Xyloproct Mechanism of Action

Pharmacotherapeutic group: Anti-haemorrhoid preparations, agents for external use. ATC code: C05A A01.
Pharmacology: Pharmacodynamics: Lidocaine has analgesic effects and acts via reversible block of the impulses from the nerve fibres.
Hydrocortisone has anti-inflammatory properties. Xyloproct also contains aluminium acetate and zincoxide, which have astringent and disinfectant properties.
Pharmacokinetics: The rate of absorption and the absorbed amount of lidocaine are dose-dependent, but are also influenced by the site of application and exposure time. Lidocaine is well absorbed from the gastrointestinal tract, but on account of first-pass metabolism only a small proportion reaches the circulation in unchanged form. Lidocaine is eliminated primarily through metabolism. Dealkylation to monoethylglycine-xylidide (MEGX) is mediated mainly by cytochrome P450 3A4. MEGX is metabolised to 2,6-xylidine and glycinexylidide (GX). 2,6-xylidine is converted further by CYP2A6 to 4-hydroxy-2,6-xylidine, which constitutes the principal metabolite in the urine (80%) and is excreted as a conjugate. MEGX has a convulsant activity equivalent to that of lidocaine, while GX is devoid of convulsant activity. MEGX appears to occur in plasma concentrations similar to that of the parent substance. The elimination half-lives of lidocaine and MEGX after an intravenous bolus dose, are approximately 1.5-2 and 2.5 hours respectively.
Binding to plasma protein occurs principally to alpha-1-acid glycoprotein. On account of the rapid hepatic metabolism the kinetics are sensitive to all effects on the liver. The half-life can be more than doubled in patients with impaired hepatic function. Impaired renal function does not affect the kinetics, but can increase the accumulation of metabolites.
Lidocaine crosses the blood-brain barrier and the placenta; this probably takes place through passive diffusion.
Less than 50% of hydrocortisone is absorbed following rectal application. In the circulation corticosteroids are extensively bound to plasma proteins, mainly to globulin and less to albumin. Corticosteroids are metabolised mainly in the liver, and are excreted in the urine.
Toxicology: Preclinical safety data: Lidocaine: Genotoxicity and Carcinogenicity: Genotoxicity tests with lidocaine was negative. The metabolite 2,6-xylidine has been shown to have carcinogenicity potential in vitro.
For 2,6-xylidine, tumours in nasal cavity, subcutis and liver were seen in a carcinogenicity study in rats with an exposure both in uterus and post-natal during the entire life cycle.
High doses of 2,6-xylidine was needed for inducing tumours in animal studies.
The clinical relevance for the observed tumour inducing effect of these metabolites after intermittent use of lidocaine as local anaesthesia is unknown. Frequently used high doses of lidocaine and/or prilocaine is not recommended.
Hydrocortisone: In animal studies corticosteroids have shown the potential to cause different malformations (e.g. cleft palate, skeletal malformations). After per oral long-term treatment of animals reduced weight of placenta and reduced birth weight has been observed.
Besides the above there is no more preclinical data of relevance for the safety assessment except that already mentioned in the monograph.