Analysis of pharmacological effects of drugs used for treatment of urinary disturbance based on anticholinergic and smooth muscle-relaxing effects.
Propiverine hydrochloride, oxybutynin hydrochloride and terodiline hydrochloride have both anticholinergic and antispasmodic effects, and are used for the management of urinary frequency and incontinence. The average standard therapeutic doses of these drugs differ greatly. We retrospectively analyzed their pharmacological effects with consideration given to muscarinic acetylcholine receptor binding affinities, anticholinergic activities, and inhibitory effects on KCl-induced contraction. Muscarinic acetylcholine receptor occupancies and the inhibitory ratios of the drugs for both acetylcholine-induced and KCl-induced contraction in a steady state after oral administration of standard doses were calculated based on pharmacokinetics and the receptor occupancy theory. The average muscarinic acetylcholine receptor occupancy and inhibitory ratio of acetylcholine-induced contraction were estimated to be 12.6+/-1.06% and 3.27+/-0.74%, respectively, with no significant differences found between the drugs for those parameters. A significant linear relationship was found between muscarinic acetylcholine receptor occupancy and the maximum ratio of increase in bladder urinary capacity. On the other hand, the inhibitory ratios of KCl-induced contraction varied from 0.01 to 0.48%. The present results suggest that muscarinic acetylcholine receptor occupancy is a principal determinant of the therapeutic effect of a drug used for treatment of urinary disturbance.
Takayanagi
Risa
R
Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
Mizushima
Haruhi
H
Ozeki
Takeshi
T
Yokoyama
Haruko
H
Iga
Tatsuji
T
Yamada
Yasuhiko
Y
D000818:Animals; D001561:Benzilates / Q000494:pharmacology; D002082:Butylamines / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D008333:Mandelic Acids / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D009119:Muscle Contraction / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology; D014549:Urinary Incontinence / Q000188:drug therapy
D001561:Benzilates; D002082:Butylamines; D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D010276:Parasympatholytics; C015586:propiverine; C010637:terodiline; C005419:oxybutynin