Patients with COPD, a condition that occurs more frequently in older patients, particularly chronic smokers, benefit from bronchodilators, especially antimuscarinic agents. Ipratropium, tiotropium (see Figure 8–3), aclidinium, and umeclidinium, synthetic analogs of atropine, are used as inhalational drugs in COPD either alone or in combination with a long-acting β-adrenoceptor agonist. The aerosol route of administration has the advantage of maximal concentration at the bronchial target tissue with reduced systemic effects. This application is discussed in greater detail in Chapter 20. Tiotropium (t1/2 25 hours) and umeclidinium (t1/2 11 hours) have a longer bronchodilator action than ipratropium (t1/2 2 hours) and can be given once daily because they dissociate slowly from M3 receptors. Aclidinium (t1/2 6 hours) is administered twice daily. Glycopyrrolate is now available in inhalational form for twice daily treatment of COPD. Tiotropium reduces the incidence of COPD exacerbations and is a useful adjunct in pulmonary rehabilitation to increase exercise tolerance. The hyperactive neural bronchoconstrictor reflex present in most individuals with asthma is mediated by the vagus, acting on muscarinic receptors on bronchial smooth muscle cells. Ipratropium and tiotropium are also used as inhalational drugs in asthma.
D. Cardiovascular Disorders
Marked reflex vagal discharge sometimes accompanies the pain of myocardial infarction (eg, vasovagal attack) and may depress sinoatrial or atrioventricular node function sufficiently to impair cardiac output. Parenteral atropine or a similar antimuscarinic drug is appropriate therapy in this situation. Rare individuals without other detectable cardiac disease have hyperactive carotid sinus reflexes and may experience faintness or even syncope as a result of vagal discharge in response to pressure on the neck, eg, from a tight collar. Such individuals may benefit from the judicious use of atropine or a related antimuscarinic agent.
Pathophysiology can influence muscarinic activity in other ways as well. Circulating autoantibodies against the second extracellular loop of cardiac M2 muscarinic receptors have been detected in some patients with idiopathic dilated cardiomyopathy and those afflicted with Chagas’ disease caused by the protozoan Trypanosoma cruzi. Patients with Graves’ disease (hyperthyroidism) also have such autoantibodies that may facilitate the development of atrial fibrillation. These antibodies exert parasympathomimetic actions on the heart that are prevented by atropine. In animals immunized with a peptide from the second extracellular loop of the M2 receptor, the antibody is an allosteric modulator of the receptor. Although their role in the pathology of heart diseases is unknown, these antibodies have provided clues to the molecular basis of receptor activation because their site of action differs from the orthosteric site where acetylcholine binds (see Chapter 2) and they favor the formation of receptor dimers.
E. Gastrointestinal Disorders
Antimuscarinic agents were used for peptic ulcer disease in the USA but are now obsolete for this indication (see Chapter 62). Antimuscarinic agents can provide some relief in the treatment of common traveler’s diarrhea and other mild or self-limited conditions of hypermotility. They are often combined with an opioid antidiarrheal drug, an extremely effective therapy. In this combination, however, the very low dosage of the antimuscarinic drug functions primarily to discourage abuse of the opioid agent. The classic combination of atropine with diphenoxylate, a nonanalgesic congener of meperidine, is available under many names (eg, Lomotil) in both tablet and liquid form (see Chapter 62).
F. Urinary Disorders