Chemistry - Phenobarbital, a barbiturate, occurs as white, glistening, odorless, small crystals or as a white, crystalline powder with a melting point of 174°-178°C and a pKa of 7.41. One gram is soluble in approximately 1000 ml of water, and 10 ml of alcohol. Compared to other barbiturates it has a low lipid solubility.
Phenobarbital sodium occurs as bitter-tasting, white, odorless, flaky crystals or crystalline granules or powder. It is very soluble in water, soluble in alcohol, and freely soluble in propylene glycol. The injectable 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 of phenobarbital sodium should not be added to acidic solutions nor used if they contain a precipitate or are grossly discolored.
The following solutions and drugs have been reported to be compatible with phenobarbital sodium: Dextrose IV solutions, Ringer’s injection, lactated Ringer’s injection, Saline IV solutions, dextrose-saline combinations, dextrose-Ringer’s combinations, dextrose-Ringer’s lactate combinations, amikacin sulfate, aminophylline, atropine sulfate (for at least 15 minutes, not 24 hours), 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 - 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 to be the drug of first choice when treating idiopathic epilepsy in dogs and cats. It is also occasionally used as an oral sedative agent in these species. Because it has a slightly longer onset of action, it is used principally in the treatment of status epilepticus in dogs, cats and horses to prevent the recurrence of seizures after they have been halted with either a benzodiazepine or short-acting barbiturate.
In cattle, the microsomal enzyme stimulating properties of phenobarbital have been suggested for its use in speeding the detoxification of organochlorine (chlorinated hydrocarbon) insecticide poisoning. Additionally, phenobarbital has been used in the treatment and prevention of neonatal hyperbilirubinemia in human infants. It is unknown if hyperbilirubinemia is effectively treated in veterinary patients with phenobarbital.
Pharmacokinetics - The pharmacokinetics of phenobarbital have been thoroughly studied in humans and studied in a more limited fashion in dogs and horses. Phenobarbital is slowly absorbed from the GI tract. Bioavailabilities range from 70-90% in humans, approximately 90% in dogs and absorption is practically complete in adult horses. Peak levels occur in 4-8 hours after oral dosing in dogs, and in 8-12 hours in humans.
Phenobarbital is widely distributed throughout the body, but because of its lower lipid solubility it does not distribute as rapidly as most other barbiturates into the CNS. The amount of phenobarbital bound to plasma proteins has been reported to be 40-50%. The reported apparent volumes of distribution 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 in humans 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 13 hours in foals and 18 hours in adult horses. Phenobarbital will induce hepatic microsomal enzymes and it can be expected that elimination half-lives will decrease with time. Approximately 25% of a dose is excreted unchanged by the kidney. By alkalinizing the urine and/or substantially increasing urine flow, excretion rates can be increased. Anuric or oliguric patients may accumulate unmetabolized drug and dosage adjustments may need to be made in these patients.
Contraindications/Precautions - Use cautiously in patients who are hypovolemic, anemic, have borderline hypoadrenal function, or cardiac or respiratory disease. Large doses are contraindicated in patients with nephritis or severe respiratory dysfunction. Barbiturates are contraindicated in patients with severe liver disease or who have demonstrated previous hypersensitivity reactions to them.
When administering IV, give slowly (not more than 60 mg/minute). Too rapid IV administration may cause respiratory depression. Commercially available injectable preparations (excluding the sterile powder) must not be administered subcutaneously or perivascularly as significant tissue irritation 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 agitation when initiating therapy. These effects may be transitory in nature and often will resolve with small dosage increases. Occasionally dogs will exhibit profound depression at lower dosage ranges (and plasma levels). Polydipsia, polyuria, and polyphagia are also quite commonly displayed at moderate to high serum levels; these are best controlled by limiting intake of both food and water. Sedation and/or ataxia often become significant concerns as serum levels reach the higher ends of the therapeutic range. Increases in liver enzymes and anemias are more rare, but these potentially serious adverse effects have been reported in dogs. Cats may display a similar adverse reaction picture. Although there is much less information regarding its use in horses (and in particular foals), 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 from the gut if appropriate and offering respiratory and cardiovascular support. Activated charcoal has been demonstrated to be of considerable benefit in enhancing the clearance of phenobarbital, even when the drug was administered parenterally. Charcoal acts as a “sink” for the drug to diffuse from the vasculature back into the gut. Forced alkaline diuresis can also be of substantial benefit in augmenting the elimination of phenobarbital in patients with normal renal function. Peritoneal dialysis or hemodialysis may be helpful in severe intoxications or in anuric patients.
Drug Interactions - The following drugs may increase the effect of phenobarbital: Other CNS depressants (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 postural hypotension. Barbiturates may effect the metabolism of phenytoin; monitoring of blood levels may 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 be administered within the 24 hours before BSP retention tests; or if they must, (e.g., for seizure control) the results be interpreted accordingly.
a) 1 - 10 mg/kg IV (Robinson 1987)
b) Loading dose of 12 mg/kg IV over 20 minutes, then 6.65 mg/kg IV over 20 minutes every 12 hours (Duran et al. 1987)
c) 11 mg/kg PO q24 hours (Ravis et al. 1987)
d) Foals; for seizures: 20 mg/kg diluted with normal saline to a volume of 30-35 ml infused over 25-30 minutes IV, then 9 mg/kg diluted and infused as above q8h. Recommend monitoring serum levels if possible. (Spehar et al. 1984)
Monitoring Parameters -
1) Anticonvulsant (or sedative) efficacy
2) Adverse effects (CNS related, PU/PD, weight gain)
3) Serum phenobarbital levels if lack of efficacy or adverse reactions noted. Although there is some disagreement among clinicians, therapeutic serum levels in dogs are thought to mirror those in people (15 - 40 micrograms/ml).
4) If used chronically, routine CBC’s and liver enzymes at least every 6 months.
Client Information - Compliance with therapy must be stressed to clients for successful epilepsy treatment. Encourage client to give doses at the same time each day. Keep medications out of reach of children and stored in child-resistant packaging. Veterinarian should be contacted if animal develops significant adverse reactions (including symptoms of anemia and/or liver disease) or seizure control is unacceptable.
Dosage Forms/Preparations/FDA Approval Status/Withholding Times -
Veterinary-Approved Products: None
Phenobarbital Tablets 15 mg, 16 mg, 16.2 mg, 30 mg, 60 mg, 100 mg; Capsules 16 mg
Phenobarbital Elixir 15 mg/5ml in pt and UD 5, 10 & 20 ml, 20 mg/5ml in pt, gal, UD 5 and 7.5 ml
Phenobarbital Sodium for Injection 30 mg/ml, 60 mg/ml, 65 mg/ml, 130 mg/ml; in 1 ml amps, Tubex and vials
Also known as phenyethylmalonylurea or phenobarbitone . Other trade names may include: Luminal® (Winthrop-Breon), and Barbita® (Vortech). Phenobarbital is a Class-IV controlled substance and is available by prescription (Rx) only.
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