Diphenoxylate

Absorption

90%

Toxicity

Coma, dry skin and mucous membranes, enlarged pupils of the eyes, extremely high body temperature, flushing, involuntary eyeball movement, lower than normal muscle tone, pinpoint pupils, rapid heartbeat, restlessness, sluggishness, suppressed breathing

Originator

Lomotil,Searle,US,1960

The Uses of Diphenoxylate

Antiperistaltic.

The Uses of Diphenoxylate

This drug is a structural analog of meperidine and loperamide; however, it practically duplicates all of the pharmacological properties of loperamide. Being analogous to loperamide, it is mainly used for treating diarrhea. Synonyms for this drug are fentanest, leprofen, and others.

Background

A meperidine congener used as an antidiarrheal, usually in combination with atropine. At high doses, it acts like morphine. Its unesterified metabolite difenoxin has similar properties and is used similarly. It has little or no analgesic activity. This medication is classified as a Schedule V under the Controlled Substances Act by the Food and Drug Administration (FDA) and the DEA in the United States when used in preparations. When diphenoxylate is used alone, it is classified as a Schedule II.

Indications

For as adjunctive therapy in the management of diarrhea

Definition

ChEBI: A piperidinecarboxylate ester that is the ethyl ester of difenoxin.

Indications

Diphenoxylate (marketed in combination with atropine as Lomotil in the United States) is chemically related to both analgesic and anticholinergic compounds. It is as effective in the treatment of diarrhea as the opium derivatives, and at the doses usually employed, it has a low incidence of central opioid actions. Diphenoxylate is rapidly metabolized by ester hydrolysis to the biologically active metabolite difenoxylic acid.

Manufacturing Process

A mixture of 23 parts of the ethyl ester of 4-phenylisonipecotic acid and 15 parts of 2,2-diphenyl-4-
omobutyronitrile in 19 parts of xylene is heated for 24 hours at 100-120°C and then cooled and filtered to remove the precipitate of the hydro
omide of the ethyl ester of 4-phenylisonipecotic acid. The filtrate is then extracted with dilute hydrochloric acid and the extract is rendered alkaline by addition of concentrated aqueous potassium hydroxide and extracted with ether. This ether extract is treated with gaseous hydrogen chloride. The resulting precipitate is collected on a filter. The hydrochloride of the ethyl ester of 2,2-diphenyl-4-(4'-carboxy-4'-phenyl-1'- piperidino)butyronitrile thus obtained melts at about 220.5-222°C. See meperidine hydrochloride for synthesis of 4-phenyl-isonipecotic acid ethyl ester.

brand name

Diarphem;Diarsed-neomycin;Diatro;Eldox;Logen;Lomanate;Lomax;Lomotil liquid;Lonox;Protector;Reasec;Saleton;Sedistal.

Therapeutic Function

Antidiarrheal

World Health Organization (WHO)

Diphenoxylate, a derivative of pethidine without analgesic activity, is used in the symptomatic treatment of acute and chronic diarrhoea to reduce intestinal motility. There is no clear evidence that it has any beneficial effect in diminishing fluid losses and it has been associated with central nervous system toxicity, particularly in children, which results in anorexia, nausea and vomiting, headache, drowsiness, confusion, insomnia, dizziness, restlessness, euphoria and depression. The World Health Organization recommends that diphenoxylate should not be used for the management of diarrhoea in children and many countries have since withdrawn products containing this compound indicated for paediatric use. (Reference: (WHORUD) The Rational Use of Drugs, , , 1990)

General Description

Diphenoxylate is a weak opioid agonist and isavailable combined with atropine (Lomotil) for use as an antidiarrhealagent. At low doses, the opioid effect is minimal,and the atropine is added to dissuade abuse. One studyfound both codeine and loperamide to be superior to diphenoxylatefor treating chronic diarrhea.83 The manufacturerhas strict dosing guidelines for pediatric use because opioidintoxication and deaths from diphenoxylate have beenreported.

Pharmacokinetics

Diphenoxylate, an antidiarrheal, is effective as adjunctive therapy in the management of diarrhea. Diphenoxylate is rapidly and extensively metabolized in man by ester hydrolysis to diphenoxylic acid (difenoxine), which is biologically active and the major metabolite in the blood.

Clinical Use

Lomotil is recommended as adjunctive therapy in the management of diarrhea. It is contraindicated in children under 2 years old and in patients with obstructive jaundice.

Side Effects

Adverse reactions often caused by the atropine in the preparation include anorexia, nausea, pruritus, dizziness, and numbness of the extremities.

Synthesis

Diphenoxylate, ethyl ester of 1-(3-cyano-3,3-diphenylpropyl)- 4-phenylpiperidine-4-carboxylic acid (3.1.58), is also a drug of 4-phenylpiperidine series. In practice there are two ways of making it. The first way is by the alkylation of the ethyl ester of 4-phenylpiperidine-4-carboxylic acid (3.1.56) with 2,2-diphenyl-4-bromobutyronitrile, which in turn is synthesized from 1-benzyl-4-phenyl-4-cyanopiperidine. The product undergoes ethanolysis in the presence of acid, followed by benzylation. The second way is a synthesis accomplished by alkylation of diphenylacetonitrile using ethyl ester of 1-(2-chloroethyl)-4-phenylpiperidine-4-carboxylic acid (3.1.57), which is synthesized by reaction of ethyl ester of 4-phenylpiperidine-4-carboxylic acid with |?-chloroethanol or ethylenoxide with the subsequent substitution of hydroxyl group, which results from the opening of the epoxide ring, by chlorine via action of thionyl chloride [37,38].

Metabolism

Hepatic