The Function of Darifenacin Hydrobromide in over Active Bladder

2018-08-18

Introduction 

Studies on the binding affinities of darifenacin hydrobromide and human muscarinic receptor subtypes show strong selectivity for M receptors, a competitive muscarinic M3 receptor antagonist. M3 receptor excitation can cause bladder smooth muscle contraction and salivation, especially for the bladder, which can increase bladder volume and urinary urgency time. Darifenacin hydrobromide is becoming an effective drug for the treatment of over active bladder (OAB).

Pharmacologic Action

The muscarinic M3 receptor is involved in bladder smooth muscle, gastrointestinal smooth muscle, saliva production, and iris sphincter function. Therefore, controlling M3receptor is an important measure to improve bladder function. Darifenacin hydrobromide has a high affinity for the M receptor and is 59 times more selective for the M3 receptor than other receptor subtypes, so when darifenacin hydrobromide is used, which competitively binds to the M3 receptor, blocks M3-mediated smooth muscle contraction, inhibits involuntary contraction of the detrusor, and reduces bladder excitability. In this way, the threshold of unstable bladder contraction is increased, the frequency is decreased, and the bladder capacity is increased, which effectively relieves the symptoms of overactive bladder.

Function

Currently, the drugs used to treat overactive bladder syndrome are mainly anticholinergic receptor drugs. These drugs are mostly non-selective, such as tolterodine, which not only blocks the M3 receptor, but also blocks other receptor subtypes, which can cause many adverse reactions while treating OAB. Clinical safety data showed that after multiple doses of darifenacin treatment, the number of urinary incontinence and urination was reduced, the bladder volume increased, urgency was reduced, and the number of weekly urinary incontinence was reduced by 83%. In a multicenter, randomized and double-blind study, OAB patients were significantly less likely to have urinary incontinence, urinary frequency, urgency episodes, and severity than placebo after oral administration of darifenacin. At the same time, it was found that darifenacin was well tolerated and caused less adverse reactions in the central nervous system.

Pharmacokinetics and Metabolism

Darifenacin hydrobromide oral bioavailability is 15% to 19%, and food has no effect on absorption. After multi-dose oral darifenacin sustained-release tablets, the plasma concentration reached a peak at about 7 hours, and the plasma concentration reached a steady state after 6 days of continuous administration. The plasma protein binding rate of darifenacin hydrobromide is about 98%, which is mainly combined with α1-acid glycoprotein, and the apparent volume of distribution is about 163L. Darifenacin is metabolized by CYP2D6 and CYP3A4 of the liver microsomal cytochrome P450 enzyme system, and the main metabolites have no physiological activity. 60% of darifenacin hydrobromide is excreted by the kidneys, and 40% is excreted in the feces, mainly in the form of metabolites. The unmetabolized parent drug accounts for only 3%, the clearance rate is 32-40L, and the elimination half-life is about 13-19h.

References:

1. Zinner N, Susset J, Gittelman M, et al. Efficacy, tolerability and safety of darifenacin, an M(3) selective receptor antagonist: an investigation of warning time in patients with OAB[ J] .Int J Clin Pract , 2006, 60(1):119.

2. ANDERSSONKE. Antimuscarinics for treatment of overactive bladder [J]. Lancet Neurol, 2004, 3l(l): 46-53.

3. Newgreen DT, Naylor AM. Characterization of functional muscarinic receptors in human bladder[J]. Br J pharmacol, 1996, 119(Suppl): S218.

4. Kerbusch T, Wahlby U, Milligan PA, et al. Population pharmacokinetic modelling of darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first-pass metabolism CYP2D6 genotype and formulation-dependent bioavailability[J]. Br J Clin Pharmacol, 2003, 56(6): 639-652.

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