Receptor pharmacology: GABA, NMDA, opioid, adrenergic, cholinergic

GABA-A is a chloride channel — a pentameric ligand-gated ionotropic receptor. When GABA binds, chloride flows IN, hyperpolarizing the neuron and suppressing firing. Propofol, etomidate, midazolam, barbiturates, and volatiles all enhance GABA-A activity (different binding sites, same end effect). Propofol and etomidate both have direct gating at high doses — they open the channel without GABA. Midazolam needs GABA present (allosteric modulator). This is why benzo overdose alone is rarely fatal but adding propofol drops the floor.

NMDA is a glutamate-gated cation channel — excitatory. Ketamine, xenon, nitrous oxide, and magnesium block NMDA. Ketamine is a non-competitive antagonist binding inside the open channel (use-dependent block). NMDA blockade explains dissociation, analgesia, sympathomimetic effects, and rare emergence reactions. NMDA receptors mediate central sensitization — which is why low-dose ketamine reduces post-op opioid requirement.

Three G-protein-coupled receptors. Mu (μ) is the main analgesia + respiratory depression + euphoria receptor. Delta (δ) modulates analgesia and mood. Kappa (κ) mediates spinal analgesia and dysphoria — which is why nalbuphine and butorphanol cause dysphoria; they are κ-agonists / μ-antagonists. All three reduce cAMP via Gi/Go, hyperpolarize neurons via K+ channels, and reduce calcium influx. Tolerance develops at μ via receptor desensitization and internalization — explains escalating doses in chronic users.

All GPCRs. Alpha-1 (Gq → IP3/DAG → smooth muscle contraction) — phenylephrine, norepinephrine. Alpha-2 (Gi → less cAMP → presynaptic inhibition of NE release + central sedation) — dexmedetomidine, clonidine. Beta-1 (Gs → more cAMP → cardiac inotropy + chronotropy) — dobutamine, isoproterenol. Beta-2 (Gs → bronchodilation + vasodilation) — albuterol, terbutaline, ritodrine.

Muscarinic (M1-M5): GPCRs. M2 in heart (Gi → bradycardia, blocked by atropine + glycopyrrolate). M3 on smooth muscle and glands (Gq → bronchoconstriction, secretions). Nicotinic: ligand-gated cation channels. Nm at the NMJ — blocked by rocuronium and the other non-depolarizers. Nn in autonomic ganglia and adrenal medulla. The NMJ Nm receptor needs TWO acetylcholine molecules to open — this two-site geometry is why sugammadex's molecular cage works so cleanly.