Parasympatholytics Dr. Zaker

Cholinergic receptors Nicotinic receptors Muscarinic receptors Present in Autonomic ganglia (NN) Adrenal medulla (NN) Motor endplate (NM) CNS (Spinal cord mainly) (NN) Effector organ supplied by Parasymp Sweat glands & BV CNS (Brain Mainly) Blocked By Ganglion blocker (Nicotine, LD, in ganglia) Neuromucular blocker (eg. Curare in skeletal muscles) Blocked by Atropine

Drug affecting ANS & neuromuscular junction Sympathetic Parasympathetic Drugs acting on NMJ Sympatho-mimetics Sympatho-lytics Parasympatho-mimetics Parasympatho-lytics NMJ Blocking Agents Adrenergic agonists antagonists Cholinergic Cholinergics 1. α receptors 2. β receptors α-antagonist β-antagonist Selective β Mixed type Nicotinic Muscarinic 1. Muscarinic antagonists 2. Ganglion blocking drugs 1. Competitive non-depolarizing (Curare, Pancuronium) Direct acting Indirect acting 2. Non competitive depolarizing (Decamethonium, Succinylcholine)

Classification of Cholinergic drugs Muscarinic antagonists (Parasympatholytics) (Atropine, hyoscine, homatropine) Ganglion blocking drugs (Hexamethonium, gallamine) Neuromuscular blocking drugs (Calcium antagonists, hemicholinium, magnesium ions)

MUSCARINIC RECEPTOR ANTAGONISTS They produce reversible blockade of the action of ACh at muscarinic receptors competitively. They have affinity for muscarinic receptors, no efficacy, and slow dissociation rate. Classified as Natural belladonna Alkaloids: Atropine, Hyoscine (Scopolamine) Both are tertiary ammonium alkaloids Synthetic derivatives: Homatropine, Ipratropium, Pirenzepine (Selective M1 antagonist)

Atropine Pharmacokinetics Absorbed orally, can be given by Inj. Metabolized in liver, distribution to all tissue, t1/2 2hr, urinary excretion, 60% unchanged Actions Eye: Mydriasis due to block of muscarinic receptors in constrictor papillae muscle (passive mydriasis) Loss of reaction to light (light reflex loss) Relaxation of ciliary muscle (cycloplegia--- Loss of accommodation for near vision) Impaired aq. Humor drainage (↑IOP) Decrease lacrimation (local application- effects last for 7-10 days) Secretions: Decreases saliva, bronchial, gastric and sweat secretions Bronchi: Bronchodilatation, dryness of secretions CVS: ↑ HR, ↑AV conduction due to vagal block. Low doses produce bradycardia followed by tachycardia BV – no effect at therapeutic doses (Most BVs have no parasymp supply). Blocks VD induced by muscarinic agonists. Toxic doses cause cutaneous VD in upper part of body esp. face (Atropine flush) GIT: ↓ motility and secretions Urinary tract: Relaxes detrusor muscle and contract sphincters CNS: Mainly excitatory, antiemetic and antiparkinsonian effect

Atropine- Therapeutic uses Preanesthetic medication to Decrease salivary and bronchial secretions Antagonize RC depressants Protect heart from bradycardia induced by general anesthetics Prevent vomiting Fundus examination (derivatives are better) Heart block, marked bradycardia and carotid sinus syndrome Bronchial asthma (secretions become vicid, better to use ipratropium) Colics, gut hypermotility and duodenal ulcers Nocturnal enuresis and urinary urgency to reduce bladder motility Parkinsonism Motion sickness but Hyoscine is better Hyperhidrosis (excessive sweating) In cholinergic poisoning to antagonize muscarinic effects as in organophospate poisoning or physostigmine poisoning Adverse effects Dry mouth, blurred vision, tachycardia, constipation, urine retention, glaucoma, flush, agitation, delirium and hyperthermia (esp. in children). Treatment of toxicity (symptomatic) Care for respiration and stomach wash Cold foamentation to reduce hyperthermia Physostigmine slowly I.V. to antagonize both central and peripheral effects of atropine. Neostigmine can be used to antagonize peripheral actions. Control excitation by diazepam Contraindications Prostatic hypertrophy Glaucoma (Closed angle esp.)

Hyoscine Given orally, also absorbed by skin, Shorter duration of action with potent effects on eye and secretions, Less effects on heart Tertiary amine like atropine, stimulates RC and CIC, inhibits vomiting centre and basal ganglia. Produces more marked CNS effects (Sedation, drowsiness and amnesia). Toxic doses produce excitation, agitation, hallucination, coma Uses Used like atropine and preferred in preanesthetic medication of cardiac and thyrotoxic patients In motion sickness (Hyosine patch on skin) In Meniere’s disease to prevent vertigo Antispasmodic

Synthetic atropine substitutes Mydriatic group: Homatropine Antisecretory antispasmodic group: These show muscarinic effects on GIt, insignificant central effects (Quaternary amine) eg. Hyoscine butyl bromide (Buscopan) Ipratropium (Atrovent) is muscarinic blocker, produces bronchodilatation without dryness of secretions. Quaternary amine, by inhalation in bronchial asthma

ANS As mydriatics: Cyclopentolate eye drops –long acting Tropicamide eye drops -- short acting As Antispasmodic / Anti-ulcer: Glycopyrrolate, Dicyclomine For Overactive Bladder : Tolterodine.

DRUGS AFFECTING GANGLIA Ganglion blockers Classified as Depolarizing ganglion blockers Produce initial stimulation then block (Nicotine large dose) Competitive ganglion blocker Quaternary amines, Hexametonium and chlorisondamine Secondary amine (Mecamylamine) Trimetaphan – short acting histamine liberator, by I.V., No CNS effects Actions Effects like atropine Postural hypotension Impotence USES Trimetaphan used in hypertensive emergency, to induce controlled hypotension in surgery

Act by blocking effects of ACh at the skeletal NMJ Competitive non depolarizing agents (Gallamine, Pancuronium) Compete with ACh for nicotinic receptors at the NMJ. ↓EPP, depolarization threshold is not reached USES Promote sk muscle relaxation Promote endotracheal intubation Adjunct to surgical anesthesia Limit trauma due to Electroconvulsive shock Adverse effects Respiratory paralysis Histamine release Bronchospasm hypotension

Act by blocking effects of ACh at the skeletal NMJ Non-competitive depolarizing agents (succinylcholine, decamethonium) Desensitize the nicotinic receptors at NMJ, ↓ receptor sensitivity USES Promote sk muscle relaxation Promote endotracheal intubation Adjunct to surgical anesthesia Limit trauma due to Electroconvulsive shock Adverse effects Respiratory paralysis Muscle facciculation and pain Increased IOP Bradycardia (muscarinic effect)

Autonomic nervous system 15

Autonomic nervous system 16

Good Bye to PANS References Pharmacology by Rang and Dale Katzung Pharmacology