OPIATE ANTIDIARRHEALS, PAREGORIC, DIPHENOXALATE HCL / ATROPINE SULFATE, LOPERAMIDE HCL
Chemistry - Paregoric, also known as camphorated tincture of opium, contains 2 mg of anhydrousmorphine (usually as powdered opium or opium tincture). Also included (per 5 ml) is 0.02 ml aniseoil, 0.2 ml glycerin, 20 mg benzoic acid, 20 mg camphor and a sufficient quantity of diluted alcoholto 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-derivativeopiate agonist. It occurs as an odorless, white, crystalline powder that is slightly soluble in waterand sparingly soluble in alcohol. Commercially available preparations also contain a small amountof atropine sulfate to discourage the abuse of the drug for its narcotic effects. At therapeutic dosesthe 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.
Avoid exposure to excessive heat or direct exposure to sunlight.
Diphenoxalate/atropine tablets should be stored at room temperature in well-closed, light-resistantcontainers. 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.
Uses, Indications - The opiate antidiarrheal products are generally considered to be the motilitymodifiers of choice in dogs with diarrhea. Their use in cats is controversial and many clinicians donot recommend their use in this species. Paregoric has also been used in large animals (see Dosesbelow).
It is rapidly metabolized in the liver and serum morphine levels are considerably less than whenmorphine is administered parenterally.
In humans, diphenoxylate is rapidly absorbed after administration of either the tablets or oralsolution. 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 diphenoxylicacid, an active metabolite. The serum half-lives of diphenoxylate and diphenoxylic acid, areapproximately 2.5 hours and 3-14 hours respectively.
In dogs, loperamide reportedly has a faster onset of action and longer duration of action thandiphenoxylate, but clinical studies confirming this appear to be lacking. In humans, loperamide'shalf-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 geriatricor severely debilitated patients. Opiate antidiarrheals are contraindicated in cases where the patient ishypersensitive to narcotic analgesics and in patients taking monoamine oxidase inhibitors(MAOIs). They are also contraindicated in patients with diarrhea caused by a toxic ingestion untilthe 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 orclinical course of these conditions. It should be used with extreme caution in patients sufferingfrom respiratory disease or from acute respiratory dysfunction (e.g., pulmonary edema secondaryto smoke inhalation). Opiate antidiarrheals should be used with extreme caution in patients withhepatic disease with CNS symptoms of hepatic encephalopathy. Hepatic coma may result.
Many clinicians recommend not using diphenoxylate or loperamide in dogs weighing less than 10kg, but this is probably a result of the potency of the tablet or capsule forms of the drugs. Dosagetitration using the liquid forms of these agents should allow their safe use in dogs when indicated.
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-induceddiarrhea) may have a detrimental effect. Opiates may enhance bacterial proliferation, delay thedisappearance of the microbe from the feces and prolong the febrile state.
Overdosage - Acute overdosage of the opiate antidiarrheals could result in CNS, cardiovascular, GIor respiratory toxicity. Because the opiates may significantly reduce GI motility, absorption fromthe GI may be delayed and prolonged. For more information, refer to the meperidine and morphinemonographs 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 tothe atropine monograph for more information.
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 inhibitorsin humans.
Drug/Laboratory Interactions - Plasma amylase and lipase values may be increased for up to24 hours following administration of opiates.
Structurally related to meperidine, diphenoxylate HCl is a synthetic phenylpiperidine-derivativeopiate agonist. It occurs as an odorless, white, crystalline powder that is slightly soluble in waterand sparingly soluble in alcohol. Commercially available preparations also contain a small amountof atropine sulfate to discourage the abuse of the drug for its narcotic effects. At therapeutic dosesthe 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-resistantcontainers. 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 - OPIATE ANTIDIARRHEALS, PAREGORIC, DIPHENOXALATE HCL/ATROPINE SULFATE, LOPERAMIDE HCL
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 motilitymodifiers of choice in dogs with diarrhea. Their use in cats is controversial and many clinicians donot recommend their use in this species. Paregoric has also been used in large animals (see Dosesbelow).
Pharmacokinetics - OPIATE ANTIDIARRHEALS, PAREGORIC, DIPHENOXALATE HCL/ATROPINE SULFATE, LOPERAMIDE HCL
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 whenmorphine is administered parenterally.
In humans, diphenoxylate is rapidly absorbed after administration of either the tablets or oralsolution. 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 diphenoxylicacid, an active metabolite. The serum half-lives of diphenoxylate and diphenoxylic acid, areapproximately 2.5 hours and 3-14 hours respectively.
In dogs, loperamide reportedly has a faster onset of action and longer duration of action thandiphenoxylate, but clinical studies confirming this appear to be lacking. In humans, loperamide'shalf-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 geriatricor severely debilitated patients. Opiate antidiarrheals are contraindicated in cases where the patient ishypersensitive to narcotic analgesics and in patients taking monoamine oxidase inhibitors(MAOIs). They are also contraindicated in patients with diarrhea caused by a toxic ingestion untilthe 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 orclinical course of these conditions. It should be used with extreme caution in patients sufferingfrom respiratory disease or from acute respiratory dysfunction (e.g., pulmonary edema secondaryto smoke inhalation). Opiate antidiarrheals should be used with extreme caution in patients withhepatic disease with CNS symptoms of hepatic encephalopathy. Hepatic coma may result.
Many clinicians recommend not using diphenoxylate or loperamide in dogs weighing less than 10kg, but this is probably a result of the potency of the tablet or capsule forms of the drugs. Dosagetitration 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 adversereactions 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-induceddiarrhea) may have a detrimental effect. Opiates may enhance bacterial proliferation, delay thedisappearance of the microbe from the feces and prolong the febrile state.
Overdosage - Acute overdosage of the opiate antidiarrheals could result in CNS, cardiovascular, GIor respiratory toxicity. Because the opiates may significantly reduce GI motility, absorption fromthe GI may be delayed and prolonged. For more information, refer to the meperidine and morphinemonographs 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 tothe 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 depressionwhen 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 inhibitorsin humans.
Drug/Laboratory Interactions - Plasma amylase and lipase values may be increased for up to24 hours following administration of opiates.