Pharmacodynamics Histamine H2 receptor antagonism The mechanism of action of<unk>  as an antacid is as a histamine H2 receptor antagonist. It has been found to bind to the H2 receptor with a Kd of 42 nM. Cytochrome P450 inhibition<unk>  is a potent inhibitor of certain cytochrome P450 (CYP) enzymes, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. The drug appears to primarily inhibit CYP1A2, CYP2D6, and CYP3A4, of which it is described as a moderate inhibitor. This is notable since these three CYP isoenzymes are involved in CYP-mediated drug biotransformations; however, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 are also involved in the oxidative metabolism of many commonly used drugs. As a result,<unk>  has the potential for a large number of pharmacokinetic interactions.<unk>  is reported to be a competitive and reversible inhibitor of several CYP enzymes, although mechanism-based (suicide) irreversible inhibition has also been identified for<unk> 's inhibition of CYP2D6. It reversibly inhibits CYP enzymes by binding directly with the complexed heme-iron of the active site via one of its imidazole ring nitrogen atoms, thereby blocking the oxidation of other drugs. Antiandrogenic and estrogenic effects<unk>  has been found to possess weak antiandrogenic activity at high doses. It directly and competitively antagonizes the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). However, the affinity of<unk>  for the AR is very weak; in one study, it showed only 0.00084% of the affinity of the anabolic steroid metribolone (100%) for the human AR (Ki = 140 μM and 1.18 nM, respectively). In any case, at sufficiently high doses,<unk>  has demonstrated weak but significant antiandrogenic effects in animals, including antiandrogenic effects in the rat ventral prostate and mouse kidney, reductions in the weights of the male accessory glands like the prostate gland and seminal vesicles in rats, and elevated gonadotropin levels in male rats (due to reduced negative feedback on the axis by androgens). In addition to AR antagonism,<unk>  has been found to inhibit the 2-hydroxylation of estradiol (via inhibition of CYP450 enzymes, which are involved in the metabolic inactivation of estradiol), resulting in increased estrogen levels. The medication has also been reported to reduce testosterone biosynthesis and increase prolactin levels in individual case reports, effects which might be secondary to increased estrogen levels. At typical therapeutic levels,<unk>  has either no effect on or causes small increases in circulating testosterone concentrations in men. Any increases in testosterone levels with<unk>  have been attributed to the loss of negative feedback on the HPG axis that results due to AR antagonism. At typical clinical dosages, such as those used to treat peptic ulcer disease, the incidence of gynecomastia (breast development) with<unk>  is very low at less than 1%. In one survey of over 9,000 patients taking<unk> , gynecomastia was the most frequent endocrine-related complaint but was reported in only 0.2% of patients. At high doses however, such as those used to treat Zollinger–Ellison syndrome, there may be a higher incidence of gynecomastia with<unk> . In one small study, a 20% incidence of gynecomastia was observed in 25 male patients with duodenal ulcers who were treated with 1,600 mg/day<unk> . The symptoms appeared after 4 months of treatment and regressed within a month following discontinuation of<unk> . In another small study,<unk>  was reported to have induced breast changes and erectile dysfunction in 60% of 22 men treated with it. These adverse effects completely resolved in all cases when the men were switched from<unk>  to ranitidine. A study of the United Kingdom General Practice Research Database, which contains over 80,000 men, found that the relative risk of gynecomastia in<unk>  users was 7.2 relative to non-users. People taking a dosage of<unk>  of greater than or equal to 1,000 mg showed more than 40 times the risk of gynecomastia than non-users. The risk was highest during the period of time of 7 to 12 months after starting<unk> . The gynecomastia associated with<unk>  is thought to be due to blockade of ARs in the breasts, which results in estrogen action unopposed by androgens in this tissue, although increased levels of estrogens due to inhibition of estrogen metabolism is another possible mechanism.<unk>  has also been associated with oligospermia (decreased sperm count) and sexual dysfunction (e.g., decreased libido, erectile dysfunction) in men in some research, which are hormonally related similarly. In accordance with the very weak nature of its AR antagonistic activity,<unk>  has shown minimal effectiveness in the treatment of androgen-dependent conditions such as acne, hirsutism (excessive hair growth), and hyperandrogenism (high androgen levels) in women. As such, its use for such indications is not recommended. Pharmacokinetics<unk>  is rapidly absorbed regardless of route of administration. The oral bioavailability of<unk>  is 60 to 70%. The onset of action of<unk>  when taken orally is 30 minutes, and peak levels occur within 1 to 3 hours.<unk>  is widely distributed throughout all tissues. It is able to cross the blood–brain barrier and can produce effects in the central nervous system (e.g., headaches, dizziness, somnolence). The volume of distribution of<unk>  is 0.8 L/kg in adults and 1.2 to 2.1 L/kg in children. Its plasma protein binding is 13 to 25% and is said to be without pharmacological significance.<unk>  undergoes relatively little metabolism, with 56 to 85% excreted unchanged. It is metabolized in the liver into<unk>  sulfoxide, hydroxycimetidine, and guanyl urea<unk> . The major metabolite of<unk>  is the sulfoxide, which accounts for about 30% of excreted material.<unk>  is rapidly eliminated, with an elimination half-life of 123 minutes, or about 2 hours. It has been said to have a duration of action of 4 to 8 hours. The medication is mainly eliminated in urine.
Cimetidine
Azacitidine
Ranitidine
Sucralfate
Dexlansoprazole
Lansoprazole
Rabeprazole
Pantoprazole