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Chapter: Modern Pharmacology with Clinical Applications: Muscarinic Blocking Drugs

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Muscarinic Blocking Drugs: Clinical Uses

Atropine can be useful in patients with carotid sinus syncope. This condition results from excessive activity of afferent neurons whose stretch receptors are in the carotid sinus.

CLINICAL USES

Cardiovascular Uses

Atropine can be useful in patients with carotid sinus syncope. This condition results from excessive activity of afferent neurons whose stretch receptors are in the carotid sinus. By reflex mechanisms, this excessive affer-ent input to the medulla oblongata causes pronounced bradycardia, which is reversible by atropine.

Atropine can be used in the differential diagnosis of S-A node dysfunction. If sinus bradycardia is due to ex-tracardiac causes, atropine can generally elicit a tachy-cardic response, whereas it cannot elicit tachycardia if the bradycardia results from intrinsic causes. Under cer-tain conditions, atropine may be useful in the treatment of acute myocardial infarction. Bradycardia frequently occurs after acute myocardial infarction, especially in the first few hours, and this probably results from ex-cessive vagal tone. The increased tone and bradycardia facilitate the development of ventricular ectopy. Although atropine sulfate has proved beneficial in pa-tients whose bradycardia is accompanied by hypoten-sion or ventricular ectopy, it is generally not otherwise recommended in this condition. Use of atropine is not without hazard, because cardiac work can be increased without improved perfusion, and ventricular arrhyth-mias may occur. Atropine can also be used to induce positive chronotropy during cardiopulmonary resusci-tation.

Uses in Anesthesiology

At one time, atropine or scopolamine was routinely ad-ministered before the induction of general anesthesia to block excessive salivary and respiratory secretions in-duced by certain inhalation anesthetics (e.g., diethyl ether). With the newer, less irritating anesthetics, an-timuscarinic premedication is not routinely required as an antisialagogue (i.e., to counteract the formation of saliva). Sedation can occur following scopolamine administration, and preanesthetic or postoperative agitation has been observed in some patients. High serum levels of drugs with antimuscarinic activity can produce postoperative delirium. Glycopyrrolate bro-mide (Robinul) has also been given intramuscularly as a preanesthetic medication with satisfactory results. This agent is a quaternary ammonium compound and therefore produces no central effects.

Use With Cholinesterase Inhibitors

During reversal of competitive neuromuscular block-ade with neostigmine or other anticholinesterase agents and in the management of myasthenia gravis with cholinesterase inhibitors, atropine or another mus-carinic antagonist should be given to prevent the stimu-lation of muscarinic receptors that accompanies exces-sive inhibition of AChE. However, extra care must be exercised because the prevention of muscarinic recep-tor stimulation eliminates an important early sign of cholinergic crisis .

Uses in Ophthalmology

Antimuscarinic drugs are widely used in ophthalmology to produce mydriasis and cycloplegia. These actions permit an accurate determination of the refractive state of the eye, and the antimuscarinics are also useful in treating specific ocular diseases and for the treatment of patients following iridectomy.

Atropine, scopolamine, cyclopentolate (Cyclogyl, AK-Pentolate, and others) and tropicamide (Mydriacyl, Tropicacyl, and others) are among the antimuscarinic drugs used in ophthalmology. All of these agents are tertiary amines that reach the iris and ciliary body after topical application to the eye. Systemic absorption of these drugs from the conjunctival sac is minimal, but significant absorption and toxicity can occur if the an-timuscarinic drugs come into contact with the nasal and pharyngeal mucosa via the nasolacrimal duct. To mini-mize this possibility, pressure should be applied to the lacrimal sac for a few minutes after topical application of muscarinic blockers.

The mydriatic and cycloplegic actions of atropine and scopolamine can persist for a week after topical ap-plication to the eye. Shorter-acting drugs, such as cy-clopentolate and tropicamide, are now favored for this application because complete recovery of accommoda-tion occurs within 6 to 24 hours and 2 to 6 hours, re-spectively.

Uses in Disorders of the Digestive System

Nonselective antimuscarinic drugs have been employed in the therapy of peptic ulcers  because they can reduce gastric acid secretion; they also have been used as adjunctive therapy in the treatment of ir-ritable bowel syndrome. Antimuscarinic drugs can de-crease the pain associated with postprandial spasm of intestinal smooth muscle by blocking contractile re-sponses to ACh. Some of the agents used for this disor-der have only antimuscarinic activity (e.g., propanthe-line), while other drugs have additional properties that contribute to their antispasmodic action. Dicyclomine (Bentyl) and oxybutynin (Ditropan) at therapeutic con-centrations primarily have a direct smooth muscle re-laxant effect with little antimuscarinic action.

Uses in Urology

Propantheline (Pro-Banthine), oxybutynin, dicyclo-mine, and several other agents have been used for unin-hibited bladder syndrome, bladder spasm, enuresis, and urge incontinence. Tolterodine (Detrol), a nonselective muscarinic antagonist, exhibits functional specificity for blocking muscarinic receptors in the bladder, with fewer side effects than oxybutynin. However, total prevention of involuntary bladder contractions is difficult to achieve. The participation of noncholinergic, nonadren-ergic nerves in bladder contraction may explain this ap-parent resistance to muscarinic blocking agents.

Uses in Respiratory Disorders

For a long time, muscarinic receptor–blocking drugs oc-cupied a major place in the therapy of asthma, but they have been largely displaced by the adrenergic drugs . The problems associated with the use of antimuscarinic alkaloids in respiratory disorders are low therapeutic index and impaired expectoration. The latter is a consequence of their inhibition of mucous se-cretion, ciliary activity, and mucous transport.

Ipratropium bromide (Atrovent), in contrast, is a synthetic muscarinic blocking drug that has gained widespread use in recent years for the treatment of res-piratory disorders. The drug is a quaternary ammonium compound, and it is applied topically to the airways through the use of a metered-dose inhaler. A substantial portion of the dose is swallowed, but absorption from the airways and gastrointestinal tract is negligible and most of the drug is eliminated in the feces. Conse-quently, systemic antimuscarinic effects are not ob-served with ipratropium. Dryness of the mouth, cough, and a bad taste have been reported by some patients, but the drug appears to have no other significant ad-verse effects. Ipratropium does not affect mucociliary transport or the volume and viscosity of sputum.

Clinical studies have demonstrated the effectiveness of ipratropium in chronic obstructive lung disease, for which it is equal or better in effectiveness than β2-adren-ergic agonists. Maximum bronchodilator responses to ipratropium develop in 1.5 to 2 hours. Consequently, it would be less suitable than a rapidly acting β-adrenergic agonist in emergencies. Ipratropium is less effective than the β2-receptor agonists in asthma, but it may be useful when combined with other bronchodilators.

Uses in Parkinsonism

Antimuscarinic agents can have beneficial effects in the treatment of parkinsonism, since there is an appar-ent excess of cholinergic activity in the striatum of pa-tients suffering from this disorder. Although therapy of Parkinson’s disease is directed toward replacement of the dopaminergic deficiency rather than blocking the cholinergic excess, antimuscarinics are sometimes employed for mild cases and in combination with other agents (e.g., levodopa) for treatment of ad-vanced cases. Side effects due to peripheral muscarinic blockade are common, and CNS side effects (e.g., con-fusion and hallucinations) can occasionally limit their use.

Uses in Motion Sickness

Scopolamine is useful for prevention of motion sick-ness when the motion is very stressful and of short du-ration. A transdermal preparation (Transderm-Scop) with a 72-hour duration of action has been marketed for this purpose. Blockade of cholinergic sites in the vestibular nuclei and reticular formation may account for the effectiveness of this agent. When the motion is less stressful and lasts longer, the antihistamines (H1-antagonists) are probably preferable to the antimus- carinic drugs, especially for the prophylactic treatment of motion sickness.

Uses as Antidotes for Cholinomimetic Poisoning

Atropine is used as an antidote in poisoning by an over-dose of a cholinesterase inhibitor . It also is used in cases of poisoning from species of mush-room that contain high concentrations of muscarine and related alkaloids (e.g., Clitocybe dealbata).

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