Trospium Chloride in the Management of Overactive Bladder

Abstract

Trospium chloride is an orally active, quaternary ammonium compound with antimuscarinic activity. It binds specifically and with high affinity to muscarinic receptors M(1), M(2) and M(3), but not nicotinic, cholinergic receptors. It is hydrophilic and does not cross the normal blood-brain barrier in significant amounts and, therefore, has minimal central anticholinergic activity. Peak plasma trospium chloride concentrations are attained approximately 5-6 hours after oral administration, which should occur before meals as concurrent food ingestion significantly reduces trospium bioavailability. Trospium chloride undergoes negligible metabolism by the hepatic cytochrome P450 system; few metabolic drug interactions are known. While trospium chloride dosage adjustments based on age or sex appear unwarranted, such adjustments may be needed in patients with severe renal impairment. Direct comparative studies in patients with overactive bladder indicate that trospium chloride is at least as effective as oxybutynin and tolterodine. Placebo-controlled studies have also confirmed the efficacy of trospium chloride in terms of improved urodynamic parameters; small-scale, noncomparative studies have documented significant trospium chloride-induced improvements in patients with reflex neurogenic bladder, postoperative bladder irritation and radiation-induced cystitis; and observational studies including >10,000 patients have also revealed favourable findings for trospium chloride, including a marked decrease in incontinence episodes and substantial improvement in health-related quality of life. Trospium chloride is generally well tolerated, and significantly more so than immediate-release oxybutynin. The most frequent adverse events, occurring in >1% of trospium chloride-treated patients, are dry mouth, dyspepsia, constipation, abdominal pain and nausea. Available for many years in several countries outside North America, trospium chloride is likely to develop an important role in the management of overactive bladder following its approval in the US on 28 May 2004.

Pharmacodynamics of Overactive Bladder Drugs: Shifting the Curve

“…This means that the antagonist molecule maintains the receptor in its inactive state while it is bound but can be reversibly displaced by an agonist, depending on the concentrations of agonist and drug; both compete reversibly for the receptor [4]. The antimuscarinics used in the treatment of OAB, such as oxybutynin, tolterodine, darifenacin, solifenacin, fesoterodine, and trospium, bind competitively to the muscarinic receptor, inhibit acetylcholine binding, and prevent involuntary bladder contractions but can be displaced by acetylcholine, depending on the relative concentrations of acetylcholine or the antimuscarinic agent [5,7].…”

“…Most antimuscarinics bind to more than one muscarinic receptor subtype [7,26]; however, there are differences in the degree of drug selectivity for the five subtypes (Table 2). For OAB, the variation in the M 3 :M 2 binding ratio among the different drugs seems to bestow specific efficacy and tolerability characteristics.…”

“…Because M 1 and to a lesser extent M 2 predominate in the CNS, antimuscarinics with greater selectivity for M 3 over M 1 and M 2 receptors and limited CNS penetration (eg, trospium) will have a reduced risk of adverse cognitive events, which is particularly bothersome in cholinergically challenged older patients or patients with a high cholinergic polypharmacy burden [7,33]. Other agents relatively selective for M 3 but able to cross the BBB (eg, darifenacin) cause some CNS events (eg, dizziness and asthenia), but these may be limited because of the small proportion of M 3 receptors in the brain and the potential for darifenacin to be pumped out of the brain.…”

“…In the case of fesoterodine, the parent is inactive and is rapidly and extensively metabolized to 5-HMT [37]. Trospium has a very low propensity for interaction with CNS-targeting agents because its ability to cross the human BBB is limited [7,21], and it has been shown that concomitant administration of trospium does not affect the efficacy of galantamine in patients with Alzheimer's disease [55].…”

Comparison of the efficacy and tolerability of solifenacin succinate with or without previous use of trospium chloride

“…This is an anticholinergic that mainly has an anti-muscarinic activity, but also with ganglionar action. Trospium chloride has the advantage of not crossing the blood-brain barrier and therefore has very few metabolic and drug interactions-it is not metabolized by cytochrome P450 isozymes [4,5]; only 15% has hepatic metabolization and 80% is eliminated by the kidneys as an unchanged drug. It seems to be as effective as oxybutynin and tolterodine with an important decrease in incontinence episodes and improvement in health-related quality of life [6].…”