Trospium chloride
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| Systematic (IUPAC) name | |
|---|---|
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3‑(2‑hydroxy-2,2‑diphenylacetoxy)spiro[bicyclo[3.2.1]octane-8,1'‑pyrrolidin]-1'‑ium chloride | |
| Clinical data | |
| Trade names | Sanctura,Inkontan, Spasmolyt, Trosec and SpasmexTrospamexin |
| AHFS/Drugs.com | monograph |
| Pregnancy category |
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| Legal status | |
| Legal status |
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| Pharmacokinetic data | |
| Protein binding | 50–85% |
| Biological half-life | 20 hours |
| Identifiers | |
| CAS Number | 10405-02-4 |
| ATC code | G04BD09 (WHO) |
| PubChem | CID 107979 |
| DrugBank | DB00209 |
| ChemSpider |
10482307  |
| UNII |
1E6682427E |
| ChEMBL | CHEMBL1201344 |
| Chemical data | |
| Formula | C25H30ClNO3 |
| Molar mass | 427.964 g/mol |
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Trospium chloride (INN) is a muscarinic antagonist urinary antispasmodic.[1]
It was developed and patented[2] by Dr. Robert Pfleger GmbH (Germany) and is sold under the brand name Sanctura in the US, Tropez OD in India, Trosec in Canada, Regurin and Flotros in the United Kingdom, Spasmex in Germany, Russia, Turkey, Argentina, Chile and Israel and Spasmolyt manufactured by Madaus in Germany and marketed in Germany, Austria, Bulgaria, Denmark, Finland, Luxembourg, Poland, Thailand, Malaysia and Middle-East countries. It is available in Egypt under the brand name Spasmex by Ferring pharmaceuticals. Also it is manufactured by Montavit in Europe under the trade name Inkontan and it is available as 15 mg and 30 mg film-coated tablets.
Medical uses
Trospium chloride tablets, a muscarinic antagonist, are indicated for the treatment of overactive bladder with symptoms of urge incontinence and frequent urination.[3][4][5][6][7][8]
Adverse effects
Contraindications
Trospium chloride is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma and in patients who are at risk for these conditions. Trospium chloride is also contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.
Risk of urinary retention
Trospium chloride should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.
Decreased gastrointestinal motility
Trospium chloride should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention . Trospium chloride, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis, intestinal atony and myasthenia gravis.
Narrow-angle glaucoma
In patients being treated for narrow-angle glaucoma, trospium chloride should only be used if the potential benefits outweigh the risks and in that circumstance only with careful monitoring.
Renal impairment
Dose modification is recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min). In such patients, trospium chloride should be administered as 20 mg once a day at bedtime .
Hepatic impairment
Caution should be used when administering trospium chloride in patients with moderate or severe hepatic impairment .
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of trospium chloride in pregnant women. Trospium chloride was not teratogenic at statistically significant levels in rats or rabbits administered doses up to 200 mg/kg/day. This corresponds to systemic exposures up to approximately 9 and 16 times, respectively (based on AUC), the clinical exposure at the maximum recommended human dose (MRHD) of 40 mg. However, in rabbits, one fetus in each of the three treated dose groups (0.5, 0.3, and 16 times the exposures at the MRHD) demonstrated multiple malformations, including umbilical hernia and skeletal malformations. A no effect level (20 mg/kg/day in rats and rabbits) for maternal and fetal toxicity was observed at levels approximately equivalent to the clinical exposure at the MRHD. No developmental toxicity was observed in the offspring of female rats exposed pre- and post-natally to up to 200 mg/kg/day. Trospium chloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing mothers
Trospium chloride (2 mg/kg PO and 50 μg/kg IV) was excreted, to a limited extent (<1%), into the milk of lactating rats (primarily parent compound). It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when trospium chloride is administered to a nursing woman. Trospium chloride should be used during lactation only if the potential benefit justifies the potential risk to the newborn.
Pediatric use
The safety and effectiveness of trospium chloride in pediatric patients have been studied in some papers suggesting a 20 mg/day for children older than 6 years,some studies suggested 40 mg/day divided q12h (adult dose) for children with a body weight >40 kg.
Mechanism of action
Trospium chloride is a muscarinic antagonist. Trospium chloride antagonizes the effect of acetylcholine on muscarinic receptors in cholinergically innervated organs including the bladder. Its parasympatholytic action reduces the tonus of 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.
Placebo-controlled studies employing urodynamic variables were conducted in patients with conditions characterized by involuntary detrusor contractions. The results demonstrate that trospium chloride increases maximum cystometric bladder capacity and volume at first detrusor contraction.
Pharmacokinetics
Review[9]
Absorption
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 to 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.
Effect of food
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.
Distribution
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.
Metabolism
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.
Excretion
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
References
- ↑ Pak RW, Petrou SP, Staskin DR (December 2003). "Trospium chloride : a quaternary amine with unique pharmacologic properties". Curr Urol Rep 4 (6): 436–40. doi:10.1007/s11934-003-0023-1. PMID 14622495.
- ↑ DE patent 1194422, Bertholdt H, Pfleger R, Schulz W, "[Verfahren zur Herstellung von Azoniaspironortropanderivaten] (A process for preparing azonia-spirono-tropane derivatives)", issued 1965-06-10, assigned to Dr. Robert Pfleger Chemische Fabrik GmbH
- ↑ Rovner ES (2004). "Trospium chloride in the management of overactive bladder". Drugs 64 (21): 2433–46. doi:10.2165/00003495-200464210-00005. PMID 15482001.
- ↑ Singh-Franco D, Machado C, Tuteja S, Zapantis A (May 2005). "Trospium chloride for the treatment of overactive bladder with urge incontinence". Clin Ther 27 (5): 511–30. doi:10.1016/j.clinthera.2005.05.008. PMID 15978301.
- ↑ Zinner NR (July 2005). "Trospium chloride: an anticholinergic quaternary ammonium compound for the treatment of overactive bladder". Expert Opin Pharmacother 6 (8): 1409–20. doi:10.1517/14656566.6.8.1409. PMID 16013990.
- ↑ Madersbacher H, Rovner E (July 2006). "Trospium chloride: the European experience". Expert Opin Pharmacother 7 (10): 1373–80. doi:10.1517/14656566.7.10.1373. PMID 16805722.
- ↑ Staskin DR (November 2006). "Trospium chloride: Distinct among other anticholinergic agents available for the treatment of overactive bladder". Urol. Clin. North Am. 33 (4): 465–73, viii. doi:10.1016/j.ucl.2006.06.006. PMID 17011382.
- ↑ Biastre K, Burnakis T (February 2009). "Trospium chloride treatment of overactive bladder". Ann Pharmacother 43 (2): 283–95. doi:10.1345/aph.1L160. PMID 19193592.
- ↑ Doroshyenko O, Jetter A, Odenthal KP, Fuhr U (2005). "Clinical pharmacokinetics of trospium chloride". Clin Pharmacokinet 44 (7): 701–20. doi:10.2165/00003088-200544070-00003. PMID 15966754.
External links
- Trospium chloride at the US National Library of Medicine Medical Subject Headings (MeSH)
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