Difenoxin, 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). 

Difenoxin hydrochloride with atropine sulfate is not innocuous strictly adhere to dosage recommendations. Overdosage may result in severe respiratory depression and coma, possibly leading to permanent brain damage or death. 

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

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. 

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. 

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. 

Difenoxin, a diphenoxylate derivative, is also combined with atropine and has the same uses, precautions, and side effects. Marketed as 1-mg tablet, the adult dosage is 2 mg initially followed by 1 mg after each loose stool, not to exceed 8 mg/day. 

DIFENOXIN HYDROCHLORIDE (with Atropine Sulfate) (Motofen)... 

Diphenoxylate is a meperidine congener that is approved for the treatment of diarrhea (see Chapter 37). Diphenoxylate hydrochloride is available only in combination with atropine sulfate (LOMOTIL, Others). The recommended daily dosage of diphenoxylate for the treatment of diarrhea in adults is 20 mg in divided doses. Difenoxin (motofen), a metabolite of diphenoxylate, has actions similar to those of the parent compound. 

Diphenoxylate HCI (2.5 mg) and atropine (0.025 mg) are combined in tablets or 5 mL liquid and are used effectively as symptomatic treatment for diarrhea. The typical dose is two tablets or 10 mL every 3 to 4 hours. The combination with atropine enhances the block of acetylcholine-stimulated peristalsis, and the adverse effects of atropine helps to limit the abuse of the opioid. The combination is Schedule V under the Controlled Substances Act. Diphenoxylate itself has low p opioid agonist activity. It is metabolized rapidly by ester hydrolysis to the zwitterionic free carboxylate (difenoxin), which is five times more potent after oral dosing. The zwitterionic properties of difenoxin probably limits its penetration into the CNS and explains the low abuse potential of this agent. High doses of diphenoxylate (40-60 mg) will cause euphoria and addiction. 

Lomotil is a combination product containing diphenoxyiate and atropine that Is commonly prescribed for symptomatic treatment of diarrhea. Children are especially sensitive to small doses of Lomotil and may develop delayed toxicity after accidental ingestion. Motofen is a similar drug which contains difenoxin and atropine. Loperamide (Imodium ) is a nonprescription drug with similar properties. 

Morphine and opiates decrease propulsive contractions and have long been used to arrest diarrhea. They are now often replaced by diphenoxylate and difenoxine, often in combination with atropine. Allergic side effects are unusual. Fixed drug eruption can occur from opium (Welsh 1961) but it is rare. In Sweden a few cases of urticaria, angioedema, exanthema, and purpura have been reported. A preparation containing diphenoxylate and atropine (Retardin) caused urticaria and angioedema in three patients and exanthema in one. 

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