Clinical Pharmacology of the Cholinomimetics

CLINICAL PHARMACOLOGY OF THE CHOLINOMIMETICS

The major therapeutic uses of the cholinomimetics are to treat diseases of the eye (glaucoma, accommodative esotropia), the gas-trointestinal and urinary tracts (postoperative atony, neurogenic bladder), and the neuromuscular junction (myasthenia gravis, curare-induced neuromuscular paralysis), and to treat patients with Alzheimer’s disease. Cholinesterase inhibitors are occasion-ally used in the treatment of atropine overdosage and, very rarely, in the therapy of certain atrial arrhythmias.

Clinical Uses

A. The Eye

Glaucoma is a disease characterized by increased intraocular pres-sure. Muscarinic stimulants and cholinesterase inhibitors reduce intraocular pressure by causing contraction of the ciliary body so as to facilitate outflow of aqueous humor and perhaps also by dimin-ishing the rate of its secretion (see Figure 6–9). In the past, glau-coma was treated with either direct agonists (pilocarpine, methacholine, carbachol) or cholinesterase inhibitors (physostig-mine, demecarium, echothiophate, isoflurophate). For chronic glaucoma, these drugs have been largely replaced by topical blockers and prostaglandin derivatives.

Acute angle-closure glaucoma is a medical emergency that is frequently treated initially with drugs but usually requires surgery for permanent correction. Initial therapy often consists of a com-bination of a direct muscarinic agonist and a cholinesterase inhibitor (eg, pilocarpine plus physostigmine) as well as other drugs. Once the intraocular pressure is controlled and the danger of vision loss is diminished, the patient can be prepared for correc-tive surgery (iridectomy). Open-angle glaucoma and some cases of secondary glaucoma are chronic diseases that are not amenable to traditional surgical correction, although newer laser techniques appear to be useful. Other treatments for glaucoma are described in the Box, Treatment of Glaucoma.

Accommodative esotropia (strabismus caused by hyperme-tropic accommodative error) in young children is sometimes diagnosed and treated with cholinomimetic agonists. Dosage is similar to or higher than that used for glaucoma.

B. Gastrointestinal and Urinary Tracts

In clinical disorders that involve depression of smooth muscle activity without obstruction, cholinomimetic drugs with direct or indirect muscarinic effects may be helpful. These disorders include postoperative ileus (atony or paralysis of the stomach or bowel following surgical manipulation) and congenital megacolon. Urinary retention may occur postoperatively or postpartum or may be secondary to spinal cord injury or disease (neurogenic bladder). Cholinomimetics are also sometimes used to increase the tone of the lower esophageal sphincter in patients with reflux esophagitis. Of the choline esters, bethanechol is the most widely used for these disorders. For gastrointestinal problems, it is usually administered orally in a dose of 10–25 mg three or four timesdaily. In patients with urinary retention, bethanechol can be given subcutaneously in a dose of 5 mg and repeated in 30 minutes if necessary. Of the cholinesterase inhibitors, neostigmine is the most widely used for these applications. For paralytic ileus or atony of the urinary bladder, neostigmine can be given subcutane-ously in a dose of 0.5–1 mg. If patients are able to take the drug by mouth, neostigmine can be given orally in a dose of 15 mg. In all of these situations, the clinician must be certain that there is no mechanical obstruction to outflow before using the cholinomi-metic. Otherwise, the drug may exacerbate the problem and may even cause perforation as a result of increased pressure.

Pilocarpine has long been used to increase salivary secretion. Cevimeline, a quinuclidine derivative of acetylcholine, is a new direct-acting muscarinic agonist used for the treatment of dry mouth associated with Sjögren’s syndrome and that caused by radiation damage of the salivary glands.

C. Neuromuscular Junction

Myasthenia gravis is an autoimmune disease affecting skeletal muscle neuromuscular junctions. In this disease, antibodies are produced against the main immunogenic region found on α1 subunits of the nicotinic receptor-channel complex. Antibodies are detected in 85% of myasthenic patients. The antibodies reduce nicotinic receptor function by (1) cross-linking receptors, a pro-cess that stimulates their internalization and degradation; (2) caus-ing lysis of the postsynaptic membrane; and (3) binding to the nicotinic receptor and inhibiting function. Frequent findings are ptosis, diplopia, difficulty in speaking and swallowing, and extremity weakness. Severe disease may affect all the muscles, including those necessary for respiration. The disease resembles the neuromuscular paralysis produced by d-tubocurarine and similar nondepolarizing neuromuscular blocking drugs . Patients with myasthenia are exquisitely sensitive to the action of curariform drugs and other drugs that interfere with neuromuscular transmission, eg, aminoglycoside antibiotics.

Cholinesterase inhibitors—but not direct-acting acetylcholine receptor agonists—are extremely valuable as therapy for myasthe-nia. Patients with ocular myasthenia may be treated with cholin-esterase inhibitors alone (Figure 7–4B). Patients having more widespread muscle weakness are also treated with immunosup-pressant drugs (steroids, cyclosporine, and azathioprine). In some patients, the thymus gland is removed; very severely affected patients may benefit from administration of immunoglobulins and from plasmapheresis.

Edrophonium is sometimes used as a diagnostic test for myasthe-nia. A 2 mg dose is injected intravenously after baseline muscle strength has been measured. If no reaction occurs after 45 seconds, an additional 8 mg may be injected. If the patient has myasthenia gravis, an improvement in muscle strength that lasts about 5 minutes can usually be observed.

Clinical situations in which severe myasthenia (myasthenic crisis) must be distinguished from excessive drug therapy (cholin-ergic crisis) usually occur in very ill myasthenic patients and must be managed in hospital with adequate emergency support systems (eg, mechanical ventilators) available. Edrophonium can be used to assess the adequacy of treatment with the longer-acting cholinesterase inhibitors usually prescribed in patients with myas-thenia gravis. If excessive amounts of cholinesterase inhibitor have been used, patients may become paradoxically weak because of nicotinic depolarizing blockade of the motor end plate. These patients may also exhibit symptoms of excessive stimulation of muscarinic receptors (abdominal cramps, diarrhea, increased sali-vation, excessive bronchial secretions, miosis, bradycardia). Small doses of edrophonium (1–2 mg intravenously) will produce no relief or even worsen weakness if the patient is receiving excessive cholinesterase inhibitor therapy. On the other hand, if the patient improves with edrophonium, an increase in cholinesterase inhibi-tor dosage may be indicated.

Long-term therapy for myasthenia gravis is usually accom-plished with pyridostigmine; neostigmine or ambenonium are alternatives. The doses are titrated to optimum levels based on changes in muscle strength. These drugs are relatively short-acting and therefore require frequent dosing (every 6 hours for pyri-dostigmine and ambenonium and every 4 hours for neostigmine; Table 7–4). Sustained-release preparations are available but should be used only at night and if needed. Longer-acting cholinesterase inhibitors such as the organophosphate agents are not used, because the dose requirement in this disease changes too rapidly to permit smooth control of symptoms with long-acting drugs.

If muscarinic effects of such therapy are prominent, they can be controlled by the administration of antimuscarinic drugs such as atropine. Frequently, tolerance to the muscarinic effects of the cholin-esterase inhibitors develops, so atropine treatment is not required.

Neuromuscular blockade is frequently produced as an adjunct to surgical anesthesia, using nondepolarizing neuromuscular relaxants such as pancuronium and newer agents . After surgery, it is usually desirable to reverse this pharmacologic paralysis promptly. This can be easily accomplished with cholinesterase inhibitors; neostigmine and edrophonium are the drugs of choice. They are given intravenously or intramuscularly for prompt effect.

D. Heart

The short-acting cholinesterase inhibitor edrophonium was used to treat supraventricular tachyarrhythmias, particularly paroxys-mal supraventricular tachycardia. In this application, edropho-nium has been replaced by newer drugs with different mechanisms (adenosine and the calcium channel blockers verapamil and dilti-azem).

E. Antimuscarinic Drug Intoxication

Atropine intoxication is potentially lethal in children  and may cause prolonged severe behavioral disturbances and arrhythmias in adults. The tricyclic antidepressants, when taken in overdosage (often with suicidal intent), also cause severe muscar-inic blockade . The muscarinic receptor blockade produced by all these agents is competitive in nature and can be overcome by increasing the amount of endogenous acetylcholine at the neuroeffector junctions. Theoretically, a cholinesterase inhibi-tor could be used to reverse these effects. Physostigmine has been used for this application because it enters the central nervous sys-tem and reverses the central as well as the peripheral signs ofmuscarinic blockade. However, as described below, physostigmine itself can produce dangerous central nervous system effects, and such therapy is therefore used only in patients with dangerous elevation of body temperature or very rapid supraventricular tachycardia.

F. Central Nervous System

Tacrine is a drug with anticholinesterase and other cholinomi-metic actions that has been used for the treatment of mild to moderate Alzheimer’s disease. Tacrine’s efficacy is modest, and hepatic toxicity is significant. Donepezil, galantamine, and rivastigmine are newer, more selective acetylcholinesterase inhibi-tors that appear to have the same modest clinical benefit as tacrine in treatment of cognitive dysfunction in Alzheimer’s patients. Donepezil may be given once daily because of its long half-life, and it lacks the hepatotoxic effect of tacrine. However, no trials comparing these newer drugs with tacrine have been reported.

Toxicity

The toxic potential of the cholinoceptor stimulants varies mark-edly depending on their absorption, access to the central nervous system, and metabolism.

A. Direct-Acting Muscarinic Stimulants

Drugs such as pilocarpine and the choline esters cause predictable signs of muscarinic excess when given in overdosage. These effects include nausea, vomiting, diarrhea, urinary urgency, salivation, sweating, cutaneous vasodilation, and bronchial constriction. The effects are all blocked competitively by atropine and its congeners.

Certain mushrooms, especially those of the genus Inocybe, contain muscarinic alkaloids. Ingestion of these mushrooms causes typical signs of muscarinic excess within 15–30 minutes. These effects can be very uncomfortable but are rarely fatal. Treatment is with atropine, 1–2 mg parenterally. (Amanitamuscaria, the first source of muscarine, contains very low concen-trations of the alkaloid.)

B. Direct-Acting Nicotinic Stimulants

Nicotine itself is the only common cause of this type of poisoning. The acute toxicity of the alkaloid is well defined but much less impor-tant than the chronic effects associated with smoking. In addition to tobacco products, nicotine is also used in insecticides.

1. Acute toxicity—The fatal dose of nicotine is approximatelymg, or 1 drop of the pure liquid. This is the amount of nicotine in two regular cigarettes. Fortunately, most of the nicotine in ciga-rettes is destroyed by burning or escapes via the “sidestream” smoke. Ingestion of nicotine insecticides or of tobacco by infants and children is usually followed by vomiting, limiting the amount of the alkaloid absorbed.

The toxic effects of a large dose of nicotine are simple extensions of the effects described previously. The most dangerous are (1) central stimulant actions, which cause convulsions and may progress to coma and respiratory arrest; (2) skeletal muscle end plate depolariza-tion, which may lead to depolarization blockade and respiratory paralysis; and (3) hypertension and cardiac arrhythmias.

Treatment of acute nicotine poisoning is largely symptom-directed. Muscarinic excess resulting from parasympathetic gan-glion stimulation can be controlled with atropine. Central stimulation is usually treated with parenteral anticonvulsants such as diazepam. Neuromuscular blockade is not responsive to phar-macologic treatment and may require mechanical ventilation.

Fortunately, nicotine is metabolized and excreted relatively rapidly. Patients who survive the first 4 hours usually recover com-pletely if hypoxia and brain damage have not occurred.

2. Chronic nicotine toxicity—The health costs of tobaccosmoking to the smoker and its socioeconomic costs to the general public are still incompletely understood. However, the 1979 Surgeon General’s Report on Health Promotion and Disease Prevention stated that “cigarette smoking is clearly the largest single prevent-able cause of illness and premature death in the United States.” This statement has been supported by numerous subsequent stud-ies. Unfortunately, the fact that the most important of the tobac-co-associated diseases are delayed in onset reduces the health incentive to stop smoking.

Clearly, the addictive power of cigarettes is directly related to their nicotine content. It is not known to what extent nicotine per se contributes to the other well-documented adverse effects of chronic tobacco use. It appears highly probable that nicotine contributes to the increased risk of vascular disease and sudden coronary death associated with smoking. Also, nicotine probably contributes to the high incidence of ulcer recurrences in smokers with peptic ulcer.

There are several approaches to help patients stop smoking. One approach is replacement therapy with nicotine in the form of gum, transdermal patch, nasal spray, or inhaler. All these forms have low abuse potential and are effective in patients motivated to stop smok-ing. Their action derives from slow absorption of nicotine that occupies α4β2 receptors in the central nervous system and reduces the desire to smoke and the pleasurable feelings of smoking.

Another quite effective agent for smoking cessation is vareni-cline, a synthetic drug with partial agonist action atα4β2 nicotinicreceptors. Varenicline also has antagonist properties that persist because of its long half-life; this prevents the stimulant effect of nico-tine at presynaptic α4β2 receptors that causes release of dopamine. However, its use is limited by nausea and insomnia and also by exac-erbation of psychiatric illnesses, including anxiety and depression. Suicidal ideation has also been reported in some patients; this is cur-rently being evaluated. The efficacy of varenicline is superior to that of bupropion, an antidepressant . Some of bupro-pion’s efficacy in smoking cessation therapy stems from its noncom-petitive antagonism  of nicotinic receptors where it displays some selectivity among neuronal subtypes.

C. Cholinesterase Inhibitors

The acute toxic effects of the cholinesterase inhibitors, like those of the direct-acting agents, are direct extensions of their pharma-cologic actions. The major source of such intoxications is pesticide use in agriculture and in the home. Approximately 100 organo-phosphate and 20 carbamate cholinesterase inhibitors are available in pesticides and veterinary vermifuges used in the USA. Cholinesterase inhibitors used in agriculture can cause slowly or rapidly developing symptoms, as described in the Case Study, which persist for days. The cholinesterase inhibitors used as chemical warfare agents (soman, sarin, VX) induce effects rapidly because of the large concentrations present.

Acute intoxication must be recognized and treated promptly in patients with heavy exposure. The dominant initial signs are those of muscarinic excess: miosis, salivation, sweating, bronchial constriction, vomiting, and diarrhea. Central nervous system involvement (cognitive disturbances, convulsions, and coma) usually follows rapidly, accompanied by peripheral nicotinic effects, especially depolarizing neuromuscular blockade. Therapy always includes (1) maintenance of vital signs—respiration in particular may be impaired; (2) decontamination to prevent fur-ther absorption—this may require removal of all clothing and washing of the skin in cases of exposure to dusts and sprays; andatropine parenterally in large doses, given as often as required to control signs of muscarinic excess.

Preventive therapy for cholinesterase inhibitors used as chem-ical warfare agents has been developed to protect soldiers and civilians. Personnel are given autoinjection syringes containing a carbamate, pyridostigmine, and atropine. Protection is provided by pyridostigmine, which, by prior binding to the enzyme, impedes binding of organophosphate agents and thereby prevents prolonged inhibition of cholinesterase. The protection is limited to the peripheral nervous system because pyridostigmine does not readily enter the central nervous system. Enzyme inhibition by pyridostigmine dissipates within hours (Table 7–4), a duration of time that allows clearance of the organophosphate agent from the body.

Chronic exposure to certain organophosphate compounds, including some organophosphate cholinesterase inhibitors, causes delayed neuropathy associated with demyelination of axons. Triorthocresyl phosphate, an additive in lubricating oils, is theprototype agent of this class. The effects are not caused by cholin-esterase inhibition but rather by neuropathy target esterase (NTE) inhibition whose symptoms (weakness of upper and lower extrem-ities, unsteady gait) appear 1–2 weeks after exposure. Another nerve toxicity called intermediate syndrome occurs 1–4 days after exposure to organophosphate insecticides. This syndrome is also characterized by muscle weakness; its origin is not known but it appears to be related to cholinesterase inhibition.