A 52-year-old woman comes to the office due to episodic incontinence for the last several months. She states that these episodes occur almost every day and are very embarrassing. They begin as an urge to urinate, and most of the time she cannot make it to the bathroom before urinating on herself. Physical examination, including pelvic examination, is unremarkable. A urinalysis is within normal limits. Urodynamic evaluation is significant for detrusor instability. Initial non-pharmacologic measures are unsuccessful and pharmacologic therapy is considered. The appropriate treatment for this patient's condition includes an agent with which of the following effects?
Characteristics of muscarinic acetylcholine receptors | |||
Receptor | Target organ(s) | Effect of stimulation | Effect of inhibition |
M1 | Brain | Memory formation/cognitive functioning | Confusion |
M2 | Heart | Decreased heart rate & atrial contraction | Increased heart rate & contractility |
M3 | Peripheral | Smooth muscle relaxation, vasodilation, hypotension | Smooth muscle contraction, vasoconstriction, hypertension |
Lungs | Bronchoconstriction | Bronchodilation | |
Bladder | Detrusor contraction | Detrusor relaxation, urinary retention | |
Eyes | Pupillary sphincter muscle contraction (miosis), ciliary muscle contraction (accommodation) | Mydriasis, cycloplegia, may precipitate acute angle glaucoma in elderly patients | |
Gastrointestinal | Increased peristalsis, increased salivary & gastric secretions | Constipation, dry mouth, decreased acid production | |
Skin | Increased sweat production | Increased temperature | |
This patient has urge incontinence, or overactive bladder syndrome, which is caused by uninhibited bladder contractions (detrusor instability). This causes a sudden sensation of urgency, with involuntary leakage of urine often occurring before reaching the toilet.
Pharmacologic therapy with anticholinergic drugs is useful for treating the condition. These agents (eg, oxybutynin) antagonize muscarinic receptors, primarily the M3 receptors present on smooth muscle cells in the bladder. Antagonism of M3 receptors decreases the production of IP3 and the release of calcium, leading to smooth muscle relaxation. This causes decreased involuntary detrusor contractions, increased bladder capacity, and decreased sense of urgency.
Antimuscarinic agents often act on several types of muscarinic receptors and should be used with caution, especially in elderly patients. These agents should be started at the lowest possible dose and titrated as needed to minimize anticholinergic side effects (dry mouth, blurred vision, tachycardia, drowsiness, and constipation).
(Choice A) Alpha1-blockers such as doxazosin, prazosin and terazosin are useful for the treatment of both benign prostatic hyperplasia (BPH) and hypertension. They cause relaxation of the smooth muscle in arterial and venous walls, leading to a decrease in peripheral vascular resistance. In patients with BPH, they also induce relaxation of the smooth muscle in the bladder neck and prostate, leading to a decrease in urinary obstruction.
(Choice B) Beta-1 receptors are found in cardiac tissue and on renal juxtaglomerular cells. Selective beta-1 blockers (eg, metoprolol) decrease heart rate and contractility, and block catecholamine-induced renin release by the kidney.
(Choice D) Nicotinic cholinergic receptors are found on postganglionic neurons in sympathetic and parasympathetic ganglia and on skeletal muscle cells at the neuromuscular junction. Drugs that block skeletal muscle nicotinic receptors, such as tubocurarine, are often used during general anesthesia to induce paralysis.
(Choice E) Central sympatholytics such as methyldopa and clonidine stimulate alpha-2 receptors centrally, which causes a decrease in generalized sympathetic outflow and a decrease in blood pressure. Rebound hypertension is a concern with abrupt cessation.
(Choice F) Beta-2 adrenergic receptors are located in the smooth muscle of airways, peripheral vasculature, and uterus. Stimulation of these receptors causes bronchodilation, vasodilation, and tocolysis, respectively. In contrast, bladder relaxation is mediated primarily by beta-3 adrenergic receptors.
Educational objective:
Urge incontinence, or overactive bladder syndrome, is caused by uninhibited bladder contractions (detrusor instability). It results in a sense of urgency accompanied by an involuntary loss of urine. If behavioral therapy alone is unsuccessful, pharmacologic therapy with an antimuscarinic drug (targeting M3 receptors) can help improve symptoms.