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Darifenacin: Mechanism of Action, Side Effects, Contraindications, and Dosage

• Anticholinergics: general pharmacology
• Trospium chloride
• Oxybutynin
• Propiverine
• Tolterodine
• Fesoterodine
• Darifenacin
• Solifenacin
• Butylscopolamine

Mechanism of Action

Darifenacin is a lipophilic tertiary amine with selective anticholinergic effects on M₃ muscarinic receptors. The negligible impact on M₁ receptors reduces CNS side effects, and the lack of effect on M₂ receptors minimizes cardiac side effects.

The inhibition of M₃ receptors with Darifenacin reduces smooth muscle detrusor contraction, increases functional bladder capacity, and alleviates symptoms of urgency. Darifenacin is used to treat overactive bladder, urge incontinence, and neurogenic lower urinary tract dysfunction.

Pharmacokinetics of Darifenacin:

About 20% bioavailability, hepatic metabolism to inactive metabolites, long half-life of 13–19 hours, depending on the speed of cytochrome enzymes. Excretion of metabolites via feces (60%) and urine (40%).

Side Effects of Darifenacin

Muscarinic receptors are present in numerous organs. M₃ receptors are mainly found in smooth muscle and glands. Darifenacin lacks organ specificity for the bladder, causing a high rate of unwanted side effects. The negligible impact on M₁ and M₂ receptors reduces CNS and cardiac side effects.

Eye:

• Mydriases
• Disturbed accommodation
• Dry eyes due to inhibited lacrimal gland
• Risk of increased intraocular pressure in patients with glaucoma

Gastrointestinal tract:

• Dry mouth due to inhibited salivary glands
• Inhibition of intestinal motility (constipation)

CNS:

• Dizziness, loss of concentration, drowsiness
• Aggravation of dementia
• Headache
• Fear, anxiety, and confusion are possible psychiatric side effects.

Skin:

• Dry skin due to inhibited sweat glands.
• Impaired temperature regulation in fever.

Drug Interactions

Increased anticholinergic effect with antiparkinson drugs, antihistamines, antipsychotics, and tricyclic antidepressants. Darifenacin mitigates the effects of gastrointestinal prokinetics. Increased plasma concentrations are caused by paroxetine, cimetidine, ketoconazole, or macrolide antibiotics due to inhibition of cytochrome enzymes.

Contraindications of Darifenacin

• Risk of urinary retention
• Narrow-angle glaucoma
• Ileus, gastrointestinal stenosis
• Myasthenia gravis
• Pregnancy
• Children
• Severe liver failure

Dosage of Darifenacin:

The starting dose is 7.5 mg 1-0-0; if necessary, increase the dose to 15 mg once daily after two weeks. Do not increase the dosage in cases of liver failure or when concomitant administration of cytochrome P450 enzyme inhibitors is present.

References

Ouslander 2004 OUSLANDER, J. G.: Management of overactive bladder.
In: N Engl J Med
350 (2004), Nr. 8, S. 786–99

Yoshimura und Chancellor 2002 YOSHIMURA, N. ; CHANCELLOR, M. B.: Current and future pharmacological treatment for overactive bladder.
In: J Urol
168 (2002), Nr. 5, S. 1897–913

  Deutsche Version: Nebenwirkungen und Dosierung von Fesoterodin

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