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Phenobarbital
Authors

Cassaundra B. Lewis1; Preeti Patel; Ninos Adams2.

Affiliations
1 Ross University SOM
2
Kern Medical
Last Update: February 28, 2024.

Continuing Education Activity

Phenobarbital is a member of the barbiturate drug class that holds versatile therapeutic applications. This drug is
effective in anti-seizure management, treatment for status epilepticus, and insomnia; it also plays a pivotal role in
addressing benzodiazepine and alcohol withdrawal. This mechanism involves interaction with GABA-A receptor
subunits, facilitating the sustained opening of chloride ion gates and a continuous influx of ions into neuronal cells. By
elongating the opening duration of chloride channels, phenobarbital induces a depression in the central nervous
system. The resultant hyperpolarization of the cell membrane elevates the action potential threshold, rendering
phenobarbital an effective solution for seizure treatment. In the event of a phenobarbital overdose, a critical situation
demanding coordinated efforts from the interprofessional team, this educational session meticulously examines its
indications, mechanism of action, toxicity, contraindications, administration, adverse effects, and monitoring. The aim
is to equip the interprofessional team with comprehensive insights for adeptly managing a phenobarbital overdose.

Objectives:

Identify appropriate indications for phenobarbital therapy based on patient-specific factors and clinical
guidelines.

Screen patients for contraindications and potential drug interactions before initiating phenobarbital therapy.

Implement appropriate dosing regimens and administration techniques for phenobarbital, considering age,
weight, and underlying medical conditions.

Develop collaboration with other healthcare professionals, such as pharmacists and specialists, to ensure
coordinated and comprehensive care for patients receiving phenobarbital therapy.

Access free multiple choice questions on this topic.

Indications
Phenobarbital is a sedative-hypnotic agent belonging to the barbiturates class of drugs. Phenobarbital has multiple
clinical uses that include anti-seizure management.[1] Phenobarbital is also recommended as an agent to treat status
epilepticus.[2]

A study in China compared valproic acid to phenobarbital to treat status epilepticus. Results showed that intravenous
phenobarbital had better clinical outcomes in the study population than valproic acid.[3] Although proven effective for
status epilepticus, phenobarbital has been replaced with other drugs with less harmful side effects.[4][2]

Phenobarbital can also be used to manage insomnia and apprehensiveness, although addiction is a point of concern
when using phenobarbital for insomnia. This drug is also useful for benzodiazepine and alcohol

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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 indication.[7] Phenobarbital reduces intracranial pressure by suppressing cerebral
metabolism in severe brain injury management. Still, phenobarbital's adverse effect of hypotension negatively impacts
the brain's oxygen supply, thus offsetting any clinical benefit.[8]

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

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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

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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

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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.

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Review Questions

Access free multiple choice questions on this topic.

Comment on this article.

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Disclosure: Cassaundra Lewis declares no relevant financial relationships with ineligible companies.

Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.

Disclosure: Ninos Adams declares no relevant financial relationships with ineligible companies.

Copyright © 2024, StatPearls Publishing LLC.

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