Autonomic Pharmacology

Sympathetic Nervous System (Adrenergic) Mechanisms

• Alpha-1 (α1) receptors are Gq-coupled; activation increases intracellular calcium, causing vasoconstriction, mydriasis, and urinary sphincter contraction
• Alpha-2 (α2) receptors are Gi-coupled; presynaptic activation decreases norepinephrine release (negative feedback), while postsynaptic activation causes vasoconstriction and CNS effects
• Beta-1 (β1) receptors are Gs-coupled; activation increases cardiac contractility, heart rate, and AV node conduction via cAMP-mediated mechanisms
• Beta-2 (β2) receptors are Gs-coupled; activation causes bronchodilation, vasodilation, and increased lipolysis
• Beta-3 (β3) receptors mediate thermogenesis in brown adipose tissue
• Dopamine receptors (D1-D5) have distinct CNS and peripheral effects; D1/D5 are Gs-coupled (excitatory), D2-D4 are Gi-coupled (inhibitory)

Parasympathetic Nervous System (Cholinergic) Mechanisms

• Muscarinic M1 receptors (Gq-coupled) predominate in CNS and gastric glands; increase IP3 and intracellular calcium
• Muscarinic M2 receptors (Gi-coupled) are abundant in cardiac tissue; decrease cAMP, reducing heart rate and AV conduction
• Muscarinic M3 receptors (Gq-coupled) mediate airway contraction, salivation, lacrimation, and pupillary constriction
• Muscarinic M4/M5 receptors have primarily CNS distribution
• Nicotinic receptors are ligand-gated ion channels; neuronal types permit fast synaptic transmission, while muscle types mediate neuromuscular junction function
• Acetylcholinesterase hydrolyzes acetylcholine; inhibition prolongs cholinergic signaling

Receptor Regulation and Signal Transduction

• Desensitization occurs through phosphorylation by PKA/PKC and β-arrestin binding, reducing receptor responsiveness
• Upregulation compensates for chronic antagonism (e.g., β-blockers cause upregulation of β-adrenergic receptors)
• Downregulation follows chronic agonist exposure, reducing receptor density

Sympathomimetic Excess (α1/β agonist toxicity)

• Hypertensive crisis with reflex bradycardia (pure α1 effect) or tachycardia (β1 effect)
• Diaphoresis, tremor, anxiety, and headache
• Palpitations and chest pain; risk of arrhythmias and myocardial ischemia
• Urinary retention and mydriasis (α1 effects)

Sympathomimetic Deficiency (α/β antagonism)

• Hypotension, syncope, and dizziness (especially orthostatic with α-blockers)
• Bradycardia and fatigue (β-blockade)
• Erectile dysfunction and reduced sweating (α-blockade)
• Exercise intolerance and bronchospasm (β-blockade)

Cholinergic Excess (Muscarinic Agonist Toxicity - "SLUDGE" or "Killer Bs")

• Salivation, Lacrimation, Urination, Defecation, Gastrointestinal upset, Emesis
• Bronchospasm and bronchorrhea ("Killer Bs")
• Miosis (pinpoint pupils), blurred vision, and accommodation difficulty
• Bradycardia, hypotension, and cardiac arrhythmias (muscarinic M2 effects)
• Muscle fasciculations and weakness (nicotinic effects in severe poisoning)

Cholinergic Deficiency (Anticholinergic Toxicity - "Can't see, can't spit, can't pee, hot as a hare, red as a beet, mad as a hatter")

• Mydriasis and cycloplegia (blurred vision, photophobia)
• Dry mouth, dry skin, and decreased sweating (hyperthermia, especially in anticholinergic poisoning)
• Urinary retention and constipation
• Tachycardia and hypertension
• CNS: confusion, agitation, hallucinations, seizures, and coma
• Classic Pearl: Central anticholinergic toxicity ("anticholinergic crisis") is primarily seen with atropine overdose, antihistamines, antipsychotics, and tricyclic antidepressants

Clinical Diagnosis (Primary Approach)

• History and physical examination identifying signs of sympathetic or parasympathetic activation
• Medication review: recognition of drug classes causing symptoms (sympathomimetics, α/β-blockers, anticholinergics, cholinergic agents)
• Atropine challenge test: IV atropine (0.5-1 mg) causes heart rate increase if bradycardia is vagal (muscarinic-mediated); lack of response suggests intrinsic cardiac pathology

Laboratory and Diagnostic Testing

• Plasma catecholamine levels (epinephrine, norepinephrine, dopamine): elevated in pheochromocytoma or sympathomimetic toxicity; normal or low in β-blockade
• 24-hour urine metanephrines and catecholamines: screening for pheochromocytoma (highest sensitivity)
• ECG: tachycardia or bradycardia, arrhythmias, prolonged QT (anticholinergics), ischemic changes
• Pupil examination: miosis suggests cholinergic excess or opioid toxicity; mydriasis suggests anticholinergic toxicity or sympathomimetic excess

Toxidrome Recognition

• Sympathomimetic toxidrome: hypertension, tachycardia, hyperthermia, diaphoresis, agitation, mydriasis
• Anticholinergic toxidrome: hyperthermia, mydriasis, dry skin, tachycardia, urinary retention, altered mental status
• Cholinergic toxidrome: SLUDGE symptoms + bradycardia, muscle fasciculations (nicotinic)

Sympathomimetic Overdose/Toxicity

• First-line: Phentolamine (α-antagonist, 5-15 mg IV bolus, may repeat) for hypertensive crisis; vasodilators (nitroprusside, nitroglycerin) if α-blockade insufficient
• Cardiac management: β-blockers (labetalol, esmolol) ONLY AFTER α-blockade established to prevent unopposed α-mediated vasoconstriction
• Benzodiazepines (lorazepam 2-4 mg IV) for anxiety and agitation
• Cooling measures for hyperthermia
• Avoid: pure β-blockers before α-blockade; this causes paradoxical hypertension

Sympathomimetic Deficiency (β-blocker or α-blocker toxicity)

• First-line: IV fluids for hypotension; atropine (0.5-1 mg IV) for bradycardia unresponsive to fluid resuscitation
• High-dose glucagon (5-10 mg IV bolus, then infusion 1-5 mg/hour): bypasses β-

Adrenergic antagonists

• Non-selective beta blockers (propranolol): β2 blockade causes bronchospasm, blunted glycogenolysis, and masking of hypoglycemic warning signs (tremor, tachycardia) — the ADA Standards of Care flags this in insulin-treated patients, in whom glucose monitoring should be intensified. Cardioselective agents (metoprolol, bisoprolol) are preferred and, per GOLD, are not contraindicated in COPD.
• Abrupt beta-blocker withdrawal: chronic antagonism upregulates β receptors, so sudden discontinuation produces rebound tachycardia, hypertension, and ischemia. Taper rather than stop.
• Beta-blocker overdose: bradycardia, AV block, and hypotension; hypoglycemia occurs inconsistently and is most characteristic in children and in propranolol overdose. Lipophilic, membrane-stabilizing agents such as propranolol additionally produce CNS depression, seizures, and QRS widening. Glucagon is the antidote — its Gs-coupled receptor raises cardiac cAMP downstream of the blocked β1 receptor; high-dose insulin/euglycemia therapy is the escalation step.
• Alpha-1 blockers (prazosin, doxazosin): first-dose orthostatic syncope from venodilation and reduced preload, with baroreceptor-mediated reflex tachycardia driven by the fall in arterial pressure after arteriolar dilation. Tamsulosin is associated with intraoperative floppy iris syndrome; the AUA advises disclosing use before cataract surgery.
• Clonidine (α2 agonist): sedation, dry mouth, and — after abrupt cessation — rebound hypertension from surging norepinephrine release. Treat by reinstituting clonidine or with an alpha blocker; a beta blocker alone worsens it via unopposed alpha stimulation.

Cholinergic drugs

• Muscarinic antagonists (atropine, scopolamine, oxybutynin, plus antihistamines, TCAs, antipsychotics): anticholinergic toxidrome; relatively contraindicated in narrow-angle glaucoma, BPH with outlet obstruction, and the elderly (delirium risk — AGS Beers criteria). Benzodiazepines are first-line for agitation. Physostigmine, a tertiary amine that crosses the blood–brain barrier, is reserved for pure antimuscarinic delirium and is contraindicated in tricyclic overdose (asystole, seizures), where sodium bicarbonate is used; also avoid it with bradycardia, AV block, or QRS >100 ms.
• Cholinesterase inhibitors / organophosphates: SLUDGE plus bronchorrhea and bronchospasm — the actual killers. Atropine is titrated upward to drying of pulmonary secretions (not to pupil size or heart rate), and pralidoxime regenerates acetylcholinesterase but only before aging of the enzyme–phosphate bond.
• Direct muscarinic agonists (bethanechol, pilocarpine): avoid in asthma, peptic ulcer disease, and bowel or bladder obstruction; atropine reverses.
• Beta-2 agonists: tremor, tachycardia, hypokalemia from intracellular potassium shift — monitor potassium in high-dose nebulized therapy.

• Alpha before beta, always: in pheochromocytoma or cocaine/sympathomimetic toxicity, beta blockade given first leaves α1-mediated vasoconstriction unopposed and precipitates hypertensive crisis. Phenoxybenzamine (irreversible) preoperatively, then a beta blocker for reflex tachycardia — the single most tested sequencing question in this topic.
• Glucagon is the beta-blocker antidote: it raises cardiac cAMP through its own Gs-coupled receptor, bypassing the blockaded β1 receptor entirely. Atropine typically fails because the problem is not vagal.
• Organophosphate poisoning = atropine + pralidoxime: atropine treats muscarinic effects (endpoint is drying of bronchial secretions), pralidoxime reverses nicotinic effects such as fasciculations and diaphragmatic weakness — and must be given before aging. Distractor to avoid: atropine alone does nothing for the neuromuscular junction.
• Physostigmine, not neostigmine, for central anticholinergic delirium — the tertiary amine crosses the blood–brain barrier while quaternary neostigmine does not. Give benzodiazepines first for agitation, and do not give physostigmine in tricyclic overdose (sodium bicarbonate is the answer there) or with bradycardia, AV block, or a widened QRS.
• Atropine 1 mg IV is the ACLS (AHA 2020) first drug for symptomatic bradycardia, repeatable every 3–5 minutes to 3 mg total; escalate to transcutaneous pacing or a chronotropic infusion (dopamine, epinephrine) if refractory.
• Epinephrine 0.3 mg IM in the anterolateral thigh is first-line for anaphylaxis — α1 vasoconstriction reverses hypotension and airway edema, β2 bronchodilates. Patients on non-selective beta blockers may be refractory; glucagon is the adjunct.
• Watch the receptor-selectivity trap: isoproterenol (β1 = β2) drops diastolic pressure and raises heart rate; phenylephrine (pure α1) raises pressure with reflex bradycardia; norepinephrine's α1 predominance likewise produces reflex bradycardia despite β1 activity.
• Two different withdrawal mechanisms, one stem: chronic β-antagonism upregulates β receptors, so abrupt beta-blocker withdrawal causes rebound tachycardia, hypertension, and ischemia; chronic α2-*agonism* with clonidine suppresses central sympathetic outflow, so abrupt cessation unleashes a norepinephrine surge (with peripheral adrenergic supersensitivity) and rebound hypertension. Both present as the patient who "ran out of pills" — but do not merge the mechanisms.