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Autonomic Pharmacology

Name: Autonomic Pharmacology
Creator: Veli Bakalov, MD

Cholinergic and adrenergic receptors, and the drugs that push each lever

Pharmacology Principles·Autonomic Pharmacology·4 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Nicotinic receptors (Nn in ganglia, Nm at the neuromuscular junction) are ligand-gated ion channels; muscarinic, adrenergic, and dopamine receptors are all GPCRs.
Gq (↑ IP3/DAG/Ca²⁺) = α1, M1, M3, H1, V1; Gi (↓ cAMP) = α2, M2, D2; Gs (↑ cAMP) = all β receptors, D1, H2, V2.
Bethanechol treats postoperative/neurogenic urinary retention and ileus; carbachol and pilocarpine treat glaucoma; methacholine is the asthma challenge agent.
Neostigmine (no CNS entry) treats myasthenia and reverses nondepolarizing block; physostigmine crosses the blood-brain barrier and is the antidote for anticholinergic toxicity.
Organophosphates irreversibly inhibit AChE (DUMBBELSS + fasciculations): give atropine for muscarinic effects plus pralidoxime to reactivate AChE before aging.
Anticholinergic toxidrome = hot, dry, red, blind, mad, with urinary retention; dry skin distinguishes it from the sweaty sympathomimetic toxidrome.
Indirect sympathomimetics raise synaptic NE: amphetamine (release), ephedrine (release + direct), cocaine (reuptake block), tyramine (displacement; hypertensive crisis with MAO inhibitors).
Pheochromocytoma: α blockade with phenoxybenzamine (irreversible) must precede β blockade to avoid unopposed α vasoconstriction.
β1-selective blockers (A–M: acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol) are safer in asthma; nonselective propranolol, nadolol, and timolol can trigger bronchospasm.

Receptors and signal transduction

Wiring. All preganglionic autonomic neurons release ACh onto nicotinic receptors in the ganglia. Parasympathetic postganglionic fibers release ACh onto muscarinic receptors; most sympathetic postganglionic fibers release norepinephrine onto adrenergic receptors. Exceptions: sweat glands are sympathetic but cholinergic (muscarinic), and the adrenal medulla is stimulated directly by preganglionic fibers to secrete epinephrine.

Receptor classes. Nicotinic receptors, Nn (ganglia, adrenal medulla) and Nm (neuromuscular junction), are ligand-gated ion channels. Muscarinic (M1–M5), adrenergic (α1, α2, β1, β2, β3), and dopamine (D1, D2) receptors are all G-protein-coupled receptors.

G-protein coupling. Gq activates phospholipase C (↑ IP3, DAG, Ca²⁺): α1, M1, M3, H1, V1. Gi inhibits adenylyl cyclase (↓ cAMP): α2, M2, D2. Gs stimulates adenylyl cyclase (↑ cAMP): β1, β2, β3, D1, H2, V2. Mnemonic, reading α1-α2-β1-β2, M1-M2-M3, D1-D2-H1, H2-V1-V2: "qiss, qiq, siq, sqs."

Autonomic receptors

Receptor	G protein	Key effects
α1	Gq	Vasoconstriction, mydriasis, bladder sphincter and prostate contraction
α2	Gi	↓ Sympathetic outflow, ↓ insulin release, ↓ aqueous humor
β1	Gs	↑ Heart rate and contractility, ↑ renin release
β2	Gs	Bronchodilation, vasodilation, uterine relaxation, glycogenolysis
M2	Gi	↓ Heart rate and atrial contractility
M3	Gq	↑ Secretions and gut motility, bladder contraction, bronchoconstriction, miosis
D1	Gs	Renal vasodilation

Cholinergic agonists and antagonists

Direct muscarinic agonists. Bethanechol resists AChE and activates bladder and bowel smooth muscle: postoperative or neurogenic urinary retention and ileus. Carbachol and pilocarpine treat glaucoma by contracting the ciliary muscle to increase aqueous outflow. Pilocarpine enters the CNS and stimulates sweat, tears, and saliva (used for Sjögren dry mouth). Methacholine is the bronchial challenge agent for diagnosing asthma.

Acetylcholinesterase (AChE) inhibitors. Raise ACh indirectly at muscarinic and nicotinic sites. The key distinction is CNS entry: neostigmine (a quaternary amine) stays peripheral; physostigmine (a tertiary amine) crosses the blood-brain barrier.

Neostigmine: myasthenia gravis, reversal of nondepolarizing neuromuscular block, postoperative ileus and urinary retention
Pyridostigmine: long-term myasthenia gravis
Physostigmine: antidote for atropine and other anticholinergic toxicity ("phyxes" atropine overdose)
Donepezil, rivastigmine, galantamine: Alzheimer disease

Muscarinic antagonists by organ. Atropine (bradycardia; mydriasis), scopolamine (motion sickness), ipratropium and tiotropium (COPD, asthma), oxybutynin and tolterodine (overactive bladder), glycopyrrolate (drying secretions), benztropine (Parkinson disease, antipsychotic-induced extrapyramidal symptoms), and tropicamide (pupil dilation). Use caution in angle-closure glaucoma and in older men with BPH (urinary retention).

Cholinergic and anticholinergic toxidromes

Muscarinic excess (DUMBBELSS). Diarrhea, Urination, Miosis, Bradycardia, Bronchospasm, Emesis, Lacrimation, Salivation, Sweating. This cholinergic toxidrome follows AChE inhibitor excess and organophosphate exposure; nicotinic excess adds muscle fasciculations progressing to weakness and paralysis.

Organophosphate poisoning. Insecticides (parathion, malathion) and nerve gas (sarin) irreversibly inhibit AChE, producing a cholinergic crisis. Treatment is atropine PLUS pralidoxime (2-PAM). Atropine blocks the muscarinic signs (secretions, bronchospasm, bradycardia) but not nicotinic receptors, so only pralidoxime, by reactivating AChE, rescues muscle strength. Pralidoxime must be given before the phosphorylated enzyme "ages" into a permanently inactive form.

Organophosphate exposureInsecticide or nerve gas
Irreversible AChE inhibitionACh accumulates at all cholinergic synapses
Cholinergic crisisDUMBBELSS + fasciculations and weakness
Atropine + pralidoximeBlock muscarinic effects + reactivate AChE before aging

Organophosphate poisoning

Anticholinergic toxidrome. Hot as a hare (hyperthermia from absent sweating), dry as a bone, red as a beet (flushing), blind as a bat (mydriasis, blurred vision), mad as a hatter (delirium), plus tachycardia, urinary retention, and constipation. Antidote: physostigmine. Dry skin separates it from the sympathomimetic toxidrome, which shares tachycardia, mydriasis, and agitation but causes sweating.

Sympathomimetics

α agonists. The α1 agonist phenylephrine is a nasal decongestant, mydriatic, and vasopressor. The α2 agonists clonidine and α-methyldopa act centrally to REDUCE sympathetic outflow and lower blood pressure; methyldopa is used in pregnancy, and clonidine also treats ADHD and withdrawal states (stopping it abruptly causes rebound hypertension).

Direct β and mixed agonists

Drug	Receptor action	Classic use
Isoproterenol	β1 = β2	Nonselective β stimulation
Dobutamine	β1 > β2	Inotrope (heart failure, cardiogenic shock)
Albuterol, terbutaline	β2	Asthma; terbutaline for tocolysis
Epinephrine	α and β; β effects (including β2 vasodilation) dominate at low dose	Anaphylaxis
Norepinephrine	α1 > β1	Vasopressor in shock
Dopamine	D, then β, then α as dose rises	Dose-dependent pressor/inotrope

Indirect sympathomimetics. Increase synaptic norepinephrine rather than binding receptors directly: amphetamine promotes NE release; ephedrine releases NE and also has direct action; cocaine blocks NE and dopamine reuptake; tyramine displaces stored NE, so tyramine-rich foods (aged cheese, wine) taken with MAO inhibitors cause a hypertensive crisis.

Adrenergic antagonists

α blockers. Phenoxybenzamine blocks α receptors irreversibly (noncompetitive) and is the preoperative drug for pheochromocytoma; phentolamine blocks reversibly. The α1-selective "-osins" (prazosin, terazosin, doxazosin, tamsulosin) treat BPH and hypertension (tamsulosin, α1A-selective, is not used for hypertension); first-dose orthostatic hypotension is characteristic.

Pheochromocytoma: give the α blocker BEFORE any β blocker. β blockade alone removes β2 vasodilation and leaves catecholamine-driven α vasoconstriction unopposed, precipitating a hypertensive crisis.

β blockers. Reduce heart rate, contractility, AV conduction, renin release, and blood pressure. β1-selective agents (A through M: acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol) are safer in asthma. Nonselective agents (propranolol, nadolol, timolol) also block β2 and can trigger bronchospasm. Carvedilol and labetalol block both α1 and β receptors. Adverse effects include bradycardia, AV block, and masking of hypoglycemia warning signs; glucagon treats β-blocker overdose.