What is the mechanism of action of Tolterodine (generic name)?

Mechanism of Action of Tolterodine

Tolterodine acts as a competitive muscarinic receptor antagonist that selectively blocks muscarinic receptors in the urinary bladder, inhibiting bladder contractions and reducing symptoms of overactive bladder. 1

Primary Mechanism

• Tolterodine competitively antagonizes muscarinic receptors, which are responsible for mediating urinary bladder contraction via cholinergic pathways 1, 2
• After oral administration, tolterodine is metabolized in the liver to form a 5-hydroxymethyl derivative, which is a major pharmacologically active metabolite with similar antimuscarinic activity 1
• Both tolterodine and its active metabolite exhibit high specificity for muscarinic receptors, with negligible activity or affinity for other neurotransmitter receptors and cellular targets such as calcium channels 1, 3

Functional Effects on the Bladder

• Tolterodine produces pronounced effects on bladder function, including:
  • Increased residual urine volume (reflecting incomplete bladder emptying) 1
  • Decreased detrusor pressure 1, 2
  • These effects are consistent with antimuscarinic action on the lower urinary tract 1

Tissue Selectivity

• Unlike some other antimuscarinic agents, tolterodine demonstrates functional selectivity for bladder muscarinic receptors over salivary gland receptors 2, 3
• In animal studies, tolterodine was significantly more potent in inhibiting acetylcholine-induced urinary bladder contraction than electrically-induced salivation 3
• This tissue selectivity is not attributed to selectivity for a single muscarinic receptor subtype, but rather to differential tissue effects 3

Receptor Binding Profile

• Tolterodine binds with high affinity to muscarinic receptors in various tissues:
  • Urinary bladder (Ki 2.7-3.3 nM)
  • Heart (Ki 1.6 nM)
  • Cerebral cortex (Ki 0.75 nM)
  • Parotid gland (Ki 4.8 nM) 3
• Unlike some other antimuscarinic agents (e.g., oxybutynin), tolterodine does not show significant selectivity among muscarinic receptor subtypes (m1-m5) 3

Clinical Implications of Mechanism

• The functional bladder selectivity of tolterodine translates to:
  • Effective reduction in micturition frequency, urgency perception, and urge incontinence episodes 2, 4
  • Increased volume voided per micturition 2, 5
  • Lower incidence of dry mouth compared to less selective agents like oxybutynin 2, 4
• Tolterodine has a favorable tolerability profile with lower discontinuation rates due to adverse effects compared to other antimuscarinic agents 6, 4

Common Side Effects Related to Mechanism

• Dry mouth (most common adverse effect, but generally milder than with other antimuscarinic agents) 6, 4
• Constipation and blurred vision (related to antimuscarinic effects) 6, 4
• Potential for hallucinations (rare but reported) 6

The mechanism of action of tolterodine provides a favorable balance between efficacy and tolerability in the management of overactive bladder symptoms, with fewer antimuscarinic side effects than less selective agents 2, 4.