Medical uses
Trospium chloride is used for the treatment of overactive bladder with symptoms of urge incontinence and frequent urination. It shouldn't be used with people who urinary retention, retain urine, who have severe Human gastrointestinal tract#Disease, digestive conditions, myasthenia gravis, narrow-angle glaucoma, or tachyarrhythmia. It should be used in caution with 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. Trospium chloride is rated Pregnancy Category C, as there are no adequate and well-controlled studies of trospium chloride in pregnant women and there were 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.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.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 (pharmacology), 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. Area under the curve (pharmacokinetics), 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 Phase II metabolism#Phase II .E2.80.93 conjugation, 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.Chemical properties
Anticholinergic drugs used to treat overactive bladder were all Amine#Classification of amines, 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.History
The synthesis of trospium was described by scientists from Dr. Robert Pfleger Chemische Fabrik GmbH, Heinz Bertholdt, Robert Pfleger, and Wolfram Schulz, in US. Pat. No. 3,480,626 (the US equivalent to DE119442), and its activity was first published in the literature in 1967. The first regulatory approval was granted in Germany in August 1999 to Madaus AG for Regurin 20 mg Tablets.Medicines and Healthcare products Regulatory Agency. April 7, 201Society and culture
Marketing rights to the drug became subject to parallel import litigation in Europe in the case of Speciality European Pharma Ltd v Doncaster Pharmaceuticals Group Ltd / Madaus GmbH (Case No. A3/2014/0205) which was resolved in March 2015. Madaus had exclusively licensed the right to use the Regurin trademark to Speciality European Pharma Ltd. In 2009, when European patents expired on the drug, Doncaster Pharmaceuticals Group, a well known parallel importer, which had been selling the drug in the UK under another label, Ceris, which was used in France, began to put stickers on their packaging with the Regurin name. Speciality and Madaus sued and initially won based on the argument that 90% of prescriptions were already generic, but Doncaster appealed and won the appeal based on the argument that it could not charge a premium with a generic label. The case has broad implications for trade in the EU.Lexology. March 6, 2015Research
In 2007 Indevus partnered with Alkermes to develop and test an inhaled form of trospium chloride as a treatment for COPD; it was in Phase II trials at that time.UPI April 25, 200References
External links
* {{Muscarinic acetylcholine receptor modulators Tertiary alcohols Carboxylate esters Quaternary ammonium compounds Muscarinic antagonists Nitrogen heterocycles Spiro compounds Peripherally selective drugs Chlorides