restricted access 15. Iatrogenic Effects of Urologic Drugs on the Cardiovascular System
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Man survives earthquakes, epidemics, the horrors of disease, and agonies of the soul, but all the time his most tormenting tragedy has been, is, and ­ will always be, the tragedy of the bedroom. Leo Tolstoy INTRODUCTION Pharmacological agents for the management of urological disorders may exert cardiovascular effects. Medi­ cations for the treatment of overactive bladder syndrome, benign prostatic hyperplasia (BPH), hypogonadism, and erectile dysfunction may have hemodynamic effects via actions on the myocardium and peripheral vasculature. In par­ tic­ u­ lar, anticholinergic agents and beta-3 agonists are used for patients with overactive bladder syndrome, alpha-­ blockers for patients with BPH, testosterone replacement therapy for patients with hypogonadism, and phosphodiesterase-5 (PDE-5) inhibitors for treatment of erectile dysfunction. All ­ these agents represent the treatment of choice for relevant conditions and are used by millions of Americans. This chapter summarizes the available data and critically discusses the cardiovascular effects of medi­ cations used for management of urological disorders. ANTICHOLINERGIC DRUGS Muscarinic receptors mediate the actions of the parasympathetic ner­ vous system all over the ­ human body (Box 15-1). Currently, five subtypes of muscarinic receptors (M1 to M5 ) have been identified by pharmacological and molecular studies. Muscarinic receptors are found in the bladder, salivary glands, brain, eyes, gastrointestinal tract, and heart. M2 and M3 are the predominant types of muscarinic receptors in ­ humans; however , their relative distribution and functions vary across the dif­ fer­ ent organs and tissues of the body (1–3). M3 receptors seem primarily to mediate the contractile responses in the bladder, whereas M2 receptors seem to mediate parasympathetic activity in the CHAPTER 15 Iatrogenic Effects of Urologic Drugs on the Cardiovascular System Konstantinos Stavropoulos, Chrysoula Boutari, Konstantinos Imprialos, Vasilios Papademetriou, and Michael Doumas 176 / Iatrogenic Effects of Urologic Drugs on the Cardiovascular System Several anticholinergic agents are available in the United States for the treatment of overactive bladder, including oxybutynin, tolterodine, fesoterodine , darifenacin, solifenacin, and trospium.­ These agents differ in pharmacological profile and especially in selectivity for receptor subtypes. It should, therefore, be anticipated that anticholinergic agents ­ will differ in efficacy and safety profile. The effects of anticholinergic agents on heart rate and QT interval (see ­ Table 15-1) are presented in brief. Darifenacin shows M3 receptor selectivity and thus seems to exert limited action on the heart. Indeed, several studies showed that darifenacin produced no difference in heart rate than placebo, and the heart rate was significantly lower with darifenacin compared with tolterodine (6,8). In addition, no risk for QT interval prolongation was found with darifenacin. Similarly , oxybutynin shows M3 receptor selectivity, and no difference in heart rate and heart rate variability was found when oxybutynin was compared with darifenacin or placebo. Likewise, oxybutynin is not associated with QT prolongation or ventricular arrhythmias. Solifenacin is also a selective M3 receptor antagonist and thus has no increased tendency for tachycardia compared with placebo. However, solifenacin is associated with QT prolongation and TdP, especially in supratherapeutic doses. Fesoterodine has equal selectivity for M2 and M3 receptors. A dose-­ related increase in heart rate by 3 to 11.6 beats per minute (bpm) has been observed with fesoterodine. Available data do not suggest any effect of fesoterodine on QT interval prolongation. Propiverine and tolterodine have equal selectivity for M2 and M3 receptors, and inhibit ­human ether-­a-­go-­go-­related gene (hERG) potassium channels. Both drugs seem to increase heart (sinus rhythm, atrioventricular conduction, and atrial and ventricular contraction) (4). Antagonists of muscarinic receptors are considered first-­ line agents for the treatment of overactive bladder, a condition characterized by micturition, urgency, incontinence, nocturia, and increased frequency (1,2). Anticholinergic agents alleviate the symptoms of overactive bladder by reducing the amplitude of involuntary detrusor contraction. Although M2 receptors dominate in the bladder (75% to 80%), their functional role is marginal (if any), and detrusor contraction seems to be mediated by M3 receptors through enhanced entrance of extracellular calcium (via L-­ type calcium channels) and downstream activation of Rho-­ kinase. Muscarinic receptor types 1, 2, 3, and 5 have been identified in the heart; however, the role of M1 and M5 receptors is negligible, and the role of M3 receptors marginal (4). The parasympathetic actions in the heart are mainly mediated though M2 receptor activation (5). Muscarinic receptor antagonism in the heart may result in tachycardia and QT prolongation, two worrisome adverse events (6–9). Accumulating evidence from epidemiological studies indicate that tachycardia is associated with increased cardiovascular morbidity and mortality, whereas QT prolongation could lead to polymorphic...