University:
Michigan State University
Course:
PHM 430 | Human Pharmacology
Academic year:

2023
Views:

239

Pages:

23
Author:

aprivantuqy

Chapter 5: Anticholinergic drugs Overview • Cholinergic antagonists: agents that bind to cholinoceptors (muscarinic or nicotinic) & prevent the effects of ACh & other cholinergic agonists. • The most clinically useful of these agents are selective blockers of muscarinic receptors. 1. Antimuscarinic agents or parasympatholytic: The effects of parasympathetic innervation are interrupted, & the actions of sympathetic stimulation are left unopposed. 2. Ganglionic blockers: shows a preference for the nicotinic receptors of the sympathetic & parasympathetic ganglia. 3. Neuromuscular-blocking agents (mostly nicotinic antagonists): interfere with transmission of efferent impulses to skeletal muscles. ▫ These agents are used as skeletal muscle relaxant adjuvants in anesthesia during surgery, intubation, and various orthopedic procedures. Cholinergic Receptors ( Cholinoceptors) Antimuscarinic Agents • Also known as anticholinergic drugs: these agents (atropine & scopolamine) block muscarinic receptors à causing inhibition of muscarinic functions. • In addition, these drugs block the few exceptional sympathetic neurons that are cholinergic, such as those innervating the salivary & sweat glands. • Because they do not block nicotinic receptors, the antimuscarinic drugs have little or no action at skeletal neuromuscular junctions (NMJs) or autonomic ganglia. • The anticholinergic drugs are beneficial in a variety of clinical situations. • [Note: A number of antihistamines & antidepressants antidepressants) also have antimuscarinic activity.] (mainly tricyclic Antimuscarinic Agents • The class of drugs includes: 1. Naturally occurring alkaloids: atropine & scopolamine. 2. 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. 3. Synthetic muscarinic antagonists (homatropine & tropicamide): some of which show selectivity from particular subtypes of M receptors. Antimuscarinic Agents-PK 1. Naturally occurring alkaloids: atropine & scopolamine. ▫ Absorption: well & rapidly absorbed from the gut & conjunctival membranes, when applied in a suitable vehicle, some ( e.g. scopolamine) are even absorbed across the skin ( transdermal route). ▫ Distribution: widely distributed in the body. Significant levels are achieved in the CNS within 30 min to 1 min. ▫ Metabolism & excretion: hepatic metabolism accounts form the elimination of about half of atropine; the remainder is excreted unchanged in urine. 2. Quaternary antimuscarinic drugs: ▫ Absorption: only 10-30% of a dose is absorbed after oral administration. ▫ Distribution: poorly taken up by the brain. Antimuscarinic Agents-mechanism of action 1. Atropine (prototype) doesn’t distinguish among M1, M2, M3 subgroups of muscarinic receptors. 2. Few synthetic antimuscarinic drugs demonstrate selectivity for one or another of these subgroups ▫ M1 selective agents: pirenzepine, telenzepine. ▫ M3 selective agents: darifenacin, solifenacin. Effects of muscarinic blockade drugs Dose Dependent Effect of Atropine Antimuscarinic Agents- Clinical uses 1. CNS disorders: • Parkinson's disease: Benztropine, biperiden, & trihexyphenidyl. • Motion sickness: Scopolamine ( injections, oral , or transdermal patches). 2. Ophthalmologic disorders: • Examination of the retina & optic disc & for the accurate measurement of refractive error administered topically as eye drop or ointments. • Agents: atropine, scopolamine, cyclopentolate, & tropicamide. • Short acting drugs (cyclopentolate, & tropicamide) are favored for ophthalmic application because compete recovery of accommodation occurs within 6-24 hours and 2-6 hours, respectively. 3. Respiratory disorders: Ipratropium & tiotropium are used as an inhalational drug in Asthma & COPD (obstruction pulmonary disease) pts. 4. GIT disorders: • Treatment of peptic ulcer: Pirenzepine. • Treatment of traveler’s diarrhea: in combination with an opioid antidiarrheal drug ( e.g. atropine & diphenoxylate combination (Lomotil). 5. Cardiovascular disorders: reflex vagal discharge: vasovagal attack & hyperactive carotid sinus reflexes in response to pressure on the neck, e.g. from a tight collar à parenteral atropine. 5. Urinary disorder: symptomatic relief in the treatment of urinary urgency caused by minor inflammatory bladder disorder. Agents: oxybutynin, darifenacin, solifenacin, tolterodine, fesoterodine (all are selective M3 antagonists), trospium ( non-selective antagonist). 6. 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 & parasympathomimetic effects of the organophosphate anticholinesterase inhibitors. Antimuscarinic Agents- Toxicity 1. Predictable toxicities: • ADEs first depend on the dose. • They may cause: dry mouth, blurred vision (sandy eyes), tachycardia, & constipation. • Children, especially infants, are very sensitive to the hyperthermic effects of atropine (atropine fever). • Elderly are especially susceptible to antimuscarinic toxicity including the eye & the bladder especially those with a history of prostatic hyperplasia. Antimuscarinic Agents- Toxicity • CNS toxicities: sedation, amnesia & delirium or hallucination, convulsion. • Cardiovascular effects: at high doses these agents can cause the following: 1. Intraventricular conduction block. 2. Atropine flush dilation of the cutaneous vessels of the arms, head, & neck. • Antimuscarinic Agents - Contraindications: 1. Pts wit glaucoma & elderly with history of prostatic hyperplasia. 2. Cause these drugs slow gastric emptying, they may increase symptoms in pts with gastric ulcer (nonselective agents should never be used to treat acid-peptic disease). II. Ganglion-blocking agents • Agents: Hexamethonium, mecamylamine, trimethaphan. • Ganglionic blockers competitively block the action of Ach & similar agonist at nicotinic receptors of both parasympathetic & sympathetic Autonomic ganglia. • These agents block the entire output of the ANS: the responses observed are complex & unpredictable (rarely used therapeutically). • The lack of selectivity confers such a broad range of undesirable effects that limit their clinical use. II. Ganglion-blocking agents Organ system effects • In any given tissue, the magnitude of the response produced by ganglionic blocking agents depends largely on the quantity & relative proportion of the total autonomic input coming from sympathetic & parasympathetic nerves at the time of administrating the drug. II. Ganglion-blocking agents- clinical uses: • Mecamylamine: blocks central nicotinic receptors a& has been advocated as possible adjunct with the transdermal nicotine patch to reduce nicotine craving in pts attempting to quite smoking. • Trimethaphan: Treatment of hypertensive emergencies & dissecting aortic aneurysm; in producing hypotension, which can e of a value in neurosurgery to reduce bleeding in the operative field; & in the treatment of pts undergoing electroconvulsive therapy. II. Ganglion-blocking agents- toxicity 1. Mild untoward ADRs: visual disturbances, dry mouth, conjunctival suffusion, urinary hesitancy, decrease potency, subjective chilliness, moderate constipation, occasional diarrhea, abdominal discomfort, anorexia, heartburn, N, burping, & bitter taste, signs & symptoms of syncope cause by postural hypotension. 2. Severe ADRs: marked hypotension, constipation, syncope, paralytic ileus, urinary retention, & cycloplegia. The end Antimuscarinic Agents • Atropine: 1. A tertiary amine belladonna alkaloid with a high affinity for muscarinic receptors. 2. It binds competitively & prevents ACh from binding to those sites by acting on both central & peripheral systems. 3. Its general actions last about 4 hours, except when placed topically in the eye, where the action may last for days. 4. Neuroeffector organs have varying sensitivity to atropine à The greatest inhibitory effects are on: A. bronchial tissue, B. the secretion of sweat & saliva. Antimuscarinic Agents • Pharmacological effects: 1. Eye: Atropine blocks muscarinic activity in the eye, resulting in mydriasis (dilation of the pupil), unresponsiveness to light, & cycloplegia (inability to focus for near vision). à In patients with angle-closure glaucoma, intraocular pressure may rise dangerously. 2. GIT: Atropine (as the active isomer, l-hyoscyamine) can be used as an antispasmodic to reduce activity of the GI tract. à Atropine & scopolamine are probably the most potent antispasmodic drugs available. à Although gastric motility is reduced, HCL production is not significantly affected. Antimuscarinic Agents • Pharmacological effects: 2. GIT: à Thus, atropine is not effective for the treatment of peptic ulcer. à [Note: Pirenzepine, an M1 muscarinic antagonist, does reduce gastric acid secretion at doses that do not antagonize other systems.] à Doses of atropine that reduce spasms also reduce saliva secretion, ocular accommodation, and urinationàThese effects decrease compliance with atropine.

Anticholinergic Drugs

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