which it is effective, summarised by the EC50). Third, the dose-response curve is sigmoidal on a semi-log plot in teaching: threshold, steep linear portion, ceiling (Emax). Fourth, agonists generate a response, antagonists block it, partial agonists generate a submaximal response (intrinsic activity less than 1) and can therefore act as antagonists in the presence of a full agonist, and inverse agonists reduce constitutive receptor activity in teaching. Fifth, competitive antagonism is surmountable (rightward parallel shift, Emax preserved) whereas irreversible or non-competitive antagonism lowers Emax in teaching. Sixth, biased agonism (functional selectivity) means one agonist can preferentially activate one downstream pathway over another at the same receptor in teaching. Seventh, receptors are dynamic in teaching: desensitisation, internalisation, down-regulation or up-regulation, explaining tachyphylaxis and withdrawal phenomena. Built on the propofol-diazepam GABA-A competition study (Pence 2022, oocyte alpha1-beta3-gamma2L plus zebrafish, micromolar diazepam inhibition surmountable with Schild slope not different from 1, in-vivo reversal of etomidate but not propofol anaesthesia), the darigabat subtype-selective GABA-A review (Iannone 2026, alpha2/alpha3/alpha5 PAM, 20 studies, heterogeneous clinical efficacy, alpha1-sparing reduces but does not eliminate sedation), the adult muscle nicotinic PAM study (Webster 2026, DC-98-LC74 adult-selective, epsilon M2-M3 loop, fast-channel rescue to wild-type burst duration), the G-protein-biased mu-opioid autonomic protocol (Zhang 2026, scoping-review protocol with no results, oliceridine FDA 2020 and tegileridine NMPA January 2024, true-bias versus low-efficacy debate), the GPCR-bias biosensor review (Ji 2026, bias as graded evidence not binary), the carvedilol functional-affinity study (Hamed 2024, HEK293 human beta2, ERK1/2 partial agonism with affinity distinct from antagonist KB, G-alpha-s transducer), the aripiprazole D2/D3 partial-agonist study (Edelstein 2026, 0.65-5 mg/kg IP rats with low-effort bias like antagonists, functional-antagonist conclusion), and the PAR1 signalling-bias review (Sinha 2026, thrombin versus APC bias via GRK5 and phosphorylation patterns).
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- Affinity is NOT efficacy, and neither is potency in teaching (definitions teaching, not quantified in any retrieved abstract). Affinity is how tightly a drug binds its receptor; efficacy is the maximum response it can produce once bound; potency (EC50) is the concentration needed for a given effect. A drug can be highly potent but have low efficacy (a partial agonist), or highly efficacious but not especially potent.
- A PARTIAL AGONIST has intrinsic activity less than 1 in teaching — it cannot reach the full Emax. In the presence of a full agonist, a partial agonist behaves as a COMPETITIVE ANTAGONIST (it occupies receptors but produces less effect), so it lowers the net response. Buprenorphine at the mu-opioid receptor is the bedside example (teaching); the retrieved partial-agonist anchor is aripiprazole at the D2 receptor acting as a functional antagonist in effort-based choice (0.65-5 mg/kg IP, low-effort bias like haloperidol/eticlopride, no agonist rescue when dopamine tone was lowered) [7].
- COMPETITIVE antagonism shifts the dose-response curve RIGHTWARD and parallel in teaching — Emax is preserved (the block is surmountable by increasing the agonist concentration). IRREVERSIBLE or non-competitive antagonism lowers Emax (the block cannot be overcome by more agonist). The retrieved competition anchor is GABA-A-exact: micromolar diazepam inhibition of propofol-potentiated currents was surmountable by high propofol with a rightward shift and a Schild slope not significantly different from 1, consistent with competition at the beta-plus/alpha-minus sites [1].
- BIASED AGONISM (functional selectivity) means one agonist can favour a different downstream pathway than another at the SAME receptor in teaching. The G-protein-biased mu-opioid agonists were designed to keep analgesia while shedding adverse effects — the principle, though the retrieved autonomic paper is a protocol with no results (oliceridine FDA 2020, tegileridine NMPA January 2024, with an open debate whether benefits come from true bias or low intrinsic efficacy) [4]; the retrieved bias-measurement anchor treats bias as graded evidence via biosensors, not a binary label [5].
- Receptors are not static in teaching. Chronic exposure to an agonist causes desensitisation, internalisation and down-regulation (tachyphylaxis — e.g. repeated ephedrine doses become less effective). Chronic antagonist exposure causes up-regulation, so abrupt withdrawal causes rebound over-activity (e.g. clonidine withdrawal hypertension). (Regulation/withdrawal examples are teaching, not in any retrieved abstract.)
Meet the patient
A 35-year-old opioid-tolerant patient on long-acting morphine presents for emergency surgery. In recovery the registrar gives buprenorphine for pain — within minutes the patient is in acute withdrawal, sweating, agitated, and in worse pain than before. (Teaching vignette — the buprenorphine-precipitated-withdrawal scenario is teaching, not in [7]; [7] is an aripiprazole D2 partial-agonist rat study.)[7]
This is pharmacodynamics at the bedside. Buprenorphine is a partial agonist at the mu-opioid receptor in teaching — it occupies receptors but produces less effect than morphine, so in the presence of a full agonist it behaves as a competitive antagonist (bedside mechanism teaching; the retrieved partial-agonist anchor shows the same tone-dependent behaviour for aripiprazole at D2, which acted as a functional antagonist rather than showing agonist activity when dopamine tone was low [7]). Understanding affinity, efficacy, and the shape of the dose-response curve is what separates a controlled anaesthetic from a series of surprises.[7]
References8ShowHide
- [1]Pence A, et al. Competitive Interactions Between Propofol and Diazepam: Studies in GABA(A) Receptors and Zebrafish J Pharmacol Exp Ther, 2022.PMID 36167415
- [2]Iannone LF, et al. Darigabat and subtype-selective GABA-A modulation: pharmacology, clinical development, and translational challenges Expert Opin Investig Drugs, 2026.PMID 42252536
- [3]Webster RG, et al. Positive allosteric modulator selective for adult muscle nicotinic acetylcholine receptor Proc Natl Acad Sci U S A, 2026.PMID 42228531
- [4]Zhang Y, et al. Autonomic nervous system modulation by G protein-biased mu-opioid receptor agonists: A translational scoping review protocol PLoS One, 2026.PMID 42139241
- [5]Ji RL, et al. Biosensors for translatable GPCR bias Trends Pharmacol Sci, 2026.PMID 42285785
- [6]Hamed O, et al. The β-Blocker Carvedilol and Related Aryloxypropanolamines Promote ERK1/2 Phosphorylation in HEK293 Cells with K (A) Values Distinct From Their Equilibrium Dissociation Constants as β (2)-Adrenoceptor Antagonists: Evidence for Functional Affinity J Pharmacol Exp Ther, 2024.PMID 38129128
- [7]Edelstein GA, et al. Dopamine antagonist effects of the D2/D3 receptor partial agonist aripiprazole on effort-based choice tasks in male and female rats Cogn Affect Behav Neurosci, 2026.PMID 40993487
- [8]Sinha S, et al. Orchestrating the signaling-bias at the protease-activated receptor, PAR1 Trends Cell Biol, 2026.PMID 42342503