SWEAT GLANDS AND TEMPERATURE
Small doses of atropine or scopolamine inhibit the activity of sweat glands innervated by sympa-thetic cholinergic fibers, making the skin hot and dry. After large doses or at high environmental temperatures, sweating may be sufficiently depressed to raise the body temperature.
Pharmacologic Properties: The Quaternary Derivatives Ipratropium
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GENITOURINARY TRACT
Overactive urinary bladder disease can be successfully treated with muscarinic antagonists, prima-rily tolterodine and trospium chloride, which lower intravesicular pressure, increase capacity, and reduce the frequency of contractions by antagonizing parasympathetic control of the bladder. Oxybu-tynin is used as a transdermal system (OXYTROL) that delivers 3.9 mg/day and is associated with a lower incidence of side effects than the oral immediate- or extended-release formulations. Tolterodine is metabolized by CYP2D6 to a 5-hydroxymethyl metabolite; since this metabolite possesses similar activity to the parent drug, variations in CYP2D6 levels do not affect the duration of drug action. Tro-spium is as effective as oxybutynin, with better tolerability. Solifenacin is newly approved for overac-tive bladder with a favorable efficacy: side effect ratio. Stress urinary incontinence has been treated with some success with duloxetine (YENTREVE), which acts centrally to influence 5-HT and NE levels.
GASTROINTESTINAL TRACT In the management of acid-peptic disease, antisecretory doses of muscarinic antagonists produce limiting side effects (Table 7–2) and, consequently, poor patient compliance. Pirenzepine has selectivity for M1over M2and M3receptors. However, piren-zepine’s affinities for M1and M4receptors are comparable, so it does not possess total M1selectivity.
Telenzepineis an analog of pirenzepine that has higher potency and similar selectivity for M1muscarinic receptors. Both drugs are used in the treatment of acid-peptic disease in Europe, Japan, and Canada, but not currently in the U.S. At therapeutic doses of pirenzepine, the incidence of dry mouth, blurred vision, and central muscarinic disturbances are relatively low. Central effects are not seen because of the drug’s limited penetration into the CNS. Pirenzepine’s relative selectivity for M1receptors is a marked improvement over atropine. Pirenzepine (100–150 mg/day) produces about the same rate of healing of duodenal and gastric ulcers as the H2antagonists cimetidine or ran-itidine. Side effects necessitate drug withdrawal in <1% of patients. H2-receptor antagonists and proton pump inhibitors generally are drugs of choice to reduce gastric acid secretion (see Chapter 36).
The belladonna alkaloids and synthetic substitutes are very effective in reducing excessive salivation, such as drug-induced salivation and that associated with heavy-metal poisoning and parkinsonism.
The belladonna alkaloids (atropine, belladonna tincture, l-hyoscyamine sulfate [ANASPAZ,LEVSIN, others], and scopolamine), and combinations with sedatives (e.g., phenobarbital [DONNATAL, others]
or butabarbital [BUTIBEL]), antianxiety agents (e.g., chlordiazepoxide [LIBRAX, others], or ergotamine [BELLAMINE]) also have been used in a wide variety of conditions of irritable bowel and increased tone (spasticity) or motility of the GI tract. Pharmacotherapy of inflammatory bowel disease is discussed in Chapter 38. Therapy of disorders of bowel motility and water flux are discussed in Chapter 37.
USES IN OPHTHALMOLOGY
Effects limited to the eye are obtained by local administration of muscarinic receptor antagonists to produce mydriasis and cycloplegia. Cycloplegia is not attainable without mydriasis and requires higher concentrations or more prolonged application of a given agent. In instances in which complete cycloplegia is required, more effective agents such as atropine or scopolamine are preferred to drugs such as cyclopentolate and tropicamide. Homatropine hydrobromide (ISOPTO HOMATROPINE, others), a semisynthetic derivative of atropine (Figure 7–2) cyclopentolate hydrochloride (CYCLOGYL, others), and tropicamide (MYDRIACYL, others) are preferred to topical atropine or scopolamine because of their shorter duration of action (see Chapter 63).
CARDIOVASCULAR SYSTEM
The cardiovascular effects of muscarinic receptor antagonists are of limited clinical application.
Atropine may be considered in the initial treatment of patients with acute myocardial infarction in whom excessive vagal tone causes sinus or nodal bradycardia. Dosing must be judicious; doses that are too low can cause a paradoxical bradycardia; excessive doses will cause tachycardia that may extend the infarct by increasing O2demand. Atropine occasionally is useful in reducing the severe bradycardia and syncope associated with a hyperactive carotid sinus reflex. Atropine will protect the SA and AV nodes from the effects of excessive ACh in instances of poisoning with anti-cholinesterase pesticides.
CENTRAL NERVOUS SYSTEM
Certain muscarinic antagonists are effective against motion sickness. They should be given pro-phylactically; they are much less effective after severe nausea or vomiting has developed. Scopo-lamine is the most effective prophylactic agent for short (4–6 hours) exposures to severe motion, and probably for exposures of up to several days. A transdermal preparation of scopolamine (TRANSDERM SCOP) is highly effective when used prophylactically. Scopolamine, incorporated into a multilayered adhesive unit, is applied to the postauricular mastoid region, where transdermal
absorption is especially efficient, and over a period of about 72 hours, ∼0.5 mg of scopolamine is delivered. Dry mouth is common, drowsiness is not infrequent, and blurred vision occurs in some individuals. Mydriasis and cycloplegia can occur by inadvertent transfer of the drug to the eye from the fingers after handling the patch. Rare but severe psychotic episodes have been reported.
Benztropine mesylate (COGENTIN, others), biperiden (AKINETON),procyclidine (KEMADRIN), and trihexyphenidyl hydrochloride (ARTANE, others) are tertiary-amine muscarinic receptor antago-nists (together with the ethanolamine antihistamine diphenhydramine [BENADRYL, others]) that gain access to the CNS and can therefore be used when anticholinergics are indicated to treat parkinsonism and the extrapyramidal side effects of antipsychotic drugs (see Chapter 20).
USES IN ANESTHESIA
Atropine commonly is given to block responses to vagal reflexes induced by surgical manipulation of visceral organs. Atropine or glycopyrrolate is used with neostigmine to block its parasympathomimetic effects when the latter agent is used to reverse skeletal muscle relaxation after surgery (see Chapter 9).
ANTICHOLINESTERASE POISONING
The use of atropine in large doses for the treatment of poisoning by anticholinesterase organophos-phorus insecticides is discussed in Chapter 8. Atropine also may be used to antagonize the parasympathomimetic effects of pyridostigmine or other anticholinesterase agents administered in the treatment of myasthenia gravis.
OTHER MUSCARINIC ANTAGONISTS METHSCOPOLAMINE
Methscopolamine bromide (PAMINE), a quaternary ammonium derivative of scopolamine, lacks the central actions of scopolamine and is used chiefly in GI diseases. It is less potent than atropine and is poorly absorbed; however, its action is more prolonged, the usual oral dose (2.5 mg) acting for 6–8 hours.
HOMATROPINE METHYLBROMIDE
Homatropine methylbromide is the quaternary derivative of homatropine. It is less potent than atropine in antimuscarinic activity, but it is four times more potent as a ganglionic blocking agent.
It is available in combination with hydrocodone as an antitussive combination (HYCODAN) and has been used for relief of GI spasms and as an adjunct in peptic ulcer disease.
GLYCOPYRROLATE
Glycopyrrolate (ROBINUL, others) is employed orally to inhibit GI motility and is used parenterally to block the effects of vagal stimulation during anesthesia and surgery.
FIGURE 7–2 Muscarinic Antagonists: belladonna alkaloids and quaternary analogs. The blue C identifies an asymmetric carbon atom.
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MISCELLANEOUS ANTISPASMODICS
Dicyclomine hydrochloride (BENTYL, others), flavoxate hydrochloride (URISPAS, others), oxybu-tynin chloride (DITROPAN, others), and tolterodine tartrate (DETROL) are tertiary amines; trospium chloride (SANCTURA) is a quaternary amine; in therapeutic doses they decrease spasm of the GI tract, biliary tract, ureter, and uterus.
MEPENZOLATE BROMIDE
Mepenzolate bromide (CENTIL), a quaternary amine, has peripheral actions similar to those of atropine. It is indicated for adjunctive therapy of peptic ulcer disease and has been used as a GI antispasmodic.
PROPANTHELINE
Propantheline bromide (PRO-BANTHINE) is a widely used synthetic nonselective muscarinic recep-tor antagonist. High doses produce the symptoms of ganglionic blockade; toxic doses block the skeletal neuromuscular junction. Its duration of action is comparable to that of atropine.
POISONING BY MUSCARINIC RECEPTOR ANTAGONISTS AND OTHER DRUGS WITH ANTICHOLINERGIC PROPERTIES
The deliberate or accidental ingestion of natural belladonna alkaloids is a major cause of poison-ings. Many histamine H1-receptor antagonists, phenothiazines, and tricyclic antidepressants also block muscarinic receptors, and in sufficient dosage, produce syndromes that include features of atropine intoxication.
Among the tricyclic antidepressants, protriptyline and amitriptyline are potent muscarinic receptor antagonists, with an affinity for the receptor that is approximately one-tenth that reported for atropine. Since these drugs are administered in therapeutic doses considerably higher than the effective dose of atropine, antimuscarinic effects often are observed clinically (see Chapter 17), and overdose with suicidal intent is a danger in the population using antidepressants. Fortunately, most of the newer antidepressants and SSRIs are far less anticholinergic. In contrast, the newer antipsy-chotic drugs (“atypical”, characterized by their low propensity for inducing extrapyramidal side effects) include agents that are potent muscarinic receptor antagonists (e.g., clozapine, olanzapine).
Accordingly, dry mouth is a prominent side effect of these drugs (a paradoxical side effect of cloza-pine is increased salivation and drooling, possibly the result of its partial agonist properties).
Infants and young children are especially susceptible to the toxic effects of muscarinic antago-nists. Indeed, cases of intoxication in children have resulted from conjunctival instillation for oph-thalmic purposes. Systemic absorption occurs either from the nasal mucosa after the drug has traversed the nasolacrimal duct or from the GI tract if the drug is swallowed. Poisoning with diphe-noxylate-atropine (LOMOTIL, others), used to treat diarrhea, has been extensively reported in the pediatric literature. Transdermal preparations of scopolamine used for motion sickness may cause toxic psychoses, especially in children and in the elderly. Serious intoxication may occur in chil-dren who ingest berries or seeds containing belladonna alkaloids. Poisoning from ingestion and smoking of jimson weed, or thorn apple, is seen with some frequency.
Table 7–2 shows the oral doses of atropine causing undesirable responses or symptoms of over-dosage. Measures to limit intestinal absorption should be initiated without delay if the poison has been taken orally (see Chapter 64). For symptomatic treatment, intravenous physostigmine rap-idly abolishes the delirium and coma caused by large doses of atropine, but carries some risk of overdose in mild atropine intoxication. Since physostigmine is metabolized rapidly, the patient may again lapse into coma within 1–2 hours, and repeated doses may be needed (see Chapter 8).
If marked excitement is present and more specific treatment is not available, a benzodiazepine is the most suitable agent for sedation and for control of convulsions. Phenothiazines or agents with antimuscarinic activity should not be used, because their antimuscarinic action is likely to intensify toxicity. Support of respiration and control of hyperthermia may be necessary.
For a complete Bibliographical listing see Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th ed., or Goodman & Gilman Online at www.accessmedicine.com.
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