Autonomic nervous system drugs

In short

The autonomic nervous system (ANS) controls involuntary function - heart rate, blood pressure, airway calibre, gut motility, bladder, pupil and secretions - through two divisions, sympathetic (adrenergic) and parasympathetic (cholinergic). ANS drugs either mimic (agonist/mimetic) or block (antagonist/lytic) these transmitters, and they form the mechanistic backbone of almost every other pharmacology chapter. B.Pharm Pharmacology I (PCI/AICTE curriculum) devotes a full unit to it, and GPAT, NIPER-JEE and GATE-XL style papers test receptor-effect matching, drug classification and poisoning management every year. In practice it matters for organophosphate poisoning (very common in rural India), anaphylaxis, asthma, glaucoma and anaesthesia - knowledge expected in hospital pharmacy, clinical research, medical affairs and medical-representative interviews at Sun Pharma, Cipla, Dr Reddy's, Lupin, Zydus, Torrent, Glenmark and Alkem.

Explained

Organisation of the ANS and the steps of neurotransmission

• Two divisions, two neurons each: preganglionic (myelinated) and postganglionic. Sympathetic - short preganglionic from T1-L2/L3 (thoracolumbar), long postganglionic, ganglia in paravertebral chains. Parasympathetic - long preganglionic from cranial nerves III, VII, IX, X and S2-S4 (craniosacral), short postganglionic in or near the organ.
• Transmitters: *all* preganglionic fibres (both divisions) and parasympathetic postganglionic fibres release acetylcholine (ACh); sympathetic postganglionic fibres release noradrenaline (NA). Exceptions: sweat glands (sympathetic but cholinergic, muscarinic), adrenal medulla (a modified ganglion - releases ~80% adrenaline, 20% NA into blood), renal vascular dopaminergic fibres.
• Somatic nerve to skeletal muscle is cholinergic, single neuron, nicotinic (NM) - studied with ANS drugs because of neuromuscular blockers.
• Cholinergic transmission steps: choline uptake (by choline transporter, blocked by hemicholinium) → synthesis by choline acetyltransferase → storage in vesicles by VAChT (blocked by vesamicol) → Ca²⁺-dependent release (blocked by botulinum toxin) → receptor action → hydrolysis by acetylcholinesterase (AChE) within milliseconds (blocked by neostigmine, organophosphates).
• Adrenergic transmission steps: tyrosine → DOPA (tyrosine hydroxylase, rate-limiting; blocked by metyrosine) → dopamine → vesicular uptake by VMAT (blocked by reserpine) → noradrenaline by dopamine β-hydroxylase → release (blocked by guanethidine; triggered extra by tyramine/amphetamine) → action → termination mainly by reuptake-1 (NET) (blocked by cocaine, imipramine) and metabolism by MAO (mitochondrial) and COMT (cytoplasmic).
• Autonomic tone: most organs get dual, opposing innervation; the division with dominant tone decides the effect of blockade - blocking vagal tone on the heart (atropine) causes tachycardia; blocking sympathetic tone on vessels (prazosin) causes vasodilatation.

Receptors: types, coupling and responses

• Muscarinic (M1-M5), G-protein coupled: M1 (ganglia, gastric parietal cells - Gq), M2 (heart - Gi, slows SA node, slows AV conduction), M3 (smooth muscle, glands, ciliary muscle, sphincter pupillae - Gq), M4/M5 mainly CNS.
• Nicotinic, ligand-gated cation channels: NN (autonomic ganglia, adrenal medulla; blocked by hexamethonium) and NM (skeletal muscle end-plate; blocked by d-tubocurarine).
• Adrenergic: α1 (Gq - vasoconstriction, mydriasis via radial muscle, prostate/bladder-neck contraction), α2 (Gi - presynaptic autoinhibition, central sympathetic outflow reduction, platelet aggregation), β1 (Gs - heart rate, contractility, renin release), β2 (Gs - bronchodilatation, vasodilatation, uterine relaxation, glycogenolysis, K⁺ shift into cells), β3 (Gs - lipolysis, detrusor relaxation - mirabegron), D1 (renal/mesenteric vasodilatation), D2 (presynaptic inhibition).
• Second messengers: Gq → IP₃/DAG → Ca²⁺ rise; Gs → ↑cAMP; Gi → ↓cAMP; M2/α2 also open K⁺ channels (hyperpolarisation).

Cholinergic drugs (parasympathomimetics)

• Direct-acting choline esters: acetylcholine (not used therapeutically - hydrolysed instantly), methacholine (bronchial challenge test), carbachol and bethanechol (resistant to AChE; bethanechol for post-operative/post-partum urinary retention and paralytic ileus, non-obstructive only).
• Direct-acting alkaloids: pilocarpine (tertiary amine; topical for glaucoma - contracts ciliary muscle, opens trabecular meshwork; oral for xerostomia), muscarine, nicotine (NN agonist then depolarising blocker; nicotine replacement therapy), varenicline (partial α4β2 agonist for smoking cessation).
• Reversible anticholinesterases: neostigmine (quaternary - no CNS entry; myasthenia gravis, reversal of non-depolarising blockade, post-operative ileus/retention), physostigmine (tertiary - crosses blood-brain barrier; antidote for atropine/anticholinergic delirium), pyridostigmine (longer-acting, oral, myasthenia gravis maintenance), edrophonium (very short, diagnostic Tensilon test), donepezil/rivastigmine/galantamine (CNS-selective - Alzheimer's disease).
• Irreversible anticholinesterases (organophosphates): malathion, parathion, dichlorvos, fenthion (insecticides); echothiophate (ophthalmic); nerve agents sarin, tabun. They phosphorylate the esteratic site; the bond "ages" over hours and becomes irreversible. Carbamates (carbaryl, propoxur) are intermediate.
• Effects of cholinergic excess - mnemonic DUMBBELSS: Diarrhoea, Urination, Miosis, Bradycardia, Bronchospasm/Bronchorrhoea, Emesis, Lacrimation, Salivation, Sweating; plus nicotinic fasciculations, weakness, paralysis, and CNS convulsions/coma.
• Myasthenia gravis: autoimmune loss of NM receptors; treated with pyridostigmine ± immunosuppression. Myasthenic crisis (too little drug) improves with edrophonium; cholinergic crisis (overdose - miosis, fasciculation, excess secretions) worsens.

Anticholinergics, ganglion blockers and neuromuscular blockers

• Antimuscarinics - natural: atropine (tertiary, crosses BBB), hyoscine/scopolamine (most CNS-sedating; motion sickness patch), hyoscine butylbromide (quaternary, antispasmodic - Buscopan).
• Semisynthetic/synthetic: homatropine, tropicamide, cyclopentolate (mydriatic-cycloplegics; tropicamide shortest), ipratropium/tiotropium (inhaled, COPD), glycopyrrolate (pre-anaesthetic antisialagogue, no CNS effect), dicyclomine, propantheline (GI spasm), oxybutynin, tolterodine, solifenacin (overactive bladder), pirenzepine (M1, peptic ulcer - largely obsolete), trihexyphenidyl/benztropine (drug-induced parkinsonism).
• Atropine dose-dependent effects: 0.5 mg - dry mouth, bradycardia (central vagal); 1 mg - thirst, tachycardia, mild mydriasis; 2 mg - palpitations, blurred vision; 5 mg - hot dry flushed skin, difficulty in micturition, restlessness; >10 mg - delirium, hallucinations, hyperthermia, coma. Classic picture: *"dry as a bone, blind as a bat, red as a beet, mad as a hatter, hot as a hare."*
• Contraindicated/cautioned in narrow-angle glaucoma (raises intraocular pressure) and benign prostatic hyperplasia (retention).
• Ganglion blockers (NN): hexamethonium, trimethaphan, mecamylamine - historical; they remove tone from *both* divisions, so effects are predicted by which division dominates (hypotension, tachycardia, cycloplegia, constipation, retention, impotence).
• Neuromuscular blockers: non-depolarising (competitive) - d-tubocurarine, pancuronium, vecuronium, atracurium/cisatracurium (Hofmann elimination - safe in renal/hepatic failure), rocuronium (fastest onset of this class); flaccid paralysis, no fasciculation, fade on train-of-four, reversed by neostigmine + glycopyrrolate, or rocuronium/vecuronium by sugammadex.
• Depolarising - succinylcholine (suxamethonium): persistent depolarisation, initial fasciculations, short action (plasma pseudocholinesterase), *not* reversible by neostigmine; risks are hyperkalaemia, myalgia, raised intraocular/intragastric pressure, malignant hyperthermia (treated with dantrolene) and prolonged apnoea in pseudocholinesterase deficiency.
• Directly acting muscle relaxants: dantrolene (blocks RyR1 Ca²⁺ release); centrally acting: baclofen, tizanidine.

Adrenergic drugs (sympathomimetics)

• Classification by mechanism: direct (adrenaline, NA, phenylephrine, isoprenaline, salbutamol, dobutamine), indirect (tyramine, amphetamine - release stored NA; cocaine - blocks reuptake), mixed (ephedrine, pseudoephedrine, dopamine).
• Non-selective: adrenaline (α1, α2, β1, β2 - and β3), NA (α1, α2, β1; weak β2), isoprenaline (β1, β2).
• Selective agonists: phenylephrine, methoxamine (α1); clonidine, dexmedetomidine, α-methyldopa (α2 - central sympatholytic, so they *lower* BP); dobutamine (β1); salbutamol, terbutaline, salmeterol, formoterol (β2 - asthma, and terbutaline/isoxsuprine as uterine relaxants); mirabegron (β3).
• Adrenaline's dose-dependent BP pattern: low dose - β2 vasodilatation dominates, diastolic BP falls; high dose - α1 constriction dominates, BP rises. Vasomotor reversal (Dale's phenomenon): after an α-blocker, the pressor response to adrenaline becomes a fall in BP (unmasked β2); NA's pressor response is only abolished, not reversed.
• Uses: anaphylaxis and cardiac arrest (adrenaline - drug of choice), septic/cardiogenic shock (noradrenaline first-line vasopressor, dobutamine for low output), nasal decongestion (xylometazoline, phenylephrine), with local anaesthetics to prolong action and limit bleeding, asthma (inhaled β2), premature labour, hypoglycaemia, mydriatic without cycloplegia (phenylephrine).
• Dopamine is dose-dependent: ~1-3 µg/kg/min D1 (renal), 3-10 β1 (inotropic), >10 α1 (vasoconstrictor). "Renal-dose" dopamine for renal protection is no longer recommended.
• Adverse effects: tachyarrhythmia, anxiety, tremor, headache, hypertensive crisis, hyperglycaemia, hypokalaemia (β2), tissue necrosis on extravasation of NA (treat with local phentolamine).

Adrenergic antagonists

• α-blockers - non-selective: phenoxybenzamine (irreversible, long - pre-operative preparation in phaeochromocytoma), phentolamine (reversible, short - NA extravasation, hypertensive crisis in phaeochromocytoma).
• α1-selective: prazosin, terazosin, doxazosin (hypertension; first-dose postural hypotension), tamsulosin, silodosin, alfuzosin (uroselective α1A - BPH). α2-selective: yohimbine (little clinical use).
• β-blockers - non-selective: propranolol (also membrane-stabilising), timolol (topical for glaucoma - reduces aqueous secretion), sotalol (also class III), nadolol. β1-selective (cardioselective): atenolol, metoprolol, bisoprolol, esmolol (ultra-short IV), nebivolol (also NO-mediated vasodilatation). With α-blockade: labetalol, carvedilol. With partial agonist activity (ISA): pindolol, acebutolol.
• Uses: hypertension, angina, post-MI secondary prevention, arrhythmias, heart failure (bisoprolol, metoprolol succinate, carvedilol), thyrotoxicosis and thyroid storm, migraine prophylaxis, essential tremor, performance anxiety, portal hypertension, glaucoma.
• Cautions: asthma/COPD (β2 blockade - bronchospasm), bradycardia and AV block, masking of hypoglycaemic warning signs in insulin-treated diabetes, worsening of peripheral vascular disease, fatigue, nightmares, sexual dysfunction. Never stop abruptly - receptor upregulation causes rebound angina, arrhythmia or hypertension; taper over 1-2 weeks.
• Drugs acting on neuronal stores/release: reserpine (VMAT), guanethidine (release), metyrosine (synthesis) - mostly of exam interest now.

Indian practice, poisoning and regulation

• Organophosphate (OP) poisoning is a leading cause of poisoning deaths in India (agricultural insecticides, often self-harm). Management: decontamination with PPE, airway and oxygen, atropine titrated to drying of chest secretions (not to pupil size or heart rate), pralidoxime (2-PAM) to reactivate non-aged enzyme, diazepam for convulsions, ventilation for intermediate syndrome (24-96 h) and watch for OPIDN (delayed neuropathy). Atropine, pralidoxime, adrenaline, salbutamol, neostigmine, glycopyrrolate, succinylcholine and atracurium are in the National List of Essential Medicines (NLEM 2022); ceiling prices for scheduled formulations come under the DPCO 2013 administered by NPPA.
• Diagnosis/monitoring: red-cell (true) cholinesterase reflects severity better than plasma (pseudo) cholinesterase, which falls earlier and is used for screening of sprayers.
• Regulatory frame: manufacture, quality and sale are governed by the Drugs and Cosmetics Act, 1940 and Rules, 1945, with CDSCO as the central regulator; clinical trials and new drug approvals under the New Drugs and Clinical Trials Rules, 2019; monographs and tests in the Indian Pharmacopoeia (IP 2026, the 10th edition, in effect from 1 July 2026, published by IPC, Ghaziabad). Most of these drugs are Schedule H (prescription-only); anticholinergics such as atropine and the muscle relaxants are hospital-use injections. Pharmacy practice and registration fall under the Pharmacy Act, 1948 and PCI regulations; adverse reactions are reported to the Pharmacovigilance Programme of India (PvPI) at IPC. Narcotic-type scheduling does not apply here, but Schedule X applies to some sedatives used alongside.
• Cold-chain and light protection matter: adrenaline and noradrenaline injections oxidise (pink/brown discolouration means discard); succinylcholine ampoules need refrigeration as per label.

Key points

• Cholinergic sites - all ganglia (NN), all parasympathetic post-ganglionic endings (M), skeletal muscle end-plate (NM), sweat glands and adrenal medulla.
• Adrenergic site - sympathetic post-ganglionic endings, releasing noradrenaline; the adrenal medulla releases adrenaline into blood.
• M2 slows the heart; M3 contracts smooth muscle and stimulates glands; β1 stimulates the heart; β2 relaxes bronchi, uterus and vessels; α1 constricts vessels and contracts sphincters; α2 inhibits further NA release.
• Atropine - competitive muscarinic blocker: tachycardia, mydriasis + cycloplegia, dry mouth, raised IOP, urinary retention; antidote physostigmine.
• Pilocarpine and timolol both lower IOP but oppositely - pilocarpine by improving outflow (miosis), timolol by reducing aqueous formation.
• Neostigmine is quaternary (no CNS effect, used for myasthenia and reversal); physostigmine is tertiary (crosses BBB, used for central anticholinergic poisoning).
• Pralidoxime works only on non-aged phosphorylated AChE; it does not treat muscarinic signs - atropine does.
• Succinylcholine is depolarising, causes fasciculations, is not reversed by neostigmine; non-depolarising blockers are reversed by neostigmine plus an antimuscarinic.
• Dale's vasomotor reversal - adrenaline's pressor effect becomes depressor after α-blockade; noradrenaline's is only abolished.
• Adrenaline is the drug of choice in anaphylaxis, 0.5 mg IM (1:1000) into the anterolateral thigh, repeatable every 5-15 min.
• Noradrenaline is the first-line vasopressor in septic shock; extravasation is treated with local phentolamine.
• Dopamine acts on D1 → β1 → α1 as the infusion rate rises.
• Clonidine and α-methyldopa are α2 *agonists* that lower blood pressure by central sympathetic inhibition - a common exam trap.
• Cardioselective β1-blockers are safer but not safe in asthma; selectivity is lost at high doses.
• Never withdraw a β-blocker abruptly - rebound ischaemia and arrhythmia.
• Tamsulosin/silodosin are α1A-selective for BPH with less postural hypotension than prazosin.
• Reuptake-1 (NET) is the main way noradrenaline action ends; MAO and COMT metabolise it.
• Sweat glands - sympathetic nerves but muscarinic receptors, which is why atropine causes hot dry skin.

Formulas and examples

Example 1 - Dopamine infusion. 200 mg dopamine in 500 mL 5% dextrose for a 60 kg patient at 5 µg/kg/min.

• Concentration = 200 × 1000 ÷ 500 = 400 µg/mL.
• Dose = 5 × 60 = 300 µg/min = 18,000 µg/h.
• Rate = 18,000 ÷ 400 = 45 mL/h (= 0.75 mL/min; with a 60 drops/mL microset, 0.75 × 60 = 45 drops/min).

Example 2 - Adrenaline in anaphylaxis and arrest. Ampoule is adrenaline injection IP 1 mg/mL (1:1000).

• Adult IM anaphylaxis dose 0.5 mg → 0.5 ÷ 1 = 0.5 mL IM, thigh.
• Child 20 kg at 10 µg/kg = 200 µg = 0.2 mg → 0.2 mL of 1:1000.
• Cardiac arrest IV dose 1 mg must be given as 1:10,000: dilute 1 mL of 1:1000 to 10 mL → 0.1 mg/mL, so 10 mL = 1 mg.

Example 3 - Atropine and pralidoxime in OP poisoning (70 kg adult). Atropine sulphate injection 0.6 mg/mL.

• Initial 2 mg = 2 ÷ 0.6 = 3.33 mL IV.
• Doubling every 5 min until secretions dry: 2 + 4 + 8 + 16 = 30 mg total over 15-20 min, i.e. 50 mL of the 0.6 mg/mL solution - which is why 1.2 mg/2 mL or bulk vials are kept in casualty.
• Pralidoxime loading 30 mg/kg = 30 × 70 = 2,100 mg (2.1 g) IV over 20-30 min; maintenance 8 mg/kg/h = 8 × 70 = 560 mg/h = 13.44 g in 24 h.

Example 4 - Noradrenaline infusion. 4 mg noradrenaline in 50 mL, 70 kg patient at 0.1 µg/kg/min.

• Concentration = 4 × 1000 ÷ 50 = 80 µg/mL.
• Dose = 0.1 × 70 = 7 µg/min = 420 µg/h → rate = 420 ÷ 80 = 5.25 mL/h by syringe pump, central line preferred.

Example 5 - Potency of an antagonist (Schild). Atropine 1 × 10⁻⁸ M shifts the ACh dose-response curve 10-fold to the right.

• DR = 10 → log(DR − 1) = log 9 = 0.954.
• 0.954 = log(10⁻⁸) − log K_B = −8 − log K_B → log K_B = −8.954 → K_B ≈ 1.1 × 10⁻⁹ M, pA2 ≈ 8.95 (a slope of 1 confirms simple competitive block).

Where it is used

• Hospital and critical-care pharmacy: preparing and labelling adrenaline, noradrenaline, dopamine and dobutamine infusions; crash-cart and anaphylaxis-kit stocking; atropine-pralidoxime protocols in district hospital casualties across Maharashtra, Punjab, Telangana and Kerala.
• Formulation and manufacturing: salbutamol MDIs and rotacaps, tiotropium inhalers, timolol/brimonidine eye drops, atropine and glycopyrrolate ampoules, atenolol/metoprolol/telmisartan-metoprolol tablets - Cipla, Sun Pharma, Lupin, Zydus, Torrent, Intas, Ajanta, FDC.
• Operation theatre and anaesthesia support: succinylcholine, atracurium, vecuronium, neostigmine-glycopyrrolate reversal; cold-chain and expiry control of relaxants.
• Ophthalmology products and optometry practice: tropicamide and phenylephrine for fundus examination, pilocarpine and timolol for glaucoma.
• Pharmacovigilance and medical affairs: ADR reporting to PvPI for β-blocker-induced bronchospasm, anticholinergic burden in the elderly, mydriatic misuse; preparing prescriber briefs and MR training material.
• Clinical research and regulatory affairs: bioequivalence studies of metoprolol ER and tamsulosin MR, dossiers to CDSCO under the New Drugs and Clinical Trials Rules, 2019.

Interview questions

• Q: Which fibres are cholinergic in the sympathetic division? A: All preganglionic sympathetic fibres, the fibres to the adrenal medulla, and the postganglionic fibres to sweat glands (muscarinic).
• Q: Why does atropine cause tachycardia? A: It blocks M2 receptors at the SA node, removing the resting vagal tone that normally slows the heart.
• Q: In organophosphate poisoning, what do you titrate atropine against? A: Drying of tracheobronchial secretions and resolution of bronchospasm - not pupil size or heart rate, which are unreliable endpoints.
• Q: Why must pralidoxime be given early? A: The phosphorylated enzyme "ages" within hours into a form oximes cannot reactivate, after which only new enzyme synthesis helps.
• Q: Neostigmine or physostigmine for atropine poisoning, and why? A: Physostigmine - it is a tertiary amine and crosses the blood-brain barrier to reverse central anticholinergic delirium; neostigmine is quaternary and does not.
• Q: How do you distinguish myasthenic from cholinergic crisis? A: Edrophonium improves a myasthenic crisis but worsens a cholinergic crisis, which also shows miosis, fasciculations and excessive secretions.
• Q: What is vasomotor reversal of adrenaline? A: After α-blockade, adrenaline's unopposed β2 action causes a fall in blood pressure instead of a rise; noradrenaline's pressor effect is merely abolished.
• Q: Why is adrenaline, not an antihistamine, the first drug in anaphylaxis? A: Only adrenaline reverses the pathophysiology rapidly - α1 vasoconstriction restores BP, β1 supports the heart, β2 relieves bronchospasm and stabilises mast cells.
• Q: Why are β-blockers risky in an asthmatic and in a diabetic on insulin? A: β2 blockade precipitates bronchospasm, and β-blockade masks the adrenergic warning signs of hypoglycaemia while delaying recovery.
• Q: Why is clonidine, an α2 agonist, antihypertensive? A: It stimulates central presynaptic α2 receptors, reducing sympathetic outflow and noradrenaline release.
• Q: Which muscle relaxant is preferred in renal and hepatic failure? A: Atracurium or cisatracurium - they are inactivated by Hofmann elimination and ester hydrolysis in plasma, independent of kidney and liver.
• Q: Why is phenylephrine preferred over atropine when only mydriasis is wanted? A: Phenylephrine is an α1 agonist that contracts the radial muscle without paralysing the ciliary muscle, so accommodation is preserved and recovery is quick.

Common mistakes

• Writing that sympathetic transmission is "all adrenergic" - forgetting ganglia, adrenal medulla and sweat glands are cholinergic.
• Confusing α2 and β2 agonists with blockers: clonidine (α2 agonist) lowers BP, while prazosin (α1 blocker) also lowers BP - but by opposite mechanisms.
• Trying to reverse succinylcholine with neostigmine, or giving neostigmine without an antimuscarinic (glycopyrrolate/atropine) and causing bradycardia.
• Giving pralidoxime alone, or stopping atropine too early, in OP poisoning; and under-dosing atropine because 30-100 mg sounds alarming.
• Mixing up ratio strengths - using 1:1000 adrenaline intravenously in cardiac arrest instead of diluting to 1:10,000.
• Forgetting the units chain in infusion sums (µg/kg/min → µg/h → mL/h), or dividing by concentration in mg/mL instead of µg/mL.
• Prescribing anticholinergics or mydriatics in narrow-angle glaucoma or BPH, and stopping a β-blocker abruptly.

Related topics

Pharmacodynamics: how drugs act · Cardiovascular drugs · Central nervous system drugs · Human anatomy and physiology (nervous system) · Toxicology and antidotes · Anaesthetics and skeletal muscle relaxants