Continuing Education Activity

Pentobarbital is a medication used to manage and treat several medical conditions, including seizures, intracranial pressure control, insomnia, and as a pre-anesthetic in the operating room. This activity reviews the indications, mechanism of action, administration, adverse effects, and contraindications of pentobarbital therapy in the clinical setting. It is intended to relate the essential points needed by members of an interprofessional team managing the care of patients undergoing treatment with pentobarbital and its related conditions and sequelae.

Objectives:

• Identify the mechanism of action of pentobarbital.
• Describe the potential adverse effects of pentobarbital.
• Review the appropriate monitoring for the toxicity of pentobarbital.
• Explain interprofessional team strategies for improving care coordination and communication to advance the use of pentobarbital and improve outcomes.

Indications

Pentobarbital is a drug within the barbiturate class that works primarily on the central nervous system. At low doses, indications include short-term sedatives to treat insomnia and as a pre-anesthetic for surgery.[1] At higher doses, pentobarbital serves as an anticonvulsant for emergent seizure control and medically induced comas. Pentobarbital is often subject to comparison with phenobarbital, another barbiturate, in the use of refractory status epilepticus. Studies have found that pentobarbital is superior in that it has faster brain penetration and a shorter half-life, making it the treatment of choice.

Common off-label uses are for control of intracranial pressure in patients with severe brain injuries, cerebral ischemia, and those receiving treatment for Reye syndrome.[2] Some US states use it for capital punishment, but this remains a widely controversial topic, and some manufacturers do not allow its sale to prisons. More commonly, it is used by veterinarians for euthanasia and anesthesia.[3] 

Mechanism of Action

Pentobarbital works in the central nervous system by binding to gamma-aminobutyric acid (GABA) A subtype receptors. This action induces a change in the chloride transport receptor, leading to an increase in the duration that the chloride channels remain open, hence potentiating GABA effects. GABA is responsible for producing CNS depression and thus prolonging the time the channels remain open and intensifying the depressant effects on the CNS.[4] Pentobarbital also works by inhibiting glutamate, which is responsible for nerve depolarization in the voltage-activated calcium currents.[5] This activity is an additive effect on CNS depression. It undergoes first-pass metabolism in the liver.

Administration

Pentobarbital administration can be through three routes: intramuscular, intravenous, or oral. For intramuscular administration, it is advised to inject no more than 5 ml and only into a large muscle to avoid tissue irritation or necrosis. Intravenous administration is not to exceed 50 mg/minute and should only be given by slow IV injection in the undiluted form.[6] It is essential to avoid tissue extravasation in this process as it has been known to cause tissue necrosis. Clinicians should avoid rapid IV injection as it can result in respiratory depression, hypotension, and bronchospasm, among other adverse effects. In pediatric populations, oral administration is easier by mixing the drug with flavored syrup to improve the taste.[7]

Adverse Effects

The main adverse reactions surrounding pentobarbital use are central nervous system effects, including altered mental status, agitation, confusion, drowsiness, respiratory depression, bradycardia, hypotension, cardiovascular collapse, and syncope. Other significant side 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]

Contraindications

Contraindications to pentobarbital use include any prior hypersensitivity reactions to previous drug use or barbiturate class use. Other contraindications include patients with depressed respiratory function and porphyria. Avoid abrupt drug withdrawal in those on long-term therapy. It is advised to exercise caution using this drug in the elderly, those with renal impairment, hepatic impairment, and those with drug use history.[8]   

Barbiturates have been shown to cause fetal damage if used in pregnant women and are pregnancy category D drugs. 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. It is essential to monitor maternal blood levels for fetal safety in any pregnant female taking these drugs. There is documentation of withdrawal in infants born to mothers who took barbiturates during pregnancy. Newborns should be closely monitored for seizures and hyperirritability as this may indicate a need for withdrawal treatment. Symptoms can be delayed for up to two weeks and require prompt treatment if indicated.[9]

Monitoring

Toxic doses of pentobarbital occur at approximately 1 gram in most adults, with death occurring at 2 to 10 grams. The therapeutic values for pentobarbital depend on the intended therapeutic effect. For sedation, it is 1 to 5 mcg/mL. For intracranial pressure therapy, it is 30 to 40 mcg/mL, and for therapeutic coma, it is 20 to 50 mcg/mL. Toxic values for sedation are greater than 10 mcg/mL. The time to steady-state in adults is 3 to 6 days. Monitoring parameters include 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. Clinicians need to be aware that pentobarbital is often confused with phenobarbital, a different drug with varying dosage differences.

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 beyond 400 mg daily for greater than 90 days is the threshold for developing a dependence. Doses of 600 to 800 mg daily for greater 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 major withdrawal within 16 hours, lasting for up to one 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 two weeks.[10]

Toxicity

Treatment of pentobarbital toxicity involves supportive care, as there is no antidote. 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 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.

Special care is necessary for those with renal and hepatic impairment. The manufacturer does not provide dosage adjustment recommendations for renal impairment, but it is essential to monitor kidney function if using high doses or before undergoing prolonged treatment. Similar effects occur in those with hepatic impairment, and recommendations are for close patient monitoring.

Pentobarbital interacts with several major classes of drugs and requires close monitoring to ensure therapeutic drug levels are maintained. 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 (MAOI's), and some hormones such as estradiol, estrone, and progesterone, to name a few.[11]

Enhancing Healthcare Team Outcomes

Pentobarbital is not used widely in clinical medicine because of its poor safety, habituation, and lack of an antidote. All clinicians who prescribe should be aware of its toxicity and side effect profile.

Withdrawal from pentobarbital can be life-threatening. Managing pentobarbital withdrawal requires a well-trained interprofessional team of healthcare professionals, including nurses, pharmacists, and several physicians from different specialties. Without proper management, the morbidity and mortality from unrecognized pentobarbital withdrawal are high. Properly treating pentobarbital withdrawal begins the moment a health care provider recognizes the patient is either susceptible to or suffering from withdrawal. The moment that withdrawal is suspected, the interprofessional team must coordinate the care for the patient, including:

• Obtaining a thorough history and physical
• Ordering drug levels in the blood and or urine, appropriate labs, imaging in the emergency department
• Monitor the patient for signs and symptoms of respiratory depression, cardiovascular collapse, central nervous system dysfunction, renal or hepatic toxicity 
• Preparing to provide airway protection and vasopressor support if indicated
• Consult with the pharmacist about possible drug interactions if the patient is taking other medications
• Consult with a toxicologist
• Consult with the intensivist about ICU care and monitoring while in the hospital
• Consider 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. Nursing should monitor the patient at subsequent visits, verifying medication compliance and treatment effectiveness. With an interprofessional team approach, the morbidity of pentobarbital is reducible and clinical success optimized. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Abou Khaled KJ, Hirsch LJ. Updates in the management of seizures and status epilepticus in critically ill patients. Neurol Clin. 2008 May;26(2):385-408, viii. [PubMed: 18514819]

2.

Adelson PD, Bratton SL, Carney NA, Chesnut RM, du Coudray HE, Goldstein B, Kochanek PM, Miller HC, Partington MD, Selden NR, Warden CR, Wright DW., American Association for Surgery of Trauma. Child Neurology Society. International Society for Pediatric Neurosurgery. International Trauma Anesthesia and Critical Care Society. Society of Critical Care Medicine. World Federation of Pediatric Intensive and Critical Care Societies. Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents. Chapter 13. The use of barbiturates in the control of intracranial hypertension in severe pediatric traumatic brain injury. Pediatr Crit Care Med. 2003 Jul;4(3 Suppl):S49-52. [PubMed: 12847349]

3.

Holtkamp M, Masuhr F, Harms L, Einhäupl KM, Meierkord H, Buchheim K. The management of refractory generalised convulsive and complex partial status epilepticus in three European countries: a survey among epileptologists and critical care neurologists. J Neurol Neurosurg Psychiatry. 2003 Aug;74(8):1095-9. [PMC free article: PMC1738579] [PubMed: 12876241]

4.

Walker SE, Iazzetta J. Compatibility and stability of pentobarbital ininfusions. Anesthesiology. 1981 Oct;55(4):487-9. [PubMed: 7294399]

5.

Wermeling DP, Blouin RA, Porter WH, Rapp RP, Tibbs PA. Pentobarbital pharmacokinetics in patients with severe head injury. Drug Intell Clin Pharm. 1987 May;21(5):459-63. [PubMed: 3582175]

6.

Knodell RG, Spector MH, Brooks DA, Keller FX, Kyner WT. Alterations in pentobarbital pharmacokinetics in response to parenteral and enteral alimentation in the rat. Gastroenterology. 1980 Dec;79(6):1211-6. [PubMed: 6777235]

7.

Ehrnebo M. Pharmacokinetics and distribution properties of pentobarbital in humans following oral and intravenous administration. J Pharm Sci. 1974 Jul;63(7):1114-8. [PubMed: 4853598]

8.

By the 2019 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019 Apr;67(4):674-694. [PubMed: 30693946]

9.

Ashtarinezhad A, Panahyab A, Shaterzadeh-Oskouei S, Khoshniat H, Mohamadzadehasl B, Shirazi FH. Teratogenic study of phenobarbital and levamisole on mouse fetus liver tissue using biospectroscopy. J Pharm Biomed Anal. 2016 Sep 05;128:174-183. [PubMed: 27262993]

10.

Preuss CV, Kalava A, King KC. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Apr 29, 2023. Prescription of Controlled Substances: Benefits and Risks. [PubMed: 30726003]

11.

Singh V. Survival after fatal pentobarbital ingestion. Indian J Anaesth. 2014 Jan;58(1):85-6. [PMC free article: PMC3968666] [PubMed: 24700912]

Disclosure: Anna Johnson declares no relevant financial relationships with ineligible companies.

Disclosure: Nazia Sadiq declares no relevant financial relationships with ineligible companies.