Dulcolax Mechanism of Action

ATC code: A06AB02.
Pharmacology: Pharmacodynamics: Bisacodyl is a locally acting laxative from the diphenylmethane derivatives group. As a contact laxative, for which also antiresorptive hydragogue effects have been described, bisacodyl stimulates, after hydrolysis in the large intestine, peristalsis of the colon and promotes accumulation of water, and consequently electrolytes, in the colonic lumen. This results in a stimulation of defecation, reduction of transit time and softening of the stool.
As a laxative that acts on the colon, bisacodyl specifically stimulates the natural evacuation process in the lower region of the gastrointestinal tract. Therefore, bisacodyl is ineffective in altering the digestion or absorption of calories or essential nutrients in the small intestine.
Pharmacokinetics: Following either oral or rectal administration, bisacodyl is rapidly hydrolyzed to the active principle bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM), mainly by esterases of the enteric mucosa.
Administration as an enteric coated tablet was found to result in maximum BHPM plasma concentrations between 4 - 10 hours post administration whereas the laxative effect occurred between 6 - 12 hours post administration. In contrast, following the administration as a suppository, the laxative effect occurred on average approximately 20 minutes post administration; in some cases it occurred 45 minutes after administration. The maximum BHPM-plasma concentrations were achieved 0.5 - 3 hours following the administration as a suppository. Hence, the laxative effect of bisacodyl does not correlate with the plasma level of BHPM. Instead, BHPM acts locally in the lower part in of the intestine and there is no relationship between the laxative effect and plasma levels of the active moiety. For this reason, bisacodyl coated tablets are formulated to be resistant to gastric and small intestinal juice. This results in a main release of the drug in the colon, which is the desired site of action.
After oral and rectal administration, only small amounts of the drug are absorbed and are almost completely conjugated in the intestinal wall and the liver to form the inactive BHPM glucuronide. The plasma elimination half-life of BHPM glucuronide was estimated to be approximately 16.5 hours. Following the administration of bisacodyl coated tablets, an average of 51.8% of the dose was recovered in the faeces as free BHPM and an average of 10.5% of the dose was recovered in the urine as BHPM glucuronide. Following the administration as a suppository, an average of 3.1% of the dose was recovered as BHPM glucuronide in the urine. Stool contained large amounts of BHPM (90% of the total excretion) in addition to small amounts of unchanged bisacodyl.
Toxicology: The acute oral toxicity of bisacodyl in rodents and non-rodents is low and exceeded 2 g/kg. Dogs tolerated dose levels up to 15 g/kg. Major clinical signs of acute toxicity were diarrhoea, decreased motor activity and pilo-erection.
Repeat-dose toxicity studies up to 26 weeks were performed in rats, minipigs and rhesus monkeys. As expected, the drug caused severe dose-dependent diarrhoea in all species, except minipigs. There were no distinct histopathological changes and, in particular, no drug-related nephrotoxicity. Bisacodyl induced proliferative lesions seen in the urinary bladder of rats treated for 32 weeks. These proliferations are not attributable to bisacodyl per se; they are considered to be secondary to microcalculi formation due to changes in urinary electrolytes and, therefore, are of no biological relevance for man.
Data of a comprehensive battery of bacterial and mammalian mutagenicity test systems did not show any genotoxic potential of bisacodyl. Also, bisacodyl caused no significant increase in morphological transformation of Syrian hamster embryo (SHE) cells. In contrast to the genotoxic and carcinogenic laxative phenolphthalein, bisacodyl showed no mutagenic potential in appropriate tests.
No conventional (lifetime) carcinogenicity studies for bisacodyl are available. Because of the therapeutic similarity to phenolphthalein, bisacodyl was investigated in the p53 transgenic mouse model for 26 weeks.
No treatment-related neoplasia were observed up to oral dose levels of 8000 mg/kg/day.
No teratogenic effects were found in rats and rabbits (FDA Pregnancy Risk Category B) up to doses of 1000 mg/kg/day which exceed the maximum recommended human daily dose (MRHDD) (based on mg/m2) by at least 800-fold. In the rat, materno- and embryotoxicity was observed at doses 80-fold higher than the MRHDD.