Continuing Education Activity

Phenobarbital is included in a class of drugs called barbiturates. This drug can be used for anti-seizure management, treatment for status epilepticus, insomnia, as well as benzodiazepine and alcohol withdrawal treatment. This activity reviews phenobarbital's indications, mechanism of action, toxicity, contraindications, administration, adverse effects, monitoring, and how to enhance clinical outcomes. This activity will provide information for the interprofessional team in the management of a patient presenting with a phenobarbital overdose. Phenobarbital overdose is an emergency and requires efficient teamwork from the interprofessional team.

Objectives:

• Identify the mechanism of action of phenobarbital.
• Describe the possible adverse effects of phenobarbital.
• Explain appropriate monitoring for the toxicity of phenobarbital.
• Summarize interprofessional team strategies for enhancing care coordination and communication to advance phenobarbital overdose management and improve outcomes.

Indications

Phenobarbital is one of the sedative-hypnotic agents which belongs to the barbiturates class of drugs. Phenobarbital offers a wide array of clinical uses that commonly include anti-seizure management.[1] It is also recommended as an agent to treat status epilepticus.[2] A study in China compared valproic acid to phenobarbital for the treatment of status epilepticus. Results showed that intravenous phenobarbital had better clinical outcomes in the study population compared to valproic acid.[3] Although proven effective for status epilepticus, phenobarbital has mostly been replaced with other drugs that offer less harmful side effects.[4][2] 

Phenobarbital can also be used to relieve insomnia and apprehensiveness, although addiction is a point of concern when using phenobarbital for insomnia. This drug is also useful for benzodiazepine and alcohol withdrawal treatment due to its anti-seizure properties and sedative effect. The syndrome resulting from alcohol withdrawal has a better clinical outcome when treated with benzodiazepines, according to significant evidence-based studies.[5][6] Long-acting agents such as phenobarbital are not the preferred option for surgical induction; short-acting barbiturates are commonly used for this purpose.[7] The involvement of phenobarbital in severe brain injury management reduces intracranial pressure by suppressing cerebral metabolism. Still, phenobarbital's adverse effect of hypotension negatively impacts the brain's supply of oxygen, thus offsetting any clinical benefit.[8]

Mechanism of Action

Phenobarbital increases the amount of time chloride channels are open, consequently 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 the reason why this drug is effective in the treatment of seizures. 

Pharmacokinetics[1]

Absorption: Rapid and complete absorption occurs after oral or IV administration.

Time of Peak Plasma Concentration: 30 minutes to 1 hour for oral formulations; 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)

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

Administration

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

• 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 

When phenobarbital is given intravenously, it should be 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 the drug 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 epileptics.[13]

Specific Patients Population 

• Patient with Hepatic Impairment: There is no dose adjustment guidance in the manufacturer label for patients with hepatic impairment. However, phenobarbital may induce liver microsomal enzyme activities. Therefore, it should be taken with caution in patients with severe hepatic impairment.

• Patient with Renal Impairment: There is no dose adjustment guidance in the manufacturer label for patients with renal impairment. However, approximately 25 to 50% of phenobarbital is eliminated in the urine, so the drug should be used with caution in patients with severe renal impairment. 

• Pregnant Women: It is considered a pregnancy Category D medicine. There are no systematic and well-controlled studies reported for pregnant women. In animal studies, there has been no evidence of any harm to the fetus or any fertility impairments due to phenobarbital. This drug should be used with caution only if clearly needed during pregnancy.[14]

• Breastfeeding Women: The manufacturer recommends exercising cautions for phenobarbital therapy in nursing mothers as the drug presents in breast milk. It is also recommended to limit or discontinue phenobarbital if excessive drowsiness and poor weight gain are observed for infants.[15]

• Pediatric Patients: It is reported that phenobarbital is associated with cognitive deficits in pediatric patients who were taking it for complicated febrile seizures. It is recommended to use dose as per manufacturer label.

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

Adverse Effects

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

When used long-term, adverse events of irritability, loss of appetite, achiness in the bones, joints, or muscles, depression, and liver damage, although liver damage is a rare complication, are recorded.[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 following adverse reactions was reported.

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

Respiratory System: Apnea, hypoventilation

Cardiovascular System: Hypotension, bradycardia, syncope

Digestive System: Nausea, vomiting, constipation

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

Other Reported Reactions: 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 a patient with a history/manifest or 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 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 enzyme. The induction of this enzyme speeds up the metabolism of estrogens and progestins. Thus, a woman taking both antiepileptic medication and oral contraceptive pills can have an unexpected pregnancy due to the decreased efficacy of her oral contraceptive pills.[17]

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 and/or theophylline. 

It is imperative not to use alcohol while taking barbiturates 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

The range of phenobarbital deemed effective without causing issues to an individual is between 10 to 40 mcg/mL. Once blood levels increase above 40 mcg/mL, the patient is in a lethal range and at substantial risk.[1]

Toxicity

Barbiturate toxicity is noticeable at 1 gram via the oral route, although this varies depending on the individual. Doses above 2 grams can result in death, but the deadly dose usually is between 40 and 80 mcg/mL.[1] 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 resulted from marked respiratory depression, hypotension, and coma.[1]

Management

Phenobarbital overdose is a healthcare emergency and requires teamwork from the entire healthcare spectrum to help the patient. It is imperative to 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 be used to enhance 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]

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, it is imperative to remove the drug from the body; this can occur via gastric irrigation, forced alkaline diuresis, or dialysis.[20] For now, a specific treatment does not exist.[1]

Enhancing Healthcare Team Outcomes

Phenobarbital is a class C-IV control substance, and it is used for its sedative and anti-seizure properties in patients with status epileptics and alcohol withdrawal management. It is known for being highly addictive and, in prior years, found to be a common agent of choice for suicide attempts.[19] Phenobarbital is a drug that poses an urgent situation for the interprofessional healthcare team when a patient arrives after an attempted overdose.

Although restrictions on access to barbiturates have caused the number of overdoses to decline, it is still crucial to assess and treat patients with a phenobarbital overdose expeditiously.[1] In case of a suspected drug overdose, the healthcare team must assess patient vitals and ensure respiratory effort is optimal. If it is compromised, precautions for respiratory support must be put in place (endotracheal intubation and/or mechanical ventilation). Next, urine or blood toxicology is necessary to confirm the suspected diagnosis.

While in recovery, the patient requires proper counsel about barbiturates and proper/improper use.[1] This educational opportunity and a psychiatric evaluation are pertinent for the patient. Regarding preventing future overdoses, an interprofessional effort among patients' health care 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. An evidence level III-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 suffer an unfavorable hospital course.[22] Nursing should check for vitals and any adverse reactions at all visits. Pharmacists should verify dose, duration, drug interactions of phenobarbital and inform prescribers of any concerns.

In summary, the management of therapy with phenobarbital is the responsibility of the entire interprofessional team, including clinicians, specialists, PAs and NPs, nurses, pharmacists, and mental health practitioners, operating as a cohesive unit to optimize treatment outcomes and prevent mortality and morbidity from misuse of the drug. [Level 5]