Diphenoxylate with atropine

Antidiarrheals decrease intestinal peristalsis, which is usually increased when the patient has diarrhea. Examples of these drug s include difenoxin with atropine (Motofen), diphenoxylate witii atropine (Lomotil), and loperamide (Imodium). 

Chemically it is an opioid, related to pethidine. It is used in acute and chronic diarrhoea but since it crosses the blood brain barrier it can cause CNS effect similar to opioids. Atropine is added with diphenoxylate (LOMOFEN) to discourage abuse. 

These compounds have been used for many centuries and still find use today in their original forms or through synthetic analogs. Conditions which respond to muscarinic antagonists include irritable bowel syndrome, ulcers, diarrhea, glaucoma, acute rhinitis in addition to some CNS disorders. For example, Lomitil is a prescription treatment for diarrhea which is composed of atropine and diphenoxylate (an opiod with similar effects). 

Dryness of mucous membranes is a common side effect of anticholinergic drug use and is due to dose-dependent inhibition of glandular secretion. In one study, oral administration of atropine caused tear secretion to fall from 15 to 3 mcl/min.A similar dose of atropine given subcutaneously gave a nearly 50% reduction in lacrimal secretion. Scopolamine at a dose of 1 to 2 mg orally reduced tear secretion from 5 to 0.8 mcl/min. Atropine combined with diphenoxylate (Lomotil) has been reported to cause severe keratoconjimctivitis sicca in susceptible individuals. 

Antidiarrheal medications that reduce GI motility, such as loperamide, diphenoxylate/atropine, or codeine should be avoided in patients with active IBD due to the risk of precipitating acute colonic dilation (toxic megacolon). 

The answer is e. (Hardmanr p 926.) Diphenoxylate is a piperidine opioid that is related to meperidine, it inhibits peristalsis and, hence, increases the passage time of the intestinal bolus. Lt is combined with atropine to discourage use as a street drug. Atropine has little effect on peristalsis. Clonidine, bismuth subsalicylate, and re hydration therapy are all useful in some types of diarrhea, but none of them inhibit peristalsis. 

Children younger than 2 years of age because of greater variability of response hypersensitivity to diphenoxylate or atropine obstructive jaundice diarrhea associated with pseudomembranous enterocolitis or enterotoxin-producing bacteria. 

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

Diphenoxylate Hydrochloride. l-(3-Cyano-3,3-diphenylpropyl)-4-phenyl-4-piperidinecarboxylic acid monohydrochlorhydrate [3810-80-8] (Lomotil) (13) is a white, ododess, crystalline powder that melts at 220—226°C. It is soluble in methanol, sparingly soluble in ethanol and acetone, slightly soluble in water and isopropyl alcohol, freely soluble in chloroform, and practically insoluble in ether and hexane. The method of preparation for diphenoxylate hydrochloride is available (11). Diphenoxylate hydrochloride [3810-80-8] (13) is an antidiarrheal that acts through an opiate receptor. It has effects both on propulsive motility and intestinal secretion. Commercial forms are mixed with atropine to discourage abuse. 

Loperamide is similar in action and use to diphenoxylate however, it does not need to be formulated with atropine and is available by prescription and OTC. It is reported to have fewer central nervous system side effects than diphenoxylate. 

Commercial products often combine difenoxine or diphenoxylate [an opioid] with atropine [an anticholinergic]. 

Opiate preparations, usually given as paregoric, are effective and fast acting antidiarrheal agents. These agents are also useful postoperatively to produce solid stool following an ileostomy or colostomy. A meperidine derivative, diphenoxylate, is usually dispensed with atropine and sold as Lomotil. The atropine is added to discourage the abuse of diphenoxylate by narcotic addicts who are tolerant to massive doses of narcotic but not to the CNS stimulant effects of atropine. 

Diphenoxylate and its metabolite, difenoxin, are not used for analgesia but for the treatment of diarrhea. They are scheduled for minimal control (difenoxin is schedule IV, diphenoxylate schedule V see inside front cover) because the likelihood of their abuse is remote. The poor solubility of the compounds limits their use for parenteral injection. As anti diarrheal drugs, they are used in combination with atropine. The atropine is added in a concentration too low to have a significant antidiarrheal effect but is presumed to further reduce the likelihood of abuse. 

Oral 1 mg (with 0.025 mg atropine sulfate) tablets Diphenoxylate (generic, Lomotil, others)... 

Diphenoxylate hydrochloride Tablets with atropine sulfate HPLC Dissolution C-8 methanol (1% ammonium hydroxide) (4 1) Methanol-potassium 210 nm HPLC [3,922] enantiomers [919] USP 23, TLC, BP, p. [5]... 

Counseling and other psychosocial services play a role in withdrawal therapy.30 Supportive drugs for withdrawal therapy include diphenoxylate with atropine, promethazine, propranolol, thioridazine, benzodiazepines, and chlormethiazole—the use of which all require care and caution. Gerada et al.31 have discussed problems associated with the management of pregnant patients with opioid dependence. 

Diphenoxylate in high doses may produce dependence if coadministered with atropine. Diphenoxylate combined with thioridazine is associated with opioid withdrawal. Famotidine should be taken with care when coadministered with antacids, theophylline, and probenecid. Kaolin should not be administered with any other oral drug. Loperamide overdose should be treated with naloxone hydrochloride.174,175... 

Diphenoxylate hydrochloride Tablets with atropine sulfate HPLC Dissolution C-8... 

Disposition in the Body. Rapidly absorbed after oral administration but it is usually administered together with a small quantity of atropine and this may delay absorption, especially with high doses. It is extensively metabolised by hydrolysis, hydroxylation, and conjugation with glucuronic acid. The major metabolites are diphenoxylic acid (difenoxin), which is active, and hydroxy-diphenoxylic acid in both free and conjugated forms. About 14% and 50% of a dose, respectively, is excreted in the urine and faeces in 96 hours less than 0.1% of a dose is excreted in the urine as unchanged drug in 24 hours. 

Diphenoxylate is a synthetic compound designed to have the antidiarrheal effects of the opiates, but it also retains some less desirable opiate effects. It is generally combined with atropine, as co-phenotrope, which was originally added to the formulation in the hope of preventing misuse, although it can itself cause problems, especially if the combination is intentionally or accidentally used to excess. 

Only six of 36 children who took overdoses of co-phenotrope had signs of atropine overdose (central nervous system excitement, hypertension, fever, flushed dry skin) (1). Opioid overdose (central nervous system and respiratory depression with miosis) predominated or occurred without any signs of atropine toxicity in 33 cases (92%). Diphenoxylate-induced hjrpoxia was the major problem and was associated with slow or fast respiration, hypotonia or rigidity, cardiac arrest, and in three cases cerebral edema and death. Respiratory depression recurred 13-24 hours after the ingestion in seven cases and was probably due to accumulation of difenoxine, an active metabolite of diphenoxylate. Recommended treatment is an intravenous bolus dose of naloxone, followed by a continuous intravenous infusion, prompt gastric lavage, repeated administration of activated charcoal, and close monitoring for 24 hours. 

The only recognized use for diphenoxylate is in combination with atropine for the treatment of acute and chronic diarrhea. 

Diphenoxylate is a narcotic-like substance that slows gastrointestinal motility and depresses the central nervous system producing coma and respiratory depression. Anticholinergic effects (secondary to the presence of atropine as an abuse deterrent) can be seen early after exposure with opioid effects occurring later. There is no correlation between the dose ingested and the severity of effects in children. Severe poisonings with coma and respiratory depression have been reported in children with small ingestions. 

Diphenoxylate-atropine has been used in the past to treat cats with diarrhea, but toxicity has limited its usefulness. Lomotil should generally be avoided in cats. 

Colitis may result from various gut infections, especially amoebic colitis. Clindamycin, vancon cin or metronidazole may be used in treatment. The diarrhoea of colitis states may be treated with normal ANTIDIARRHOEALS, e.g. the opioids codeine, morphine, diphenoxylate and loperamide. The colic may respond to ANTISPASMODICS, e.g. the anticholinergics atropine, hyoscine, dicyclomine, propantheline. Meheverine is a direct-acting antispasmodic effective in some types of gut colic. 

Example Diphenoxylate with atropine Route Pregnancy Pharmacokinetic (Lomotil) Schedule V PO category C Well absorbed from GI tract metabolized in liver eliminated in feces... 

Note Diphenoxylate is almost always prescribed with atropine sulfate... 

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