Spasmomen Mechanism of Action

Pharmacotherapeutic group: synthetic anticholinergic agents, quaternary ammonium compounds. ATC code: A03AB06.
Pharmacology: Pharmacodynamics: Otilonium bromide belongs to a class of 2-aminoethyl-N-benzoylamino-benzoate quaternary salts.
Mechanism of action: Otilonium bromide acts mainly by modifying Ca(2+) ion fluxes from cellular and extracellular locations, reducing contractile activity probably through the inhibition of L-type and T-type calcium channels into intestinal smooth muscle cells, and peripheral sensory neurons.
Moreover, it interacts with NK1 and NK2 tachykinin receptors.
Pharmacodynamic effects: Otilonium bromide exerts an antispasmodic action on the smooth muscles of the distal enteric tract (colon and rectum). It has this effect at doses that do not affect gastric secretion.
In a study conducted in patients with irritable bowel syndrome, otilonium bromide, administrated at the maximum recommended dose of 40 mg 3 times daily for 4 weeks, did not increase the intestinal transit time.
Clinical efficacy and safety: An extended analysis of a double-blind, placebo-controlled, 15-week study with otilonium bromide, conducted in 378 IBS patients (SpC1M study) showed that the rate of response to treatment within 2-4 months was significantly higher in the otilonium bromide group (36.9%) than in the placebo group (22.5%; P=0.007). In each month of treatment, the rate of monthly response was higher in the otilonium bromide group compared to the placebo group (P < 0.05).
The efficacy of otilonium bromide was confirmed in a recent double-blind, placebo-controlled clinical trial (OBIS study, n=356 patients with irritable bowel syndrome) confirming its superiority over placebo in reducing the frequency of abdominal pain, the severity of abdominal bloating and in preventing the recurrence of symptoms.
Pharmacokinetics: Absorption: Otilonium bromide probably reaches the site of pharmacological effect directly through the intestinal wall, because systemic absorption of the drug after oral administration is very low (3%). The plasma concentration is therefore low.
Distribution: After oral administration, high distribution of the drug has been described in the smooth muscles of the colon and rectum.
Renal and hepatic impairment: Otilonium has not been studied in patients with renal and hepatic impairment.
Toxicology: Preclinical safety data: Acute toxicity: The minimal lethal oral doses in rats and mice are 900 and 1250 mg/kg, respectively; no mortality was observed in dogs up to 1000 mg/kg.
Chronic toxicity: No signs of severe toxicity were observed in rats and dogs after oral doses up to 80 mg/kg/day for 26 weeks.
Genotoxicity: Standard in vitro and in vivo tests have shown no mutagenic or clastogenic effects of otilonium bromide.
Carcinogenicity: No histopathological changes have been observed in long-term studies carried out in mice (87 weeks) and rats (104 weeks) with doses equal to 300 mg/kg/day.
Reproductive and developmental toxicity: No embryotoxic, fetotoxic, teratogenic effects were observed in rats up to 60 mg/kg/day. At the same dose, a reduction in maternal food intake was observed in rabbits, with weight reduction in the offspring.