Overactive urinary bladder disease can be successfully treated with muscarinic antagonists, primarily 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. Trospium is as effective as oxybutynin, with better tolerability. Solifenacin is newly approved for overactive 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 Mj over M2 and M3 receptors. However, piren-zepine's affinities for Mj and M4 receptors are comparable, so it does not possess total Mj selectivity.
Telenzepine is an analog of pirenzepine that has higher potency and similar selectivity for Mj muscarinic 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 Mj receptors 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 H2 antagonists 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.
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