Cholinoceptor-blocking drugs

Overview The cholinergic antagonists bind to cholinoceptors, but they do not trigger the usual receptor-mediated intracellular effects Also called cholinergic blockers, parasympatholytics or anticholinergic drugs Cholinoceptor antagonists are divided into muscarinic and nicotinic subgroups on the basis of their receptor affinities

Overview Cholinergic antagonists are further subdivided according to their physiological site of action: Muscarin antagonists (antamuscarinics, parasympatholytic drugs) Ganglionic blockers Neuromuscular-blocking drugs

Sympathatic innervation of adrenal medulla Neuromuscular blockers Parasympathatic Somatic Ganglionic blockers Neuromuscular junction Ganglionic transmittion NN receptor Adrenal medulla NN receptor NN receptor Neuroeffector transmittion Neuromuscular blockers antimuscarinics Acetylcholine Norepinephrine Effector organ α or β Adrenergic receptor Effector organ M receptor Neuromuscular junction NM receptor

I. Muscarinic antagonists (antimuscarinics) These are reversible (surmountable) competitive antagonists that compete with ACh and other muscarinic agonists for a common binding site on the muscarinic receptor These drugs block sympathetic neurons that are cholinergic innervating salivary and sweat glands The antimuscarinics are beneficial in a variety of clinical situations, because they do not block nicotinic receptors

I. Muscarinic antagonists (antimuscarinics) The class of drugs includes: Naturally occurring alkaloids (atropine & scopolamine) Semisynthetic derivatives of the naturally occurring alkaloids, which primarily differ from the parent compounds in their disposition in the body or their duration of action Synthetic muscarinic antagonists (homatropine & tropicamide) , some of which show selectivity for particular subtypes of muscarinic receptors

I. Muscarinic antagonists (antimuscarinics) Pharmacokinetics Natural alkaloids & tertiary antimuscarinic drugs Absorption: well & rapidly absorbed from the gut and conjunctival membranes. When applied in a suitable vehicle, some (eg, scopolamine) are even absorbed across the skin (transdermal route) Distribution: widely distributed in the body. Significant levels are achieved in the CNS within 30 minutes to 1 hour Metabolism & excretion: hepatic metabolism accounts for the elimination of about half of atropine; the remainder is excreted unchanged in the urine Quaternary antimuscarinic drug Absorption: only 10–30% of a dose is absorbed after oral administration Distribution: poorly taken up by the brain

I. Muscarinic antagonists Mechanism of action Atropine (prototype) does not distinguish among the M1, M2, and M3 subgroups of muscarinic receptors Few synthetic antimuscarinic drugs demonstrate selectivity for one or another of these subgroups: M1 selective agents: pirenzepine, telenzepine M3 selective agents: darifenacin, solifenacin

Dissociation constant (kd) M1 M2 M3 Atropine 1 Pirenzepine 25 300 500 AF-DX 116 2000 65 4000 Darifenacin 70 55 8

Effects of muscarinic blocking drugs Organ Effect Mechanism CNS Sedation, anti-motion sickness action, antiparkinson action, amnesia, delirium Block of muscarinic receptors, several subtypes Eye Cycloplegia, mydriasis Block of M3 receptors Bronchi Bronchodilation, especially if constricted GIT Relaxation, slowed peristalsis, reduced salivation Block of M1, M3 receptors Genitourinary tract Relaxation of bladder wall, urinary retention Block of M3 and possibly M1 receptors Heart Bradycardia (at low doses) Tachycardia (at high doses) Block of presynaptic M1 receptors Block of M2 receptors in the sinoatrial node Blood vessels Block of muscarinic vasodilation; not manifest unless a muscarinic agonist is present Block of M3 receptors on endothelium of vessels Glands Marked reduction of salivation; moderate reduction of lacrimation, sweating; less reduction of gastric secretion

Dose-dependent effect of atropine >10.0 mg Hallucination and delirium; coma Dose of atropine Rapid heart rate; palpitation; marked dryness of the mouth; dilation of pupil; some blurring of near vision 5.0 mg 2.0 mg Slight cardiac slowing; some dryness of the mouth; inhibition of sweating 0.5 mg

I. Muscarinic antagonists Clinical uses Central Nervous System Disorders Parkinson's Disease: Bezotropine, biperiden, and trihexylphenidyl Motion Sickness: Scopolamine (injection or by mouth or as a transdermal patch)

I. Muscarinic antagonists Clinical uses Ophthalmologic Disorders Examination of the retina and optic disc and for the accurate measurement of refractive error administered topically as eye drops or ointment Agents used: Atropine, scopolamine, cyclopentolate and tropicamide, homatropin Short-acting drugs (e.g cyclopentolate and tropicamide) are favoured for ophthalmic application b/c complete recovery of accommodation occurs within 6 to 24 hours and 2 to 6 hours, respectively

I. Muscarinic antagonists Clinical uses Ophthalmologic Disorders Prevent synechia (adhesion) formation in uveitis and iritis: homatropine

I. Muscarinic antagonists Clinical uses Respiratory disorders: Ipratropium, tiotropiumis, and aclidinium used as an inhalational drug in asthma & chronic obstruction pulmonary disease (COPD) Gastrointestinal disorders Treatment of traveler's diarrhea: in combination with an opioid antidiarrheal drug (e.g. atropine & diphenoxylate combination (Lomotil®)

I. Muscarinic antagonists Clinical uses Urinary Disorders Symptomatic relief in the treatment of urinary urgency caused by minor inflammatory bladder disorders Relief bladder spasm after urologic surgery eg. prostatectomy: Oxybutynin, darifenacin, solifenacin, tolterodine, fesoterodine (all are selective M3 antagonists), trospium (a nonselective antagonist)

I. Muscarinic antagonists Clinical uses Cholinergic poisoning Used for the treatment of poisoning caused by anticholinesterase organophosphorus insecticides or by the ingestion of mushrooms of Inocybe genus Atropine is used to antagonize/reverse the central and parasympathomimetic effects of the organophosphate anticholinesterase inhibitors

I. Muscarinic antagonists Toxicity Predictable toxicities Antimuscarinic adverse effects depend on the dose Antimuscarinic agents may cause dry mouth, blurred vision ‘sandy eyes’, tachycardia, and constipation Children, especially infants, are very sensitive to the hyperthermic effects of atropine (Atropine fever) Elderly are especially susceptible to antimuscarinic toxicities including the eye and the bladder especially those with a history of prostatic hyperplasia

I. Muscarinic antagonists Toxicity CNS toxicities: sedation, amnesia, and delirium or hallucinations; convulsions may also occur Cardiovascular Effects At very high doses, antimuscarinic can cause: Intraventricular conduction block Atropine flush: dilation of the cutaneous vessels of the arms, head, and neck

I. Muscarinic antagonists Contraindications Contraindications to the use of antimuscarinic drugs are relative, not absolute Antimuscarinic drugs are contraindicated in patients with glaucoma and elderly patients with a history of prostatic hyperplasia Because the antimuscarinic drugs slow gastric emptying, they may increase symptoms in patients with gastric ulcer (nonselective antimuscarinic agents should never be used to treat acid-peptic disease)

II. Ganglion-Blocking Drugs Agents: hexamthonium, mecamylamine, trimethaphan Ganglionic blockers competitively block the action of ACh and similar agonists at nicotinic receptors of both parasympathetic & sympathetic autonomic ganglia These drugs block the entire output of the ANS: the responses observed are complex and unpredictable (rarely used therapeutically) The lack of selectivity confers such a broad range of undesirable effects that limit their clinical use

II. Ganglion-Blocking Drugs In any given tissue, the magnitude of the response produced by ganglionic blocking drugs depends largely on the quantity and relative proportion of the total autonomic input coming from sympathetic and parasympathetic nerves at the time of drug administration

Effects of ganglion-blocking drugs Organ Effects CNS Antinicotinic action may include reduction of nicotine craving and amelioration of Tourette's syndrome (mecamylamine only) Eye Moderate mydriasis and cycloplegia Bronchi Little effect; asthmatics may note some bronchodilation Gastrointestinal tract Marked reduction of motility, constipation may be severe Genitourinary tract Reduced contractility of the bladder;impairment of erection (parasympathetic block) and ejaculation (sympathetic block) Heart Moderate tachycardia and reduction in force and cardiac output at rest; block of exercise-induced increases Vessels Reduction in arteriolar and venous tone, dose-dependent reduction in blood pressure; orthostatic hypotension usually marked Glands Reductions in salivation, lacrimation, sweating, and gastric secretion Skeletal muscle No significant effect

II. Ganglion-Blocking Drugs Clinical uses Mecamylamine blocks central nicotinic receptors and has been advocated as a possible adjunct with the transdermal nicotine patch to reduce nicotine craving in patients attempting to quit smoking

II. Ganglion-Blocking Drugs Toxicity Mild untoward ADRs: visual disturbances, dry mouth, conjunctival suffusion, urinary hesitancy, decreased potency, subjective chilliness, moderate constipation, occasional diarrhea, abdominal discomfort, anorexia, heartburn, nausea, eructation, and bitter taste and the signs and symptoms of syncope caused by postural hypotension Severe ADRs: marked hypotension, constipation, syncope, paralytic ileus, urinary retention, and cycloplegia