BUPRENORPHINE HCL
Chemistry - A thebaine derivative, buprenorphine is a synthetic partial opiate agonist. It occurs as awhite, crystalline powder with a solubility of 17 mg/ml in water and 42 mg/ml in alcohol. Thecommercially available injectable product (Buprenex® - Norwich Eaton) has a pH of 3.5-5 and is asterile solution of the drug dissolved in D5W. Terms of potency are expressed in terms ofbuprenorphine. The commercial product contains 0.324 mg/ml of buprenorphine HCl, which isequivalent to 0.3 mg/ml of buprenorphine.
C). Temperatures above 40° C or below freezing should be avoided. Buprenorphine productsshould be stored away from bright light. Autoclaving may decrease drug potency considerably. Thedrug is stable between a pH of 3.5-5.
Buprenorphine is reported to be compatible with the following IV solutions and drugs: acepromazine, atropine, diphenhydramine, D5W, D5W & normal saline, droperidol, glycopyrrolate, hydroxyzine, lactated Ringer's, normal saline, scopolamine, and xylazine. Buprenorphine is reportedly incompatible with diazepam and lorazepam.
The cardiovascular effects of buprenorphine may cause a decrease in both blood pressure andcardiac rate. Rarely, human patients may exhibit increases in blood pressure and cardiac rate.
Respiratory depression is a possibility, and decreased respiratory rates have been noted in horsestreated with buprenorphine. Gastrointestinal effects appear to be minimal with buprenorphine, butfurther studies are needed to clarify this.
The distribution of the drug has not been well studied. Data from work done in rats reflects thatbuprenorphine concentrates in the liver, but is also found in the brain, GI tract, and placenta. It ishighly bound (96%) to plasma proteins (not albumin), crosses the placenta, and it (and metabolites)are found in maternal milk at concentrations equal to or greater than those found in plasma.
Buprenorphine is metabolized in the liver by N-dealkylation and glucuronidation. Thesemetabolites are then eliminated by biliary excretion into the feces (»70%) and urinary excretion(»27%).
In the horse, onset of action is approximately 15 minutes after IV dosing. The peak effect occursin 30-45 minutes and the duration of action may last up to 8 hours. Because acepromazine exhibitsa similar onset and duration of action, many clinicians favor using this drug in combination withbuprenorphine in the horse.
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.
Rarely, patients may develop respiratory depression from buprenorphine, it therefore should beused cautiously in patients with compromised cardiopulmonary function. Like other opiates, buprenorphine must be used with extereme caution in patients with head trauma, increased CSFpressure or other CNS dysfunction (e.g., coma).
Patients with severe hepatic dysfunction may eliminate the drug more slowly than normal patients.
Buprenorphine may increase bile duct pressure and should be used cautiously in patients withbiliary tract disease.
Although no controlled studies have been performed in domestic animals or humans, the drug hasexhibited no evidence of teratogenicity or of causing impaired fertility in laboratory animals.
The drug is contraindicated in patients having known hypersensitivity to it.
Overdosage - The intraperitoneal LD50 of buprenorphine has been reported to be 243 mg/kg inrats. The ratio of lethal dose to effective dose is at least 1000:1 in rodents. Because of the apparenthigh index of safety, acute overdoses should be a rare event in veterinary medicine. In such a casehowever, treatment with naloxone and doxapram has been suggested in cases with respiratory orcardiac effects. High doses of nalaxone may be required to treat respiratory depression should itoccur.
Pancuronium if used with buprenorphine may cause increased conjunctival changes.
Buprenorphine is contraindicated in human patients receiving monamine oxidase (MOA) inhibitors (rarely used in veterinary medicine) for at least 14 days after receiving MOA inhibitors inhumans. One study done in rabbits did not demonstrate any appreciable interaction, however.
Local anesthetics (mepivicaine, bupivicaine) may be potentiated by concomitant use ofbuprenorphine.
Storage, Stability, Compatibility
Buprenorphine should be stored at room temperature (15-30°C). Temperatures above 40° C or below freezing should be avoided. Buprenorphine productsshould be stored away from bright light. Autoclaving may decrease drug potency considerably. Thedrug is stable between a pH of 3.5-5.
Buprenorphine is reported to be compatible with the following IV solutions and drugs: acepromazine, atropine, diphenhydramine, D5W, D5W & normal saline, droperidol, glycopyrrolate, hydroxyzine, lactated Ringer's, normal saline, scopolamine, and xylazine. Buprenorphine is reportedly incompatible with diazepam and lorazepam.
Pharmacology - BUPRENORPHINE HCL
Buprenorphine has partial agonist activity at the mu receptor. This is in contrast topentazocine which acts as an antagonist at the mu receptor. Buprenorphine is considered to be 30times as potent as morphine and exhibits many of the same actions as the opiate agonists; itproduces a dose-related analgesia. It appears to have a high affinity for mu receptors in the CNS, which may explain its relatively long duration of action.The cardiovascular effects of buprenorphine may cause a decrease in both blood pressure andcardiac rate. Rarely, human patients may exhibit increases in blood pressure and cardiac rate.
Respiratory depression is a possibility, and decreased respiratory rates have been noted in horsestreated with buprenorphine. Gastrointestinal effects appear to be minimal with buprenorphine, butfurther studies are needed to clarify this.
Pharmacokinetics - BUPRENORPHINE HCL
Buprenorphine is rapidly absorbed following IM injection, with 40-90% absorbed systemically when tested in humans. The drug is also absorbed sublingually (bioavailability»55%) in people. Oral doses appear to undergo a high first-pass effect with metabolism occurring in the GI mucosa and liver.The distribution of the drug has not been well studied. Data from work done in rats reflects thatbuprenorphine concentrates in the liver, but is also found in the brain, GI tract, and placenta. It ishighly bound (96%) to plasma proteins (not albumin), crosses the placenta, and it (and metabolites)are found in maternal milk at concentrations equal to or greater than those found in plasma.
Buprenorphine is metabolized in the liver by N-dealkylation and glucuronidation. Thesemetabolites are then eliminated by biliary excretion into the feces (»70%) and urinary excretion(»27%).
In the horse, onset of action is approximately 15 minutes after IV dosing. The peak effect occursin 30-45 minutes and the duration of action may last up to 8 hours. Because acepromazine exhibitsa similar onset and duration of action, many clinicians favor using this drug in combination withbuprenorphine in the horse.
Uses, Indications
Because buprenorphine is a relatively new addition to the pharmacologic armamentarium, present indications appear to be limited to its use in horses as a neuroleptanalgesic(when used in combination with either acepromazine or xylazine) and as an analgesic in dogs andcats.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.
Rarely, patients may develop respiratory depression from buprenorphine, it therefore should beused cautiously in patients with compromised cardiopulmonary function. Like other opiates, buprenorphine must be used with extereme caution in patients with head trauma, increased CSFpressure or other CNS dysfunction (e.g., coma).
Patients with severe hepatic dysfunction may eliminate the drug more slowly than normal patients.
Buprenorphine may increase bile duct pressure and should be used cautiously in patients withbiliary tract disease.
Although no controlled studies have been performed in domestic animals or humans, the drug hasexhibited no evidence of teratogenicity or of causing impaired fertility in laboratory animals.
The drug is contraindicated in patients having known hypersensitivity to it.
Adverse Effects, Warnings
Although rare, respiratory depression appears to be the major adverse effect to monitor with this agent, but because it has only recently been used in veterinary medicine, other adverse effects may be noted. The primary side effect seen in humans is sedation with an incidence of approximately 66%.Overdosage - The intraperitoneal LD50 of buprenorphine has been reported to be 243 mg/kg inrats. The ratio of lethal dose to effective dose is at least 1000:1 in rodents. Because of the apparenthigh index of safety, acute overdoses should be a rare event in veterinary medicine. In such a casehowever, treatment with naloxone and doxapram has been suggested in cases with respiratory orcardiac effects. High doses of nalaxone may be required to treat respiratory depression should itoccur.
Drug Interactions
Other CNS depressants (e.g., anesthetic agents, antihistamines, phenothiazines, barbiturates, tranquilizers, alcohol, etc.) may cause increased CNS or respiratory depressionwhen used with buprenorphine. Buprenorphine may decrease the analgesic effects of the opiateagonists (morphine, etc.).Pancuronium if used with buprenorphine may cause increased conjunctival changes.
Buprenorphine is contraindicated in human patients receiving monamine oxidase (MOA) inhibitors (rarely used in veterinary medicine) for at least 14 days after receiving MOA inhibitors inhumans. One study done in rabbits did not demonstrate any appreciable interaction, however.
Local anesthetics (mepivicaine, bupivicaine) may be potentiated by concomitant use ofbuprenorphine.