Loperamide

Absorption

Loperamide is well absorbed from the gastrointestinal tract; however, it undergoes extensive first-pass metabolism to form metabolites that are excreted in the bile. Therefore, little loperamide actually reaches the systemic circulation. The drug bioavailability is less than 1%.
Following oral administration of a 2 mg capsule of loperamide, plasma concentrations of unchanged drug were below 2 ng/mL. Plasma loperamide concentrations are highest approximately five hours after administration of an oral capsule of loperamide and 2.5 hours after the liquid formulation of the drug.

Toxicity

Oral LD50 is 185 mg/kg in rats.
Loperamide overdose can lead to a range of cardiac and non-cardiac effects. Chronic ingestion of doses ranging from 70 mg to 1600 mg daily - which is four to 100 times the recommended dose - resulted in life-threatening cardiac adverse reactions, including QT/QTc and QRS interval prolongation, Torsades de Pointes, Brugada syndrome and other ventricular arrhythmias, syncope, cardiac arrest, and death. These cases included instances of loperamide misuse and abuse. In case of cardiac effects, it is recommended that loperamide is discontinued and therapies to manage and prevent cardiac arrhythmias are initiated. Cases of loperamide overdose may cause opioid toxic effects including CNS depression (e.g. altered mental status, stupor, coordination disorders, somnolence, miosis, muscular hypertonia, respiratory depression), hypotension, urinary retention, and paralytic ileus. Naloxone may reverse the opioid-related toxicity, including CNS and respiratory depression, and hypotension, associated with loperamide overdosage.

Description

Loperamide, or Imodium, is a piperidine derivative that alleviates diarrhea symptoms because it is an opioid, like morphine and methadone. Unlike other opioids, very little is absorbed by the body and brain—instead it directly acts on the large intestines to slow the journey of feces.

Originator

Imodium,Janssen,UK,1975

The Uses of Loperamide

Loperamide is presently used more often as an antidiarrheal drug than as an analgesic, and it is also included in the list of over-the-counter drugs because of its insignificant action on the CNS. It reduces intestinal smooth muscle tone and motility as a result of binding to intestinal opiate receptors. It is used for symptomatic treatment of severe and chronic diarrhea of various origins. The most popular synonym for loperamide is imodium.

Background

Loperamide is an anti-diarrheal agent that is available as various over-the-counter products for treating diarrhea. The drug was first synthesized in 1969 and used medically in 1976. It is a highly lipophilic synthetic phenylpiperidine opioid that is structurally similar to opiate receptor agonists such as diphenoxylate and haloperidol. Due to pharmacological properties, loperamide has been misused and abused to self-manage opioid withdrawal symptoms and to induce euphoria. However, loperamide is associated with a risk for experiencing a range of adverse effects, often life-threatening, if taking for non-therapeutic reasons or at doses higher than the recommended dose.

Indications

Loperamide is indicated for the relief of diarrhea, including Travelers’ Diarrhea. As an off-label use, it is often used to manage chemotherapy-related diarrhea.

Definition

ChEBI: A synthetic piperidine derivative, effective against diarrhoea resulting from gastroenteritis or inflammatory bowel disease.

Manufacturing Process

23.6 parts of 2-oxo-3,3-diphenyl-tetrahydrofuranare melted at 100°C in an oil-bath and gaseous hydrogen bromide is introduced into it during 3 hours. The reaction mixture is cooled and triturated in benzene. The product is filtered off, washed with petroleum ether and dried in an exsiccator, yielding 4-bromo-2,2-diphenylbutyric acid; MP 127.5%.
To a stirred suspension of 16 parts of 4-bromo-2,2-diphenylbutyric acid in 150 parts of chloroform are added dropwise 16 parts of thionyl chloride and the whole is stirred and refluxed for 2 hours. The reaction mixture is evaporated,yielding 4-bromo-2,2-diphenyl-butyrylchloride as a residue.
60 parts of 4-bromo-2,2-diphenylbutyrylchloride are dissolved in 400 parts of toluene and gaseous dimethylamine is introduced slowly into the solution while cooling (temperature is kept at about 0°C). The introduction is ceased when dimethylamine escapes from the cooler, and stirring is continued for 2 hours at ordinary temperature. The precipitated product is filtered off and dissolved in a minimum quantity of water. The product is extracted with chloroform. The extract is dried and evaporated. The residue solidifies on triturating in 4-methyl-2-pentanone. The solid is filtered off and dried, yielding dimethyl -(tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide; MP 169° to 171.5°C.
A mixture of 6.33 parts of 4-(p-chlorophenyl)-4-piperidinol, 8 parts of sodium carbonate, 0.2 part of potassium iodide and 240 parts of 4-methyl-2- pentanone is distilled azeotropically. Then there are added 12.12 parts of dimethyl-(tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide (from the preceding step) and the whole is stirred and refluxed for about 15 hours. The reaction mixture is filtered hot and the filtrate is evaporated.
The oily residue is dissolved in 2-propanol and to this solution is added an excess of 2-propanol previously saturated with gaseous hydrogen chloride. The whole is evaporated and the oily residue is warmed in diluted hydrochloric acid solution. Upon the addition of toluene, the salt is precipitated. It is filtered off, boiled in acetone, and filtered off again after cooling, yielding 4- (p-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenylpiperidine-1-butyramide hydrochloride; MP 222.1°C.

brand name

Ami-29;Colifelin;Colifilm;Diareze;Dissenter;Duplibiot;Elcoman;Firtasec;Loperan;Loperin;Lopermid;Motilix;Orulop;Pf 185;Pricilone;R-18553;Regulane;Seldiar;Taguinol;Telboc;Totrtasec.

Therapeutic Function

Antidiarrheal

World Health Organization (WHO)

Loperamide, an inhibitor of intestinal peristalsis, was introduced in 1975 for the treatment of acute and chronic diarrhoea. In many countries its use was discouraged in young children. In late 1989, treatment of infants in Pakistan was associated with 19 cases of paralytic ileus, 6 of which have been fatal. This has subsequently led the major manufacturer to withdraw all drop formulations of the drug worldwide as well as the lower dose syrup forms from countries where there is a programme for the control of diarrhoeal diseases. The WHO Control of Diarrhoeal Diseases Programme recommends that loperamide should not be used in children below five year of age. (Reference: (LJJ) Letter to WHO from Johnson & Johnson, , , 21 June 1990)

General Description

Loperamide (Imodium) is a 4-phenylypiperidine with amethadone-like structure attached to the piperidine nitrogen. It acts as an antidiarrheal by directly binding tothe opiate receptors in the gut wall. Loperamide inhibitsacetylcholine and prostaglandin release, decreasing peristalsisand fluid secretion thus increasing the GI transit time andreducing the volume of fecal matter.Loperamide is sufficiently lipophilic to cross the blood-brain barrier, yet itdisplays no CNS-opioid effects. The reason for this is that itis actively pumped out of the brain via the P-glycoproteinpump (MDR1). Knockout mice with the P-glycoproteinpump genetically removed were given radiolabeled loperamideand sacrificed 4 hours later. The [³H]loperamideconcentrations were measured and compared with wild-typemice. A 13.5-fold increase in loperamide concentration wasfound in the brain of the knockouts. In addition, the micelacking the P-glycoprotein pump displayed pronouncedsigns of central opiate agonism. Loperamide is availableas 2-mg capsules for treatment of acute and chronic diarrhea.Recommended dosage is 4 mg initially, with 2 mgafter each loose stool for a maximum of 16 mg/d.

Pharmacokinetics

Loperamide is an anti-diarrheal agent that provides symptomatic relief of diarrhea. It decreases peristalsis and fluid secretion in the gastrointestinal tract, delays colonic transit time, and increases the absorption of fluids and electrolytes from the gastrointestinal tract. Loperamide also increases rectal tone, reduces daily fecal volume, and increases the viscosity and bulk density of feces. It also increases the tone of the anal sphincter, thereby reducing incontinence and urgency. The onset of action is about one hour and the duration of action can be up to three days.
While loperamide is a potent mu-opioid receptor agonist, it does not mediate significant analgesic activity at therapeutic and supratherapeutic doses. However, at high doses of loperamide, inhibition of P-glycoprotein-mediated drug efflux may allow loperamide to cross the blood-brain barrier, where loperamide can exert central opioid effects and toxicity.
At very high plasma concentrations, loperamide can interfere with cardiac conduction. Because loperamide inhibits the Na+-gated cardiac channels and ether-a-go-go–related gene potassium channels, the drug can prolong the QRS complex and the QTc interval, which can lead to ventricular dysrhythmias, monomorphic and polymorphic ventricular tachycardia, torsade de pointes, ventricular fibrillation, Brugada syndrome, cardiac arrest, and death.

Clinical Use

Loperamide is a synthetic opioid subjected to extensive first-pass metabolization after oral administration. Therefore little intact drug reaches the systemic circulation and the central nervous system. Loperamide has no centrally mediated analgesic efficacy, but may have a clinically useful analgesic effect via peripheral opioid receptors . Systemic and central opioid side effects are widely missing. Orally administered loperamide acts locally in the gut by inhibition of intestinal motility and secretion . Besides the strong μ- opioid action, calcium and calmoduline antagonism are involved in the antidiarrheal activity. The compound is used in doses of 4–8 mg for the treatment of acute and chronic diarrhea and for the management of colostomies and ileostomies . Adverse effects include nausea, dry mouth, dizziness. High doses can induce toxic megacolon and paralytic ileus. The compound has no abuse and dependence potential and is meanwhile available as over the counter (OTC) product .

Synthesis

Loperamide, 1-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-|á,|á-diphenyl-1- piperidinebutyramide (3.1.55), proposed here as an analgesic, is synthesized by the alkylation of 4-(4-chlorophenyl)-4-hydroxypiperidine (3.1.50) using N,N-dimethyl(3,3- diphenyltetrahydro-2-furylidene)ammonium bromide (3.1.54) in the presence of a base. The 4-(4-chlorophenyl)-4-hydroxypiperidine (3.1.50) is synthesized by reacting 1-benzylpiperidine-4-one (3.1.48) with 4-chlorophenylmagnesiumbromide, followed by debenzylation of the product (3.1.49) by hydrogenation using a palladium on carbon catalyst.

The starting 1-benzylpiperidin-4-one (3.1.48) is synthesized by Dieckmann intermolecular condensation of N-benzyl-N,N-bis-(|?-carboethoxyethyl)amine (3.1.46), which is easily formed by reaction of benzylamine with ethyl acrylate to give 1-benzyl-3-carboethoxypiperidine-4-one (3.1.47) followed by acidic hydrolysis and thermal decarboxylation.
N,N-Dimethyl-(3,3-diphenyltetrahydro-2-furyliden)ammonium bromide (3.1.54) is synthesized from diphenylacetic acid ethyl ester, which is reacted with ethylene oxide in the presence of sodium hydroxide, giving 2,2-diphenylbutyrolactone (3.1.51). Reacting this with hydrogen bromide in acetic acid opens the lactone ring, forming 2,2-diphenyl-4-bromobutyric acid (3.1.52). This transforms into acid chloride (3.1.53) using thionyl chloride, which cyclizes upon further treatment with an aqueous solution of dimethylamine, thus forming the desired N,N-dimethyl-(3,3-diphenyltetrahydro-2-furyliden)ammonium bromide (3.1.54). Reacting this with 4-(4-chlorphenyl)-4-hydroxypiperidine (3.1.50) gives the desired loperamide (3.1.55) [34¨C36].

Veterinary Drugs and Treatments

Loperamide is used as a GI motility modifier in small animals. Use in cats is controversial and many clinicians do not recommend using in cats.

Metabolism

Loperamide is extensively metabolized. The primary metabolic pathway is oxidative N-demethylation mediated by CYP2C8 and CYP3A4, to form N-demethyl loperamide. CYP2B6 and CYP2D6 play a minor role in loperamide N-demethylation. Metabolites of loperamide are pharmacologically inactive.