VA Class:AU350

AHFS Class:

• Antimuscarinics/Antispasmodics 12:08.08

Associated Monographs

• Aclidinium

• Atropine

• Belladonna

• Clidinium

• Dicyclomine

• Glycopyrrolate

• Hyoscyamine

• Ipratropium

• Methscopolamine

• Scopolamine

• Tiotropium

Antimuscarinics competitively inhibit the muscarinic effects of acetylcholine.

Antimuscarinics have been used as adjunctive therapy in the treatment of peptic ulcer disease and irritable bowel syndrome. The drugs also have been used in the treatment of a variety of other conditions (e.g., diarrhea, hyperhidrosis, overactive bladder) in which antimuscarinic effects might produce potential therapeutic benefit. There is a general lack of information from well-controlled studies to support their use in these conditions. In addition, adverse effects of antimuscarinics often limit or preclude their use and they generally have been replaced by other more effective and/or less toxic therapies. Glycopyrrolate is used via oral inhalation or nebulization for the long-term maintenance treatment of airflow obstruction.392,393,395,396,397 Ipratropium is used via oral inhalation or nebulization for the treatment and prevention of bronchospasm. Ipratropium also is used as a nasal spray for the symptomatic relief of rhinorrhea associated with allergic or nonallergic perennial rhinitis or the common cold. Tolterodine tartrate is used in the treatment of overactive bladder to manage symptoms such as urinary frequency, urgency, and urge incontinence.354

Some antimuscarinics are or have been commercially available in combination with other antimuscarinics or with barbiturates, phenothiazines, or benzodiazepines or other anxiolytics. Some clinicians believe that sedatives and/or anxiolytic agents may have a beneficial supportive role in patients with irritable bowel syndrome who respond to sedatives or in some patients with peptic ulcer disease. However, there are no data from well-controlled studies that support the superiority of currently available fixed-ratio combination preparations over single-ingredient preparations. In addition, fixed-ratio combination preparations do not permit individual titration of dosages. Many such preparations no longer are commercially available.

Peptic Ulcer Disease and GI Hypersecretory States

Some antimuscarinics (e.g., atropine, belladonna, clidinium, glycopyrrolate, methscopolamine, propantheline) have been used as adjunctive therapy for peptic ulcer disease. However, there are no conclusive data from well-controlled studies which indicate that, in usually recommended dosages, antimuscarinics aid in the healing, decrease the rate of recurrence, or prevent complications of peptic ulcers. The efficacy of antimuscarinics for the treatment of gastric ulcers has also been questioned by many clinicians. In addition, in patients with gastric ulcer, antimuscarinics may delay gastric emptying and result in antral stasis.

When used as adjunctive therapy in the treatment of peptic ulcer disease, none of the synthetic or semisynthetic antimuscarinics has been shown to be therapeutically superior to effective doses of any of the naturally occurring alkaloids (i.e., atropine, belladonna). Claims of specificity, increased efficacy, or improved tolerance reported for specific antimuscarinics usually arise from uncontrolled studies, use of ineffective dosages, or complete inactivity of the drug. Although minor differences in receptor-selectivity (organ-specificity) among the various drugs have been reported, resultant differences in adverse effects do not generally appear to be clinically important enough to warrant the preferential use of any one drug, and the cost of the drug to the patient may be an important consideration. If an antimuscarinic is indicated, some clinicians recommend that belladonna tincture be used, since it usually is the most economical and easily titrated of the currently available antimuscarinics.

Current epidemiologic and clinical evidence supports a strong association between gastric infection with Helicobacter pylori and the pathogenesis of duodenal and gastric ulcers; H. pylori infection usually is treated with a multiple-drug regimen that includes 2 or 3 anti-infectives (e.g., clarithromycin, amoxicillin, metronidazole, tetracycline or doxycycline, levofloxacin) and a proton-pump inhibitor (e.g., omeprazole) with or without a bismuth salt.399 Antimuscarinics are not included in American College of Gastroenterology (ACG) guidelines for the management of peptic ulcer disease and H. pylori infection.399

Antimuscarinics have been administered before meals to prolong and potentiate the effects of postprandial antacid therapy. However, controlled studies have failed to demonstrate a substantial difference in gastric pH when combined antimuscarinic and antacid therapy was compared to antacid therapy alone. Some clinicians use an antimuscarinic in conjunction with a histamine H₂-receptor antagonist to potentiate the inhibitory effects on food-stimulated gastric acid secretion. A regimen that included antacids, an antimuscarinic, and a histamine H₂-receptor antagonist has also been used effectively to reduce gastric acidity.

Antimuscarinics (except those that act mainly as antispasmodics) have been used in the treatment of GI hypersecretory states (e.g., Zollinger-Ellison syndrome) in conjunction with a histamine H₂-receptor antagonist. However, other therapy (e.g., surgical resection of the gastrinoma, high-dosage proton-pump inhibitor therapy) currently is recommended.388 Antimuscarinics appear to prolong and/or augment the inhibitory effects of histamine H₂-receptor antagonists on gastrin- and pentagastrin-induced gastric acid secretion in patients with the Zollinger-Ellison syndrome. In one study in patients with Zollinger-Ellison syndrome, 20 mg of oral isopropamide iodide (no longer commercially available in the US) given in conjunction with 600 mg of oral cimetidine hydrochloride reduced the rate of gastric acid secretion to less than 10% of the pretreatment basal secretion rate. In another study in patients with Zollinger-Ellison syndrome, propantheline 30 mg decreased gastric emptying and increased intragastric volume, but was ineffective in controlling gastric acid output or concentrations; when used in conjunction with cimetidine, oral combination therapy (propantheline 30 mg and cimetidine 300 mg) was effective in a patient who did not respond to cimetidine alone. In patients with the Zollinger-Ellison syndrome, a histamine H₂-receptor antagonist used in conjunction with an antimuscarinic may be more effective than an H₂-antagonist alone, especially in patients who fail to respond to usual dosages of an H₂-antagonist. Antimuscarinics should not be used alone to treat Zollinger-Ellison syndrome, since they may delay gastric emptying and produce gastric retention.

Irritable Bowel Syndrome

Antimuscarinics, including those that act principally as antispasmodics, have been used in the treatment of irritable bowel syndrome; however, supportive evidence for the efficacy of these drugs is minimal. Many antimuscarinics in combination with phenobarbital were previously considered possibly or probably effective for the treatment of irritable bowel syndrome, but attempts to substantiate these claims of efficacy have generally failed and these combinations are generally considered as lacking substantial evidence of efficacy in the treatment of this condition.

The majority of patients with irritable bowel syndrome do not require drug therapy; placebo produces a satisfactory response in 35% or more of those treated. If used at all in patients with irritable bowel syndrome, antimuscarinics should usually be reserved for patients failing to respond to other therapies (e.g., diet, placebo, sedation, counseling, amelioration of environmental factors). However, antimuscarinics may provide symptomatic relief in patients with spastic colon in whom pain and/or constipation are major symptoms.

Cardiac Disorders

Atropine sulfate is used in advanced cardiovascular life support (ACLS) for the management of symptomatic bradycardia and is considered the initial drug of choice in adults with unstable bradycardia (e.g., that which is accompanied by altered mental status, cardiac ischemia, acute heart failure, hypotension, or other signs of shock).400,401,403 In pediatric advanced life support (PALS), atropine is used for bradycardia secondary to increased vagal activity or primary atrioventricular (AV) block.403 Atropine was previously included in ACLS guidelines for the treatment of asystole or pulseless electrical activity (PEA) during cardiopulmonary resuscitation (CPR);106 however, routine use of the drug during cardiac arrest is no longer recommended because of the lack of evidence demonstrating clinical benefit.400,401,402,403 (See Uses: Advanced Cardiovascular Life Support and Bradyarrhythmias, in Atropine 12:08.08.)

Because atropine can increase conduction through the AV node, the drug also may be beneficial in the management of AV nodal block.401,403 However, atropine is not likely to be effective in patients with type II second-degree AV block or third-degree AV block, including third-degree AV block accompanied by a new wide QRS complex when the conduction block is at or below the His-Purkinje level.401

Atropine's principal cardiac use in patients with myocardial infarction (MI) is for the management of sinus bradycardia. Sinus bradycardia caused by increased vagal tone commonly occurs after ST-segment-elevation MI (STEMI), especially in patients with an inferior infarction.201 However, some data and case reports indicate that atropine may increase ventricular irritability and that increased vagal tone is not necessarily harmful in patients with MI. In addition, uncontrolled atropine-induced tachycardia may increase the size of the infarct. Although some clinicians have questioned the usefulness of atropine in patients with MI, the drug is currently recommended in expert guidelines for the management of symptomatic or hemodynamically unstable sinus bradycardia during an acute MI.201,202 Atropine also has been used for the management of symptomatic type I second- or third-degree AV block in patients with acute MI;202 however, the incidence of abnormal conduction in STEMI patients has decreased considerably in the current reperfusion era.201 Other uses of atropine in the MI setting include treatment of sustained bradycardia and hypotension associated with nitroglycerin use, and treatment of nausea and vomiting associated with morphine use.202

Antimuscarinics, principally atropine, also have been used in the diagnosis of sinus node dysfunction and in the evaluation of coronary artery disease during atrial pacing. Atropine also has been used to assist in the diagnosis of MI in patients with Wolff-Parkinson-White (WPW) syndrome by normalizing the QRS complex and facilitating ECG evaluation of the suspected infarction.

Surgery

Antimuscarinics, particularly atropine, scopolamine, or glycopyrrolate, have been used effectively as preoperative medications. When used preoperatively, these drugs inhibit salivation and excessive secretions of the respiratory tract; however, the current practice of using thiopental (no longer commercially available in the US), halothane, or similar general anesthetics that do not stimulate the production of salivary and tracheobronchial secretions, rather than ether, has reduced the need to control excessive respiratory secretions during surgery. Scopolamine is also used preoperatively in conjunction with analgesics or sedatives to produce tranquilization and amnesia; however, benzodiazepines (e.g., diazepam, lorazepam) appear to produce a more rapid onset of and possibly more marked amnesia than does scopolamine, and benzodiazepines may be preferred by some clinicians as preoperative amnestic agents.

Although atropine and glycopyrrolate have been used prophylactically to prevent acid-aspiration pneumonitis during surgery, preoperative administration of atropine (0.4-0.6 mg IM) or glycopyrrolate (0.2-0.3 mg IM) has not been shown to be effective in increasing gastric pH or reducing gastric fluid volume. Neither the frequency nor the severity of acid-aspiration pneumonitis was reduced in several studies when the drugs were given prophylactically. In addition, by decreasing lower esophageal sphincter tone, antimuscarinics may increase the risk of regurgitation and subsequent aspiration during surgery.

Atropine and glycopyrrolate are used to prevent cholinergic effects during surgery, such as cardiac arrhythmias, hypotension, and bradycardia, which may result from traction on viscera (with resultant vagal stimulation), stimulation of the carotid sinus, or administration of drugs (e.g., succinylcholine).

Atropine, glycopyrrolate, and hyoscyamine are used concurrently with anticholinesterase agents (e.g., neostigmine, pyridostigmine) to block the muscarinic effects of these latter agents when they are used after surgery to reverse the effects of neuromuscular blocking agents. Atropine, glycopyrrolate, and hyoscyamine do not block the effects of anticholinesterase agents at the neuromuscular junction.

The transdermal scopolamine system is used for the prevention of nausea and vomiting associated with recovery from anesthesia and surgery. Although results of some clinical studies have indicated that the transdermal scopolamine system was more effective than placebo in preventing postoperative nausea and vomiting, results of other clinical studies have failed to demonstrate any benefit.368,369,370,371,372,373 Some clinicians believe that the transdermal scopolamine system has some efficacy in the prevention of postoperative nausea and vomiting, particularly when it is applied several hours prior to surgery.372,373

Genitourinary Tract Disorders

In patients with uninhibited or reflex neurogenic bladder, atropine, oxybutynin (see Oxybutynin Chloride 86:12), and propantheline have been effective in reducing the amplitude and frequency of uninhibited contractions of the bladder and in increasing bladder capacity. In addition, incontinence associated with uninhibited contractions is relieved and the volume of residual urine and the frequency of urination are returned to normal in these patients. The diagnosis of neurogenic bladder should be confirmed by cystometry and other appropriate diagnostic procedures before therapy with an antimuscarinic is initiated. In addition, the patient's response to therapy should be periodically evaluated by cystometry. Appropriate anti-infective therapy should be administered whenever urinary tract infection is present. Antimuscarinics are ineffective in the treatment of nonneurogenic nocturnal or functional enuresis. (See Pharmacology: Genitourinary Effects.)

Tolterodine tartrate is used in the treatment of overactive bladder to manage symptoms such as urinary frequency, urgency, and urge incontinence.354 (See Tolterodine Tartrate 86:12.) The drug is used for the management of symptoms associated with both neurogenic and nonneurogenic overactive bladder.366,367 Oxybutynin chloride is used in the treatment of overactive bladder for the relief of symptoms associated with voiding (e.g., urge urinary incontinence, urgency, frequency, urinary leakage, dysuria).386,387 Analysis of pooled data from comparative studies of 12 weeks' duration using tolterodine tartrate at a dosage of 2 mg twice daily and oxybutynin 5 mg 3 times daily indicated that tolterodine at this dosage was approximately equivalent to oxybutynin in decreasing the mean number of micturitions per 24 hours and the mean number of episodes of incontinence.352,353,356 Both drugs increased the mean volume voided per micturition, although the increase was greater with oxybutynin than with tolterodine.352,353 Some clinicians consider tolterodine to be less effective than older agents used for treatment of overactive bladder (e.g., oxybutynin), although it is better tolerated.355

Oxybutynin also has been reportedly effective in relieving mild to moderate urinary tract discomfort resulting from prostatectomy, radiation therapy, or infection; however, controlled studies to determine the efficacy of this or other antimuscarinics in relieving urinary tract discomfort have not been conducted to date.

Bronchospasm

Antimuscarinics (i.e., atropine, ipratropium) are potent bronchodilators. Atropine sulfate has been used effectively by oral inhalation or in a combined regimen of oral inhalation and IM injection to prevent antigen-, methacholine-, histamine-, or exercise-induced bronchospasm. Certain antimuscarinics (i.e., atropine or ipratropium) administered by oral inhalation have been shown to be effective bronchodilators in the treatment of chronic bronchitis and asthma, and atropine sulfate has been used by oral inhalation for the short-term treatment and prevention of bronchospasm associated with chronic bronchial asthma, bronchitis, and chronic obstructive pulmonary disease (COPD). The bronchodilator effect of orally inhaled atropine is similar to that of orally inhaled isoproterenol and, although its onset is delayed, its effect is more prolonged than that of orally inhaled isoetharine.

Glycopyrrolate is used alone or in fixed combination with other respiratory agents via oral inhalation or nebulization for the long-term maintenance treatment of airflow obstruction associated with COPD, including chronic bronchitis and emphysema.392,393,395,396,397 Ipratropium (a derivative of atropine) is used by oral inhalation for chronic treatment and prevention of bronchospasm associated with COPD, including bronchitis and emphysema. The efficacy of ipratropium in the management of COPD generally has been similar to or greater than that of β-adrenergic agonists (e.g., albuterol, metaproterenol) in comparative studies with oral inhalation or nebulization. Orally inhaled ipratropium does not appear to have substantial effects on sputum viscosity or volume or on mucociliary clearance.

Some clinicians state that repeated oral or parenteral administration of antimuscarinics to patients with chronic lung disease may be hazardous, since these drugs can reduce the volume and fluidity of bronchial secretions, obstruct airflow, and predispose these patients to infection; however, such hazards do not appear to be a substantial problem when the drugs are administered by oral inhalation.

Other Uses

Antimuscarinics have been used in the treatment of GI hypermotility and diarrhea caused by reserpine, guanethidine, or cholinergic stimulation. Although antimuscarinics have been used in the treatment of diarrhea from other causes (e.g., ulcerative colitis, dysentery, shigellosis), they should be used with extreme caution, if at all, in patients with ulcerative colitis or GI infections. (See Cautions: Precautions and Contraindications.)

Antimuscarinics have been used in the management of parkinsonian syndrome and drug-induced extrapyramidal reactions. In general, the maximum therapeutic response attainable with antimuscarinics is in the range of 20-30% symptomatic improvement in 50-80% of parkinsonian patients. Although some antimuscarinics (e.g., trihexyphenidyl) continue to be used as initial therapy in mild cases of parkinsonian syndrome, in patients who do not tolerate other agents, or as adjunctive therapy to other agents, antimuscarinics generally have been replaced with dopaminergic drugs (e.g., levodopa, bromocriptine). Antimuscarinics may be especially useful in the treatment of excessive salivation associated with parkinsonian syndrome.

Parenterally administered antimuscarinics (e.g., atropine 1 mg IV, propantheline 30-60 mg IV or IM) have been used to facilitate hypotonic duodenography or contrast examination of the colon by reducing duodenal or colonic motility and spasm; however, glucagon appears to be more effective and generally is preferred in these examinations. Antimuscarinics also have been used to enhance visualization of esophageal varices during radiographic examinations and enhance visualization of the urinary tract in excretion urography.

Antimuscarinics have been used to decrease gastric and pancreatic secretions in the treatment of acute pancreatitis; however, there is little, if any, evidence that antimuscarinics improve the prognosis of the disease. It has been suggested that supportive measures and intensive care are probably more important determinants of prognosis than pharmacologic treatment.

Topically applied antimuscarinics have been used to inhibit muscarinic-mediated sweating; topical application of propantheline has been used effectively to treat plantar and palmar hyperhidrosis without adverse systemic effects.

Antimuscarinics also have been used effectively as prophylactic therapy in the prevention of motion sickness; of the currently available antimuscarinics, scopolamine appears to be the most effective. (See Scopolamine 12:08.08.)

In patients with myasthenia gravis, antimuscarinics have been used to minimize unwanted muscarinic effects (e.g., diarrhea, excessive salivation) of anticholinesterase agents (e.g., neostigmine). Although concomitant antimuscarinic and anticholinesterase therapy usually reduces muscarinic effects without interfering with the therapeutic effect of the anticholinesterase agent, antimuscarinics may mask the signs of anticholinesterase overdosage and prevent early detection of cholinergic crisis. Antimuscarinics, principally atropine, have also been used effectively to reverse the muscarinic effects associated with toxic exposure to organophosphate and carbamate anticholinesterase pesticides (e.g., parathion) and ingestion of cholinomimetic plants and fungi (e.g., Amanita muscaria mushroom) and drugs having cholinergic effects.

Glycopyrrolate oral solution is used for the symptomatic management of chronic severe drooling in certain pediatric patients with neurologic conditions (e.g., cerebral palsy) associated with problematic drooling.394,398

Antimuscarinics have been used in combination with other drugs (e.g., antihistamines, bronchodilators, expectorants, vasoconstrictors) for the symptomatic treatment of cold and cough. However, there is no evidence from well-designed clinical studies to support their use in combination with other drugs for the management of cold and cough, and most cold and cough combination preparations that previously contained antimuscarinics have been reformulated without these drugs.

Ipratropium nasal spray is used for the symptomatic relief of rhinorrhea associated with allergic or nonallergic perennial rhinitis or the common cold. The drug generally does not relieve nasal congestion, sneezing, or postnasal drip associated with these conditions.

Hyoscyamine sulfate injection is used as an antidote in the treatment of cholinesterase inhibitor toxicity. Hyoscyamine sulfate oral and sublingual preparations also are used in the treatment of cholinesterase inhibitor toxicity.

Atropine combined with a cholinesterase reactivator (pralidoxime chloride) is used in the treatment of organophosphate pesticide poisoning and chemical warfare poisoning. (See Uses in Atropine 12:08.08.)

Antimuscarinics and antispasmodics have been used alone or in combination with phenobarbital in the treatment of infant colic. However, there is minimal evidence from well-designed clinical studies of the efficacy of these drugs in the management of this condition. Infant colic is considered a benign, self-limiting condition that tends to resolve spontaneously and not require medical treatment. Combination preparations are generally considered as lacking substantial evidence of efficacy in the treatment of infant colic.

Antimuscarinics also have been used in the treatment of other conditions (e.g., achalasia, biliary dyskinesia, dysmenorrhea, enuresis, urinary frequency) in which the various antimuscarinic effects of the drugs have been applied for potential therapeutic benefit. However, there is a general lack of information from well-designed clinical studies to support their use in the management of these conditions.

For ophthalmic uses of antimuscarinics, see the individual monographs in 52:24.

Administration

Antimuscarinics usually are administered orally. Atropine sulfate, dicyclomine hydrochloride, glycopyrrolate, hyoscyamine sulfate, propantheline bromide, and scopolamine hydrobromide also may be administered parenterally, although a parenteral preparation of propantheline bromide is no longer commercially available. Glycopyrrolate also may be administered by oral inhalation.392,393,395,396,397 Ipratropium bromide may be administered by oral inhalation or intranasally, and scopolamine may be administered topically. Atropine sulfate also has been administered by oral inhalation, but a solution of the drug for oral inhalation no longer is commercially available in the US.

When IV access is not readily available, atropine sulfate has been administered by intraosseous (IO) injection† in the setting of advanced cardiovascular life support (ACLS); onset of action and systemic concentrations are comparable to those achieved with venous administration.401,403 The drug also may be administered via an endotracheal tube when vascular access (IV or IO) is not possible;403 however, IV or IO administration is preferred because of more predictable drug delivery and pharmacologic effect.403

Dosage

Dosage of an antimuscarinic should be adjusted according to the patient's response and tolerance. Dosage usually is increased until adverse effects become intolerable; then, a slight reduction in dosage generally yields the maximum dosage tolerated by the patient. Dosages higher than those recommended by the manufacturers are often required to produce a therapeutic effect. Dosage may have to be increased if tolerance to the therapeutic and adverse effects of the drug develops.

Quaternary ammonium antimuscarinics are poorly absorbed orally and are much less effective orally than parenterally; higher oral than parenteral dosages are usually required to achieve the same effect.

Adverse Effects

Most adverse effects observed with antimuscarinics are manifestations of the pharmacologic effects of the drugs at muscarinic-cholinergic receptors and usually are reversible when therapy with the drug is discontinued. Antimuscarinics share the toxic potential of atropine, and the usual precautions associated with atropine therapy should be observed with these agents. The frequency and severity of adverse effects of antimuscarinics generally are dose related and adverse effects occasionally may be obviated by a reduction in dosa however, dosage reduction also may eliminate any potential therapeutic effect of the drugs.

To some extent, adverse effects of antimuscarinics correlate with their structural class. Naturally occurring alkaloids possess the full range of antimuscarinic and antinicotinic activities of atropine and thus have the potential for producing adverse central and peripheral effects associated with atropine. Quaternary ammonium compounds are completely ionized at physiologic pH and are less lipid soluble than tertiary amine compounds. As a result, quaternary ammonium compounds are relatively less active orally than tertiary amine compounds and exhibit fewer effects in the CNS and the eye. Quaternary ammonium compounds generally have the greatest nicotinic (ganglionic) blocking activity of the antimuscarinics. Antimuscarinics that act principally as antispasmodics (e.g., dicyclomine, oxybutynin) have minimal antimuscarinic effects at usual dosages; however, as dosage is increased these drugs also may elicit various antimuscarinic effects. Differences in pharmacologic effects among the antimuscarinics may result in minor differences in adverse effects. (See Pharmacology.)

Adverse reactions frequently associated with the use of antimuscarinics include xerostomia (dry mouth), dry skin, blurred vision, cycloplegia, mydriasis, photophobia (especially with scopolamine), anhidrosis, urinary hesitancy and retention, tachycardia, palpitation, xerophthalmia, and constipation. These adverse effects may appear at therapeutic or subtherapeutic doses. In many patients, xerostomia is the dose-limiting adverse effect of antimuscarinics. Saliva substitutes (e.g., Xero-lube^®) have been effective in alleviating xerostomia in patients taking drugs that produce this antimuscarinic effect.

Other reported adverse effects of antimuscarinics include increased ocular tension (especially in patients with angle-closure glaucoma), loss of taste, headache, nervousness, drowsiness, weakness, dizziness, flushing, insomnia, nausea, vomiting, and bloated feeling. Mental confusion and/or excitement also may occur, especially in geriatric patients. Abuse and/or dependence on dicyclomine for its anticholinergic effects has been reported rarely.

Some patients may exhibit excessive susceptibility to the effects of scopolamine and toxic symptoms may occur with therapeutic doses. Marked CNS disturbances, ranging from complete disorientation to an active delirium resembling that encountered in atropine overdosage may occur in these patients. Some patients may exhibit marked somnolence. Other manifestations may include dilated pupils, accelerated pulse rate, and dryness of mouth with a husky quality of the voice apparently caused by laryngeal paralysis. IM or IV administration of antimuscarinics may cause a temporary sensation of lightheadedness and local irritation.

Apparent hypersensitivity reactions have occurred in patients receiving antimuscarinic therapy. Parabens contained in multiple-dose vials of injectable antimuscarinics, lecithin in orally inhaled ipratropium, or other preservatives in antimuscarinic preparations may cause hypersensitivity reactions in patients allergic to these preservatives. Anaphylaxis, urticaria, rash that may progress to exfoliation, delayed hypersensitivity reactions, and various dermal manifestations also have been reported. As with other inhaled drugs for asthma, paradoxical bronchospasm has been reported in a few patients receiving ipratropium via nebulized solution or inhalation aerosol, although a causal relationship to the drug has not been definitely established.

Infants, patients with Down's syndrome (mongolism), and children with spastic paralysis or brain damage may be hypersensitive to antimuscarinic effects (e.g., mydriasis, positive chronotropic effect). Hypersensitivity to antimuscarinic effects of these drugs has also been reported in other patients.

Precautions and Contraindications

Use of antimuscarinics in patients exposed to high environmental temperatures may result in heat prostration. In patients with fever, the risk of hyperthermia may be increased; therefore, antimuscarinics should be used with caution in patients who may be exposed to elevated environmental temperatures or in patients who are febrile. Patients should be advised of the risk of hyperthermia. Since antimuscarinics may produce drowsiness, dizziness, or blurred vision, patients should be warned not to engage in activities requiring mental alertness and/or visual acuity (e.g., operating a motor vehicle or other machinery, performing hazardous work) while taking these drugs.

Antimuscarinics should be used with caution in geriatric patients and children (see Cautions: Pediatric Precautions) since they may be more susceptible to adverse effects of these drugs. Antimuscarinics should also be used with caution in patients with hyperthyroidism, hepatic or renal disease, or hypertension. Antimuscarinics block vagal inhibition of the SA nodal pacemaker and thus should be used with caution in patients with tachyarrhythmias, congestive heart failure, or coronary artery disease. Systemically administered antimuscarinics should be used cautiously in debilitated patients with chronic pulmonary disease, since a reduction in bronchial secretions may lead to inspissation and formation of bronchial plugs; however, antimuscarinics have been used effectively as bronchodilators when administered via oral inhalation. (See Uses: Bronchospasm.) Antimuscarinics should be used with extreme caution in patients with autonomic neuropathy.

Antimuscarinics may produce a delay in gastric emptying with possible antral stasis in patients with gastric ulcer; therefore these drugs should be used cautiously in these patients. Antimuscarinics should be used with caution in patients with esophageal reflux or hiatal hernia associated with reflux esophagitis, since the drugs decrease gastric motility and relax the lower esophageal sphincter (decrease lower esophageal pressure); these effects promote gastric retention and aggravate reflux in these patients.

Antimuscarinics should be administered with extreme caution to patients with known or suspected GI infections (e.g., Clostridium difficile -associated diarrhea and colitis [also known as antibiotic-associated pseudomembranous colitis], shigellosis, dysentery), since these drugs may decrease GI motility and prolong symptomatology by causing retention of the causative organism or toxin(s). Because diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy, antimuscarinics should also be used with extreme caution in patients with diarrhea. In addition, antimuscarinics may further aggravate the diarrhea. Antimuscarinics should be used with extreme caution in patients with mild to moderate ulcerative colitis, since antimuscarinics may suppress intestinal motility and produce paralytic ileus with resultant precipitation or aggravation of toxic megacolon; the drugs are contraindicated in patients with severe ulcerative colitis or toxic megacolon complicating ulcerative colitis. Antimuscarinics also are contraindicated in patients with obstructive disease of the GI tract (e.g., pyloroduodenal stenosis, achalasia), cardiospasm, paralytic ileus, or intestinal atony (especially in geriatric or debilitated patients).

Antimuscarinics are contraindicated in patients with known hypersensitivity to the drugs. The drugs also are contraindicated in patients with angle-closure glaucoma; however, antimuscarinics can be administered safely to patients with open-angle glaucoma who are being treated with miotics. Antimuscarinics should be used with extreme caution in patients with partial obstructive uropathy and are contraindicated in patients with obstructive uropathy (e.g., bladder neck obstruction caused by prostatic hypertrophy). Antimuscarinics are also contraindicated in patients with myasthenia gravis unless the antimuscarinic is used to reduce adverse muscarinic effects of an anticholinesterase agent (e.g., neostigmine). (See Uses: Other Uses.)

Antimuscarinics are contraindicated in patients with acute hemorrhage whose cardiovascular status is unstable.

Pediatric Precautions

Antimuscarinics generally should be used with caution in infants, since there have been a few isolated reports of respiratory distress, seizures, asphyxia, muscular hypotonia, and coma in children 6 weeks of age or younger who received dicyclomine orally. These symptoms reportedly occurred within minutes of ingestion, lasted 20-30 minutes, and eventually resolved with no long-term sequelae. The manufacturer states that because of the timing and nature of these reactions, they probably resulted from local irritation and/or aspiration rather than a direct pharmacologic effect; however, caution should be exercised in this age group. The manufacturer of Bentyl^® states that dicyclomine is contraindicated in infants younger than 6 months of age.

Safety and efficacy of clidinium (as a fixed-combination preparation with chlordiazepoxide hydrochloride), dicyclomine, homatropine, methscopolamine, propantheline, or tolterodine have not been established in children. Safety in children has been established for belladonna, glycopyrrolate, and hyoscyamine. Safety and efficacy of scopolamine soluble tablets and transdermal system in children have not been established. Safety in children 12 years of age or older has been established for ipratropium bromide. (See the individual monographs in 12:08.08.)

Because glycopyrrolate injection contains benzyl alcohol as a preservative, the manufacturer recommends that the drug not be used in neonates younger than 1 month of age. Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.359,360,361,362,363,364 Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates.359,360,361,362,363,364 Although use of drugs preserved with benzyl alcohol should be avoided in neonates whenever possible, the American Academy of Pediatrics (AAP) states that the presence of small amounts of the preservative in a commercially available injection should not proscribe its use when indicated in neonates.359

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies with antimuscarinics have generally not been performed. Although some manufacturers state that uncontrolled clinical experience with the drugs (e.g., clidinium, glycopyrrolate, propantheline) has revealed no evidence of toxicity to the mother or fetus, there are no adequate and controlled studies to date using the drugs in pregnant women. Antimuscarinics should generally be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Fertility

The effects of antimuscarinics on fertility in animals and humans have not been fully determined. Impotence has occurred during therapy with antimuscarinics. Antimuscarinics inhibit penile erection by blocking cholinergically mediated vasodilation, thereby preventing the increased blood flow to the sinuses (corpora cavernosa and corpus spongiosum) and the resultant penile rigidity that usually occurs during male sexual stimulation. Although studies in dogs indicate that high doses of glycopyrrolate diminish seminal secretion (emission), other evidence suggests that antimuscarinics block cholinergically induced depression of α-adrenergically mediated seminal secretion.

Lactation

Although information indicating that antimuscarinics inhibit lactation and are distributed into milk is minimal and has been questioned, some manufacturers and clinicians state that these drugs should not be used in nursing women since infants may be particularly sensitive to antimuscarinic effects if the drugs were present in milk.

Drugs with Anticholinergic Effects

Additive adverse effects resulting from cholinergic blockade (e.g., xerostomia, blurred vision, constipation) may occur when antimuscarinics are administered concomitantly with phenothiazines, amantadine, antiparkinsonian drugs, glutethimide, meperidine, tricyclic antidepressants, muscle relaxants, antiarrhythmic agents that possess anticholinergic activity (e.g., quinidine, disopyramide, procainamide), or some antihistamines (including meclizine). Patients receiving concomitant therapy with an antimuscarinic and any of these drugs may be at increased risk of developing adverse anticholinergic effects and should be informed of this possibility.

Effects on GI Absorption of Drugs

By inhibiting the motility of the GI tract and prolonging GI transit time, antimuscarinics have the potential to alter GI absorption of various drugs.

In one study, propantheline bromide reduced the rate of absorption of acetaminophen while having little or no effect on the extent of absorption as determined by 24-hour urinary excretion. Propantheline (and probably other antimuscarinics) inhibits gastric emptying and thus apparently delays the delivery of acetaminophen to its site of absorption in the intestine. Although not specifically determined, antimuscarinics could potentially delay the onset of therapeutic effects (e.g., analgesia, antipyresis) of acetaminophen.

Concurrent administration of an antimuscarinic and levodopa may decrease the extent of absorption of levodopa in the small intestine by causing increased metabolism of levodopa in the stomach. If the antimuscarinic is discontinued without a concomitant reduction in levodopa dosage, toxicity may result from the increased absorption of levodopa.

Concurrent use of propantheline and slow-dissolving tablets of digoxin may result in increased serum digoxin concentrations. This interaction can be avoided by using digoxin oral solution or tablets that dissolve rapidly (e.g., Lanoxin^®). Patients receiving an antimuscarinic and digoxin should be closely observed for signs of digitalis toxicity.

Because antimuscarinics may decrease gastric acid output and/or increase gastric pH, they may decrease the GI absorption of ketoconazole which depends on gastric acidity for dissolution and absorption. If concomitant therapy is necessary, the antimuscarinic should be given at least 2 hours after ketoconazole tablets.

Prior administration of propantheline bromide delayed the rate of absorption of riboflavin but increased the total amount absorbed, presumably by increasing the residence time of the drug at GI absorption sites.

Antacids

Antacids may decrease the extent of absorption of some oral antimuscarinics when these drugs are administered simultaneously. Therefore, oral antimuscarinics should be administered at least 1 hour before antacids. Antimuscarinics may be administered before meals to prolong the effects of postprandial antacid therapy. However, controlled studies have failed to demonstrate a substantial difference in gastric pH when combined antimuscarinic and antacid therapy was compared with antacid therapy alone.

Other Drugs

Concurrent administration of glycopyrrolate and a wax-matrix potassium chloride preparation (Slow-K^®) increased the severity of potassium chloride-induced GI mucosal lesions (as determined endoscopically) compared with potassium chloride administration alone; antimuscarinics slow GI transit time and thus apparently potentiate the local GI mucosal effects of potassium chloride. Minimal endoscopic evidence of GI mucosal lesions was seen when glycopyrrolate was administered concurrently with a microencapsulated potassium chloride preparation (Micro-K^®). Antimuscarinics should be used cautiously with potassium chloride preparations (especially wax-matrix preparations) and patients should be carefully monitored for evidence of GI mucosal lesions.

Concomitant administration of antimuscarinics and corticosteroids may result in increased intraocular pressure.

Caution should be exercised if scopolamine is administered concomitantly with other CNS depressants (e.g., sedatives, tranquilizers, alcohol).

Laboratory Test Interferences

Scopolamine (and probably other antimuscarinics) may interfere with the gastric secretion test.

Acute Toxicity

Pathogenesis

Overdosage of antimuscarinics produces symptoms that are principally extensions of common adverse effects of the drugs. Single 10-mg oral doses of atropine may produce signs and symptoms of acute toxicity in adults; however, one adult male reportedly survived a single 1-g oral dose of the drug. Children may be more susceptible than adults to the toxic effects of atropine; deaths have been reported in children following ingestion of 10 mg of atropine.

The LD₅₀ of hyoscyamine in rats is 375 mg/kg. The oral LD₅₀ of methscopolamine bromide in rats is 1.4-2.6 g/kg. The oral LD₅₀ of propantheline bromide in mice and rats is 780 mg/kg and 370 mg/kg, respectively.

Manifestations

Acute overdosage with antimuscarinics produces both peripheral and CNS symptomatology. The quaternary ammonium compounds do not readily penetrate the CNS and thus exhibit minimal central effects even at toxic doses. Peripheral symptoms may include dilated and unreactive pupils; blurred vision; hot, dry, and flushed skin; dryness of mucous membranes; difficulty in swallowing; foul breath; diminished or absent bowel sounds; urinary retention; tachycardia; hyperthermia; hypertension; and increased respiratory rate. In addition to tachycardia, cardiac manifestations may include ECG abnormalities similar to those produced by quinidine toxicity (e.g., ventricular arrhythmias, extrasystoles); these abnormalities result from enhanced reentrant excitation secondary to reduced conduction velocity. Widening of the QRS complex, prolongation of the QT interval, and ST-segment depression may also be seen. Other peripheral signs and symptoms may include nausea, vomiting, and a scarlatiniform or maculopapular rash over the face, neck, and upper trunk. Acute overdosage with quaternary ammonium antimuscarinics may produce a curariform neuromuscular block and ganglionic blockade manifested as respiratory paralysis.

Acute overdosage with antimuscarinics generally produces CNS stimulation followed by depression. CNS manifestations may resemble acute psychosis characterized by various neuropsychiatric signs and symptoms including disorientation, incoherence, confusion, stupor, hallucinations (usually visual, but may also be auditory or tactile), delusions, paranoia, disturbed speech (e.g., dysarthria, pressure to keep talking), periods of hyperactivity (sometimes alternating with somnolence), anxiety, abnormal motor behavior (e.g., ataxia, incoordination), agitation, seizures, and restlessness. In severe overdosage, CNS depression, circulatory collapse, and hypotension may occur. Scopolamine may cause CNS excitement and delirium, especially in patients with painful conditions.358 Coma and skeletal muscle paralysis may also occur and may be followed by death from respiratory failure. Comatose patients may also exhibit clonic movements, upgoing plantar reflexes (positive Babinski sign), and hyperreflexia. Death has also reportedly resulted from hyperpyrexia (especially in children), cardiac depression, or from environmental exposure or drowning in patients who were delirious.

Blurred vision, numbness on the left side, cold fingertips, abdominal and flank pain, decreased appetite, dry mouth, and nervousness were reported in an adult who ingested 320 mg of dicyclomine hydrochloride daily for 4 days; these adverse effects resolved when the drug was discontinued.

It is necessary to distinguish the signs and symptoms of scopolamine overdosage from the withdrawal symptoms that are observed occasionally in patients who discontinue the transdermal scopolamine system. (See Adverse Effects: CNS Effects in the Cautions section of Scopolamine 12:08.08.) Although mental confusion and dizziness may be observed with both acute toxicity and withdrawal, patients with anticholinergic toxicity also may exhibit signs and symptoms including tachyarrhythmias, dry skin, and decreased bowel sounds, while bradycardia, headache, nausea, abdominal cramps, and sweating may suggest symptoms associated with scopolamine withdrawal.

Treatment

Treatment of acute antimuscarinic overdosage consists of symptomatic and supportive therapy. Patients should be hospitalized and closely monitored, including continuous ECG monitoring. If the patient is conscious, has not lost the gag reflex, and is not having seizures, the stomach should be emptied immediately by inducing emesis. If emesis is unsuccessful or contraindicated, gastric lavage (preferably accompanied by instillation of activated charcoal) may be performed with a cuffed endotracheal tube, inflated and in place, to prevent aspiration of gastric contents. Saline cathartics may also be administered. In patients who exhibit manifestations of severe poisoning, use of exchange transfusions should be considered. Hemodialysis or peritoneal dialysis is apparently not useful.

Because physostigmine has the potential for producing severe adverse effects (e.g., seizures, asystole), routine use of physostigmine as an antidote for antimuscarinic overdosage is controversial. The American Psychiatric Association (APA) states that, unless contraindicated, use of physostigmine can be considered for severe cases of delirium induced by anticholinergics.374 (See Cautions: Precautions and Contraindications.) Many clinicians believe that the drug should be used only in the treatment of severe or life-threatening symptoms of anticholinergic toxicity (e.g., extensive delirium or agitation, hallucinations, hyperthermia, severe sinus or supraventricular tachycardia, seizures) in patients who fail to respond to alternative therapy.375,376,377,378,379,380 Relative contraindications to the use of physostigmine include asthma, gangrene, cardiovascular disease, and mechanical obstruction of the GI or genitourinary tract. Physostigmine should be used in these situations only if a life-threatening emergency occurs.

Delirium, hallucinations, coma, and cardiac arrhythmias often respond to physostigmine. Physostigmine will reverse supraventricular tachycardia produced by antimuscarinic overdosage. IV propranolol may be useful for treating supraventricular tachyarrhythmias unresponsive to physostigmine or when physostigmine is contraindicated. Physostigmine should not be used to treat cardiac conduction defects or ventricular tachyarrhythmias. Frequent administration of physostigmine may be necessary as it is short-acting and patients may suddenly relapse; however, excessive doses of physostigmine may produce cholinergic toxicity (e.g., bradycardia, increased salivation, diarrhea, seizures, respiratory arrest). If indicated, physostigmine salicylate usually is administered by slow IV injection. The usual initial adult dose is 2 mg. If there is no response, 1-2 mg may be given every 20 minutes until reversal of toxic antimuscarinic effects occurs or adverse cholinergic effects develop. If initial doses of the drug are effective, additional doses of 1-4 mg may be given every 30-60 minutes as necessary. The usual initial pediatric IV dose of physostigmine salicylate recommended by the manufacturer is 0.02 mg/kg. Additional doses may be repeated at 5- to 10-minute intervals until a response is obtained, adverse cholinergic effects develop, or a total dose of 2 mg has been administered; thereafter, the lowest effective dose may be repeated as necessary. Adverse effects of physostigmine (e.g., life-threatening bronchoconstriction, bradycardia, seizures) can be reversed with IV administration of 0.5-1 mg of atropine sulfate.

Fluid therapy and other standard treatments of shock should be administered as needed. Hyperthermia is usually treated with cold packs, mechanical cooling devices, or sponging with tepid water. Diazepam may be administered to control excitement, delirium, or other symptoms of acute psychosis. Phenothiazines should not be used as they may contribute to anticholinergic effects. Conjunctival application of pilocarpine may be used to counteract mydriasis. Maintenance of an adequate airway is important, and respiratory assistance may be necessary. If the patient is comatose, urinary catheterization should be performed to avoid urinary retention.

If overdosage of scopolamine occurs following application of multiple transdermal systems and/or ingestion of the transdermal system, measures to ensure that the patient has an adequate airway and to provide cardiac and respiratory support should be instituted, followed by rapid removal of all transdermal systems from the skin and/or mouth. If there is evidence of ingestion of the transdermal system, gastric lavage, endoscopic removal of the swallowed transdermal system, or administration of activated charcoal should be considered depending on the clinical situation. ECG and vital signs should be monitored continuously, IV access should be established, and oxygen should be administered if a serious overdosage has occurred or there are evolving signs of acute toxicity.

Manifestations of overdosage of illicit drugs (apparently mixed or “cut” with scopolamine) that were injected or “snorted” included lethargy, agitation, hallucinations, paranoia, tachycardia, mild hypertension, mydriasis, dry skin or mucous membranes, diminished or absent bowel sounds, and urinary retention. Following administration of parenteral naloxone by emergency room personnel, some patients with lethargy experienced agitation and combativeness. In some patients, manifestations of toxicity resolved with physostigmine and/or sedation (e.g., diazepam, lorazepam); however, physostigmine should be administered with extreme caution by health-care personnel experienced in the use of the drug, since severe adverse effects (e.g., seizures, bronchospasm, bradycardia) have been associated with its use. Assessment of the described cases of overdosage is difficult since manifestations of opiate overdosage (e.g., lethargy, respiratory depression, miosis) and those associated with overdosage of antimuscarinics, including scopolamine (e.g., mydriasis, flushing, dry skin and mucous membranes, absent bowel sounds, tachycardia, altered mental status), are different, and some manifestations may obscure the classic effects associated with overdosage of the individual drugs. Timely recognition of these toxicities is important; therefore, the US Centers for Disease Control and Prevention (CDC) states that all new cases of these overdosages should be reported promptly to the local poison control center and health department.

Pharmacology

General Pharmacology

Antimuscarinics

Antimuscarinics competitively inhibit the actions of acetylcholine or other cholinergic stimuli at autonomic effectors innervated by postganglionic cholinergic nerves, and to a lesser extent, on smooth muscles that lack cholinergic innervation. These drugs are referred to as antimuscarinics because at usual doses they principally antagonize cholinergic stimuli at muscarinic receptors and have little or no effect on cholinergic stimuli at nicotinic receptors. Antimuscarinics also have been referred to as anticholinergics (cholinergic blocking agents), but this term is appropriate only when it describes the antagonism of cholinergic stimuli at any cholinergic receptor, whether muscarinic or nicotinic. Since the functions antagonized by antimuscarinics principally are under the parasympathetic division of the nervous system, these drugs also have been referred to as parasympatholytics.

At autonomic ganglia, where cholinergic transmission involves nicotinic receptors, atropine or other tertiary amine antimuscarinics produce a partial cholinergic block only at relatively high doses. At the neuromuscular junction, where cholinergic receptors are principally or exclusively nicotinic, only extremely high doses of atropine or other tertiary amine antimuscarinics produce any degree of blockade. However, quaternary ammonium antimuscarinics generally possess varying degrees of nicotinic blocking activity and may interfere with ganglionic or neuromuscular transmission at doses that block muscarinic receptors. At high doses, quaternary ammonium antimuscarinics may produce substantial ganglionic blockade with resultant adverse effects (e.g., impotence, postural hypotension) and, in overdosage, they may cause a curariform neuromuscular block.

There are considerable differences among antimuscarinics in the degree to which various pharmacologic effects are produced; this may result in part from existence of 4 or more subtypes of muscarinic receptors.350,351 The convention commonly used to classify muscarinic receptors designates pharmacologically defined muscarinic receptor subtypes as M₁, M₂, M₃, and M₄. These correspond to the genetically cloned receptor subtypes m1-m4.351 Although a fifth muscarinic gene product (designated m5) has been cloned, no functional correlate for this receptor has been unambiguously demonstrated, and its pharmacology appears to differ from that of other muscarinic receptor subtypes.350 Determining the precise location and role of the muscarinic receptor subtypes has been difficult, since multiple subtypes may be expressed in a tissue or cell, and much research remains to be done.350,351

Receptors at various sites are not equally sensitive to inhibitory effects of antimuscarinics; therefore, the degree of inhibition at each site is dose-dependent. In general, the relative sensitivity of physiologic functions, proceeding from the most sensitive, is as follows: secretions of the salivary, bronchial, and sweat glands; pupillary dilation, ocular accommodation, and heart rate; contraction of the detrusor muscle of the bladder and smooth muscle of the GI tract; and gastric secretion and motility. An antimuscarinic, in a dose sufficient to depress gastric secretion, will usually also inhibit other, more sensitive functions to some degree. Therefore, if antimuscarinics are used to decrease gastric secretions, they are very likely to cause dryness of the mouth (xerostomia) and interfere with visual accommodation, and possibly cause difficulty in urinating.

Antispasmodics

Dicyclomine, oxybutynin, and tolterodine are structurally related to the antimuscarinics and are often referred to as antispasmodic or antimuscarinic-antispasmodic agents. Although the exact mechanism(s) of action of these drugs has not been established, they appear to act as nonselective smooth muscle relaxants. It has been suggested that they have a nonspecific direct action on smooth muscle. These drugs generally have little or no antimuscarinic activity, except at high doses, and little or no effect on gastric secretion. Oxybutynin exhibits one-fifth the anticholinergic activity but 4-10 times the antispasmodic activity of atropine on the rabbit detrusor muscle. Since dicyclomine and oxybutynin, like the antimuscarinics, have been used as adjunctive therapy for irritable bowel syndrome, they generally are included in discussions on antimuscarinics. (See Uses: Irritable Bowel Syndrome.)

In vitro, the relative binding affinity of tolterodine at the muscarinic receptors of the bladder is similar to that of oxybutynin,352,382,389 while at the muscarinic receptors in the parotid gland the potency of oxybutynin appears to be eightfold greater than that of tolterodine.352,356,382,383,384,389 Because tolterodine is used for the management of overactive bladder,354,355,356,384,389 it is described with other genitourinary smooth muscle relaxants. (See Tolterodine Tartrate 86:12.)

GI Effects

Antimuscarinics have various antisecretory effects in the GI tract.

The drugs reduce the volume of saliva and produce xerostomia. Receptors mediating these salivary effects usually are more sensitive to antimuscarinic blockade than other muscarinic receptors (e.g., those mediating gastric secretion). Antimuscarinics also generally reduce the volume of gastric secretions; however, the concentration of gastric acid is not necessarily reduced. Secretion during the gastric and psychic phases of gastric acid secretion is decreased but not eliminated. The intestinal phase of gastric acid secretion also may be inhibited. Relatively large doses of antimuscarinics (i.e., more than 1 mg of atropine IV, 4 mg of glycopyrrolate orally, or 0.8 mg of hyoscyamine orally) usually are required to reduce gastric acid secretion. These doses generally decrease basal or nocturnal gastric acid secretion by about 50%, histamine- or pentagastrin-stimulated gastric acid secretion by about 40%, and food-stimulated gastric acid secretion by about 30%. These relatively large doses of antimuscarinics may eliminate fasting gastric acid secretion in healthy individuals; however, this action is less prominent in patients with peptic ulcers. In a study comparing oral doses of pirenzepine (not commercially available in the US) with hyoscyamine in healthy adults using a placebo-controlled baseline, pirenzepine (50 mg twice daily) and hyoscyamine (0.6 mg twice daily) reduced gastric acid secretion by 57 and 54%, respectively, and reduced pentagastrin-stimulated gastric secretion by 22 and 31%, respectively; neither drug showed a substantial effect on gastric emptying. Antimuscarinics generally do not appear to provide effective control of gastric acid secretion at doses that are devoid of substantial adverse effects. However, in one study in patients with duodenal ulcer, a single, oral, 15-mg dose of propantheline reduced food-stimulated gastric acid secretion to the same extent as a single, oral, 45-mg dose without the pronounced adverse effects of the higher dosage.

Gastric acid secretion stimulated by choline esters (e.g., methacholine, carbachol) or pilocarpine is completely blocked by atropine. Histamine-, alcohol-, or caffeine-stimulated gastric acid secretion is reduced but not abolished by atropine. Antimuscarinics may decrease the concentration of mucin and enzymes in GI secretions. Atropine and other antimuscarinics have little direct effect on pancreatic, biliary, or intestinal secretions, since these secretions are principally controlled by hormonal rather than vagal mechanisms. Although the exact mechanism of action has not been determined, it has been suggested that antimuscarinic-induced delayed emptying can delay the release of secretin by slowing the entry of the acid stimulus into the duodenum and that this may indirectly decrease the volume and activity of pancreatic secretions. Antimuscarinics (e.g., atropine, propantheline) have been shown to reduce the volume of amylase secretion in some patients whose pancreatic secretion was stimulated by secretin, secretin and insulin, or secretin and pancreozymin, and in some patients with acute pancreatitis; however, there has been little, if any, evidence that antimuscarinics improve the prognosis of acute pancreatitis.

Antisecretory effects of antimuscarinics apparently do not persist for any prolonged period (generally less than 48 hours) following discontinuance of the drugs.

Therapeutic doses of antimuscarinics produce prolonged inhibitory effects on the motility of the esophagus, stomach, duodenum, jejunum, ileum, and colon; these effects are characterized by a decrease in tone and in the amplitude and frequency of peristaltic contractions. Antimuscarinics prolong GI transit time and thus have the potential to alter absorption of other drugs. (See Drug Interactions: Effects on GI Absorption of Drugs.) Increases in GI tone and motility resulting from insulin-induced hypoglycemia, emotional stimulation, or the administration of morphine or parasympathomimetic drugs are usually readily inhibited by antimuscarinics; however, some increases in GI tone and motility are resistant to antimuscarinic inhibition (e.g., direct GI stimulation secondary to vasopressin or histamine). Antimuscarinics relax the lower esophageal sphincter with a resultant decrease in lower esophageal sphincter pressure. Antimuscarinics exert a weak antispasmodic action on the gallbladder and bile ducts which is usually insufficient for therapeutic effect. It has been suggested that drugs that act principally as antispasmodics decrease spasm of the smooth muscle of the GI tract through some direct action without producing antimuscarinic effects on salivary or gastric secretions; however, dosages required to decrease GI hypermotility are probably not devoid of antimuscarinic effects.

Although the mechanism of action has not been determined, atropine and propantheline have been shown to decrease gastric plasma protein loss in patients with giant hypertrophic gastritis (Menetrier's disease).

Genitourinary Effects

Atropine and other antimuscarinics decrease the tone and amplitude of contractions of the ureters and bladder; however, cholinergic innervation is not completely blocked by these drugs. In addition, the bladder smooth muscle appears to be less sensitive to the antimuscarinic effects of these drugs than are other smooth muscles (e.g., GI). In healthy individuals, atropine (0.5 mg IM) has no effect on urinary bladder capacity, micturition pressure, or urethral pressure. In one study, 30 mg of propantheline IM had no effect on empty bladder tone or sphincter pressure; however, in most of these patients, this dose produced an increase in bladder capacity and completely abolished the micturition reflex resulting in urinary retention. In a cystometric study in patients with overactive bladder, tolterodine increased the volume at first bladder contraction, the residual volume, and the maximum cystometric capacity after 4 weeks of therapy.352,353 In patients with obstructive uropathy, antimuscarinics may cause urinary retention. (See Cautions: Precautions and Contraindications.)

Antimuscarinics exhibit more pronounced effects on neurogenic bladders. In patients with uninhibited or reflex neurogenic bladder, the amplitude and frequency of uninhibited contractions are reduced and bladder capacity is increased by atropine (1-4 mg orally or 1.2 mg IV) or propantheline (60-120 mg orally or 30-60 mg IV). In addition, incontinence associated with uninhibited contractions is relieved and volume of residual urine and frequency of urination are returned to normal in these patients. Cystometric studies in patients with uninhibited neurogenic or reflex neurogenic bladder indicate that oxybutynin increases urinary bladder capacity, diminishes the frequency of uninhibited contractions of the detrusor muscle, and delays the initial desire to void. These effects are more evident in individuals with uninhibited neurogenic bladder than in those with reflex neurogenic bladder. Antimuscarinics are ineffective in inhibiting nonneurogenic or functional enuresis. Tolterodine tartrate is used for the management of symptoms associated with both neurogenic and nonneurogenic overactive bladder.366,367

Atropine (1.2 mg IV) produces dilation of the pelves, calyces, and ureters and has been used to enhance visualization of the urinary tract in excretion urography. Some antimuscarinics may inhibit penile erection and may produce impotence. (See Cautions: Pregnancy, Fertility, and Lactation.) Atropine does not appear to exert any substantial pharmacologic effect on the uterus. When given as a preanesthetic to women in labor, scopolamine does not appear to have any effect on the frequency or duration of uterine contractions during labor. Except in large doses, drugs that act principally as antispasmodics may decrease spasm of the smooth muscle of the ureters and uterus without producing usual antimuscarinic effects (e.g., mydriasis).

Cardiovascular Effects

Cardiac effects of antimuscarinics are dose dependent. Average doses of antimuscarinics (e.g., 0.4-0.6 mg of atropine) may produce a slight decrease in heart rate attributable to central vagal stimulation which occurs prior to peripheral cholinergic blockade; the decrease in heart rate is more prominent with scopolamine (0.1-0.2 mg) than with atropine (0.4-0.6 mg). Larger doses of antimuscarinics (e.g., 1-2 mg of atropine) cause progressively increasing tachycardia by blocking normal vagal inhibition of the sinoatrial (SA) node. Cardiac effects of antimuscarinics are sometimes unpredictable and paradoxical, depending on the component of the specialized cardiac conduction system and of the myocardium showing the predominant effect and on the physiologic condition of the heart.

Atropine is the principal antimuscarinic studied for its cardiac effects and used for the diagnosis, evaluation, and treatment of cardiac disorders. Atropine has a positive chronotropic effect (increased sinoatrial [SA] node automaticity), accelerating sinus rate by direct parasympathetic blockade. Although atropine is effective in reversing sinus bradycardia secondary to extracardiac causes, it has little, if any, effect on sinus bradycardia caused by intrinsic disease of the SA node. Atropine has been shown to shorten SA-conduction time in healthy individuals and in patients with sinus bradycardia; however, its effect on refractoriness of atrial muscle has not been fully determined. Atropine stimulates the atrioventricular (AV) functional pacemaker in healthy individuals and in patients with sinus node disease and facilitates AV nodal conduction in individuals with a normal AV node. Atropine shortens AV nodal conduction time and decreases effective and functional refractory periods of the AV node. The effects of atropine on first-degree AV block are variable and unpredictable. Generally, type I second-degree AV block responds to atropine, while the drug is ineffective in type II second-degree AV block. Response to atropine of the subjunctional portion of the specialized cardiac conduction system (i.e., His-Purkinje system) is unpredictable.

Atrial arrhythmias, AV dissociation, ventricular tachycardia, and ventricular fibrillation may occur during antimuscarinic therapy. Young healthy adults appear to be more susceptible to these effects than other age groups because of an apparent increased importance of cardiac vagal tone in this age group. Antimuscarinics can reverse reflex vagal cardiac slowing or asystole such as that induced by inhalation of irritant vapors or by vagal stimulation (e.g., carotid sinus stimulation, pressure on the eyeball).

Antimuscarinics may cause cutaneous vasodilation, especially at toxic doses; this effect is sometimes referred to as atropine flush. It is not known if this vasodilation is a compensatory response to dissipate an increase in body temperature or a direct effect of the drugs on cutaneous blood vessels.

Respiratory Tract Effects

Antimuscarinics reduce the volume of secretions from the nose, mouth, pharynx, and bronchi. Ipratropium, a derivative of atropine, inhibits secretions from the serous and seromucous glands lining the nasal mucosa when applied locally. Antimuscarinics cause relaxation of smooth muscles of the bronchi and bronchioles with a resultant decrease in airway resistance. Atropine and ipratropium are potent bronchodilators, particularly in large bronchial airways, and are especially effective in reversing bronchoconstriction induced by parasympathetic stimulation. The autonomic control of bronchoconstriction and the release of bronchoconstrictor substances from mast cells appear to be mediated by cyclic nucleotides. Antimuscarinics block acetylcholine-induced stimulation of guanyl cyclase and thus reduce tissue concentrations of cyclic guanosine monophosphate (cGMP), a mediator of bronchoconstriction. Although some clinicians caution against the use of antimuscarinics in asthmatic patients because of the drying effect of the drugs, orally inhaled atropine and ipratropium have been effective in preventing antigen-, methacholine-, and exercise-induced bronchospasm in these patients.

Atropine and scopolamine effectively reduce the incidence of laryngospasm that occurs during general anesthesia. They act indirectly by reducing secretions that may stimulate reflex laryngospasm; a direct blockade of laryngeal skeletal muscle does not appear to occur.

For additional information on the respiratory tract effects of antimuscarinics, see Pharmacology in Ipratropium Bromide 12:08.08.

CNS Effects

With the exception of quaternary ammonium compounds and scopolamine, antimuscarinics stimulate the medulla and higher cerebral centers and exhibit CNS effects similar to those produced by antimuscarinics used in the treatment of parkinsonian syndrome (e.g., trihexyphenidyl). Cholinergic transmission in the CNS mainly involves nicotinic receptors in the spinal cord and both muscarinic and nicotinic receptors in the brain. CNS effects of usual doses of atropine and related drugs result from their central antimuscarinic actions and are usually confined to mild vagal stimulation with a resultant decrease in heart rate. At toxic doses, CNS effects (i.e., prominent central stimulation leading to restlessness, irritability, disorientation, hallucinations, and delirium) of atropine and related drugs probably result from antimuscarinic and other effects. Antimuscarinics appear to cause an increased release and turnover of acetylcholine in the CNS which may result in activation of nicotinic receptors in the brain. As the dose of antimuscarinic is progressively increased, stimulation eventually gives way to depression, coma, medullary paralysis, and death. Quaternary ammonium compounds do not readily penetrate the CNS and thus exhibit minimal central effects even at toxic doses.

Unlike atropine and most other antimuscarinics, scopolamine, at usual dosages, produces CNS depression manifested as drowsiness, euphoria, amnesia, fatigue, and dreamless sleep (with a reduction in rapid eye movement [REM] sleep). However, excitement, restlessness, hallucinations, or delirium may paradoxically occur, especially when scopolamine is used in the presence of severe pain. High doses of scopolamine produce CNS effects (e.g., restlessness, disorientation, irritability, hallucinations) similar to those produced by toxic doses of other antimuscarinics.

Although other antimuscarinics have been used in the prevention of motion sickness, it appears that scopolamine is most effective. Scopolamine apparently corrects some central imbalance of acetylcholine and norepinephrine that may occur in patients with motion sickness. It has been suggested that antimuscarinics may block the transmission of cholinergic impulses from the vestibular nuclei to higher centers in the CNS and from the reticular formation to the vomiting center; these effects result in prevention of motion-induced nausea and vomiting.

Ophthalmic Effects

Antimuscarinics block the responses of the sphincter muscle of the iris and the ciliary muscle of the lens to cholinergic stimulation. Mydriasis and cycloplegia result from these ocular effects and result in a decrease in ocular accommodation. Antimuscarinics usually have little effect on intraocular pressure except in patients with angle-closure glaucoma in whom intraocular pressure may increase. Drugs that act principally as antispasmodics generally have little or no ocular effects at usual doses. For information on ophthalmic effects of topical antimuscarinics, see the individual monographs in 52:24.

Other Effects

Antimuscarinics reduce the volume of perspiration by inhibiting sweat-gland secretions. In toxic doses, antimuscarinics may suppress sweating sufficiently to increase body temperature.

Pharmacokinetics

Little information is available on the pharmacokinetics of most antimuscarinics.

Absorption

Generally, those antimuscarinics having a quaternary ammonium group are incompletely absorbed from the GI tract since they are completely ionized. Generally, the tertiary amine antimuscarinics are readily absorbed from the GI tract. Tolterodine is well absorbed following oral administration, and absorption of the drug is rapid, with maximum serum concentrations of tolterodine occurring usually within 1-2 hours after administration of a dose.354 The presence of food in the GI tract may affect absorption of antimuscarinics. Scopolamine is well absorbed percutaneously following topical application. (See Scopolamine 12:08.08.) Following IM administration, atropine and glycopyrrolate are rapidly absorbed, reportedly reaching peak concentrations 15-50 minutes and peak antimuscarinic effects 30-45 minutes after administration, respectively. Following oral inhalation of usual doses, limited amounts of atropine or ipratropium reach systemic circulation. Systemic absorption of ipratropium following administration as a nasal spray also is limited but exceeds that resulting from oral inhalation of the drug as a nebulized solution or aerosol.

Distribution

Distribution of most antimuscarinics has not been determined. Atropine and glycopyrrolate are apparently rapidly distributed throughout the body since the drugs disappear rapidly from blood after IV administration. Glycopyrrolate is distributed into bile; however, it is not known if other antimuscarinics undergo similar distribution. Quaternary ammonium antimuscarinics exhibit poor lipid solubility; they do not readily cross the blood-brain barrier and thus exhibit minimal CNS effects. In addition, because of their poor lipid solubility, quaternary ammonium antimuscarinics do not readily penetrate the eye. Atropine and hyoscyamine readily cross the blood-brain barrier; other tertiary amine antimuscarinics apparently penetrate the CNS since central effects have been observed. Although atropine, glycopyrrolate, hyoscyamine, and scopolamine cross the placenta, it is not known whether other antimuscarinics cross the placenta. Although atropine has been stated to distribute into milk in small quantities, there are minimal data to support this statement. It is unlikely that quaternary ammonium antimuscarinics distribute into milk; however, studies to determine this have apparently not been conducted.

Elimination

Elimination of most antimuscarinics has not been determined. Atropine is apparently metabolized in the liver to tropic acid, tropine (or a chromatographically similar compound), and possibly, esters of tropic acid and glucuronide conjugates. Oxybutynin and tolterodine are metabolized by the cytochrome P-450 microsomal enzyme system.354,357 Metabolites of other antimuscarinics also have been identified. (See the individual monographs in 12:08.08.) Propantheline bromide is extensively hydrolyzed in the upper small intestine; however, it is not known if other antimuscarinics undergo similar inactivation.

Antimuscarinics mainly are eliminated in the urine. The drugs generally are excreted in urine as unchanged drug and metabolites. Following IM administration of atropine, about 30-50% of a dose is excreted in urine unchanged; tropine, tropic acid, and other metabolites are also excreted in urine. Small amounts (up to 3% of a dose in one study) of atropine may also be eliminated as carbon dioxide in expired air. Following oral administration, substantial amounts of antimuscarinics (especially quaternary ammonium compounds) may be eliminated in feces as unabsorbed drug. It is not known whether tertiary amine or quaternary ammonium antimuscarinics are removed by peritoneal dialysis or hemodialysis; however, atropine apparently is not removed by hemodialysis.

Chemistry

Antimuscarinics competitively inhibit the muscarinic effects of acetylcholine. Atropine ( dl -hyoscyamine) is the prototype of the antimuscarinics and many of the currently available antimuscarinics were developed as structural derivatives of atropine. However, other antimuscarinics have been synthesized that have little structural similarity to atropine, and other drugs with a variety of structural characteristics also exhibit antimuscarinic activity. Most antimuscarinics are aminoalcohols or their derivatives (usually esters or ethers), aminoamides, or other amines.

All commercially available antimuscarinics contain a cationic site at X which is important in determining antimuscarinic activity. This cationic site results from a nitrogen atom in the chemical substituent at X and exists in a tertiary or quaternary form. Although other drugs exhibit antimuscarinic activity without having a cationic site, they generally are less effective inhibitors of acetylcholine. The type of amine, tertiary or quaternary, is the most important structural characteristic of antimuscarinics in determining pharmacologic differences among the drugs; discussion of this structural characteristic as it affects the pharmacology, pharmacokinetics, and adverse effects of these drugs is included in the sections that follow.

Antimuscarinics usually are classified on the basis of their source (natural, semisynthetic, or synthetic) and/or on their cationic nature (tertiary amine or quaternary ammonium compounds). Antimuscarinics can be divided into 2 groups— naturally occurring alkaloids and their semisynthetic derivatives and synthetic amine compounds.

Naturally Occurring Alkaloids and Semisynthetic Derivatives

All commercially available naturally occurring alkaloids and their semisynthetic derivatives are aminoalcohol esters.

Hyoscyamine and scopolamine are naturally occurring tertiary amines which are formed by combining tropic acid and tropine or scopine, respectively. Structurally, the integrity of the ester must be maintained for antimuscarinic activity; neither the free acid nor the free base exhibits substantial antimuscarinic activity. Presence of a free hydroxyl group in the acid portion of the ester also is important for antimuscarinic activity. Tropic acid contains an asymmetric carbon which results in optical isomers. Alkaloids containing these isomers differ in antimuscarinic activity and potency. Atropine is a racemic mixture of d - and l -hyoscyamine which is probably formed during the extraction process. l -Hyoscyamine possesses approximately twice the antimuscarinic potency of the racemic mixture (atropine). d -Hyoscyamine has essentially no peripheral antimuscarinic activity. l -Hyoscyamine is 8-50 times as potent in central antimuscarinic activity as d -hyoscyamine. l -Hyoscine (scopolamine) is more potent than d -hyoscine. Belladonna leaf is a mixture of hyoscyamine, scopolamine, and minor alkaloids. The principal alkaloid is hyoscyamine, which occurs as a racemic mixture (atropine). Pharmacologic activity of belladonna preparations results principally from the atropine content.

Homatropine occurs as a racemic mixture and is a semisynthetic tertiary amine derivative of mandelic acid and tropine. Methscopolamine bromide and homatropine methylbromide are the quaternary ammonium derivatives of scopolamine and homatropine, respectively; they differ structurally from their respective parent compounds by addition of a second methyl group at the nitrogen.

Synthetic Amine Compounds

Like the naturally occurring alkaloids and their semisynthetic derivatives, most synthetic tertiary amines and quaternary ammonium compounds are aminoalcohol esters; only tridihexethyl is not an ester. Because the structure-activity relationships of the synthetic amine compounds are complex, specialized references on medicinal chemistry should be consulted for more specific information.

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