Overactive Bladder Agents

The bladder wall muscle, the detrusor, contracts when acetylcholine acts on its muscarinic receptors — the same receptor type that drives salivation. In overactive bladder (OAB) the result is urgency, frequency and urge urinary incontinence. The antimuscarinics — tolterodine, solifenacin, darifenacin, trospium and fesoterodine — are competitive muscarinic receptor antagonists: they reduce detrusor pressure and raise the volume the bladder holds before it contracts. The price is that they also leave more urine behind after voiding.

The β3 agonists — mirabegron and vibegron — work from the other side. Activating β3 adrenergic receptors relaxes the detrusor during the filling (storage) phase, which increases bladder capacity without blocking acetylcholine. The WHO stems mark the newer agents: -fenacin (solifenacin, darifenacin) and -begron (mirabegron, vibegron); trospium carries the -ium ending of a quaternary ammonium compound.

Oxybutynin, another muscarinic antagonist used for overactive bladder, is taught on the Autonomic › Anticholinergics page with the rest of the atropine-like drugs.

Because muscarinic receptors are everywhere, the antimuscarinics share a predictable set of effects: dry mouth, constipation, blurred vision, dry eyes and urinary retention. Less sweating can cause heat prostration in a hot environment. They also cause CNS effects — dizziness, headache, somnolence, confusion and hallucinations — most often after starting or raising the dose. In older adults with cognitive impairment or dementia, antimuscarinics may worsen the dementia, and stacking other anticholinergic medicines worsens the outlook. Extended-release forms have caused fewer adverse events than immediate-release ones, and the more selective darifenacin and solifenacin are sometimes preferred to limit cognitive side effects.

The same effects define the contraindications shared by all five: urinary retention, gastric retention and uncontrolled narrow-angle glaucoma. Bladder outlet obstruction, slowed gut motility, treated narrow-angle glaucoma and myasthenia gravis call for caution; with outlet obstruction, an antimuscarinic can cause further retention and kidney injury.

Two pairs are worth linking. Tolterodine is converted by CYP2D6 to 5-hydroxymethyl tolterodine (5-HMT), an active metabolite that does much of the work; fesoterodine is a prodrug that nonspecific esterases turn into the same 5-HMT. That is why each drug is contraindicated in anyone hypersensitive to the other. Trospium is a quaternary ammonium compound that is substantially excreted by the kidney, with active tubular secretion a major route, so moderate renal impairment raises the risk of its anticholinergic effects.

Mirabegron and vibegron work without muscarinic blockade, but they still share urinary retention — reported in patients with bladder outlet obstruction and in those also taking an antimuscarinic for OAB — and angioedema. Their most common adverse reactions are headache, urinary tract infection and nasopharyngitis.

Mirabegron can raise blood pressure, so blood pressure is checked periodically, especially in hypertension, and it is not recommended in severe uncontrolled hypertension. It is also a moderate CYP2D6 inhibitor that raises levels of CYP2D6 substrates such as metoprolol and desipramine, and it raises digoxin levels. Vibegron showed no clinically significant blood-pressure change in an ambulatory monitoring study, but it also raises digoxin levels.