Trospium chloride is a muscarinic antagonist used to treat overactive bladder. It has side effects typical of this class of drugs, namely dry mouth, stomach upset, and constipation; these side effects cause problems with people taking their medicine as directed. However it does not cause central nervous system side effects like some other muscarinic antagonists. Chemically it is a quaternary ammonium cation which causes it to stay in periphery rather than crossing the blood–brain barrier. It works by causing the smooth muscle in the bladder to relax. It was patented in 1966 and approved for medical use in 1974. It was first approved in the US in 2004, and an extended release version was brought to market in 2007. It became generic in the EU in 2009, and the first extended-release generic was approved in the US in 2012.
Medical uses Trospium chloride is used for the treatment of overactive bladder with symptoms of urge incontinence and frequent urination. It is also used in a combination drug, xanomeline/trospium chloride (Cobenfy), where it reduces the peripheral side effects of the antipsychotic drug xanomeline. It should not be used with people who retain urine, who have severe digestive conditions, myasthenia gravis, narrow-angle glaucoma, or tachyarrhythmia. It should be used with caution in people who have problems with their autonomous nervous system (dysautonomia) or who have gastroesophageal reflux disease, or in whom fast heart rates are undesirable, such as people with hyperthyroidism, coronary artery disease and congestive heart failure. There are no adequate and well-controlled studies of trospium chloride in pregnant women and there are signs of harm to the fetus in animal studies. The drug was excreted somewhat in the milk of nursing mothers. The drug was studied in children.
Side effects Side effects are typical of gastrointestinal effects of anticholinergic drugs, and include dry mouth, indigestion, and constipation. These side effects lead to problems with adherence, especially for older people. The only CNS side effect is headache, which was very rare. Tachycardia is a rare side effect.
Pharmacology
Mechanism of action
Trospium chloride is a muscarinic antagonist. Trospium chloride blocks the effect of acetylcholine on muscarinic receptors organs that are responsive to the compounds, including the bladder. Its parasympatholytic action relaxes the smooth muscle in the bladder. Receptor assays showed that trospium chloride has negligible affinity for nicotinic receptors as compared to muscarinic receptors at concentrations obtained from therapeutic doses. The drug has high and similar affinity for all five of the muscarinic acetylcholine receptor subtypes, including the M1, M2, M3, M4, and M5 receptors.
Pharmacokinetics After oral administration, less than 10% of the dose is absorbed. Mean absolute bioavailability of a 20 mg dose is 9.6% (range: 4.0 to 16.1%). Peak plasma concentrations (Cmax) occur between 5 and 6 hours post-dose. Mean Cmax increases greater than dose-proportionally; a 3-fold and 4-fold increase in Cmax was observed for dose increases from 20 mg to 40 mg and from 20 mg to 60 mg, respectively. AUC exhibits dose linearity for single doses up to 60 mg. Trospium chloride exhibits diurnal variability in exposure with a decrease in Cmax and AUC of up to 59% and 33%, respectively, for evening relative to morning doses. Administration with a high fat meal resulted in reduced absorption, with AUC and Cmax values 70 to 80% lower than those obtained when trospium chloride was administered while fasting. Therefore, it is recommended that trospium chloride should be taken at least one hour prior to meals or on an empty stomach.
Protein binding ranged from 50 to 85% when concentration levels of trospium chloride (0.5 to 50 ng/mL) were incubated with human serum in vitro. The 3H-trospium chloride ratio of plasma to whole blood was 1.6:1. This ratio indicates that the majority of 3H-trospium chloride is distributed in plasma. The apparent volume of distribution for a 20 mg oral dose is 395 (± 140) liters. The metabolic pathway of trospium in humans has not been fully defined. Of the 10% of the dose absorbed, metabolites account for approximately 40% of the excreted dose following oral administration. The major metabolic pathway is hypothesized as ester hydrolysis with subsequent conjugation of benzylic acid to form azoniaspironortropanol with glucuronic acid. Cytochrome P450 is not expected to contribute significantly to the elimination of trospium. Data taken from in vitro human liver microsomes investigating the inhibitory effect of trospium on seven cytochrome P450 isoenzyme substrates (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4) suggest a lack of inhibition at clinically relevant concentrations. The plasma half-life for trospium chloride following oral administration is approximately 20 hours. After oral administration of an immediate-release formulation of 14C-trospium chloride, the majority of the dose (85.2%) was recovered in feces and a smaller amount (5.8% of the dose) was recovered in urine; 60% of the radioactivity excreted in urine was unchanged trospium. The mean renal clearance for trospium (29 L/hour) is 4-fold higher than average glomerular filtration rate, indicating that active tubular secretion is a major route of elimination for trospium. There may be competition for elimination with other compounds that are also renally eliminated.
Chemistry Anticholinergic drugs used to treat overactive bladder were all amines as of 2003. Quaternary ammonium cations in general are more hydrophilic than other amines and don't cross membranes well, so they tend to be poorly absorbed from the digestive system, and to not cross the blood–brain barrier. Oxybutynin, tolterodine, darifenacin, and solifenacin are tertiary amines while trospium chloride and propantheline are quaternary amines.
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