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Pronunciation:

(pen toe BAR bi tal)

U.S. Brand Names:

Nembutal®

Synonyms:

Pentobarbital Sodium

Generic Available:

Canadian Brand Names:

Nembutal® Sodium

Use:

Sedative/hypnotic; preanesthetic; high-dose barbiturate coma for treatment of increased intracranial pressure or status epilepticus unresponsive to other therapy

Restrictions:

C-II

Pregnancy Risk Factor:

Lactation:

Enters breast milk/contraindicated

Contraindications:

Hypersensitivity to barbiturates or any component of the formulation; marked hepatic impairment; dyspnea or airway obstruction; porphyria; pregnancy

Warnings/Precautions:

Tolerance to hypnotic effect can occur; do not use for >2 weeks to treat insomnia. Potential for drug dependency exists, abrupt cessation may precipitate withdrawal, including status epilepticus in epileptic patients. Do not administer to patients in acute pain. Use caution in elderly, debilitated, renally impaired, hepatic dysfunction, or pediatric patients. May cause paradoxical responses, including agitation and hyperactivity, particularly in acute pain and pediatric patients. Use with caution in patients with depression or suicidal tendencies, or in patients with a history of drug abuse. Tolerance, psychological and physical dependence may occur with prolonged use.

May cause CNS depression, which may impair physical or mental abilities. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Effects with other sedative drugs or ethanol may be potentiated. Use of this agent as a hypnotic in the elderly is not recommended due to its long half-life and potential for physical and psychological dependence.

May cause respiratory depression or hypotension, particularly when administered intravenously. Use with caution in hemodynamically unstable patients or patients with respiratory disease. High doses (loading doses of 15-35 mg/kg given over 1-2 hours) have been utilized to induce pentobarbital coma, but these higher doses often cause hypotension requiring vasopressor therapy.

Adverse Reactions:

Frequency not defined.

Cardiovascular: Bradycardia, hypotension, syncope

Central nervous system: Drowsiness, lethargy, CNS excitation or depression, impaired judgment, "hangover" effect, confusion, somnolence, agitation, hyperkinesia, ataxia, nervousness, headache, insomnia, nightmares, hallucinations, anxiety, dizziness

Dermatologic: Rash, exfoliative dermatitis, Stevens-Johnson syndrome

Gastrointestinal: Nausea, vomiting, constipation

Hematologic: Agranulocytosis, thrombocytopenia, megaloblastic anemia

Local: Pain at injection site, thrombophlebitis with I.V. use

Renal: Oliguria

Respiratory: Laryngospasm, respiratory depression, apnea (especially with rapid I.V. use), hypoventilation

Miscellaneous: Gangrene with inadvertent intra-arterial injection

Overdosage/Toxicology:

Symptoms of overdose include unsteady gait, slurred speech, confusion, jaundice, hypothermia, hypotension, respiratory depression, and coma. Treat symptomatically. Charcoal hemoperfusion may be beneficial in stage IV coma due to high serum concentration.

Drug Interactions:

Induces CYP2A6 (strong), 3A4 (strong)

Acetaminophen: Barbiturates may enhance the hepatotoxic potential of acetaminophen overdoses

Antiarrhythmics: Barbiturates may increase the metabolism of antiarrhythmics, decreasing their clinical effect; includes disopyramide, propafenone, and quinidine

Anticonvulsants: Barbiturates may increase the metabolism of anticonvulsants; includes ethosuximide, felbamate (possibly), lamotrigine, phenytoin, tiagabine, topiramate, and zonisamide; does not appear to affect gabapentin or levetiracetam

Antineoplastics: Limited evidence suggests that enzyme-inducing anticonvulsant therapy may reduce the effectiveness of some chemotherapy regimens (specifically in ALL); teniposide and methotrexate may be cleared more rapidly in these patients

Antipsychotics: Barbiturates may enhance the metabolism (decrease the efficacy) of antipsychotics; monitor for altered response; dose adjustment may be needed

Beta-blockers: Metabolism of beta-blockers may be increased and clinical effect decreased; atenolol and nadolol are unlikely to interact given their renal elimination

Calcium channel blockers: Barbiturates may enhance the metabolism of calcium channel blockers, decreasing their clinical effect

Chloramphenicol: Barbiturates may increase the metabolism of chloramphenicol and chloramphenicol may inhibit barbiturate metabolism; monitor for altered response

Cimetidine: Barbiturates may enhance the metabolism of cimetidine, decreasing its clinical effect

CNS depressants: Sedative effects and/or respiratory depression with barbiturates may be additive with other CNS depressants; monitor for increased effect; includes ethanol, sedatives, antidepressants, narcotic analgesics, and benzodiazepines

Corticosteroids: Barbiturates may enhance the metabolism of corticosteroids, decreasing their clinical effect

Cyclosporine: Levels may be decreased by barbiturates; monitor

CYP2A6 substrates: Pentobarbital may decrease the levels/effects of CYP2A6 substrates. Example substrates include ifosfamide and rifampin.

CYP3A4 substrates: Pentobarbital may decrease the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, clarithromycin, cyclosporine, erythromycin, estrogens, mirtazapine, nateglinide, nefazodone, nevirapine, protease inhibitors, tacrolimus, and venlafaxine.

Doxycycline: Barbiturates may enhance the metabolism of doxycycline, decreasing its clinical effect; higher dosages may be required

Estrogens: Barbiturates may increase the metabolism of estrogens and reduce their efficacy

Felbamate may inhibit the metabolism of barbiturates and barbiturates may increase the metabolism of felbamate

Griseofulvin: Barbiturates may impair the absorption of griseofulvin, and griseofulvin metabolism may be increased by barbiturates, decreasing clinical effect

Guanfacine: Effect may be decreased by barbiturates

Immunosuppressants: Barbiturates may enhance the metabolism of immunosuppressants, decreasing its clinical effect; includes both cyclosporine and tacrolimus

Loop diuretics: Metabolism may be increased and clinical effects decreased; established for furosemide, effect with other loop diuretics not established

MAO inhibitors: Metabolism of barbiturates may be inhibited, increasing clinical effect or toxicity of the barbiturates

Methadone: Barbiturates may enhance the metabolism of methadone resulting in methadone withdrawal

Methoxyflurane: Barbiturates may enhance the nephrotoxic effects of methoxyflurane

Oral contraceptives: Barbiturates may enhance the metabolism of oral contraceptives, decreasing their clinical effect; an alternative method of contraception should be considered

Theophylline: Barbiturates may increase metabolism of theophylline derivatives and decrease their clinical effect

Tricyclic antidepressants: Barbiturates may increase metabolism of tricyclic antidepressants and decrease their clinical effect; sedative effects may be additive

Valproic acid: Metabolism of barbiturates may be inhibited by valproic acid; monitor for excessive sedation; a dose reduction may be needed

Warfarin: Barbiturates inhibit the hypoprothrombinemic effects of oral anticoagulants via increased metabolism; this combination should generally be avoided

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol (may increase CNS depression).

Stability:

Protect from freezing; aqueous solutions are not stable, commercially available vehicle (containing propylene glycol) is more stable; low pH may cause precipitate; use only clear solution

Compatibility:

Stable in dextran 6% in dextrose, dextran 6% in NS, D5LR, D5¹/4NS, D5¹/2NS, D5NS, D10W, LR, ¹/2NS; variable stability (consult detailed reference) in D5W, NS

Y-site administration: Compatible: Acyclovir, gatifloxacin, insulin (regular), linezolid, propofol. Incompatible: Amphotericin B cholesteryl sulfate complex

Compatibility in syringe: Compatible: Aminophylline, ephedrine, hyaluronidase, hydromorphone, neostigmine, scopolamine, sodium bicarbonate, thiopental. Incompatible: Atropine with cimetidine, butorphanol, chlorpromazine, cimetidine, dimenhydrinate, diphenhydramine, droperidol, fentanyl, glycopyrrolate, hydroxyzine, meperidine, midazolam, nalbuphine, pentazocine, perphenazine, prochlorperazine edisylate, promazine, promethazine, ranitidine. Variable (consult detailed reference): Atropine, morphine

Compatibility when admixed: Compatible: Amikacin, aminophylline, calcium chloride, chloramphenicol, dimenhydrinate, erythromycin lactobionate, lidocaine, thiopental, verapamil. Incompatible: Cefazolin, chlorpheniramine, cimetidine, clindamycin, droperidol, ephedrine, fentanyl, hydrocortisone sodium succinate, hydroxyzine, insulin (regular), levorphanol, norepinephrine, pancuronium, penicillin G potassium, pentazocine, phenytoin, promazine, promethazine, streptomycin, triflupromazine, vancomycin. Variable (consult detailed reference): Chlorpromazine, isoproterenol, metaraminol, methyldopate, norepinephrine, sodium bicarbonate, succinylcholine

Mechanism of Action:

Short-acting barbiturate with sedative, hypnotic, and anticonvulsant properties. Barbiturates depress the sensory cortex, decrease motor activity, alter cerebellar function, and produce drowsiness, sedation, and hypnosis. In high doses, barbiturates exhibit anticonvulsant activity; barbiturates produce dose-dependent respiratory depression.

Pharmacodynamics/Kinetics:

Onset of action: I.M.: 10-15 minutes; I.V.: ~1 minute

Duration: I.V.: 15 minutes

Distribution: Vd: Children: 0.8 L/kg; Adults: 1 L/kg

Protein binding: 35% to 55%

Metabolism: Extensively hepatic via hydroxylation and oxidation pathways

Half-life elimination: Terminal: Children: 25 hours; Adults: Healthy: 22 hours (range: 15-50 hours)

Excretion: Urine (<1% as unchanged drug)

Dosage:

Children:

Hypnotic: I.M.: 2-6 mg/kg; maximum: 100 mg/dose

Preoperative/preprocedure sedation: 6 months:

Note: Limited information is available for infants <6 months of age.

I.M.: 2-6 mg/kg; maximum: 100 mg/dose

I.V.: 1-3 mg/kg to a maximum of 100 mg until asleep

Conscious sedation prior to a procedure: Children 5-12 years: I.V.: 2 mg/kg 5-10 minutes before procedures, may repeat one time

Adolescents: Conscious sedation: I.V.: 100 mg prior to a procedure

Children and Adults: Barbiturate coma in head injury patients: I.V.: Loading dose: 5-10 mg/kg given slowly over 1-2 hours; monitor blood pressure and respiratory rate; Maintenance infusion: Initial: 1 mg/kg/hour; may increase to 2-3 mg/kg/hour; maintain burst suppression on EEG

Status epilepticus: I.V.: Note: Intubation required; monitor hemodynamics

Children: Loading dose: 5-15 mg/kg given slowly over 1-2 hours; maintenance infusion: 0.5-5 mg/kg/hour

Adults: Loading dose: 2-15 mg/kg given slowly over 1-2 hours; maintenance infusion: 0.5-3 mg/kg/hour

Adults:

Hypnotic:

I.M.: 150-200 mg

I.V.: Initial: 100 mg, may repeat every 1-3 minutes up to 200-500 mg total dose

Preoperative sedation: I.M.: 150-200 mg

Dosing adjustment in hepatic impairment: Reduce dosage in patients with severe liver dysfunction

Administration:

Pentobarbital may be administered by deep I.M. or slow I.V. injection.

I.M.: No more than 5 mL (250 mg) should be injected at any one site because of possible tissue irritation.

I.V.: I.V. push doses can be given undiluted, but should be administered no faster than 50 mg/minute; parenteral solutions are highly alkaline; avoid extravasation; avoid rapid I.V. administration >50 mg/minute; avoid intra-arterial injection

Monitoring Parameters:

Respiratory status (for conscious sedation, includes pulse oximetry), cardiovascular status, CNS status; cardiac monitor and blood pressure monitor required

Reference Range:

Therapeutic:

Hypnotic: 1-5 mcg/mL (SI: 4-22 mol/L)

Coma: 10-50 mcg/mL (SI: 88-221 mol/L)

Toxic: >10 mcg/mL (SI: >44 mol/L)

Patient Education:

Patient instructions and information are determined by patient condition and therapeutic purpose. Drug may cause physical and/or psychological dependence. While using this medication, do not use alcohol and other prescription or OTC medications (especially pain medications, sedatives, antihistamines, or hypnotics) without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience drowsiness, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, or loss of appetite (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); or constipation (increased exercise, fluids, fruit, or fiber may help). Report skin rash or irritation; CNS changes (confusion, depression, increased sedation, excitation, headache, insomnia, or nightmares); respiratory difficulty or shortness of breath; changes in urinary pattern or menstrual pattern; muscle weakness or tremors; or difficulty swallowing or feeling of tightness in throat. Pregnancy/breast-feeding precautions: Do not get pregnant; use appropriate contraceptive measures to prevent possible harm to the fetus. Do not breast-feed.

Nursing Implications:

Monitor blood pressure closely with I.V. administration

Anesthesia and Critical Care Concerns/Other Considerations:

Pentobarbital 50 mg/mL contains propylene glycol 414.4 mg/mL (40% v/v).

Pentobarbital is one of the standard choices for refractory status epilepticus. Most patients will require systemic and pulmonary arterial catheterization with fluid and vasoactive therapy to maintain blood pressure. High-dose pentobarbital generally produces poikilothermia. Maintenance anticonvulsant treatment may be substantial in order to wean pentobarbital. High doses of barbiturates are potentially immunosuppressive; guard against infection.

Dental Health: Effects on Dental Treatment:

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

No information available to require special precautions

Dosage Forms:

Injection, solution, as sodium: 50 mg/mL (20 mL, 50 mL) [contains alcohol 10% and propylene glycol 40%]

International Brand Names:

Nembutal® Sodium (CA); Pentone® (AU); Prodormol® (IL); Sopental® (ZA)

References

Chapman MG, Smith M, and Hirsch NP, "Status Epilepticus,"Anaesthesia, 2001, 56(7):648-59.

Fischer JH and Raineri DL, "Pentobarbital Anesthesia for Status Epilepticus,"Clin Pharm, 1987, 6(8):601-2.

Hubbard AM, Markowitz RI, Kimmel B, et al, "Sedation for Pediatric Patients Undergoing CT and MRI,"J Comput Assist Tomogr, 1992, 16(1):3-6.

Manno EM, "New Management Strategies in the Treatment of Status Epilepticus,"Mayo Clin Proc, 2003, 78(4):508-18.

McCarron MM, Schulze BW, Walberg CB, et al, "Short-Acting Barbiturate Overdosage. Correlation of Intoxication Score With Serum Barbiturate Concentration,"JAMA, 1982, 248(1):55-61.

Pereira JK, Burrows PE, Richards HM, et al, "Comparison of Sedation Regimens for Pediatric Outpatient CT,"Pediatr Radiol, 1993, 23(5):341-4.

Schaible DH, Cupit GC, Swedlow DB, et al, "High-Dose Pentobarbital Pharmacokinetics in Hypothermic Brain-Injured Children,"J Pediatr, 1982, 100(4):655-60.

Tobias JD, Deshpande JK, Pietsch JB, et al, "Pentobarbital Sedation for Patients in the Pediatric Intensive Care Unit,"South Med J, 1995, 88(3):290-4.

Wermeling D, Record K, Bell R, et al, "Hemodialysis Clearance of Pentobarbital During Continuous Infusion,"Ther Drug Monit, 1985, 7(4):485-7.

Zeltzer LK, Altman A, Cohen D, et al, "American Academy of Pediatrics Report of the Subcommittee on the Management of Pain Associated With Procedures in Children With Cancer,"Pediatrics, 1990, 86(5 Pt 2):826-31.

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