Phenobarbital
**Phenobarbital** is a long-acting barbiturate that serves as a cornerstone in veterinary medicine for the management of seizure disorders. * **Primary Use**: It is widely considered the drug of first choice for treating idiopathic epilepsy in cats and remains one of the most common and effective first-line or adjunctive antiseizure medications in dogs and horses. * **Clinical Advantages**: It offers a favorable pharmacokinetic profile, relative safety, proven efficacy, and low cost. It can effectively control seizures at sub-hypnotic doses. * **Hepatic Auto-induction**: A unique pharmacological feature of phenobarbital is its ability to induce hepatic cytochrome P450 enzymes. Over time, the patient's liver becomes more efficient at metabolizing the drug, which often necessitates dose increases to maintain therapeutic serum levels. * **Other Uses**: Beyond seizure control, it is occasionally used as an oral sedative (e.g., for feline travel anxiety or excessive vocalization) and has been used in the management of status epilepticus after initial control with benzodiazepines.
Mecanismo: Phenobarbital exerts its antiseizure and sedative effects through multiple mechanisms within the central nervous system: * **GABA-A Receptor Modulation**: Phenobarbital binds to the allosteric barbiturate site on the **GABA-A receptor**. Unlike benzodiazepines (which increase the *frequency* of chloride channel opening), phenobarbital increases the **duration** of chloride channel opening → enhanced influx of chloride ions → hyperpolarization of the postsynaptic neuronal membrane → increased seizure threshold and decreased spread of seizure activity. * **Glutamate Inhibition**: It inhibits the release of excitatory neurotransmitters, specifically **glutamate**, thereby dampening CNS excitability. * **Calcium Channel Blockade**: At high (anesthetic) doses, it inhibits the uptake of calcium at nerve endings, further reducing neurotransmitter release. * **Other Neurotransmitters**: It has also been shown to inhibit the release of acetylcholine and norepinephrine.
Dosificación por especie
- Idiopathic epilepsy (initial dose) · 2-2.5 mg/kg · PO · q12h · Optimum therapeutic levels 23-30 mcg/mL.
- Idiopathic epilepsy (maintenance) · 1-2 mg/kg · PO · q12h · Adjust based on serum levels.
- Idiopathic epilepsy (rapid loading) · 16-20 mg/kg once IV loading dose, then 1-5 mg/kg PO q12h · IV/PO · Once then q12h
- Status epilepticus · 2-5 mg/kg bolus (repeat at 20 min intervals up to 2x), or add to diazepam infusion at 2-10 mg/hour · IV · PRN · If seizures persist after diazepam therapy.
- Emergency seizure control · 3 mg/kg (repeat q20m up to 24 mg/kg/24h) OR 10 mg/kg bolus · IV · PRN · Given along with IV diazepam.
- Sedation (situational distress/travel) · 2-3 mg/kg · PO · PRN · For controlling excessive vocalization.
- Seizures · 1-2 mg/kg · PO · q8-12h (2-3 times daily)
- Seizures (rapid loading) · Loading dose of 16-20 mg/kg once IV; maintenance dose of 1-2 mg/kg PO q8-12h · IV/PO · q8-12h
- Enzyme induction in organochlorine toxicity · 5 grams · PO · Daily · 3-4 weeks on, 3-4 weeks off, repeat
Vías de administración
Contraindicaciones
- Known hypersensitivity to barbiturates
- Severe liver disease
- Nephritis (large doses)
- Severe respiratory depression
- Hepatic dysfunction
- Severe renal impairment
- Hypersensitivity to barbiturates
Efectos adversos
- Dogs: Transient anxiety, agitation, or lethargy upon initiation
- Dogs: Polydipsia (PD), polyuria (PU), and polyphagia (PP)
- Dogs: Sedation and ataxia (especially at higher serum levels)
- Dogs: Elevated liver enzymes (ALT, ALP) - common and not always indicative of failure
- Dogs: Hepatotoxicity (uncommon, usually at levels >30-40 mcg/mL)
- Dogs: Rare blood dyscrasias (anemia, thrombocytopenia, neutropenia)
- Dogs: Rare superficial necrolytic dermatitis (SND)
- Cats: Ataxia, persistent sedation, lethargy
- Cats: Polyphagia, weight gain, PU/PD
- Cats: Rare immune-mediated reactions and bone marrow hypoplasia
- Cats: Coagulopathies (at very high doses)
- Sedation
- Ataxia
- Polyuria (PU)
- Polydipsia (PD)
Interacciones farmacológicas
- Acetaminophen · Increased risk for hepatotoxicity, particularly with large or chronic doses of barbiturates.
- Carprofen · Increased risk for hepatotoxicity secondary to carprofen metabolites.
- MAO Inhibitors (e.g., Selegiline) · May prolong phenobarbital effects.
- Phenytoin · Barbiturates may affect phenytoin metabolism, and phenytoin may alter barbiturate levels.
- Rifampin · May induce enzymes that increase the metabolism of barbiturates.
- Levetiracetam · Phenobarbital reduces levetiracetam elimination half-life by about 50% in dogs.
- Warfarin · Phenobarbital may decrease anticoagulant effects by lowering serum concentrations.
- Corticosteroids · Phenobarbital increases the metabolism and clearance of corticosteroids, potentially reducing their efficacy. · moderate
- Doxycycline · Phenobarbital decreases doxycycline serum concentrations; effect may persist for weeks after discontinuation.
- Theophylline · Phenobarbital increases theophylline metabolism, lowering its serum concentrations.
- Chloramphenicol · May increase the effects of phenobarbital while phenobarbital may decrease chloramphenicol levels. · major
- Levothyroxine · Increased hepatic metabolism and clearance of T4 · moderate
Monitoreo
- Anticonvulsant efficacy (seizure frequency and severity)
- Adverse effects (CNS depression, ataxia, PU/PD, weight gain)
- Serum phenobarbital levels (Dogs: 20-35 mcg/mL; Cats: 23-30 mcg/mL). Wait 5-6 half-lives (12-14 days in dogs, 9-10 days in cats) before measuring steady-state levels.
- Routine CBC, liver enzymes (especially ALT and AST), and bilirubin at least every 6 months during chronic therapy.
- Serum phenobarbital concentrations (trough levels)
- Liver enzymes (ALT, ALP, GGT)
- Serum bile acids
- Complete Blood Count (CBC)
- Renal function
Sobredosis
**Clinical Signs of Toxicity**: * **Dogs**: Ataxia, lethargy, sedation, recumbency, depression, hypothermia, and coma. * **Cats**: Ataxia, sedation, and recumbency. **Treatment**: * **Decontamination**: Removal of ingested product from the gut if recent. **Activated charcoal** is highly effective and acts as a 'sink' to draw the drug from the vasculature back into the gut, enhancing clearance even if the drug was given parenterally. * **Supportive Care**: Provide intensive respiratory and cardiovascular support. * **Enhanced Elimination**: Forced alkaline diuresis can substantially augment elimination in patients with normal renal function. Peritoneal dialysis or hemodialysis may be helpful in severe intoxications or anuric patients.
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