Phenobarbital

Mechanism of Action

Phenobarbital increases the duration of time chloride channels are open, depressing the central nervous system. This action occurs by acting on GABA-A receptor subunits. When phenobarbital binds to these receptors, the chloride ion gates open and stay open, allowing a steady flow of these ions into neuronal cells.[1] This action hyperpolarizes the cell membrane, increasing the action potential threshold. This increase in action potential is why this drug is effective in treating seizures. 

Pharmacokinetics

Absorption: Rapid and complete absorption occurs after oral or IV administration.[1] The time of peak plasma concentration ranges from 30 minutes to 1 hour for oral formulations and is around 5 minutes for IV injection.

Distribution: Rapidly distributed to all tissues and fluids.

Metabolism: Metabolized primarily via acetylation in the liver (hepatic microsomal enzyme system).[1]

Elimination: About 25% to 50% of the unchanged drug is excreted in the urine. Remember that clearance rates vary with patients and their specific presentations. For instance, patients who are terminally ill with cancer and on phenobarbital therapy may need dose adjustments due to reduced clearance of this drug.[9]

Administration

Available Dosage Forms and Strengths

Phenobarbital administration is via a variety of routes.[10] These include:

• Oral Elixir: 20 mg/5 mL
• Oral Tablets: 15 mg, 16.2 mg, 30 mg, 32.4 mg, 60 mg, 64.8 mg, 97.2 mg, 100 mg
• Intramuscular (IM)/Intravenous (IV) Solution: 65 mg/mL, 130 mg/mL 

Phenobarbital should only be given intravenously for emergency cases. If possible, other routes of administration should be accessed first. When given IV, check for any indurations. Studies have shown that an induration at a site of infusion results in a decreased bioavailability of phenobarbital.[11] Another study demonstrated the effectiveness of the rectal administration of phenobarbital, with a relative bioavailability reaching 90%.[12] 

Patients can experience withdrawal symptoms if they stop taking the drug abruptly, so tapering off it is recommended. As per current guidelines from the American Epilepsy Society, generally, phenobarbital is given IV at 15 mg/kg in adult patients with status epilepticus.[13]

Specific Patient Populations 

Hepatic impairment: The manufacturer label provides no dose adjustment guidance for patients with hepatic impairment. However, phenobarbital is a potent inducer of cytochrome P450 enzymes, leading to interactions with other drugs by increasing their clearance. Therefore, phenobarbital should be used cautiously in patients with severe hepatic impairment.

Renal impairment: The manufacturer label does not provide dose adjustment guidance for patients with renal impairment. However, approximately 25% to 50% of phenobarbital is eliminated in the urine, so the drug should be used cautiously in patients with severe renal impairment. 

Pregnancy considerations: Phenobarbital is considered a pregnancy Category D medicine. Barbiturates are reported to cause fetal damage when administered to a pregnant female patient. No systematic and well-controlled studies have been reported for pregnant women. Maternal administration of barbiturates reportedly has a higher-than-expected incidence of fetal abnormality in retrospective, case-controlled studies.

Barbiturates, including phenobarbital, readily cross the placental barrier and are distributed throughout fetal tissues, and high concentrations are detected in the placenta, brain, and fetal liver. Withdrawal symptoms can occur in infants born to females who are administered barbiturates throughout the last trimester of pregnancy. If phenobarbital is administered during pregnancy or the patient gets pregnant while taking the drug. The patient should be informed and counseled about the potential hazard to the fetus. This drug should be used with caution only if needed during pregnancy.[14]

Breastfeeding considerations: The manufacturer recommends caution for phenobarbital therapy in nursing mothers as the drug is present in breast milk. If infants' excessive drowsiness and poor weight gain are observed, limiting or discontinuing phenobarbital is also recommended.[15]

Pediatric patients: Reports indicate phenobarbital is associated with cognitive deficits in pediatric therapy for complicated febrile seizures. Using the dose as per the manufacturer's label is recommended.

Older patients: The safety and efficacy of phenobarbital are not systematically studied in older patients. However, it is recommended to use the drug cautiously as it may cause excitement, depression, or confusion in some older patients.

Adverse Effects

Complications associated with phenobarbital use include coma, impaired breathing effort, low blood pressure, incoordination, poor balance, and drowsiness.[1] These adverse effects, stemming from phenobarbital usage, impact older patients to a greater degree. Therefore, newer antiepileptics (lamotrigine, levetiracetam) are preferred as seizure treatment in this patient population.[16] 

When used long-term, adverse events of phenobarbital include irritability, loss of appetite, achiness in the bones, joints, or muscles, depression, and, rarely, liver damage.[1] When taking barbiturates such as phenobarbital, patients may experience withdrawal symptoms if they stop taking the drug abruptly; tapering off the medication is necessary.

In post-marketing surveillance of hospitalized patients using phenobarbital, the following adverse reactions have been reported:

Nervous system: Agitation, somnolence, confusion, CNS depression, hyperkinesia, ataxia,  nervousness, nightmares, psychiatric disturbance,  thinking abnormality, insomnia, anxiety, hallucinations, dizziness

Respiratory: Apnea, hypoventilation

Cardiovascular: Hypotension, bradycardia, syncope

Gastrointestinal: Nausea, vomiting, constipation

Dermatologic: Exfoliative dermatitis, toxic epidermic necrolysis, Stevens-Johnson syndrome (rare) 

Others: Headache; hypersensitivity reactions, including but not limited to angioedema and skin rashes, injection site reactions, fever, liver damage and megaloblastic anemia in chronic users

Contraindications

Phenobarbital is contraindicated in patients with known barbiturate sensitivity. Barbiturates, including phenobarbital, are contraindicated in patients with a history of latent porphyria, liver impairment, and large doses in patients with nephritic syndrome. Phenobarbital should not be given to persons with a known history of addiction to sedative-hypnotic medicines. Injectable preparation should not be given via intraarterial or subcutaneous routes.

Phenobarbital is a potent cytochrome P450 inducer, so careful consideration is necessary when given concurrently with other medications. For instance, a woman with epilepsy who takes oral contraceptive pills and phenobarbital at the same time must be fully aware of the possible interaction between the medications. Phenobarbital is known to induce the liver's cytochrome p450 enzymes, speeding up the metabolism of estrogens and progestins. Thus, a woman taking both antiepileptic medication and oral contraceptive pills may experience an unexpected pregnancy due to the decreased efficacy of her oral contraceptive pills.[17] Patients taking warfarin must have close monitoring of INR due to drug interactions.

Patients with underlying obstructive lung disease will have an increased risk of complications.[1] The depression of the respiratory system associated with barbiturate toxicity compounded with an already compromised respiratory system can contribute to complications. Research has also found that the drug interaction from combined oral theophylline medication and phenobarbital negatively impacted theophylline blood levels compared to plain oral theophylline pills. Phenobarbital has shown a capacity to decrease levels of steroids and theophylline via the cytochrome p450 liver metabolism system.[18] Therefore, patients receiving combined oral therapy for their lung condition may experience issues with subtherapeutic blood levels of corticosteroids or theophylline. 

Abstinence from alcohol while taking barbiturates is crucial because of the danger of severe respiratory depression when both drugs are in the patient's system. When taken simultaneously, both drugs' individual effects on GABA-A are additive, potentially resulting in a life-threatening scenario.[1]

Monitoring

Phenobarbital's effective dosage is between 10 to 40 μg/mL. Once blood levels exceed 40 μg/mL, the patient is in a lethal range and at substantial risk.[1]

Toxicity

Barbiturate toxicity is noticeable at 1 g orally, although this varies depending on the individual. Doses above 2 g can result in death, but the deadly dose usually is between 40 and 80 μg/mL.[1] 

Signs and Symptoms of Overdose

Toxicity from barbiturates varies, but common symptoms include the following:

• Cognitive impairment
• Decreased heart rate
• Incoordination
• Nausea
• Muscle weakness
• Polydipsia
• Below-normal urine output
• Decreased body temperature
• Mydriasis

Deaths have occurred due to respiratory depression, hypotension, and coma.[1]

Management of Overdose

Phenobarbital overdose is a healthcare emergency and requires teamwork from the entire healthcare spectrum to help the patient. The healthcare team must implement the management of cardiac and respiratory status quickly.[1][19] Alkalinizing the urine can help eliminate the drug, but if prior interventions fail to advance patients in a positive direction, hemodialysis or hemoperfusion can expedite drug clearance.[1][20][21] 

Hemoperfusion was thought to be more effective in phenobarbital overdose due to increased protein binding; however, a case of severe phenobarbital intoxication treated with high-efficiency dialyzers and increased rates of blood flow showed that hemodialysis is the better option for drug clearance in compromised patients. The patient experienced a positive clinical outcome after phenobarbital levels dropped rapidly.[20]

Recommendations

Treatment of phenobarbital toxicity is supportive, comprising maintenance of airway function (through endotracheal intubation and mechanical ventilation), correction of bradycardia, and hypotension (with IV fluids and vasopressors, if necessary).[18] 

After properly evaluating and correcting the patient's airway, breathing, and circulation, removing the drug from the body is imperative; this can occur via gastric irrigation, forced alkaline diuresis, or dialysis.[20] A specific treatment does not currently exist.[1]

Enhancing Healthcare Team Outcomes

Phenobarbital is a class IV control substance, and it is used for its sedative and anti-seizure properties in patients with status epileptics and alcohol withdrawal management. However, it is no longer a first-line agent. Phenobarbital is known for being highly addictive and was historically a common agent of choice for suicide attempts.[19] Phenobarbital is a drug that poses an emergent situation for the interprofessional healthcare team when a patient arrives after an attempted or accidental overdose.

Although restrictions on access to barbiturates have led to a decline in the number of overdoses, expeditiously assessing and treating patients with a phenobarbital overdose is still crucial.[1] In case of a suspected drug overdose, the healthcare team must evaluate the patient's vitals and ensure optimal respiratory effort. If respiration is compromised, precautions for respiratory support must be implemented (endotracheal intubation or mechanical ventilation). As a next step, urine or blood toxicology is necessary to confirm the suspected diagnosis.

While in recovery, patients require counsel about barbiturates and proper use.[1] This educational opportunity and a psychiatric evaluation are pertinent for the patient. Regarding preventing future overdoses, an interprofessional effort among patients' healthcare providers is necessary to ensure that the patient is not prescribed many pills at once. Prescribers can also evaluate whether the patient can be switched to an alternative medication.

A cohort study showed that subjects who purposely overdosed on barbiturates showed an increased risk of an adverse ICU course. If clinicians judiciously prescribe barbiturates, the patient is less likely to overdose and thus less likely to have an unfavorable hospital course.[22] Nurses should check for vitals and any adverse reactions at all visits; they must be aware of the signs of toxicity or misuse to alert the prescriber. Pharmacists should verify phenobarbital's dose, duration, and drug interactions and inform prescribers of any concerns.

In summary, the management of therapy with phenobarbital is the responsibility of the interprofessional healthcare team, including clinicians, specialists, pharmacists, and mental health practitioners, operating as a cohesive unit to optimize treatment outcomes and prevent mortality and morbidity from phenobarbital misuse.