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Loperamide

Loperamide

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Encyclopedia
Loperamide a synthetic piperidine
Piperidine
Piperidine is an organic compound with the molecular formula 5NH. This heterocyclic amine consists of a six-membered ring containing five methylene units and one nitrogen atom...

 derivative, is an opioid drug
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

 used against diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

 resulting from gastroenteritis
Gastroenteritis
Gastroenteritis is marked by severe inflammation of the gastrointestinal tract involving both the stomach and small intestine resulting in acute diarrhea and vomiting. It can be transferred by contact with contaminated food and water...

 or inflammatory bowel disease
Inflammatory bowel disease
In medicine, inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis.-Classification:...

. In most countries it is available generically and under brand names such as Lopex, Imodium, Dimor, Fortasec, and Pepto Diarrhea Control. It was developed at Janssen Pharmaceutica
Janssen Pharmaceutica
Janssen Pharmaceutica is pharmaceutical company, established in Belgium in 1953 by Paul Janssen. Its headquarters are located in Beerse, in the Campine region of the province of Antwerp, Belgium. It was created not as a subsidiary of a chemical factory but solely with the aim of conducting...

.

Mechanism of action


Loperamide is an opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...

-receptor agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...

 and acts on the μ-opioid receptors
Mu Opioid receptor
The μ-opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...

 in the myenteric plexus of the large intestine; by itself it does not affect the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 like other opioids, unless extremely high doses are taken (in which case it can produce psychoactive effects on its own).

It works by decreasing the activity of the myenteric plexus
Auerbach's plexus
A part of the enteric nervous system, Auerbach's plexus , exists between the longitudinal and circular layers of muscularis externa in the gastrointestinal tract and provides motor innervation to both layers of the mucosa, having both parasympathetic and sympathetic input, whereas Meissner's plexus...

, which, like morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...

, decreases the tone of the longitudinal smooth muscle
Smooth muscle
Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...

s but increases the tone of circular smooth muscles of the intestinal wall. This increases the amount of time substances stay in the intestine, allowing for more water to be absorbed out of the fecal matter. Loperamide also decreases colonic mass movements and suppresses the gastrocolic reflex
Gastrocolic reflex
The gastrocolic reflex or gastrocolic response is one of a number of physiological reflexes controlling the motility, or peristalsis, of the gastrointestinal tract. It involves an increase in motility of the colon in response to stretch in the stomach and byproducts of digestion in the small...

.

Many physicians and pharmacists believe that loperamide does not cross the blood–brain barrier. In fact, however, loperamide does cross this barrier, although it is immediately pumped back out into non–central nervous system (CNS) circulation by P-glycoprotein. While this mechanism effectively shields the CNS from exposure (and thus risk of CNS addiction) to loperamide, many drugs are known to inhibit P-glycoprotein and may thus render the CNS vulnerable to opiate agonism by loperamide.

Only when very high doses are taken does enough accumulate in the brain to produce typical opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...

 effects, lasting for a number of hours (just as typical opioids would). Tolerance in response to long-term use has not been reported.

However, loperamide has been shown to cause a mild physical dependence
Physical dependence
Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...

 during preclinical studies, specifically in mice, rats, and rhesus monkeys. Symptoms of mild opiate withdrawal have been observed following abrupt discontinuation of long-term therapy with loperamide.

Contraindications


The use of Loperamide (Imodium) 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
Dysentery
Dysentery is an inflammatory disorder of the intestine, especially of the colon, that results in severe diarrhea containing mucus and/or blood in the faeces with fever and abdominal pain. If left untreated, dysentery can be fatal.There are differences between dysentery and normal bloody diarrhoea...

, overdose, and with very young children less than two years of age. In 1990, all
pediatric formulations of the antidiarrheal loperamide (Imodium and others) were banned in Pakistan
Pakistan
Pakistan , officially the Islamic Republic of Pakistan is a sovereign state in South Asia. It has a coastline along the Arabian Sea and the Gulf of Oman in the south and is bordered by Afghanistan and Iran in the west, India in the east and China in the far northeast. In the north, Tajikistan...

.

Treatment should be avoided in the presence of fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

 or if the stool is bloody (dysentery
Dysentery
Dysentery is an inflammatory disorder of the intestine, especially of the colon, that results in severe diarrhea containing mucus and/or blood in the faeces with fever and abdominal pain. If left untreated, dysentery can be fatal.There are differences between dysentery and normal bloody diarrhoea...

). It is of no value in diarrhea caused by cholera
Cholera
Cholera is an infection of the small intestine that is caused by the bacterium Vibrio cholerae. The main symptoms are profuse watery diarrhea and vomiting. Transmission occurs primarily by drinking or eating water or food that has been contaminated by the diarrhea of an infected person or the feces...

, Shigella
Shigella
Shigella is a genus of Gram-negative, nonspore forming, non-motile, rod-shaped bacteria closely related to Escherichia coli and Salmonella. The causative agent of human shigellosis, Shigella causes disease in primates, but not in other mammals. It is only naturally found in humans and apes. During...

 or Campylobacter
Campylobacter
Campylobacter is a genus of bacteria that are Gram-negative, spiral, and microaerophilic. Motile, with either unipolar or bipolar flagella, the organisms have a characteristic spiral/corkscrew appearance and are oxidase-positive. Campylobacter jejuni is now recognized as one of the main causes...

. Treatment is not recommended for patients that could suffer detrimental effects from rebound constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...

. If there is a suspicion of diarrhea associated with organisms that can penetrate the intestinal walls, such as E. coli O157:H7
Escherichia coli O157:H7
Escherichia coli O157:H7 is an enterohemorrhagic strain of the bacterium Escherichia coli and a cause of foodborne illness. Infection often leads to hemorrhagic diarrhea, and occasionally to kidney failure, especially in young children and elderly persons...

 or salmonella
Salmonella
Salmonella is a genus of rod-shaped, Gram-negative, non-spore-forming, predominantly motile enterobacteria with diameters around 0.7 to 1.5 µm, lengths from 2 to 5 µm, and flagella which grade in all directions . They are chemoorganotrophs, obtaining their energy from oxidation and reduction...

, loperamide is contraindicated.

Loperamide treatment is not used in symptomatic C. difficile infections, as it increases the risk of toxin retention and precipitation of toxic megacolon
Toxic megacolon
Toxic megacolon is an acute form of colonic distension. It is characterized by a very dilated colon , accompanied by abdominal distension , and sometimes fever, abdominal pain, or shock....

.

Adverse effects


Adverse drug reaction
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

s (ADRs) associated with Loperamide include abdominal pain and bloating, nausea, vomiting and constipation. Rare side-effects associated with Loperamide are paralytic ileus, dizziness and rashes.

Hepatic


It is not recommended for use in hepatic failure
Liver failure
Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage . The complications are hepatic encephalopathy and impaired protein synthesis...

 since it can precipitate hepatic encephalopathy
Hepatic encephalopathy
Hepatic encephalopathy is the occurrence of confusion, altered level of consciousness and coma as a result of liver failure. In the advanced stages it is called hepatic coma or coma hepaticum...

.

Marketing in the developing world


In Pakistan, seven infants died in 1989 and 1990 after parents treated their babies' diarrhea with Imodium, a medicine sold by a subsidiary of Johnson & Johnson.

Since 1980, the World Health Organization has warned Third World doctors not to use Imodium because it can paralyze a child's intestines. For months a local doctor begged the company to pull the product from stores, but it didn't do so until a British television program broadcast footage of dying babies.

Crossing the blood-brain barrier


Concurrent administration of P-glycoprotein inhibitors such as quinidine
Quinidine
Quinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...

 and its other isomer quinine
Quinine
Quinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic...

 (although much higher doses must be used), PPI
Proton pump inhibitor
Proton-pump inhibitors are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available today. The group followed and has largely superseded another group of pharmaceuticals with similar...

s like omeprazole
Omeprazole
Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease , laryngopharyngeal reflux and Zollinger–Ellison syndrome...

 (Prilosec OTC) and even black pepper
Black pepper
Black pepper is a flowering vine in the family Piperaceae, cultivated for its fruit, which is usually dried and used as a spice and seasoning. The fruit, known as a peppercorn when dried, is approximately in diameter, dark red when fully mature, and, like all drupes, contains a single seed...

 (piperine
Piperine
Piperine is the alkaloid responsible for the pungency of black pepper and long pepper, along with chavicine . It has also been used in some forms of traditional medicine and as an insecticide. Piperine forms monoclinic needles, is slightly soluble in water and more so in alcohol, ether or...

 as the active ingredient) could potentially allow loperamide to cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

. It should however be noted that only quinidine with loperamide was found to produce respiratory depression, indicative of central opioid action.

See also

  • Simethicone
    Simethicone
    Simethicone is an oral anti-foaming agent used to reduce bloating, discomfort and pain caused by excess gas in the stomach or intestinal tract. It is a mixture of polydimethylsiloxane and silica gel.-Chemical action and pharmaceutical effects:...

     - an anti-gas frequently combined with Loperamide in medications
  • Gastroenteritis
    Gastroenteritis
    Gastroenteritis is marked by severe inflammation of the gastrointestinal tract involving both the stomach and small intestine resulting in acute diarrhea and vomiting. It can be transferred by contact with contaminated food and water...

  • Traveler's diarrhea
    Traveler's diarrhea
    Traveler's diarrhea , is the most common illness affecting travelers. An estimated 10 million people—20% to 50% of international travelers—develop it annually. TD is defined as three or more unformed stools in 24 hours passed by a traveler, commonly accompanied by abdominal cramps, nausea, and...

  • Methylnaltrexone
    Methylnaltrexone
    Methylnaltrexone is one of the newer agents of peripherally-acting μ-opioid antagonists that act to reverse some of the side effects of opioid drugs such as constipation without affecting analgesia or precipitating withdrawals...

    - a Mu opioid antagonist (in contrast to Loperamide as an Mu opioid agonist) that doesn't cross the blood brain barrier so as to not affect CNS

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