Pharmacodynamics of Overactive Bladder Drugs: Shifting the Curve

Abstract

Understanding the role of pharmacodynamics in determining a drug's effect helps prescribing physicians choose the most appropriate agent and regimen to achieve the optimal balance of beneficial and adverse effects. The pharmacodynamic profile describes how a drug exerts its effects on the body, whether by physical, chemical, or enzymatic activity, or through receptor interaction at a cellular level. Drug-receptor binding results in biologic and physiologic effects, while the nature of binding defines the drug activity and dose-response relationship. Muscarinic receptor antagonists (antimuscarinics) are used in the treatment of overactive bladder. Antimuscarinics competitively block acetylcholine binding to muscarinic receptors in the detrusor smooth muscle and urothelium/suburothelium of the bladder. To make pharmacodynamic principles more relevant to the clinical urologist, this review summarizes clinical pharmacodynamic concepts, using the current antimuscarinics prescribed for overactive bladder and other urologic disorders as examples.

Are we shortchanging frail older people when it comes to the pharmacological treatment of urgency urinary incontinence?

“… 5‐HMT, 5‐hydroxymethyl tolterodine; CNS, central nervous system; CYP450, cytochrome P450; FES, fesoterodine; NA, not available; P‐gp, permeability glycoprotein; TOL, tolterodine. Adapted from Staskin and Callegari . …”

“…Pharmacological characteristics of orally administered antimuscarinics approved for treatment of overactive bladder -hydroxymethyl tolterodine; CNS, central nervous system; CYP450, cytochrome P450; FES, fesoterodine; NA, not available; P-gp, permeability glycoprotein; TOL, tolterodine. Adapted from Staskin(74) and Callegari(75).…”

Rationale for the Use of Anticholinergic Agents in Overactive Bladder With Regard to Central Nervous System and Cardiovascular System Side Effects

“…M 2 receptors located in the bladder may play a role in detrusor contraction by reversing β-adrenoceptor-mediated smooth muscle relaxation, indirectly enhancing M 3 receptor mediated contractions, or increasing urgency sensations [68-71]. …”

“…Although M 2 receptors dominate M 3 receptors in the bladder in a 3:1 ratio, M 3 receptors seem to be the most important muscarinic receptors for detrusor contraction [ 2 , 67 ]. M 2 receptors located in the bladder may play a role in detrusor contraction by reversing β-adrenoceptor-mediated smooth muscle relaxation, indirectly enhancing M 3 receptor mediated contractions, or increasing urgency sensations [ 68 - 71 ].…”

“…In another review article about the pharmacodynamics of OAB drugs it was stated that it was not possible to show causal relationships between the receptor binding properties and the adverse effects of these drugs owing to the lack of clinical head-to-head studies, but general acceptance existed for such a relationship between the two [ 68 ]. In this context, darifenacin and solifenacin, which had high and moderate M 3 versus M 2 selectivity, respectively ( Table 2 ), were found to cause dry mouth and constipation more than trospium, tolterodine, and fesoterodine, which had no M 3 versus M 2 selectivity [ 2 , 7 , 74 ].…”