China
Africa
Explore chapters and articles related to this topic
Cholinergic Antagonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Vishal S. Gulecha, Manoj S. Mahajan, Aman Upaganlawar, Abdulla Sherikar, Chandrashekhar Upasani
Darifenacin is a drug meant for the treatment of UI. Its mechanism of action includes blocking of muscarinic M3 receptor responsible for bladder muscle contractions, thereby decreases the urgency to urinate. About 98% of darifenacin is bound to plasma proteins mainly α1-acid–glycoprotein (α1-AGP). The drug has high aVd, which is about 163 l (Steers, 2006). Darifenacin is extensively metabolized by cytochrome P450 (CYP450) enzymes, CYP2D6 and CYP3A4. The metabolic pattern of this drug has three steps including monohydroxylation in the dihydrobenzofuran ring, opening of previously formed dihydrobenzofuran ring, and at last pyrrolidine nitrogen undergoes N-dealkylation. Darifenacin is contraindicated in urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. The adverse effects of darifenacin are similar to other antimuscarinics and include dry mouth, dry eyes, constipation, dyspepsia, abdominal pain, nausea, diarrhea, and dizziness (Steers, 2006).
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Darifenacin is a competitive muscarinic antagonist indicated for treatment of overactive bladder (Abrams and Andersson 2007; Steers 2006). Darifenacin has a greater affinity for the M3 receptor than for the other known muscarinic receptors (9- and 12-fold greater affinity for M3 compared to M1 and M5, respectively, and 59-fold greater affinity for M3 compared to both M2 and M4 receptors). Darifenacin is mainly metabolized by hepatic CYP2D6 and 3A4 (Leone Roberti Maggiore et al. 2012). The initial products of the hydroxylation and N-dealkylation pathways are the major circulating metabolites (Leone Roberti Maggiore et al. 2012), but they are unlikely to contribute significantly to the overall clinical effect of darifenacin.
D
Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
After an oral dose, darifenacin is subject to extensive first-pass metabolism and has a bioavailability of about 15–19%. Darifenacin is metabolised in the liver by the cytochrome P450 isoenzymes CYP2D6 and CYP3A4.
Evaluating vibegron for the treatment of overactive bladder
Published in Expert Opinion on Pharmacotherapy, 2021
Tomasz Rechberger, Andrzej Wróbel
In vitro studies have shown that vibegron inhibits EFS-induced bladder detrusorcontractile activity. Studies have also been carried out to assess the effect of the combined use of the drug with darifenacin, tolterodine, and oxybutynin. The synergistic effect was visible in all combinations. The strongest was in the case of tolterodine, slightly weaker for oxybutynin and the weakest for darifenacin. The combined use of methoctramine (the M2 selective antagonist) with vibegron did not show a synergistic effect. However, its administration before darifenecin and vibegron has been shown to increase their inhibitory effect on bladder contractile activity [7]. The combined use of the β3AR agonist with antimuscarinic drugs has been shown to induce a more pronounced relaxation effect if a nonselective cholinolytic agents blocking both M2 and M3 receptors are used than if a selective M3 antagonist was administered.
Managing autonomic dysfunction in Parkinson’s disease: a review of emerging drugs
Published in Expert Opinion on Emerging Drugs, 2020
Dinkar Kulshreshtha, Jacky Ganguly, Mandar Jog
Oxybutynin and tolterodine are nonselective muscarinic blockers with maximum risk of central side effects. Darifenacin and solifenacin are M3- selective antagonists. Trospium chloride is a nonselective muscarinic antagonist but it does not cross BBB because of low lipid solubility [54]. However, a review of concomitant medications is necessary to assess a patient’s anticholinergic burden, and just adding an anti-muscarinic medication may increase the risk for falls, cognitive impairment and all-cause mortality [55]. In one study, amantadine, as an N-methyl-D-aspartate (NMDA) antagonist in a dose of 150 mg/day decreased urinary frequency, urgency, and urge incontinence without cognitive side effects [56]. α-adrenoceptor blockers decrease urethral resistance during voiding. There is a significant risk of postural hypotension with this class of medications and in PD patients, they should be used sparingly, if at all.
Managing urinary incontinence in women - a review of new and emerging pharmacotherapy
Published in Expert Opinion on Pharmacotherapy, 2018
Riccardo Bientinesi, Emilio Sacco
Vibegron is a novel, potent, and selective β3-adrenoreceptor agonist that showed pharmacological activity in vitro and in vivo; in fact, it dose-dependently increased bladder capacity, decreased micturition pressure, and increased bladder compliance in rhesus monkeys [24,25]. In a recent study in vitro and on rhesus monkeys, the relaxation effect of vibegron was enhanced when combined with muscarinic antagonists, but differentially influenced by muscarinic receptor subtype selectivity. The effect was greater when vibegron was co-administered with tolterodine, a nonselective antimuscarinic, compared with co-administration with darifenacin, a selective M3 antagonist. Furthermore, a synergistic effect for bladder strip relaxation was observed with the combination of a β3-AR agonist and tolterodine in contrast to simple additivity with darifenacin [25]. This may lead to achieve, in clinical practice, additional efficacy (with potential for an improved tolerability profile) by combining standard of care antimuscarinics with β3-AR agonists. A phase 2b, double-blind, placebo- and tolterodine-controlled RCT demonstrated that vibegron was effective and well tolerated in a total of 1,395 patients with OAB [26]. A recent multicenter, four-arm, parallel-group, placebo-controlled phase 3 RCT in 1,232 patients with OAB showed that vibegron 50 mg and 100 mg once daily for 12 weeks provided superior efficacy over placebo in the treatment of patients with OAB and was generally well tolerated, while no major safety issues were identified [27].