Autonomic Nervous System Pharmacology | Sympathetic & Parasympathetic

Beta blockers are used for: (1) Hypertension (all types); (2) Glaucoma (timolol eye drops); (3) Chronic heart failure (carvedilol); (4) Arrhythmias (sotalol); (5) Performance anxiety (propranolol). Non-selective beta blockers are contraindicated in asthma and COPD. Beta blockers are classified as: (1) Non-selective (propranolol, timolol, sotalol); (2) Cardioselective (atenolol, metoprolol, bisoprolol); (3) Beta blockers with alpha-1 blocking activity (carvedilol, labetalol). Understanding these classifications is essential for appropriate patient selection.

The autonomic nervous system (ANS) regulates involuntary body functions through two opposing systems: the sympathetic system (fight-or-flight response) and the parasympathetic system (rest-and-digest response). Drugs affecting the ANS work by modulating neurotransmitters—primarily acetylcholine (ACh) and catecholamines (epinephrine/norepinephrine)—through mechanisms including receptor agonism/antagonism, enzyme inhibition, and reuptake blockade. The cholinergic system responds to ACh at both ganglia and target organs, while the adrenergic system responds to catecholamines primarily at sympathetic post-ganglionic sites. Clinically, these drugs are used for conditions like glaucoma (muscarinic agonists), hypertension (ganglionic blockers), asthma (beta-2 agonists), and organophosphate poisoning (acetylcholinesterase inhibitors).

Alpha-1 agonists like phenylephrine have diverse clinical applications: ocular/nasal decongestants cause vasoconstriction reducing mucus production, but systemic absorption causes hypertension and increased blood glucose mimicking fight-or-flight response; in BPH, alpha-1 receptor activation worsens urinary obstruction by constricting urethral and bladder neck muscles. Beta-2 selective agonists like albuterol are rescue medications for asthma, causing airway smooth muscle relaxation through beta-2 receptor activation. Mirabegron represents a beta-3 agonist for overactive bladder, relaxing the detrusor muscle despite being an odd-numbered receptor. Midodrine treats neurogenic orthostatic hypotension by converting to norepinephrine, replacing deficient neurotransmitter in conditions like Parkinson's disease. Alpha-1 blockers (ending in '-osin') treat BPH (relaxing urethral muscles), hypertension (vasodilation), Raynaud's disease (blocking vasoconstriction), pheochromocytoma (pre-op BP control), and glaucoma (pupillary dilation). Side effects include nasal congestion and orthostatic hypotension. Beta-blockers decrease cardiac output for hypertension, heart failure, arrhythmias, angina, and post-MI management. Non-selective blockers (timolol, propranolol) can cause bronchoconstriction in asthma; selective blockers (metoprolol, atenolol) are preferred.

The adrenergic system, also called the sympathetic nervous system, mediates physiological responses through catecholamines (adrenaline, noradrenaline, dopamine) synthesized from tyrosine via tyrosine hydroxylase (rate-limiting enzyme). Adrenergic receptors belong to the GPCR family with seven transmembrane domains, classified into alpha (alpha-1, alpha-2) and beta (beta-1, beta-2) subtypes. Alpha-1 receptors activate phospholipase C causing calcium-mediated muscle contraction in blood vessels, eyes, and uterus. Alpha-2 receptors provide negative feedback by inhibiting adenylate cyclase and limiting catecholamine release. Beta receptors activate adenylate cyclase: beta-1 receptors in the heart cause positive inotropic, chronotropic, and dromotropic effects; beta-2 receptors in lungs cause bronchodilation (asthma treatment), uterus cause relaxation, and coronary arteries cause vasodilation. Clinically, adrenergic agonists include alpha-1 agonists (midodrine, pseudoephedrine) for orthostatic hypotension and migraines; alpha-2 agonists (clonidine, methyldopa) as central antihypertensives and for glaucoma; beta-1 agonists (dobutamine) for cardiac support; beta-2 agonists (salbutamol, formoterol) for asthma. Adrenergic antagonists include alpha-blockers (doxazosin, alfuzosin) for hypertension, retinopathy, and BPH; beta-blockers (bisoprolol, propranolol) for hypertension, heart disease, rhythm disorders, glaucoma, and migraines. Selectivity determines therapeutic profile and side effects.

Adrenergic drugs interact with the sympathetic nervous system, which controls the fight-or-flight response; these drugs either mimic (sympathomimetics) or block (sympatholytics) the effects of noradrenaline (norepinephrine), the primary neurotransmitter released by sympathetic neurons to activate adrenergic receptors (alpha-1, alpha-2, beta-1, beta-2) on target organs like the heart, blood vessels, and airways, with clinical applications ranging from treating hypertension and asthma to managing depression and anxiety.

Myasthenic crisis presents with dilated pupils, tachycardia, hypertension, absent cough/gag reflex, dysphagia, and incontinence due to lack of acetylcholine reaching receptors. Cholinergic crisis presents with miosis, bradycardia, hypotension, increased secretions, vomiting/diarrhea, and muscle fasciculations from receptor overstimulation. Despite sharing severe muscle weakness and respiratory failure, these distinct presentations allow clinical differentiation. The key diagnostic approach involves understanding that myasthenic crisis requires more acetylcholine availability while cholinergic crisis requires reducing acetylcholine levels.

The parasympathetic nervous system, with its craniosacral distribution, uses acetylcholine as its primary neurotransmitter acting on nicotinic and muscarinic receptors. Cholinergic syndrome (from increased acetylcholine) presents with miosis, increased secretions, bronchoconstriction, and fasciculations, while anticholinergic syndrome (from receptor blockade) presents with midriasis, decreased secretions, urinary retention, and tachycardia. Treatment involves acetylcholinesterase inhibitors (like pyridostigmine) for cholinergic effects and muscarinic receptor antagonists (like atropine) for anticholinergic effects.

This video explains two opposing toxidromes: anticholinergic toxicity (remembered by 'Alice in Wonderland' with signs like flushed skin, dryness, hyperthermia, delirium, urinary retention, and tachycardia caused by antihistamines, tricyclic antidepressants, or sleeping aids) and cholinergic toxicity (remembered by 'SLUDGE Triple B' with symptoms including excessive salivation, lacrimation, urination, defecation, vomiting, bronchospasm, bradycardia, miosis, and increased bowel sounds, typically from organophosphate insecticides).

This segment covers the fundamental differentiation between cholinergic and anticholinergic toxidromes. Organophosphate poisoning causes cholinergic syndrome with muscarinic features (bradycardia, miosis, salivation, lacrimation, rhinorrhea - making the patient 'wet') and nicotinic features (muscle fasciculations). Anticholinergic syndrome, caused by tricyclic antidepressants, presents with tachycardia, midriasis, rubor, and hallucinations. The key principle is that cholinergic syndrome causes 'wet' patients with bradycardia and miosis, while anticholinergic syndrome causes 'dry' patients with tachycardia and midriasis. Muscle fasciculations indicate nicotinic involvement. The presence of hallucinations strongly suggests anticholinergic syndrome.

Cholinergic toxicity affects muscarinic and nicotinic receptors differently. Muscarinic effects include diarrhea, diaphoresis, urination, miosis, bronchospasm, bradycardia, emesis, lacrimation, and salivation. Nicotinic effects include muscle weakness, paralysis, and fasciculations. Anticholinergic toxicity presents with 'hot as a hare, dry as a bone, red as a beet, blind as a bat, mad as a hatter' - hyperthermia, decreased secretions, flushed skin, cycloplegia, and altered mental status. Organophosphate poisoning (acetylcholinesterase inhibitors) causes depolarizing blockade with muscarinic overstimulation. Anticholinergic receptor antagonists (atropine, scopolamine) cause vasodilation, anhidrosis, and delirium without affecting nicotinic receptors.

G-protein coupled receptors (GPCRs) have three main signaling pathways: (1) Gs stimulates adenylate cyclase, increasing cAMP, (2) Gi inhibits adenylate cyclase, decreasing cAMP, (3) Gq activates phospholipase C, increasing IP3 and DAG. The beta-gamma subunit can directly open potassium channels (G-protein regulated inward rectifying potassium channels). Examples include muscarinic, alpha-2 adrenergic, 5-HT1, GABA-B, somatostatin, and P2Y receptors.

G protein-coupled receptors transmit signals through different G proteins: Gq stimulates phospholipase C (alpha-1, M1, M3, M5), Gi inhibits adenylate cyclase (alpha-2, M2, M4), and Gs stimulates adenylate cyclase (beta receptors). Alpha-1 adrenergic receptors couple to Gq, stimulating phospholipase C and increasing intracellular calcium. Alpha-2 adrenergic receptors couple to Gi, inhibiting adenylate cyclase. Beta adrenergic receptors couple to Gs, stimulating adenylate cyclase and increasing cAMP. This determines tissue-specific responses to neurotransmitters.

Muscarinic receptors (M1-M5) are G-protein coupled receptors responding to acetylcholine. Odd-numbered subtypes (M1, M3, M5) are excitatory, coupling to Gq proteins and activating phospholipase C. Even-numbered subtypes (M2, M4) are inhibitory, coupling to Gi proteins and inhibiting adenylate cyclase. Adrenergic receptors are similarly classified: beta receptors couple to GS proteins and stimulate adenylate cyclase, producing excitatory effects. Alpha-1 receptors couple to Gq proteins and cause vasoconstriction. Alpha-2 receptors couple to Gi proteins and provide presynaptic feedback inhibition, preventing excessive neurotransmitter release. The GS pathway activates adenylate cyclase, converting ATP to cyclic AMP (cAMP), which activates protein kinase A. The Gi pathway inhibits adenylate cyclase, reducing cAMP and decreasing cellular activity. The Gq pathway activates phospholipase C, generating inositol trisphosphate (IP3) and diacylglycerol (DAG), which trigger calcium release and protein kinase C activation respectively.

G-protein-coupled receptors activate three main signaling pathways: Gs (stimulatory) activates adenylyl cyclase, increasing cAMP. Gi (inhibitory) inhibits adenylyl cyclase, decreasing cAMP. Gq activates phospholipase C, producing IP3 and DAG. IP3 releases calcium from intracellular stores, while DAG activates protein kinase C. Second messengers relay signals from activated receptors to intracellular targets. cAMP activates protein kinase A. IP3 releases calcium from the sarcoplasmic reticulum. DAG activates protein kinase C. Adrenergic receptors are classified as alpha (α1, α2) and beta (β1, β2, β3). Alpha-1 receptors are Gq-coupled and mediate contraction of vascular smooth muscle (vasoconstriction), pupillary dilator muscle (mydriasis), and intestinal and bladder sphincter muscles. Alpha-2 receptors are Gi-coupled and mediate inhibition of neurotransmitter release, decreased insulin release, decreased lipolysis, increased platelet aggregation, and decreased aqueous humor production. Beta-1 receptors are Gs-coupled and mediate increased heart rate, increased cardiac contractility, increased renin release, and increased lipolysis. Beta-2 receptors are Gs-coupled and mediate vasodilation, bronchodilation, increased lipolysis, increased glycogenolysis, decreased uterine tone, increased aqueous humor production, and increased cellular potassium uptake.

Muscarinic receptors are G-protein coupled receptors (GPCRs) passing through the membrane seven times. Five subtypes exist (M1-M5), with M1, M2, and M3 most clinically relevant. They use two main signaling pathways: Gq pathway for M1, M3, M5 receptors - activates phospholipase C, producing IP3 (triggers calcium release from intracellular stores) and diacylglycerol (activates protein kinase C); Gi pathway for M2, M4 receptors - splits into alpha and beta-gamma subunits; beta-gamma opens potassium channels causing hyperpolarization, while alpha inhibits adenylate cyclase. These pathways phosphorylate proteins affecting membrane permeability, metabolism, and gene transcription.