PHENOBARBITAL SODIUM, PHENOBARBITAL
Chemistry - Phenobarbital, a barbiturate, occurs as white, glistening, odorless, small crystals or asa white, crystalline powder with a melting point of 174°-178°C and a pKa of 7.41. One gram issoluble in approximately 1000 ml of water, and 10 ml of alcohol. Compared to other barbiturates ithas a low lipid solubility.
Phenobarbital sodium occurs as bitter-tasting, white, odorless, flaky crystals or crystalline granulesor powder. It is very soluble in water, soluble in alcohol, and freely soluble in propylene glycol. Theinjectable product has a pH of 8.5-10.5.
Propylene glycol is often used in injectable products to help stabilize the solution. Solutions ofphenobarbital sodium should not be added to acidic solutions nor used if they contain a precipitateor are grossly discolored.
The following solutions and drugs have been reported to be compatible with phenobarbitalsodium: Dextrose IV solutions, Ringer's injection, lactated Ringer's injection, Saline IV solutions, dextrose-saline combinations, dextrose-Ringer's combinations, dextrose-Ringer's lactatecombinations, amikacin sulfate, aminophylline, atropine sulfate (for at least 15 minutes, not 24hours), calcium chloride and gluconate, cephapirin sodium, dimenhydrinate, polymyxin B sulfate, sodium bicarbonate, thiopental sodium, and verapamil HCl.
The following drugs have been reported to be incompatible with phenobarbital sodium: benzquinamide HCl, cephalothin sodium, chlorpromazine HCl, codeine phosphate, ephedrine sulfate, fentanyl citrate, glycopyrrolate, hydralazine HCl, hydrocortisone sodium succinate, hydroxyzine
HCl, insulin (regular), meperidine HCl, morphine sulfate, nalbuphine HCl, norepinephrine bitartrate, oxytetracycline HCl, pentazocine lactate, procaine HCl, prochlorperazine edisylate, promazine HCl, promethazine HCl, and streptomycin sulfate. Compatibility is dependent upon factors such as pH, concentration, temperature, and diluents used and it is suggested to consult specialized references(e.g., Trissel - see bibliography) for more specific information.
In cattle, the microsomal enzyme stimulating properties of phenobarbital have been suggested forits use in speeding the detoxification of organochlorine (chlorinated hydrocarbon) insecticidepoisoning. Additional y, phenobarbital has been used in the treatment and prevention of neonatalhyperbilirubinemia in human infants. It is unknown if hyperbilirubinemia is effectively treated inveterinary patients with phenobarbital.
Phenobarbital is widely distributed throughout the body, but because of its lower lipid solubility itdoes not distribute as rapidly as most other barbiturates into the CNS. The amount of phenobarbitalbound to plasma proteins has been reported to be 40-50%. The reported apparent volumes ofdistribution are approximately: Horse » 0.8 L/kg; Foals » 0.86 L/kg; Dogs » 0.75 L/kg.
The drug is metabolized in the liver primarily by hydroxylated oxidation to p-hydroxyphenobarbital. Sulfate and glucuronide conjugates are also formed. The elimination half-lives reported inhumans range from 2-6 days; in dogs from 37-75 hours with an average of approximately 2 days.
Elimination half lives in horses are considerably shorter with values reported of approximately 13hours in foals and 18 hours in adult horses. Phenobarbital will induce hepatic microsomal enzymesand it can be expected that elimination half-lives will decrease with time. Approximately 25% of adose is excreted unchanged by the kidney. By alkalinizing the urine and/or substantially increasingurine flow, excretion rates can be increased. Anuric or oliguric patients may accumulateunmetabolized drug and dosage adjustments may need to be made in these patients.
Contraindications/Precautions - Use cautiously in patients who are hypovolemic, anemic, haveborderline hypoadrenal function, or cardiac or respiratory disease. Large doses are contraindicatedin patients with nephritis or severe respiratory dysfunction. Barbiturates are contraindicated inpatients with severe liver disease or who have demonstrated previous hypersensitivity reactions tothem.
When administering IV, give slowly (not more than 60 mg/minute). Too rapid IV administrationmay cause respiratory depression. Commercially available injectable preparations (excluding thesterile powder) must not be administered subcutaneously or perivascularly as significant tissueirritation and possible necrosis may result. Applications of moist heat and local infiltration of 0.5%procaine HCl solution have been recommended to treat these reactions.
Overdosage - Treatment of phenobarbital overdose consists of removal of ingested product fromthe gut if appropriate and offering respiratory and cardiovascular support. Activated charcoal hasbeen demonstrated to be of considerable benefit in enhancing the clearance of phenobarbital, evenwhen the drug was administered parenterally. Charcoal acts as a "sink" for the drug to diffusefrom the vasculature back into the gut. Forced alkaline diuresis can also be of substantial benefit inaugmenting the elimination of phenobarbital in patients with normal renal function. Peritonealdialysis or hemodialysis may be helpful in severe intoxications or in anuric patients.
Phenobarbital may decrease the effect of the following drugs: oral anticoagulants, chloramphenicol, corticosteroids, doxycycline, beta-Blockers (propranolol), quinidine, theophylline, metronidazole. Pentobarbital with furosemide may cause or increase posturalhypotension. Barbiturates may effect the metabolism of phenytoin; monitoring of blood levelsmay be indicated.
Rifampin may induce hepatic microsomal enzymes and reduce the half-life and effect of phenobarbital.
Phenobarbital may decrease the absorption of griseofulvin if given concurrently.
Drug/Lab Interactions - Barbiturates may cause increased retention of bromosulfopthalein (BSP;sulfobromopthalein) and give falsely elevated results. It is recommended that barbiturates not beadministered within the 24 hours before BSP retention tests; or if they must, (e.g., for seizurecontrol) the results be interpreted accordingly.
Phenobarbital sodium occurs as bitter-tasting, white, odorless, flaky crystals or crystalline granulesor powder. It is very soluble in water, soluble in alcohol, and freely soluble in propylene glycol. Theinjectable product has a pH of 8.5-10.5.
Storage, Stability, Compatibility
Aqueous solutions of phenobarbital are not very stable.Propylene glycol is often used in injectable products to help stabilize the solution. Solutions ofphenobarbital sodium should not be added to acidic solutions nor used if they contain a precipitateor are grossly discolored.
The following solutions and drugs have been reported to be compatible with phenobarbitalsodium: Dextrose IV solutions, Ringer's injection, lactated Ringer's injection, Saline IV solutions, dextrose-saline combinations, dextrose-Ringer's combinations, dextrose-Ringer's lactatecombinations, amikacin sulfate, aminophylline, atropine sulfate (for at least 15 minutes, not 24hours), calcium chloride and gluconate, cephapirin sodium, dimenhydrinate, polymyxin B sulfate, sodium bicarbonate, thiopental sodium, and verapamil HCl.
The following drugs have been reported to be incompatible with phenobarbital sodium: benzquinamide HCl, cephalothin sodium, chlorpromazine HCl, codeine phosphate, ephedrine sulfate, fentanyl citrate, glycopyrrolate, hydralazine HCl, hydrocortisone sodium succinate, hydroxyzine
HCl, insulin (regular), meperidine HCl, morphine sulfate, nalbuphine HCl, norepinephrine bitartrate, oxytetracycline HCl, pentazocine lactate, procaine HCl, prochlorperazine edisylate, promazine HCl, promethazine HCl, and streptomycin sulfate. Compatibility is dependent upon factors such as pH, concentration, temperature, and diluents used and it is suggested to consult specialized references(e.g., Trissel - see bibliography) for more specific information.
Pharmacology - PHENOBARBITAL SODIUM, PHENOBARBITAL
See the monograph: Barbiturates, Pharmacology of.Uses, Indications
Because of its favorable pharmacokinetic profile, relative safety and efficacy, low cost, and ability to treat epilepsy at sub-hypnotic doses, phenobarbital is generally considered tobe the drug of first choice when treating idiopathic epilepsy in dogs and cats. It is also occasionallyused as an oral sedative agent in these species. Because it has a slightly longer onset of action, it isused principally in the treatment of status epilepticus in dogs, cats and horses to prevent therecurrence of seizures after they have been halted with either a benzodiazepine or short-actingbarbiturate.In cattle, the microsomal enzyme stimulating properties of phenobarbital have been suggested forits use in speeding the detoxification of organochlorine (chlorinated hydrocarbon) insecticidepoisoning. Additional y, phenobarbital has been used in the treatment and prevention of neonatalhyperbilirubinemia in human infants. It is unknown if hyperbilirubinemia is effectively treated inveterinary patients with phenobarbital.
Pharmacokinetics - PHENOBARBITAL SODIUM, PHENOBARBITAL
The pharmacokinetics of phenobarbital have been thoroughly studied inhumans and studied in a more limited fashion in dogs and horses. Phenobarbital is slowly absorbedfrom the GI tract. Bioavailabilities range from 70-90% in humans, approximately 90% in dogs andabsorption is practically complete in adult horses. Peak levels occur in 4-8 hours after oral dosingin dogs, and in 8-12 hours in humans.Phenobarbital is widely distributed throughout the body, but because of its lower lipid solubility itdoes not distribute as rapidly as most other barbiturates into the CNS. The amount of phenobarbitalbound to plasma proteins has been reported to be 40-50%. The reported apparent volumes ofdistribution are approximately: Horse » 0.8 L/kg; Foals » 0.86 L/kg; Dogs » 0.75 L/kg.
The drug is metabolized in the liver primarily by hydroxylated oxidation to p-hydroxyphenobarbital. Sulfate and glucuronide conjugates are also formed. The elimination half-lives reported inhumans range from 2-6 days; in dogs from 37-75 hours with an average of approximately 2 days.
Elimination half lives in horses are considerably shorter with values reported of approximately 13hours in foals and 18 hours in adult horses. Phenobarbital will induce hepatic microsomal enzymesand it can be expected that elimination half-lives will decrease with time. Approximately 25% of adose is excreted unchanged by the kidney. By alkalinizing the urine and/or substantially increasingurine flow, excretion rates can be increased. Anuric or oliguric patients may accumulateunmetabolized drug and dosage adjustments may need to be made in these patients.
Contraindications/Precautions - Use cautiously in patients who are hypovolemic, anemic, haveborderline hypoadrenal function, or cardiac or respiratory disease. Large doses are contraindicatedin patients with nephritis or severe respiratory dysfunction. Barbiturates are contraindicated inpatients with severe liver disease or who have demonstrated previous hypersensitivity reactions tothem.
When administering IV, give slowly (not more than 60 mg/minute). Too rapid IV administrationmay cause respiratory depression. Commercially available injectable preparations (excluding thesterile powder) must not be administered subcutaneously or perivascularly as significant tissueirritation and possible necrosis may result. Applications of moist heat and local infiltration of 0.5%procaine HCl solution have been recommended to treat these reactions.
Adverse Effects, Warnings
Dogs may exhibit increased symptoms of anxiety and agitationwhen initiating therapy. These effects may be transitory in nature and often will resolve with smalldosage increases. Occasionally dogs will exhibit profound depression at lower dosage ranges (andplasma levels). Polydipsia, polyuria, and polyphagia are also quite commonly displayed at moderateto high serum levels; these are best controlled by limiting intake of both food and water. Sedationand/or ataxia often become significant concerns as serum levels reach the higher ends of thetherapeutic range. Increases in liver enzymes and anemias are more rare, but these potentiallyserious adverse effects have been reported in dogs. Cats may display a similar adverse reactionpicture. Although there is much less information regarding its use in horses (and in particularfoals), it would be generally expected that adverse effects would mirror those seen in other species.Overdosage - Treatment of phenobarbital overdose consists of removal of ingested product fromthe gut if appropriate and offering respiratory and cardiovascular support. Activated charcoal hasbeen demonstrated to be of considerable benefit in enhancing the clearance of phenobarbital, evenwhen the drug was administered parenterally. Charcoal acts as a "sink" for the drug to diffusefrom the vasculature back into the gut. Forced alkaline diuresis can also be of substantial benefit inaugmenting the elimination of phenobarbital in patients with normal renal function. Peritonealdialysis or hemodialysis may be helpful in severe intoxications or in anuric patients.
Drug Interactions
The following drugs may increase the effect of phenobarbital: Other CNSdepressants (narcotics, phenothiazines, antihistamines, etc), valproic acid, and chloramphenicol.Phenobarbital may decrease the effect of the following drugs: oral anticoagulants, chloramphenicol, corticosteroids, doxycycline, beta-Blockers (propranolol), quinidine, theophylline, metronidazole. Pentobarbital with furosemide may cause or increase posturalhypotension. Barbiturates may effect the metabolism of phenytoin; monitoring of blood levelsmay be indicated.
Rifampin may induce hepatic microsomal enzymes and reduce the half-life and effect of phenobarbital.
Phenobarbital may decrease the absorption of griseofulvin if given concurrently.
Drug/Lab Interactions - Barbiturates may cause increased retention of bromosulfopthalein (BSP;sulfobromopthalein) and give falsely elevated results. It is recommended that barbiturates not beadministered within the 24 hours before BSP retention tests; or if they must, (e.g., for seizurecontrol) the results be interpreted accordingly.