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DIPHENOXALATE HCL/ATROPINE SULFATE
Chemistry – Paregoric, also known as camphorated tincture of opium, contains 2 mg of anhydrous morphine (usually as powdered opium or opium tincture). Also included (per 5 ml) is 0.02 ml anise oil, 0.2 ml glycerin, 20 mg benzoic acid, 20 mg camphor and a sufficient quantity of diluted alcohol to make a total of 5 ml. Paregoric should not be confused with opium tincture (tincture of opium), which contains 50 mg or anhydrous morphine per 5 ml.
Structurally related to meperidine, diphenoxylate HCl is a synthetic phenylpiperidine-derivative opiate agonist. It occurs as an odorless, white, crystalline powder that is slightly soluble in water and sparingly soluble in alcohol. Commercially available preparations also contain a small amount of atropine sulfate to discourage the abuse of the drug for its narcotic effects. At therapeutic doses the atropine has no clinical effect.
A synthetic piperidine-derivative antidiarrheal, loperamide occurs as a white to faintly yellow, powder with a pKa of 8.6 that is soluble in alcohol and slightly soluble in water.
Storage/Stability/Compatibility – Paregoric should be stored in tight, light-resistant containers. Avoid exposure to excessive heat or direct exposure to sunlight.
Diphenoxalate/atropine tablets should be stored at room temperature in well-closed, light-resistant containers. Diphenoxalate/atropine oral solution should be stored at room temperature in tight, light-resistant containers; avoid freezing.
Loperamide capsules or oral solution should be stored at room temperature in well-closed containers. It is recommended that the oral solution not be diluted with other solvents.
Pharmacology – Among their other actions, opiates inhibit GI motility and excessive GI propulsion. They also decrease intestinal secretion induced by cholera toxin, prostaglandin E2 and diarrheas caused by factors in which calcium is the second messenger (non-cyclic AMP/GMP mediated). Opiates may also enhance mucosal absorption.
Uses/Indications – The opiate antidiarrheal products are generally considered to be the motility modifiers of choice in dogs with diarrhea. Their use in cats is controversial and many clinicians do not recommend their use in this species. Paregoric has also been used in large animals (see Doses below).
Pharmacokinetics – The morphine in paregoric is absorbed in a variable fashion from the GI tract. It is rapidly metabolized in the liver and serum morphine levels are considerably less than when morphine is administered parenterally.
In humans, diphenoxylate is rapidly absorbed after administration of either the tablets or oral solution. The bioavailability of the tablets is approximately 90% that of the solution, however. Generally, onset of action occurs within 45 minutes to one hour after dosing and is sustained for 3-4 hours. Diphenoxylate is found in maternal milk. Diphenoxylate is metabolized into diphenoxylic acid, an active metabolite. The serum half-lives of diphenoxylate and diphenoxylic acid, are approximately 2.5 hours and 3-14 hours respectively.
In dogs, loperamide reportedly has a faster onset of action and longer duration of action than diphenoxylate, but clinical studies confirming this appear to be lacking. In humans, loperamide’s half-life is about 11 hours. It is unknown if the drug enters milk or crosses the placenta.
Contraindications/Precautions – All opiates should be used with caution in patients with hypothyroidism, severe renal insufficiency, adrenocortical insufficiency (Addison’s) and in geriatric or severely debilitated patients. Opiate antidiarrheals are contraindicated in cases where the patient is hypersensitive to narcotic analgesics and in patients taking monoamine oxidase inhibitors (MAOIs). They are also contraindicated in patients with diarrhea caused by a toxic ingestion until the toxin is eliminated from the GI tract.
Opiate antidiarrheals should be used with caution in patients with head injuries or increased intracranial pressure and acute abdominal conditions (e.g., colic) as it may obscure the diagnosis or clinical course of these conditions. It should be used with extreme caution in patients suffering from respiratory disease or from acute respiratory dysfunction (e.g., pulmonary edema secondary to smoke inhalation). Opiate antidiarrheals should be used with extreme caution in patients with hepatic disease with CNS symptoms of hepatic encephalopathy. Hepatic coma may result.
Many clinicians recommend not using diphenoxylate or loperamide in dogs weighing less than 10 kg, but this is probably a result of the potency of the tablet or capsule forms of the drugs. Dosage titration using the liquid forms of these agents should allow their safe use in dogs when indicated.
Adverse Effects/Warnings – In dogs, constipation, bloat and sedation are the most likely adverse reactions encountered when usual doses are used. Potentially, paralytic ileus, toxic megacolon, pancreatitis and CNS effects could be seen.
Use of antidiarrheal opiates in cats is controversial; this species may react with excitatory behavior.
Opiates used in horses with acute diarrhea (or in any animal with a potentially bacterial-induced diarrhea) may have a detrimental effect. Opiates may enhance bacterial proliferation, delay the disappearance of the microbe from the feces and prolong the febrile state.
Overdosage – Acute overdosage of the opiate antidiarrheals could result in CNS, cardiovascular, GI or respiratory toxicity. Because the opiates may significantly reduce GI motility, absorption from the GI may be delayed and prolonged. For more information, refer to the meperidine and morphine monographs found in the CNS section. Naloxone may be necessary to reverse the opiate effects.
Massive overdoses of diphenoxylate/atropine sulfate may also induce atropine toxicity. Refer to the atropine monograph for more information. Drug Interactions – Other CNS depressants (e.g., anesthetic agents, antihistamines, phenothiazines, barbiturates, tranquilizers, alcohol, etc.) may cause increased CNS or respiratory depression when used with opiate antidiarrheal agents. Opiate antidiarrheal agents are contraindicated in patients receiving monoamine oxidase (MOA) inhibitors (rarely used in veterinary medicine) for at least 14 days after receiving MOA inhibitors in humans.
Drug/Laboratory Interactions – Plasma amylase and lipase values may be increased for up to 24 hours following administration of opiates.
a) Foals: 15 – 30 ml PO; Adults: 15 – 60 ml PO (Cornell 1985)
Monitoring Parameters –
1) Clinical efficacy
2) Fluid & electrolyte status in severe diarrhea
3) CNS effects if using high dosages
Client Information – If diarrhea persists, contact veterinarian. If animal appears listless or develops a high fever, contact veterinarian.
Dosage Forms/Preparations/FDA Approval Status/Withholding Times –
Veterinary-Approved Products: None
Paregoric (camphorated tincture of opium) 2 mg of morphine equiv. per 5 ml; 45% alcohol. Available in 60 ml, pints, and gallons & UD 5 ml; Generic; (Rx; Class-III controlled substance)
Diphenoxylate HCl 2.5 mg with 0.025 mg Atropine Sulfate Tablets (Class-V controlled substance; prescription only); Logen® (Goldline); Lomotil® (Searle); Lonox® (Geneva); Generic; (C-V)
Diphenoxylate HCl 2.5 mg with 0.025 mg Atropine Sulfate per 5 ml Oral Liquid in 60 ml dropper bottles, UD 4 & 10 ml. (Class-V controlled substance; prescription only). There are many trade names for this combination, included are: Lomotil® (Searle), Lonox® (Geneva), Diphenatol® (Rugby); Lofene® (Lannett), Logen® (Goldline), Generic
Loperamide HCl 1 mg/5 ml (0.2 mg/ml) & 1 mg/ml Oral Liquid; Imodium® A-D (McNeil-CPC); Pepto Diarrhea Control® (Procter & Gamble); generic (OTC)
Loperamide HCl 2 mg Capsules & Tablets; Imodium ® (Janssen) (OTC); Kaopectate II Caplets® (Upjohn) (OTC); Maalox Anti-Diarrheal Caplets® (R-P Rorer); Imodium A-D Caplets® (McNeil-CPC) (OTC); Neo-Diaral® (Roberts) (OTC); generic (OTC)