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Download Darifenacin Hydrobromide
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Darifenacin Hydrobromide Overactive Bladder Frequency • 8 or more visits to the toilet per 24 hours Urination at night • 2 or more visits to toilet during sleeping hours Urgency Urge Incontinence • Sudden, strong desire to urinate • Sudden & involuntary loss of urine OAB Muscarinic receptors Treatment Antimuscarinic drugs First-generation----e.g Oxybutynin (primarily selective) Second-generation---- e.g Tolterodine (balanced selective M2/M3) New drugs----e.g Darifenacin (M3 selective receptor antagonis) Darifenacin hydrobromide ----A potent and competitive M3 selective receptor antagonist a white to almost white, crystalline powder. Brand name : Emselex Synonyms: (S)-2-{1-[2-(2,3-Dihydrobenzofuran-5yl)Ethyl]-3-Pyrrolidinyl}-2,2-Diphenylacetamide Hydrobromide HBr Manufacturer: Novartis & Pfizer Oct.28.2004—European Commission has granted Marketing Authorization Emselex for the treatment of overactive. Dec.23.2004—FDA has approved darifenacin HBr for the treatment of OAB. The structure-activity relationship Part A imidazole ring being replaced by alkyl will significantly affect anticholinergic receptor activity and selectivity; Part B for the connecting part, usually two carbon anticholinergic activity at best. carbon chain growes, activity will decrease; The structure-activity relationship Part C of the amide or H atom, anticholinergic activity and M3 receptor selectivity better, Nmonosubstituted, N, Ndisubstituted or ester is anticholinergic activity decreases even without anticholinergic activity. The structure-activity relationship Part D benzene generally no replaced if heterocyclic or alkyl replace it activity decreases, one of benzene may be replaced by six atom ring : Oxybutynin. Synthesis: Darifenacin Darifenacin is a competitive muscarinic receptor antagonist labeled for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. The symptoms of OAB are thought to result from involuntary contractions of the detrusor muscle during the bladder filling phase. M2,M3 muscarinic receptors with a ratio of 3:1 exist in human bladder tissue. Although the density of M2 receptors is much greater than that of the M3 subtype, M3 receptor subtype is predominant in the mediation of bladder contraction. M3 are responsible for urinary bladder contraction,gastrointestinal smooth muscle contraction, saliva production, and iris sphincter regulation. Darifenacin has been shown to have high affinity and selectivity for the muscarinic M3 receptor, with low selectivity for the other muscarinic receptor subtypes. Effect Help to reduce the incidence of urinary incontinence . Increase urinary bladder reserves . Reduce the frequency of urination. Reduce the oppressive sense of eager to urinate and urinary urgency sense. dry mouth constipation blurred vision heat prostration others Pharmacokinetic properties Darifenacin is metabolised by CYP3A4 and CYP2D6. CYP3A4 CYP2D6 Absorption first-pass metabolism 7.5 mg daily doses 15 mg daily doses ENABLEX® 7.5 mg (N = 68 EM, 5 PM) AUC2 4 (ng.h/ mL) Cma Cavg Tma x (ng/ x (ng/ mL) (h) mL) ENABLEX®15 mg (N = 102 EM, 17 PM) t1/2 (h) E 12.43 29.24 2.01 1.22 6.49 M (5.64) (15.47) (1.04) (0.64) (4.19) a P 67.56 M (13.13) AUC24 (ng.h/ mL) Cma Cavg Tma x (ng/ x (ng/ mL) (h) mL) t1/2 (h) 12.05 88.90 5.76 3.70 7.61 (12.37) (67.87) (4.24) (2.83) (5.06) b 4.27 2.81 5.20 157.71 9.99 6.58 6.71 19.95 c 7.40 d (0.98) (0.55) (1.79) (77.08) (5.09) (3.22) (3.58) Distribution lipophilic base 98% bound to plasma proteins Vss =163 litres Metabolism Darifenacin metabolism (oral administration) CYP3A4 CYP2D6 in the liver CYP3A4 in the gut wall three main metabolic routes monohydroxylation in the dihydrobenzofuran ring dihydrobenzofuran ring opening N-dealkylation of the pyrrolidine nitrogen O CONH2 N CYP3A4 HO O CONH2 N O CONH2 N CYP2D6 OH CONH2 N O CONH2 N CYP2D6/CYP3A4 CONH2 NH Excretion Following administration of an oral dose of 14C-darifenacin solution to healthy volunteers, approximately 60% of the radioactivity was recovered in the urine and 40% in the faeces. Only a small percentage of the excreted dose was unchanged darifenacin (3%). Efficacy against urinary frequency NICE states that : there is NO evidence of clinically important efficacy differences among antimuscarinic drugs Adverse events Selected adverse events Selection of antimuscarinic drug for treatment of OAB NICE states that : Non-proprietary, immediate-release oxybutynin, which is the most costeffective of the available options, should be offered as first-line antimuscarinic if bladder training is ineffective. If not tolerated, darifenacin, solifenacin, tolterodine, trospium or an extendedrelease or transdermal formulations of oxybutynin should be considered. MEMBERS 0440101 0440118 0441707 0440220 0440211 Cui Sisi Wang Lutai Lu Lisha Wang Yan Gao Wei