Лоперамид: применение, побочные эффекты и противопоказания.

Medicine used to reduce diarrhea

Loperamide is effective for the treatment of a number of types of diarrhea. This includes control of acute nonspecific diarrhea, mild traveler's diarrhea, irritable bowel syndrome, chronic diarrhea due to bowel resection, and chronic diarrhea secondary to inflammatory bowel disease. It is also useful for reducing ileostomy output. Off label uses for loperamide also include chemotherapy induced diarrhea, especially related to irinotecan use. Loperamide should not be used as the primary treatment in cases of bloody diarrhea, acute exacerbation of ulcerative colitis, or bacterial enterocolitis. Loperamide is often compared to diphenoxylate. Studies suggest that loperamide is more effective and has lower neural side effects.

Adverse drug reactions most commonly associated with loperamide are constipation (which occurs in 1.7–5.3% of users), dizziness (up to 1.4%), nausea (0.7–3.2%), and abdominal cramps (0.5–3.0%). Rare, but more serious, side effects include toxic megacolon, paralytic ileus, angioedema, anaphylaxis/allergic reactions, toxic epidermal necrolysis, Stevens–Johnson syndrome, erythema multiforme, urinary retention, and heat stroke. The most frequent symptoms of loperamide overdose are drowsiness, vomiting, and abdominal pain, or burning. High doses may result in heart problems such as abnormal heart rhythms.

Treatment should be avoided in the presence of high fever or if the stool is bloody. Treatment is not recommended for people who could have negative effects from rebound constipation. If a suspicion exists of diarrhea associated with organisms that can penetrate the intestinal walls, such as E. coli O157:H7 or Salmonella, loperamide is contraindicated as a primary treatment. Additionally, caution should be used when treating people with advanced HIV/AIDS, as cases of both viral and bacterial toxic megacolon have been reported. If abdominal distension is noted, therapy with loperamide should be discontinued.

The use of loperamide in children under two years is not recommended. Rare reports of fatal paralytic ileus associated with abdominal distention have been made. Most of these reports occurred in the setting of acute dysentery, overdose, and with very young children less than two years of age. A review of loperamide in children under 12 years old found that serious adverse events occurred only in children under three years old. The study reported that the use of loperamide should be contraindicated in children who are under 3, systemically ill, malnourished, moderately dehydrated, or have bloody diarrhea. In 1990, all formulations for children of the antidiarrheal loperamide were banned in Pakistan. The National Health Service in the United Kingdom recommends that loperamide should only be given to children under the age of twelve if prescribed by a doctor. Formulations for children are only available on prescription in the UK.

Loperamide is not recommended in the United Kingdom for use during pregnancy or by nursing mothers. Studies in rat models have shown no teratogenicity, but sufficient studies in humans have not been conducted. One controlled, prospective study of 89 women exposed to loperamide during their first trimester of pregnancy showed no increased risk of malformations. This, however, was only one study with a small sample size. Loperamide can be present in breast milk, and is not recommended for breast feeding mothers. Loperamide is capable of decreasing the absorption of some other drugs. As an example, saquinavir concentrations can decrease by half when given with loperamide.

Loperamide is an opioid receptor agonist and acts on the μ opioid receptors in the myenteric plexus of the large intestine. It works like morphine, decreasing the activity of the myenteric plexus, which decreases the tone of the longitudinal and circular smooth muscles of the intestinal wall. This increases the time material stays in the intestine, allowing more water to be absorbed from the fecal matter. It also decreases colonic mass movements and suppresses the gastrocolic reflex. Loperamide's circulation in the bloodstream is limited in two ways. Efflux by P glycoprotein in the intestinal wall reduces passage of loperamide, and the fraction of drug crossing is then further reduced through first pass metabolism by the liver. Loperamide metabolizes into an MPTP like compound, but is unlikely to exert neurotoxicity.

Efflux by P glycoprotein also prevents circulating loperamide from effectively crossing the blood–brain barrier, so it can generally only antagonize muscarinic receptors in the peripheral nervous system, and currently has a score of one on the anticholinergic cognitive burden scale. Concurrent administration of P glycoprotein inhibitors such as quinidine potentially allows loperamide to cross the blood–brain barrier and produce central morphine like effects. At high doses (>70mg), loperamide is able to saturate P glycoprotein (thus overcoming the efflux) and produce euphoric effects. Loperamide taken with quinidine was found to produce respiratory depression, indicative of central opioid action. High doses of loperamide have been shown to cause a mild physical dependence during preclinical studies, specifically in mice, rats, and rhesus monkeys. Symptoms of mild opiate withdrawal were observed following abrupt discontinuation of long term treatment of animals with loperamide.

Loperamide is synthesized starting from the lactone 3,3 diphenyldihydrofuran 2(3H) one and ethyl 4 oxopiperidine 1 carboxylate, on a lab scale. On a large scale a similar synthesis is followed, except that the lactone and piperidinone are produced from cheaper materials rather than purchased.

Loperamide is typically manufactured as the hydrochloride salt. Its main polymorph has a melting point of 224 °C and a second polymorph exists with a melting point of 218 °C. A tetrahydrate form has been identified which melts at 190 °C.

Loperamide was formerly a controlled substance in the United States. First, it was a Schedule II controlled substance. However, this was lowered to Schedule V. Loperamide was finally removed from control in 1982, courtesy of the then Administrator Francis M. Mullen Jr.

Loperamide is sold as a generic medication.

Loperamide was originally marketed as Imodium, and many generic brands are sold. In 2012, no reports of loperamide abuse were made. In 2015, however, case reports of extremely high dose loperamide use were published. The primary intent of users has been to manage symptoms of opioid withdrawal such as diarrhea, although a small portion derive psychoactive effects at these higher doses. Dubbing it "the poor man's methadone", clinicians warned that increased restrictions on the availability of prescription opioids passed in response to the opioid epidemic were prompting recreational users to turn to loperamide as an over the counter treatment for withdrawal symptoms. The FDA responded to these warnings by calling on drug manufacturers to voluntarily limit the package size of loperamide for public safety reasons. However, there is no quantity restriction on number of packages that can be purchased, and most pharmacies do not feel capable of restricting its sale, so it is unclear that this intervention will have any impact without further regulation to place loperamide behind the counter. Since 2015, several reports of sometimes fatal cardiotoxicity due to high dose loperamide abuse have been published.