Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677481 (urinary frequency)
 1,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trospium chloride, a quaternary amine with anticholinergic properties, is used for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and urinary frequency. The pharmacokinetics of trospium chloride have been investigated in healthy volunteers, in patients with renal and hepatic impairment, and in those with symptoms of overactive bladder, after oral, intravenous and intravesical administration. After oral administration, absorption of the hydrophilic trospium chloride is slow and incomplete. Peak plasma concentrations (Cmax) of approximately 4 ng/mL are reached 4-5 hours after administration of a 20 mg immediate-release preparation. The mean bioavailability is approximately 10% and decreases by concomitant food intake (to a mean of 26% of the fasting area under the plasma concentration-time curve [AUC]). Trospium chloride displays dose proportional increases in AUC and Cmax after a single dose within the clinically relevant dose range (20-60 mg). The mean volume of distribution is approximately 350-800 L. The drug is minimally (mean approximately 10%) metabolised to spiroalcohol by hydrolysis, is 50% plasma protein bound and does not cross the blood-brain barrier. Urinary excretion of the parent compound plays a major role in the disposition of the drug, with a mean renal clearance of 29 L/h (accounting for approximately 70% of total clearance) and a mean elimination half-life ranging from 10 to 20 hours. Elimination of the drug is slowed in patients with renal insufficiency, and population pharmacokinetic modelling has demonstrated that drug clearance is correlated with serum creatinine concentration. Thus, dose reduction is needed in patients with severe renal impairment (i.e. creatinine clearance < 30 mL/min). To date, no clinically relevant pharmacokinetic drug-drug interactions have been identified; the drug does not bind to any of the drug metabolising cytochrome P450 enzymes. The pharmacokinetics of the drug are compatible with twice-daily administration. A once-daily schedule may also be appropriate, but this regimen needs formal clinical evaluation.
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PMID:Clinical pharmacokinetics of trospium chloride. 1596 54

The International Continence Society has defined overactive bladder (OAB) as urinary urgency, with or without urge urinary incontinence, usually with urinary frequency and nocturia. Approximately 17% of men and women in the US report OAB symptoms, which can affect quality of life. Trospium chloride, which has recently been introduced in the US as Sanctura, has been prescribed for > 10 years in Europe as, for example, Spasmo-lyt, Regurin and Spasmex. Trospium chloride has been shown to be effective in relieving OAB symptoms, and has a favourable safety profile, showing < 1% difference for all adverse events compared with placebo, except for dry mouth, constipation and headache. Metabolic drug-drug interactions are unlikely, given that trospium chloride is not metabolised by cytochrome P450 isozymes. The fast-acting efficacy of trospium chloride, coupled with its good safety profile and tolerability, make it an important new option for treatment of OAB.
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PMID:Trospium chloride: an anticholinergic quaternary ammonium compound for the treatment of overactive bladder. 1601 90

Overactive bladder (OAB) is a common condition characterised by the symptoms of urinary frequency and urgency, with or without urge incontinence and nocturia. The prevalence of OAB increases markedly with age in both men and women. OAB can have a detrimental effect on physical functioning and psychological well-being, as well as significantly reducing quality of life. Antimuscarinic therapy -- with or without behavioural therapy -- represents the most common treatment for patients with OAB. Several antimuscarinic agents are currently available for the treatment of OAB in adults, including oxybutynin, tolterodine, trospium chloride, darifenacin and solifenacin. The antimuscarinics all appear to exert their clinical effect through inhibition of the bladder muscarinic receptors, but they vary both in structure and in their functional profile. While efficacy has been demonstrated in adult populations (including patients >65 years of age), few studies have been reported specifically in a geriatric population, and antimuscarinics are often underutilised in the elderly despite the marked increase in the prevalence of OAB in this age group. One explanation for this apparent underuse of an effective treatment option may be concerns about the frequency of anticholinergic adverse events, such as dry mouth; the likelihood of detrimental CNS effects, including cognitive impairment and sleep disturbances; and the potential for harmful interactions with existing pharmacotherapy. When selecting an antimuscarinic agent for the management of an elderly patient presenting with OAB, in addition to considering evidence of clinical efficacy and tolerability, issues of safety specific to an older population should be borne in mind. In particular, the likelihood of detrimental CNS effects should be considered, including cognitive impairment and sleep disturbances, secondary to anticholinergic load. Oxybutynin and tolterodine have both been associated with cognitive adverse events and effects on sleep architecture and quality. In contrast, trospium chloride and darifenacin do not appear to be associated with cognitive adverse events and trospium chloride does not negatively affect sleep architecture or quality. Biotransformation by the cytochrome P450 (CYP450) system is an important step in the activation or elimination of a large number of drugs, including oxybutynin, tolterodine, darifenacin and solifenacin, raising the possibility of clinically relevant and potentially serious drug interactions. In elderly patients, such interactions are of particular relevance given the potential for declining activity of certain members of the CYP450 family combined with decreased hepatic blood flow, which can reduce first-pass metabolism and thus the bioavailability of drugs metabolised via this route. Of the antimuscarinic agents used to treat OAB, only trospium chloride is not extensively metabolised in the liver by the CYP450 system and is excreted largely as the active parent compound in the urine. This paper provides an overview of the pathophysiology of OAB and reviews current approaches to achieving a differential diagnosis and selecting appropriate treatment for the older patient. The pharmacology and clinical effects of current medication for the treatment of OAB symptoms in patients defined by the OAB pharmacology literature as 'elderly' are also reviewed.
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PMID:Overactive bladder in the elderly: a guide to pharmacological management. 1636 85

The cornerstone of treatment for syndrome of inappropriate antidiuretic hormone secretion (SIADH) is fluid restriction. Demeclocycline is sometimes used but its efficacy is based solely on laboratory endpoints. This drug also has the adverse effects shared by all tetracyclines. Tolvaptan antagonises receptors for arginine vasopressin, a hormone that regulates blood sodium levels by stimulating renal water resabsorption. Tolvaptan is now authorised in the European Union for the treatment of hyponatraemia due to SIADH. Clinical evaluation of tolvaptan in this setting is based on two comparative double-blind placebo-controlled trials including a total of 448 patients with SIADH or hyponatraemia from various other causes. The two trials were combined for analysis. However, because of major methodological flaws, no firm conclusions can be drawn concerning the efficacy in SIADH patients. It remains to be shown that tolvaptan improves symptoms of hyponatraemia (especially neuropsychiatric disorders) or even that it corrects hyponatraemia in these patients. The adverse effects observed in clinical trials were predictable, given the mechanism of action, and included thirst and dry mouth (respectively 16% and 8.4% of patients), hypernatraemia (1.7%), pollakiuria and polyuria. Tolvaptan is metabolised by the cytochrome P450 isoenzyme CYP 3A4, hence a high risk of pharmacokinetic interactions. In summary, there is no reason to use tolvaptan to treat the syndrome of inappropriate antidiuretic hormone secretion: its efficacy on symptoms or even on sodium levels has not been demonstrated, and its adverse effect profile is poorly documented. It is better to concentrate on non-drug management.
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PMID:Tolvaptan: any evidence of efficacy in SIADH? 2118 Mar 68