Monograph: |
Mebeverine Hydrochloride
A white or almost white crystalline powder. Very soluble in
water; freely soluble in alcohol: practically insoluble in ether.
A 2% solution in water has a pH of 4.5 to 6.5. Store in airtight
containers at a temperature not exceeding 30Β°. Protect trom
light.
Mebeverine belongs to a group of compounds called musculotropic antispasmodics. These compounds act directly on the gut muscle at the cellular level to relax them. Mebeverine is used for the symptomatic treatment of abdominal pain, bowel disturbances and intestinal discomfort associated with irritable bowel syndrome. It was first registered in 1965.
Chemistry
Mebeverine hydrochloride is a white crystalline powder with a very bitter taste. It possesses a chiral center. Its molecular formula is C25H35NO5HCI [(R.s_-3, 4-Dimethoxybenzoic acid 4-[ethyl-[2-(4-methoxyphenyl)-1methyl-ethyl] amino] butyl ester hydrochloride]
Pharmacology
Mebeverine is a musculotropic antispasmodic of the benzoate ester-type. It acts directly on the smooth muscle of the gastrointestinal tract and behaves like an antagonist of calcium at the level of the cellular membrane. It does not effect the normal gut motility. Mebeverine has a normalizing effect in the small bowel in irritable bowel syndrome, enhancing contractile activity in a similar fashion to 'prokinetic' agents, as well as producing alterations in activity consistent with an antispasmodic effect.
Toxicology
In animal toxicological studies, mebeverine appears free of teratogenic effects in rabbits and rats at doses of 100 mg/kg daily orally. There was also no effect on fertility in the rat. Behavioral and organ-specific toxicity was observed at very high doses'. No reports of mutagenicity tests are available.
Mechanism of action
Mebeverine acts directly on the smooth muscle in the gut causing it to relax. It also prevents nerve signals getting through to the muscle in the intestines. This also causes the muscle to relax, preventing painful muscle spasm. At the molecular level, mebeverine's mechanism of action seems to have two components. Firstly, it exerts an antispasmodic effect by reducing the sodium ion permeability of smooth muscle cells. Secondly, it indirectly reduces potassium ion efflux, thus avoiding hypotonia. Since mebeverine's action is not mediated by the autonomic nervous system, anticholinergic side effects are absent.
Effect of mebeverine on colonic motility in IBS
Motility studies have monitored the peristaltic activity of the colon by inserting miniature balloon catheters into the colon. Administration of mebeverine gave a marked reduction of colonic activity, but contractions were not abolished altogether, and normal peristalsis continued. Furthermore, mebeverine had the greatest effect in those patients who had high levels of colonic activity, indicating its fundamental 'normelising' action.
Pharmacokinetics
High performance liquid chromatography methods for the determination of plasma concentrations of mebeverine and its hydrolysis product veratric acid have been described. More than 90% of mebeverine is absorbed following oral administration of standard tablets. There is extensive first-pass metabolism in the gut wall and liver, and negligible plasma concentrations of the parent drug are observed after oral administration. High plasma levels of veratric acid (one of the main inactive metabolites) are achieved within 20-30 min of oral administration, with peak levels occurring after approximately 1.5h.
Studies using radiolabeled drug suggest a half-life of 2.5 h, through this probably represents the half-life of metabolites rather than of the parent compound.
Protein binding to albumin of 75% is quoted and radiolabeled tracer studies suggest a wide distribution, including the CNS. The metabolities are all rapidly excreted in the urine, excretion being virtually complete within 24 h after ingestion of a single oral dose. Thus, mebeverine does not accumulate, and dosage adjustment is not needed even in elderly patients. Small amounts of mebeverine are secreted in breast milk (approximately 10 mcg after a 100 mg dose).
Metabolism
After oral administration of mebeverine it is extensively metabolized and no quantifiable (i.e., >10 ng/ml) concentrations of the parent drug are found in humans after administration of 270 mg mebeverine. The metabolites are therefore used in pharmacokinetic analyses of mebeverine. Mebeverine is hydrolysed into veratric acid and mebeverine alcohol (MAL). Veratric acid is excreted in urine and is pharmacologically inactive. MAL is oxidiaed into mebeverinic acid (MAC). Furthermore, MAL and MAC can be converted into their 0-desmethyl derivatives (DMAL and DMAC respectively). The two major metabolites in plasma and in urine, MAC and DMAC, are pharmacologically inactive metabolites
Adverse Effects and Precautions
Although adverse effects appear rare. gastro-intestinal distur-
bances. dizziness, headache, insomnia, anorexia, and tachy-
cardia have been reported in patients receiving mebeverine. It
should be used with care in patients with marked hepatic or
renal impairment, and those with cardiac disorders.
A 24-year-old man with cystic fibrosis. prescribed mebever-
ine hydrochloride for lower abdominal pain and constipation,
was found to have a perforated stercoral ulcer with general-
ised peritonitis. It was suggested that mebeverine produced
coionic stasis which predisposed the patient to ulceration,
but the manufacturers- considered that the concomitant devel-
opment of constipation and distal intestinal syndrome (meco-
nium ileus equivalent) in this patient precipitated the
development of stercoral ulceration. It was recommended'
that antispasmodics such as mebeverine should not be used
for the symptomatic treatment of distal intestinal syndrome in
cystic fibrosis.
Uses and Administration
Mebeverine hydrochloride is an antispasmodic with a direct
action on the smooth muscle of the gastro-intestinal tract. It is
used in conditions such as the irritable bowel syndrome
in doses of 135 mg three times daily by mouth be-
fore meals, or 100 mg three or four times daily. The embonate
is also used in a dose equivalent to 150 mg of the hydrochlo-
ride three times daily.
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