Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Urologicals – drugs for urinary frequency and incontinence, ATC code: G04B D04.

Mechanism of action
Oxybutynin acts as a competitive antagonist of acetylcholine at post-ganglionic muscarinic receptors, resulting in relaxation of bladder smooth muscle.

Oxybutynin hydrochloride is an anticholinergic agent, which also exerts a direct antispasmodic effect on smooth muscle. It inhibits bladder contraction and relieves spasm induced by various stimuli; it increases bladder volume, diminishes the frequency of contractions and delays the desire to void in the disturbance of neurogenic bladder. The relaxation of smooth muscle results from the papaverin like effect of the antagonism of the processes distal to the neuromuscular junction in addition to the anticholinergic blocking action of the muscarinic type receptors. In addition, oxybutynin hydrochloride has local anaesthetic properties.

Pharmacodynamic effects
Pharmacodynamic properties of oxybutynin were studied after intravesical application to children with neurogenic detrusor overactivity. The effects on incontinence and urodynamic variables were pronounced, improving both in the majority of cases. Number of hyperactive contractions decreased significantly. Increase of mean cystometric bladder capacity and mean cystometric-to-expected bladder capacity was shown while end filling bladder pressure decreased.

Clinical efficacy and safety
The efficacy of intravesical oxybutynin treatment of neurogenic bladder dysfunction has been investigated in clinical studies in both short-term and long-term use.

In almost all studies, intravesical treatment with oxybutynin hydrochloride was efficacious and was shown to be well tolerated in patients (adults and children) suffering from neurogenic detrusor overactivity. The NDO was mainly the result of a spinal cord injury or meningomyelocele although also patients with tetraplegia, paraplegia, multiple sclerosis and Parkinson’s disease were included in the studies.

In a prospective clinical trial in 15 children, mean cystometric bladder capacity increased from 114.2 mL at baseline to 127.4 mL (p>0.05) and 161.1 mL (p=0.0091) after 1.5 hours and 4 months of intravesical treatment, respectively (Buyse et al., 1995). Mean bladder compliance was significantly increased from 2.5 mL/cm H2O at baseline to 11.495 mL/cm H2O (p=0.0114) after 4 months of therapy. In a further prospective trial in 13 children, 12 showed markedly improved continence after intravesical treatment (Åmark et al., 1998). In a retrospective long-term evaluation in 13 children, the mean end filling bladder pressure decreased from 52.5 ± 24 to 24.5 ± 14.4 cm H2O (Humblet et al., 2014).
The efficacy of intravesical vs. oral application of oxybutynin was examined in a further prospective multi-center clinical trial conducted on 35 patients (age between 18 and 70 years) suffering from NDO confirmed by previous urodynamic studies and minimum experience of 6 weeks with CIC (Schröder et al., 2016). The study confirmed that the maximum bladder capacity significantly increased upon the intravesical treatment from 18.1 mL (upon oral application) to 116.6 mL (upon intravesical application).

Additional study in a duration of 6 months subjected 25 adult patients (age between 18 and 64 years) with spinal cord injury under intravesical treatment of oxybutynin with whom standard oral oxybutynin treatment had failed (Pannek et al., 2000). Intravesical treatment led to an increase in bladder storage volume from 349 to 420 mL. The mean maximum storage pressure was significantly reduced from 54 to 26.5 cm H2O. Detrusor storage pressures returned to values less than 40 cm H2O in 21 out of 25 patients in the duration of the study.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Intravesical oxybutynin is well absorbed through the bladder wall into systemic circulation.
Measurements of oxybutynin plasma concentrations after intravesical administration revealed extensive inter-individual variability, but there was a substantial absorption of the drug also after intravesical application with maximum concentrations in plasma achieved after about one hour.

The pharmacokinetics of intravesical oxybutynin hydrochloride has been investigated in healthy volunteers. Systemic exposure (AUC) to racemic oxybutynin was significantly greater after instillation (294 %) compared to oral administration. In contrast, systemic exposure of the metabolite N-desethyl- oxybutynin was significantly lower after instillation (21 % of exposure after oral administration). As a consequence, the metabolite-to-parent ratio was 14-fold lower in case of intravesical application.

These observations clearly indicate that the mode of administration strongly influences absorption and, in particular, first-pass metabolism of oxybutynin. Obviously, the first-pass effect is significantly reduced in case of intravesical application.

Considering the reported oxybutynin bioavailability of about 6 % after oral administration, an absolute bioavailability of about 20 % might be estimated for the parent compound after intravesical instillation.

Distribution
Oxybutynin is widely distributed in body tissues following systemic absorption. The volume of distribution was estimated to be 193 l after intravenous administration of 5 mg oxybutynin hydrochloride.

Biotransformation
Oxybutynin administered orally is metabolised primarily by the cytochrome P450 enzyme systems, particularly CYP3A4, found mostly in the liver and gut wall. Metabolites include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and N-desethyloxybutynin (DEOB), which is pharmacologically active.

Intravesical administration of oxybutynin mainly circumvents the first-pass gastrointestinal and hepatic metabolism, reducing the formation of the N-desethyl metabolite.

The N-desethyl metabolite appears to produce greater anticholinergic side effects, particularly on the salivary glands, than the parent compound.
Elimination
Oxybutynin is rapidly excreted from the body after oral and intravesical administration. It was concluded from PK studies that intravesical oxybutynin exhibits a prolonged elimination compared to oral administration with reported elimination half-lives of 2.56 and 1.48 h, respectively.
Concentrations of both, oxybutynin and its main metabolity N-desethyloxybutynin were still detectable in serum 24 h after intravesical administration.