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Botulinum Toxin A: Mechanism, Adverse Effects, Contraindications, and Dosage

Mechanism of Action of Botulinum Toxin A

Botulinum toxin inhibits the exocytosis of acetylcholine and other neurotransmitters from cholinergic nerve terminals (including at the neuromuscular junction, at postganglionic parasympathetic nerve endings in smooth muscle, in glands, and in afferent nerve fibers). Botulinum toxin cleaves SNARE proteins, which are responsible for exocytosis of neurotransmitters (e.g., SNAP-25). The most urologic experience exists with botulinum toxin type A (onabotulinumtoxinA).

Urologic Indications for Botulinum Toxin A:

Botulinum toxin type A is indicated when conservative and pharmacologic therapy provides insufficient benefit or causes intolerable adverse effects in neurogenic detrusor overactivity and in overactive bladder. In selected neurogenic cases, clinicians may consider treatment of detrusor-sphincter dyssynergia as an alternative to sphincterotomy; this use is often off-label.

Pharmacokinetics of Botulinum Toxin A

Injection of botulinum toxin type A directly into the target muscle (the detrusor muscle or the urethral sphincter). The clinical effect typically begins within 3 to 14 days and reaches maximal benefit after about 2 to 6 weeks. The mean duration of effect is approximately 6 to 9 months, with substantial interindividual variability.

Adverse Effects of Botulinum Toxin A

• Hypersensitivity reactions (e.g., rash and urticaria; anaphylaxis is rare).
• Possible systemic toxin effects (very rare): dysphagia, dysarthria, ptosis, diplopia, generalized muscle weakness, or respiratory symptoms.
• Urologic adverse effects after detrusor injection include urinary tract infections, dysuria, gross hematuria, increased post-void residual volume, and urinary retention. In neurogenic detrusor overactivity, autonomic dysreflexia can also occur.

Drug Interactions:

Botulinum toxin type A can theoretically worsen muscle weakness when patients receive aminoglycosides or other medications that impair neuromuscular transmission.

Contraindications to Intravesical Use of Botulinum Toxin

• Untreated urinary tract infection.
• Urinary retention or a post-void residual volume greater than 200 mL in patients who cannot or will not perform clean intermittent catheterization.
• Clinically relevant coagulopathy.
• Known hypersensitivity.
• Use with caution in myasthenia gravis or Lambert-Eaton syndrome and in other neuromuscular disorders.

Dosing of Botulinum Toxin A in Urology

OnabotulinumtoxinA (BOTOX) and abobotulinumtoxinA (Dysport) have different urologic approvals depending on the country and indication. The dosages between the two preparations are different, and conversion is only possible to a limited extent. The dosing regimens below describe onabotulinumtoxinA (BOTOX).

Overactive Bladder With Spontaneous Voiding:

Direct injection of 100 units onabotulinumtoxinA into the detrusor muscle (e.g., reconstitute 100 units in 10 mL and administer 20 injections of 0.5 mL, delivering 5 units per injection). Distribute the injections evenly throughout the detrusor wall and spare the trigone. If patients respond inadequately, reassess diagnosis, technique, and contributing factors and consider repeat treatment at an appropriate interval.

Detrusor Overactivity Without Spontaneous Voiding:

In patients with neurogenic detrusor overactivity and clean intermittent catheterisation, intradetrusor injection of 200 units of onabotulinumtoxinA can increase bladder capacity and reduce incontinence (e.g., reconstitute 200 units in 30 mL and administer 30 injections of 1 mL, delivering approximately 6.7 units per injection). If the response to treatment is insufficient, the dose may be increased to 300 units.

Detrusor-Sphincter Dyssynergia:

For treatment of an overactive external sphincter: transurethral injection of 100 units of onabotulinumtoxinA into the sphincter region; this approach is often off-label.

References

Cruz, F.; Herschorn, S.; Aliotta, P.; Brin, M.; Thompson, C.; Lam, W.; Daniell, G.; Heesakkers, J. & Haag-Molkenteller, C. Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, double-blind, placebo-controlled trial.
Eur Urol, 2011, 60, 742-750

Karsenty, G.; Denys, P.; Amarenco, G.; Seze, M. D.; Gamé, X.; Haab, F.; Kerdraon, J.; Perrouin-Verbe, B.; Ruffion, A.; Saussine, C.; Soler, J.; Schurch, B. & Chartier-Kastler, E. Botulinum toxin A (Botox) intradetrusor injections in adults with neurogenic detrusor overactivity/neurogenic overactive bladder: a systematic literature review.
Eur Urol, 2008, 53, 275-287.

Mangera, A.; Andersson, K.; Apostolidis, A.; Chapple, C.; Dasgupta, P.; Giannantoni, A.; Gravas, S. & Madersbacher, S. Contemporary management of lower urinary tract disease with botulinum toxin A: a systematic review of botox (onabotulinumtoxinA) and dysport (abobotulinumtoxinA).
Eur Urol, 2011, 60, 784-795.

  Deutsche Version: Mechanismus, Nebenwirkungen und Kontraindikationen von Botulinum Toxin A

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