Loperamide

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Loperamide
Loperamide.svg
Loperamide 3D ball.png
Systematic (IUPAC) name
4-[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide
Clinical data
Pronunciation /lˈpɛrəmd/
Trade names Imodium, others[1]
AHFS/Drugs.com Monograph
MedlinePlus a682280
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration
Oral
Legal status
Legal status
Pharmacokinetic data
Bioavailability 0.3%
Protein binding 97%
Metabolism Liver (extensive)
Biological half-life 9-14 hours[2]
Excretion Faeces (30-40%), urine (1%)
Identifiers
CAS Number 53179-11-6 YesY
34552-83-5 (with HCl)
ATC code A07DA03 (WHO)
A07DA05 (WHO) (oxide)
PubChem CID 3955
IUPHAR/BPS 7215
DrugBank DB00836 N
ChemSpider 3818 YesY
UNII 6X9OC3H4II YesY
KEGG D08144 YesY
ChEBI CHEBI:6532 N
ChEMBL CHEMBL841 YesY
Synonyms R-18553
Chemical data
Formula C29H33ClN2O2
Molar mass 477.037 g/mol (513.506 with HCl)
 NYesY (what is this?)  (verify)

Loperamide, sold under the brand name Imodium among others,[1] is a medication used to decrease the frequency of diarrhea.[2] It is often used for this purpose in gastroenteritis, inflammatory bowel disease, and short bowel syndrome. It is not recommended for those with blood in the stool. The medication is taken by mouth.[2]

Common side effects include abdominal pain, constipation, sleepiness, vomiting, and a dry mouth. It may increase the risk of toxic megacolon.[2] Loperamide's safety in pregnancy is unclear, but there is no evidence of harm.[3] It appears to be safe in breastfeeding.[4] It is an opioid with no significant absorption from the gut and does not cross the blood brain barrier when used at normal doses.[5] It works by slowing the contractions of the intestines.[2]

Loperamide was first made in 1969 and used medically in 1976.[6] It is included on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health care system.[7] Loperamide is available as an inexpensive generic medication.[2][8] The wholesale cost in the developing world is about 0.004 to 0.04 USD per dose.[9] In March 2016, the US retail cost is about 0.34 USD per dose.[2][10]

Medical uses[edit]

Loperamide is effective for the treatment of a number of types of diarrhea.[11] 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.[12]

Loperamide is often compared to diphenoxylate. Recent studies suggest that loperamide is more effective and has lower neural side effects.[13][14][15]

Side effects[edit]

Adverse drug reactions (ADRs) 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%).[16] 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.[17] The most frequent symptoms of loperamide overdose are drowsiness, vomiting and abdominal pain or burning.[18]

High doses may result in heart problems such as abnormal heart rhythms.[19]

Contraindications[edit]

Treatment should be avoided in the presence of high fever or if the stool is bloody. Treatment is not recommended for people that could have negative effects from rebound constipation. If there is a suspicion 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.[12] Loperamide treatment is not used in symptomatic C. difficile infections, as it increases the risk of toxin retention and precipitation of toxic megacolon.

Loperamide should be administered with caution to people with liver failure due to reduced first pass metabolism.[20] Additionally, caution should be used when treating people with advanced HIV as there have been cases of both viral and bacterial toxic megacolon. If abdominal distension is noted, therapy with loperamide should be discontinued.[21]

Children[edit]

The use of loperamide in children under 2 years is not recommended. There have been rare reports of fatal paralytic ileus associated with abdominal distention. Most of these reports occurred in the setting of acute dysentery, overdose, and with very young children less than two years of age.[22] A review of loperamide in children under 12 years old, and found that serious adverse events occurred only in children under 3 years old. The study reported that the use of loperamide should be contraindicated in children under 3 years old, systemically ill, malnourished, moderately dehydrated, or have bloody diarrhea.[23] In 1990, all formulations for children of the antidiarrheal loperamide were banned in Pakistan.[24]

Pregnancy and breast feeding[edit]

Loperamide is not recommended in the UK for use during pregnancy nor by nursing mothers.[25] In the US, loperamide is classified by the FDA as pregnancy category C. Studies in rat models have shown no teratogenicity, but there have not been sufficient studies in humans.[26] One controlled, prospective study of 89 women exposed to loperamide during the first trimester showed no increased risk of malformations. This, however, was only one study with a small sample size.[27] Loperamide can be present in breast milk, and is not recommended for breast feeding mothers.[21]

Drug interactions[edit]

Loperamide is a substrate of P-glycoprotein; therefore, the concentration of loperamide will increase when given with a P-glycoprotein inhibitor.[16] Common P-glycoprotein inhibitors include quinidine, ritonavir, and ketoconazole, among others.[28] Loperamide is capable of decreasing the absorption of some other drugs. As an example, when saquinavir concentrations can decrease by half when given with loperamide.[16]

Loperamide is an anti-diarrheal agent which decreases intestinal movement. As such, when combined with other antimotility drugs, there is an increased risk of constipation. These drugs include, but are not limited to, other opioids, antihistamines, antipsychotics, and anticholinergics.[29]

Mechanism of action[edit]

Ball-and-stick model of loperamide molecule

Loperamide is an opioid-receptor agonist and acts on the μ-opioid receptors in the myenteric plexus of the large intestine. Loperamide works similarly to morphine, decreasing the activity of the myenteric plexus, which decreases the tone of the longitudinal and circular smooth muscles of the intestinal wall.[30][31] This increases the time material stays in the intestine, allowing more water to be absorbed from the fecal matter. Loperamide also decreases colonic mass movements and suppresses the gastrocolic reflex.[32]

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.[33][34]

Blood–brain barrier[edit]

Efflux by P-glycoprotein also prevents circulating loperamide from effectively crossing the blood–brain barrier, affecting the central nervous system.[35] Concurrent administration of P-glycoprotein inhibitors such as quinidine potentially allows loperamide to cross the blood–brain barrier and produce central morphine-like effects. Loperamide taken with quinidine was found to produce respiratory depression, indicative of central opioid action.[36]

Loperamide has 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.[37][38]

When originally approved for medical use in the United States, loperamide was considered a narcotic and was put into Schedule II of the Controlled Substances Act 1970. It was transferred to Schedule V on 17 July 1977 and then decontrolled as of 3 November 1982.[39]

History[edit]

Loperamide hydrochloride was first synthesized by Paul Janssen from Janssen Pharmaceutica in Beerse (Belgium), following previous discoveries of diphenoxylate hydrochloride (1956) and fentanyl citrate (1960).[40]

The first clinical on loperamide were published in 1973 in the Journal of Medicinal Chemistry[41] with the inventor being one of the authors. The trial name for it was "R-18553".[42] Loperamide oxide has a different research code: R-58425.[43]

The trial against placebo was conducted from December 1972 to February 1974, its results being published in 1977 in Gut journal, an edition of British Society of Gastroenterology.[44]

The drug was patented in the United States in 1973.[45][46]

In 1973 Janssen started to promote loperamide under the brand name Imodium.

In December 1976 Imodium got FDA approval.[47]

During the 1980s, Imodium became the best-selling prescription antidiarrheal in the United States.[48]

In March 1988 McNeil Pharmaceutical began selling loperamide as the OTC product under the brand name Imodium A-D.[49]

In the 1980s there also existed loperamide in the form of drops (Imodium Drops) and syrup. Initially it was intended for children's usage, but Johnson & Johnson voluntarily withdrew it from the market in 1990 after 18 cases of paralytic ileus (resulting in 6 deaths) has been registered in Pakistan and reported by World Health Organization.[50] In the following years (1990-1991) products containing loperamide have been restricted for children use in a number of countries (ranging from 2 to 5 years of age).[51]

In the late 1980s prior to the expiration of US patent in January 30, 1990,[48] McNeil company started to develop Imodium Advanced containing loperamide and simethicone for treating both diarrhea and flatulence. In March 1997 the company patented such combination.[52] The drug has been approved in June 1997 by FDA as Imodium Multi-Symptom Relief in the form of a chewable tablet.[53]

In November 1993 loperamide has been launched as an orally disintegrating tablet based on Zydis technology.[54][55] Imodium Instant Melts from Johnson & Johnson is currently the only loperamide available in the form of orally disintegrating tablets.[56][57]

In 2013 loperamide in the form of 2 mg tablets has been added to WHO Model List of Essential Medicines.[58]

Society and culture[edit]

Cost[edit]

It is sold as a generic medication and is not very expensive.[2][8] Wholesale the cost is about 0.004 to 0.04 USD a dose.[9] In the United States it is about 0.20 USD a dose.[2]

Brand names[edit]

Loperamide was originally marketed as Imodium, and there are many generic brands.[1]

Recreational use[edit]

Loperamide has typically been deemed to have a relatively low risk of misuse.[59] In 2012 there were no reports of loperamide abuse.[60]

In 2015 however, case reports of extremely high-dose loperamide resulting in opioid misuse were published.[61][62]

In 2016, several clinical reports of severe cardiotoxicity due to high-dose loperamide abuse, including two deaths, were published.[63][64][65] The authors of one of the reports has called for the FDA to limit the availability of loperamide for public safety reasons, in an analogous manner to restrictions put on the sales of pseudoephedrine, to be sold only in limited amounts.[66]

See also[edit]

  • Naloxegol, peripheral acting opioid inverse-agonist (indicated to reduce constipation without greatly affecting analgesia from other centrally active opioids)

References[edit]

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External links[edit]