Continuing Education Activity

Pentobarbital belongs to the barbiturate class of medications and is approved by the US Food and Drug Administration (FDA) for managing various medical conditions such as seizures, status epilepticus, and short-term treatment of insomnia. At low doses, approved indications of pentobarbital include short-term sedatives to treat insomnia and as a pre-anesthetic agent for surgery in the operating room. Pentobarbital primarily acts on the central nervous system (CNS). At elevated doses, pentobarbital functions as an anticonvulsant for emergent seizure control and for inducing medically induced comas. Studies have demonstrated the superiority of pentobarbital due to its faster brain penetration and shorter half-life, thereby making it the preferred treatment for refractory status epilepticus.

Pentobarbital functions within the CNS by binding to gamma-aminobutyric acid (GABA) A subtype receptors. This action potentiates GABA effects, resulting in CNS depression and inhibiting glutamate, further leading to an additive effect on CNS depression. Although the lack of an antidote has led to decreased first-line usage of the drug, its indications remain recognized. This activity reviews the indications, mechanism of action, administration, adverse effects, and contraindications of pentobarbital therapy in the clinical setting. This activity also entails members of an interprofessional healthcare team in treating patients undergoing treatment with pentobarbital and its related conditions and sequelae, reviewing the essential pearls.

Objectives:

• Identify appropriate indications for pentobarbital therapy in clinical practice in patients with various conditions, such as seizures, insomnia, and status epilepticus.

• Screen patients for contraindications and potential risk factors before initiating pentobarbital therapy.

• Apply evidence-based guidelines and comprehensive knowledge of pentobarbital's pharmacology, pharmacokinetics, and potential drug interactions for the safe and effective use of pentobarbital.

• Collaborate with other healthcare professionals to ensure coordinated and comprehensive care for patients receiving pentobarbital therapy.

Indications

Pentobarbital belongs to the barbiturate class of medications and primarily works primarily on the central nervous system (CNS).

FDA-Approved Indications

Pentobarbital is approved by the US Food and Drug Administration (FDA) for managing various medical conditions such as status epilepticus, pre-anesthesia or sedation, and short-term treatment of insomnia. At low doses, approved indications of pentobarbital include short-term sedatives to treat insomnia and as a pre-anesthetic agent for surgery in the operating room.[1] At elevated doses, pentobarbital functions as an anticonvulsant for emergent seizure control and for inducing medically induced comas.

According to the American Academy of Neurology (AAN) guidelines, pentobarbital is often used for refractory status epilepticus.[2] Studies have demonstrated the superiority of pentobarbital due to its faster brain penetration and shorter half-life, thereby making it the preferred treatment for refractory status epilepticus.

Off-Label Uses 

Common off-label uses of pentobarbital include controlling intracranial pressure in patients with severe brain injuries, cerebral ischemia, and those undergoing treatment for Reye syndrome.[3][4] Some US states use pentobarbital for capital punishment, but this remains controversial, and some manufacturers do not allow the sale to prisons. More commonly, it is used by veterinarians for euthanasia and anesthesia.[5]

Mechanism of Action

Pentobarbital primarily acts on the central nervous system (CNS) by binding to gamma-aminobutyric acid (GABA) A subtype receptors. This action induces a change in the chloride transport receptor, increasing the duration the chloride channels remain open, potentiating GABA effects. GABA is responsible for producing CNS depression, prolonging the time the channels remain open, and intensifying the depressant effects on the CNS.[6] 

Pentobarbital also works by inhibiting glutamate, which is responsible for nerve depolarization in the voltage-activated calcium currents.[7] This activity has an additive effect on CNS depression. Although the lack of an antidote has led to decreased first-line usage of the drug, its indications remain recognized.

Pharmacokinetics

Absorption: The onset of action of intravenous (IV) injection is immediate. CNS depression is achieved within 15 minutes. Intramuscular (IM) administration also has a rapid onset of action. Oral and rectal phenobarbital acts within 20 to 60 minutes. 

Distribution: Pentobarbital rapidly crosses the blood-brain barrier. The volume of distribution is approximately 1 L/kg.[8]

Metabolism: Pentobarbital undergoes first-pass metabolism in the liver. Pentobarbital is metabolized predominantly by the hepatic microsomal enzymes.

Elimination: The elimination half-life of pentobarbital in adults is 15 to 50 hours and is dose-dependent. Metabolic end products of pentobarbital are excreted predominantly via urine, and a minor amount is excreted in feces.[9]

Administration

Available Dosage Forms and Strengths

Pentobarbital administration is through IM, IV, or oral routes. For IM administration, injecting no more than 5 mL and only into a large muscle to avoid tissue irritation or necrosis is advised. IV administration should not exceed 50 mg/min and should only be given by slow IV injection in the undiluted form.[10]

Avoiding tissue extravasation in this process is essential as it has been known to cause tissue necrosis. Clinicians should avoid rapid IV injection as it may result in respiratory depression, hypotension, and bronchospasm, among other adverse effects.[8] The dosage should be individualized according to the clinical need, patient status, and presence of commodities. 

Adult Dosage

Status epilepticus: Pentobarbital can be administered in refractory status epilepticus according to the AAN guidelines for convulsive status epileptics. Clinicians must recognize that pentobarbital is reserved for refractory status epilepticus not responding to first or second-line treatment options.[2] 

According to Neurocritical Care Society (NCS) guidelines, the loading dose of pentobarbital is 5 to 15 mg/kg (infusion rate ≤50 mg/min). This loading dose is followed by a continuous infusion of 0.5 to 5 mg/kg/h. In patients having breakthrough seizures, an additional dosage of 5 mg/kg bolus and an increase of infusion rate by 0.5 to 1 mg/kg/h every 12 hours is recommended.[11]

Pre-anesthesia or sedation: The dosage of pentobarbital is 150 to 200 mg administered as an IM injection. 

Insomnia: American Society of Sleep Medicine guidelines do not endorse using barbiturates for sleep onset or sleep maintenance insomnia.[12]

Pediatric Dosage

Oral administration can be facilitated by mixing the drug with flavored syrup to enhance palatability in pediatric populations. Although IV pentobarbital in a dosage of 2 to 6 mg/kg can be utilized for procedural sedation, alternative medications are generally preferred.[13]

Specific Patient Populations

Hepatic impairment: As clinical data regarding the use of pentobarbital in hepatic impairment are lacking, pentobarbital should be used with caution.

Renal impairment: In cases of renal impairment, IV formulations containing propylene glycol may induce metabolic acidosis (resulting in an increased anion gap) and elevated osmolar gap. Caution is advised when using such formulations in individuals with impaired renal function.[14][15]

Pregnancy considerations: In considerations of pregnancy, avoidance of use is recommended, with reference to contraindications. If pentobarbital is utilized during pregnancy, patients should be duly informed about the potential risks to the fetus.[16]

Breastfeeding considerations: In breastfeeding considerations, it should be noted that barbiturates are present in breast milk. As clinical data regarding the use of pentobarbital during breastfeeding are lacking, it is advisable to consider alternative agents, particularly when nursing a newborn or preterm infant.[17]

Older patients: According to the American Geriatrics Society Beers Criteria^®, barbiturates, including pentobarbital, should be used cautiously due to the risk of physical dependence and increased overdose. Thus, as healthcare professionals advise, the drug should be used in low doses.[18]

Adverse Effects

The main adverse reactions surrounding pentobarbital use are CNS effects, including altered mental status, agitation, confusion, drowsiness, respiratory depression, bradycardia, hypotension, cardiovascular collapse, and syncope. Other significant adverse effects to be aware of include hallucinations, headache, insomnia, nausea, vomiting, hepatoxicity, megaloblastic anemia, angioedema, local injection site reactions, laryngospasm, bronchospasm, apnea, and hyperkinesia.[1] At high doses of pentobarbital, total loss of neurological function is observed.[11]

Drug-Drug Interactions

Pentobarbital interacts with several major classes of drugs and requires close monitoring to maintain therapeutic drug levels. As a class, barbiturates induce hepatic microsomal enzymes, which increase the rate of metabolism of other drugs metabolized by these hepatic enzymes. In particular, anticoagulants can be affected, and patients taking these drugs, predominantly warfarin, may require dosage adjustments. Other drug interactions to be aware of include levothyroxine, corticosteroids, doxycycline, phenytoin, valproic acid, alcohol, monoamine oxidase inhibitors (MAOIs), and some hormones such as estradiol, estrone, and progesterone.[19]

Barbiturates can decrease the absorption of griseofulvin. Concomitant administration requires dose adjustment.[20] Barbiturates combined with CNS depressants such as benzodiazepines and opioids can lead to profound respiratory depression.[21][22] Misusing kratom with barbiturates can lead to severe CNS depression and death.[23]

Contraindications

Contraindications to pentobarbital use include prior hypersensitivity reactions to drug use or barbiturate class use. Barbiturates can trigger hypersensitivity reactions by direct histamine release or immunoglobulin E (IgE)–mediated mechanisms and can lead to anaphylaxis.[24] Other contraindications include patients with depressed respiratory function and porphyria. Abrupt drug withdrawal in patients on long-term pentobarbital therapy should be avoided. Clinical staff should exercise caution using this drug in older patients, those with renal impairment, hepatic impairment, and those with a drug misuse history.[18]

Barbiturates are pregnancy category D drugs and have been shown to cause fetal damage if used in pregnant patients. This class of drugs can cross the placental barrier and distribute throughout the fetal tissue with the highest concentrations in the liver, brain, and placenta. Monitoring maternal blood levels for fetal safety in any pregnant patient taking these drugs is essential.

Documented evidence of withdrawal exists in infants born to mothers who took barbiturates during pregnancy. Newborns should be closely monitored for seizures and hyperirritability, which may indicate a need for withdrawal treatment. Symptoms can be delayed for up to 2 weeks and require prompt treatment if indicated.[25]

Monitoring

Toxic doses of pentobarbital occur at approximately 1 g in most adults, with death occurring at 2 to 10 g. The therapeutic concentration of pentobarbital depends on the intended therapeutic effect. The sedation dose is 1 to 5 mcg/mL. For intracranial pressure therapy, the recommended dose is 30 to 40 mcg/mL, while for therapeutic coma, it is 20 to 50 mcg/mL. Sedation is considered toxic at values exceeding 10 mcg/mL. The time to reach a steady state in adults is typically 3 to 6 days. Monitoring parameters include electroencephalogram (EEG) and serum drug levels. Other things to consider when assessing for toxicity are a complete blood count (CBC), liver function tests (LFTs), and a blood urea nitrogen (BUN) to creatinine ratio if on continuous treatment. 

Pentobarbital is a high-risk habit-forming drug categorized by the Federal Controlled Substances Act under DEA Schedule II. Tolerance, physical dependence, and psychological effects can occur in patients with long-term use. Estimates are that the threshold for developing dependence is over 400 mg daily for over 90 days. In addition, dosages of 600 to 800 mg daily for more than 35 days correlate with withdrawal seizures.

Symptoms of acute intoxication include gait and speech alterations and neurological manifestations. Chronic intoxication demonstrates confusion, agitation, insomnia, and generalized myalgias. Minor withdrawal is seen within 8 to 12 hours, and significant withdrawal within 16 hours, lasting for up to 1 week following cessation of the drug. Treatment of dependence includes close monitoring and gradual withdrawal of the drug by small dosage decreases over many weeks—infants with physical dependence commonly present with hyperactivity, sleep disturbances, and hyperreflexia. Treatment of withdrawal in this population usually spans over 2 weeks.[26]

According to AAN guidelines on convulsive status epilepticus, EEG monitoring is required when administering pentobarbital.[2] Clinicians must be aware that pentobarbital is often confused with phenobarbital, a different drug with differing dosages and a similar mechanism of action.

Toxicity

Pediatric neurotoxicity is reported with the use of pentobarbital. Barbiturates, including pentobarbital, can increase GABA activity, leading to increased neuronal apoptosis and impaired cognition when used for more than 3 hours.[27] Treatment of pentobarbital toxicity involves supportive care, as no antidote exists. Overdose can lead to airway compromise, cardiovascular collapse, coma, and death. Treatment often requires intubation, hemodynamic support with vasopressors, and maintaining body temperature with warmers, commonly in an intensive care unit (ICU) setting. In mild or early cases of toxicity, activated charcoal and alkaline diuresis have been added but show minimal benefits. Always contact poison control if poisoning or overdose is suspected.

Caution is warranted for individuals with renal and hepatic impairment. While the manufacturer does not offer specific dosage adjustment recommendations for renal impairment, monitoring kidney function when administering high doses or conducting prolonged treatment is crucial. Comparable effects are observed in individuals with hepatic impairment, necessitating close patient monitoring. Continuous venovenous hemofiltration is known to enhance the removal of pentobarbital.[28]

Enhancing Healthcare Team Outcomes

Pentobarbital is not used widely in clinical medicine because of its poor safety profile, habituation, and lack of an antidote. All prescribing clinicians should be aware of the drug's toxicity and adverse event profile. Neurologists can use pentobarbital for refractory status epilepticus.[2] Withdrawal from pentobarbital can be life-threatening. Managing pentobarbital withdrawal requires a well-trained interprofessional healthcare team, including nurses, pharmacists, and several clinicians from different specialties. Without proper management, the morbidity and mortality from unrecognized pentobarbital withdrawal are high.

Properly treating pentobarbital withdrawal begins when a clinician recognizes the patient is either susceptible to or suffering from withdrawal. When withdrawal is suspected, the interprofessional team must coordinate patient care by:

• Obtaining a thorough history and physical examinations.

• Ordering drug levels in the blood or urine, appropriate laboratory tests, and imaging in the emergency department.

• Monitoring the patient for signs and symptoms of respiratory depression, cardiovascular collapse, CNS dysfunction, and renal or hepatic toxicity.

• Preparing to provide airway protection and vasopressor support if indicated.

• Consulting with the pharmacist about drug interactions if the patient is taking other medications.

• Consulting with a medical toxicologist.

• Consulting with the intensivist about ICU care and monitoring during hospitalization.

• Considering long-term management with social work to provide outpatient follow-up.

To avoid the high potential for morbidity and mortality associated with pentobarbital, the pharmacist should recommend prescribing clinicians safer alternative agents. Nurses should monitor the patient at subsequent visits, verifying medication compliance and treatment effectiveness. With an interprofessional team approach of clinicians and specialists, toxicologists, and pharmacists, utilizing open communication and shared decision-making, the morbidity of pentobarbital can be reduced and clinical success optimized.