Antimuscarinic effects

Quinidine, the classical class IA drug, binds to the open state oftheNa+ channel, and prolongs the action potential by block of the delayed rectifier-. In higher concentrations, L-type Ca2+ channels are inhibited. Quinidine exerts antimuscarinic effects, thereby accelerating AV-nodal... 

The adverse side-effects of the TCAs, coupled with their toxicity in overdose, provoked a search for compounds which retained their monoamine uptake blocking activity but which lacked the side-effects arising from interactions with Hj, aj-adreno-ceptors and muscarinic receptors. One of the first compounds to emerge from this effort was iprindole, which has an indole nucleus (Fig. 20.3). This turned out to be an interesting compound because it has no apparent effects on monoamine uptake and is not a MAO inhibitor. This, together with its relatively minor antimuscarinic effects, led to it commonly being described as an atypical antidepressant. Mechanisms that could underlie its therapeutic actions have still not been identified but, in any case, this drug has now been withdrawn in the UK. 

Many patients discontinue oxybutynin IR because of adverse effects due to antimuscarinic effects (e.g., dry mouth, constipation, vision impairment, confusion, cognitive dysfunction, and tachycardia), a-adrenergic inhibition (e.g., orthostatic hypotension), and histamine 111 inhibition (e.g., sedation, and weight gain). 

The adverse effects of the anticholinergic drugs are due to their antimuscarinic effects in other systems (e.g., cycloplegia, dry mouth, urinary retention, and constipation). Confusion, delirium, and hallucinations may occur at higher doses. 

The answer is a. (Hardman, p 436.) The most common side effects associated with tricyclic antidepressants are their antimuscarinic effects, which may be evident in over 50% of patients. Clinically, the antimuscarinic effects may manifest as dry mouth, blurred vision, constipation, tachycardia, dizziness, and urinary retention. At therapeutic plasma concentrations, these drugs usually do not cause changes in the EKG. Direct cardiac effects of the tricyclic antidepressants are important in overdosage. 

Sympathomimetic effects (from NA re-uptake inhibition) and antimuscarinic effects can cause a sinus tachycardia. Postural hypotension may occur as a result of sympatholytic al-adrenoceptor antagonism. With overdoses of these drugs, there is a reduced re-uptake of catecholamines, resulting in arrhythmias and hypertension. Tricyclic compounds have a high... 

Naturally occurring compounds with antimuscarinic effects have been known and used for millennia as medicines, poisons, and cosmetics. Atropine is the prototype of these drugs. Many similar plant alkaloids are known, and hundreds of synthetic antimuscarinic compounds have been prepared. 

A variety of semisynthetic and fully synthetic molecules have antimuscarinic effects. The tertiary members of these classes (Figure 8-... 

Certain vestibular disorders respond to antimuscarinic drugs (and to antihistaminic agents with antimuscarinic effects). Scopolamine is one of the oldest remedies for seasickness and is as effective as any more recently introduced agent. It can be given by injection or by mouth or as a transdermal patch. The patch formulation produces significant blood levels over 48-72 hours. Useful doses by any route usually cause significant sedation and dry mouth. 

The effects of disopyramide are very similar to those of procainamide and quinidine. Its cardiac antimuscarinic effects are even more marked than those of quinidine. Therefore, a drug that slows atrioventricular conduction should be administered with disopyramide when treating atrial flutter or fibrillation. 

Flecainide is a potent blocker of sodium and potassium channels with slow unblocking kinetics. (Note that although it does block certain potassium channels, it does not prolong the action potential or the QT interval.) It is currently used for patients with otherwise normal hearts who have supraventricular arrhythmias. It has no antimuscarinic effects. 

Disopyramide Similar to procainamide but significant antimuscarinic effects may precipitate heart failure ... 

Cyproheptadine resembles the phenothiazine antihistaminic agents in chemical structure and has potent H receptor-blocking as well as 5-HT2-blocking actions. The actions of cyproheptadine are predictable from its histamine and 5-HT receptor affinities. It prevents the smooth muscle effects of both amines but has no effect on the gastric secretion stimulated by histamine. It also has significant antimuscarinic effects and causes sedation. 

Cisatracurium Similar to tubocurarine Like tubocurarine but lacks histamine release and antimuscarinic effects Prolonged relaxation of surgical procedures relaxation of respiratory muscles to facilitate mechanical ventilation in intensive care unit Not dependent on renal or hepatic function duration, 25-45 min Toxicities Prolonged apnea but less toxic than atracurium... 

Rocuronium Similar to cisatracurium Like cisatracurium but slight antimuscarinic effect Like cisatracurium useful in patients with renal impairment Hepatic metabolism duration, 20-35 min Toxicities Like cisatracurium... 

Cyclobenzaprine Poorly understood inhibition of muscle stretch reflex in spinal cord Reduction in hyperactive muscle reflexes antimuscarinic effects Acute spasm due to muscle injury inflammation Hepatic metabolism duration, 4-6 h Toxicities Strong antimuscarinic effects... 

Chlorphenesin, methocarbamol, orphenadrine, others Like cyclobenzaprine with varying degrees of antimuscarinic effect ... 

Benztropine Antagonist at M receptors in basal ganglia Reduces tremor and rigidity little effect on bradykinesia Parkinson s disease Oral Toxicity Typical antimuscarinic effects sedation, mydriasis, urinary retention, dry mouth... 

Common adverse effects of the TCAs, including dry mouth and constipation, are attributable to the potent antimuscarinic effects of many of these drugs. The TCAs also tend to be potent antagonists of the histamine Hi receptor. TCAs such as... 

Side-effects Pethidine induces morphine-type side-effects with a lower incidence of constipation. Higher doses induce central stimulation and antimuscarinic effects... 

Methantheline and propantheline are synthetic derivatives that, besides their antimuscarinic effects, are ganglionic blocking agents and block the skeletal neuromuscular junction. Propantheline and oxyphenonium reduce gastric secretion, whereas pirenzepine, in addition to reducing gastric secretion, also reduces gastric motility. 

A variety of semisynthetic and fully synthetic molecules have antimuscarinic effects. 

The tertiary members of these classes (Figure 8-2) are often used for their effects on the eye or the central nervous system. Many antihistaminic (see Chapter 16 Histamine, Serotonin, the Ergot Alkaloids), antipsychotic (see Chapter 29 Antipsychotic Agents Lithium), and antidepressant (see Chapter 30 Antidepressant Agents) drugs have similar structures and, predictably, significant antimuscarinic effects. 

Tricyclics and the second- and third-generation agents differ mainly in the degree of sedation they produce (greatest with amitriptyline, doxepin, trazodone, and mirtazapine) and their antimuscarinic effects (greatest with amitriptyline and doxepin Table 30-3). SSRIs are generally free of sedative effects and remarkably safe in overdose. Combined with the ease of once-a-day dosing, these qualities may explain why they have become the most widely prescribed antidepressants. 

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