Continuing Education Activity

Barbiturates are a group of sedative-hypnotic medications used for treating seizure disorder, neonatal withdrawal, insomnia, preoperative anxiety, and induction of coma for increased intracranial pressure. They are also useful for inducing anesthesia. This activity outlines the indications, mechanism of action, pharmacokinetics, safe administration, adverse effects, contraindications, and toxicology of phenobarbital, methohexital, butalbital, pentobarbital, primidone, and amobarbital. It also outlines the important monitoring parameters of the broad array of physiological possibilities when using barbiturates in the clinical setting and essential points needed by members of an interprofessional team managing the care of patients when using barbiturates.

Objectives:

• Identify the mechanism of action of the barbiturate class of drugs.
• Identify the approved and off-label indications for barbiturates.
• Review the adverse events of barbiturates.
• Outline interprofessional team strategies for improving care coordination and communication to advance appropriate clinical outcomes with barbiturates, leading to optimal patient outcomes and minimizing adverse events.

Indications

Barbiturates are a group of sedative-hypnotic medications used for treating seizure disorder, neonatal withdrawal, insomnia, preoperative anxiety, and induction of coma for increased intracranial pressure. They are also useful for inducing anesthesia. Thiopental was introduced in 1934 for induction of anesthesia for general anesthesia.[1] Thiopental was the predominant IV anesthetic induction agent until its replacement by propofol.[2] In refractory status epilepticus, a Cochrane Review found that thiopental was equally effective as propofol for controlling seizure activity.[3] Because of its use in lethal injection protocols, the major supplier of thiopental in the US elected to discontinue production in 2011, and it is unavailable in the USA.[4] FDA-approved barbiturates in clinical use are as below. 

• Phenobarbital: Phenobarbitone has extensive use as an antiepileptic drug in the neonatal and pediatric population. It is the most cost-effective drug treatment for epilepsy in adults in low-resource countries.[5] Intravenous barbiturates have been used for neurosurgery due to reduced cerebral metabolic rate of oxygen consumption.[6] For individuals with severe traumatic brain injury (TBI), high-dose barbiturates may be a consideration but are not indicated for prophylactic administration.[7] In a review of practice in five European countries, about 20% of patients received barbiturates.[8] In refractory status epilepticus, a Cochrane Review found that thiopental was equally effective as propofol for controlling seizure activity.[3]

• Methohexital: Methohexital has demonstrated safety and efficacy for procedural sedation of short duration for cardioversion and pediatric outpatient surgery.[9][10] Methohexital can be used for fracture reduction in the emergency department and sedation for elective intubation in neonates.[11][12] Methohexital has preferential use in electroconvulsive therapy due to its longer seizure duration.[6]

• Butalbital: Butalbital is used primarily for the treatment of headache disorders.[13]

• Pentobarbital: Pentobarbital is used as a  pre-anesthetic medication and status epilepticus.[14] Pentobarbital is used off-label for traumatic brain injury associated with refractory elevated intracranial pressure.[15]

• Primidone: Primidone is used for seizure disorders. According to the American academy of neurology, depending on comorbidities and potential ADR, primidone(barbiturate) or propranolol can be used for essential tremors.[16]

• Amobarbital: Amobarbital has a labeled indication for insomnia, but the American Association of Sleep Medicine does not endorse its use.[17]

Mechanism of Action

Barbiturates cause postsynaptic enhancement of GABA, interacting with alpha and beta subunits of the GABA-A receptor.[18] Barbiturates increase chloride ion flux, resulting in postsynaptic hyperpolarization and CNS depression. Phenobarbital and pentobarbital affect the GABA-A receptors with a dose-dependent response. These drugs activate chloride channels at higher micromolar concentrations associated with anesthetic levels.[19] Both barbiturates and benzodiazepines interact with GABA-A receptors. Still, barbiturates are unique because they potentiate GABA-A receptors while increasing chloride ion influx even with very low concentrations of the GABA neurotransmitter.[20]

Structure-Activity Relationships: The German chemist Adolf von Baeyer synthesized barbituric acid (malonylurea)in 1864.[19] The date of this discovery was December 4, the feast day of Saint Barbara, which was the inspiration for the compound’s name.[21] Barbituric acid was the basis of many other formulations patented by the Bayer company. Due to its lack of lipophilicity, barbituric acid had no innate central nervous system activity. A lipophilic derivative of barbituric acid was developed (barbital: 5,5-diethylbarbituric acid) and successfully induced sleep in dogs.[19] 

Amylobarbitone became the first intravenous anesthetic used in 1928. The formulation of parenteral dosage forms came with the addition of sodium at the C2 position.[21] Lipophilicity was enhanced by Volviler and Tabern with the addition of a sulfur group while replacing an oxygen atom, creating the thiobarbiturates in 1934.[21] In 1957 Methohexital was created by Stoelting with the addition of an aliphatic side chain at carbon 5, along with methylation of the nitrogen atom.[20] The R(+) isomer of many barbiturates produces excitatory effects, while the S(-) isomers produce more depressant effects.[22] Barbiturate classification is according to the duration of their action. The short and intermediate-acting have an effect lasting 2 to 6 hours. Long-acting barbiturates have an effect of longer than 6 hours.[23][24]

Ultra Short-Acting Barbiturates

• Methohexital
• Thiopental

 Short-Acting Barbiturates

• Pentobarbital
• Secobarbital

Intermediate-acting barbiturates

• Amobarbital
• Butalbital

Long-acting Barbiturates

• Phenobarbital
• Primidone

Pharmacokinetics

Absorption: Phenobarbital is rapidly absorbed with a time-to-peak concentration in 2-4 hours. The bioavailability of phenobarbital is approximately 90% in adults and less in neonatal populations.[25] Sodium salts of barbiturates are absorbed more rapidly, and the presence of food delays the onset of action of orally administered barbiturates. The intravenous route is usually reserved for managing status epilepticus (phenobarbital sodium) or the induction or maintenance of general anesthesia (e.g., methohexital or thiopental). Thiopental observes first-order kinetics in low doses of 5 mg/kg boluses. In high-dose or prolonged infusions, non-linear kinetics will occur due to the progressive saturation of enzyme systems.[26]

Distribution: Highly lipid-soluble barbiturates cross the blood-brain barrier rapidly, but there is rapid redistribution from the CNS to peripheral tissues.[24] Thiopental and methohexital undergo rapid redistribution after intravenous injection into less-vascular tissues, particularly muscle and fat, decreasing the concentration of barbiturates in the plasma and brain. Terminating the effect of a single bolus IV injection of thiopental occurs by redistribution from the central compartment to peripheral compartments.[27]

Metabolism: The oxidation of barbiturates is the most important biotransformation that terminates biological activity. In addition, n-glycosylation is important for the metabolism of phenobarbital. Phenobarbital is metabolized extensively by the cytochrome P450, and the maturation of this enzyme family mainly occurs during the neonatal period.[28][29] Repeated administration of phenobarbital decreases the half-life due to the induction of microsomal enzymes. The self-induced increase in barbiturate metabolism partially accounts for tolerance to barbiturates. In addition, with chronic administration, there is an increase in ALA synthetase enzymes. The effect of barbiturates on ALA synthetase can cause dangerous disease exacerbations in patients with porphyria. Primidone is metabolized to phenylethylmalonamide and phenobarbital; the effectiveness of primidone on essential tremor is independent of its phenobarbital metabolite.[16]

Excretion: About 25% of phenobarbital is excreted unchanged in the urine. The renal excretion can be increased by osmotic diuresis or alkalinization of the urine. The metabolic elimination of barbiturates is more rapid in young people than in the elderly and infants. Age-related changes have been demonstrated in pharmacokinetics due to slower clearance in the elderly, resulting in higher serum concentrations with smaller drug doses.[30] In children, a shorter elimination half-time occurs due to greater clearance.[27] The half-life of phenobarbital decreases by approximately 4.6 hours per day on chronic administration.[31]

Administration

Barbiturates are administered in oral and parenteral forms (IM and IV). Intramuscular injections of solutions of the sodium salts such as phenobarbital or amobarbital should be administered in large muscle masses to avoid potential necrosis at superficial sites.

• Phenobarbital: According to the American Epilepsy Society guidelines, phenobarbital 15 mg/kg in a single dose is suggested for status epilepticus (parenteral benzodiazepines are the first line choice).[32] When administered as an antiepileptic drug for pediatric patients, phenobarbital may be given as an IV loading dose, followed by IV or oral administration.[33] In neonates, the loading dose of phenobarbital is 20 mg/kg intravenously, and the maintenance dose is 3 to 4 mg/kg by mouth. Nonresponders should be administered additional doses of 5 to 10 mg/kg till seizure control. The indication for use typically determines the route of administration for adults. Maintenance therapy for antiepileptic drugs in adults is typically the oral route; other first-line drugs have replaced phenobarbital.[34]

• Methohexital: Methohexital and thiopental may be administered rectally in pediatrics, particularly if the child cannot cooperate with IV needle administration. This method is best suited in procedures of short duration, such as radiology or dentistry. The usual dose for methohexital is 1 to 1.5 mg/kg for induction. Barbiturates administered for the induction of anesthesia in adults are most commonly given as an IV bolus for a rapid and pleasant loss of consciousness.[35][36]

• Thiopental: When using the IV route of administration in pediatrics, wide variation in the required dose has been noted. Cote recommended a higher dose range for unpremeditated children.[37] Thiopental was removed from the US market in 2011 largely based on the diversion of the drug within the USA as a lethal injection drug.[38]

• Pentobarbital: Pentobarbital is administered by IM and IV routes. Pentobarbital is administered by intramuscular route 150 to 200 mg as a single dose pre-anesthetic medication. For status epilepticus, pentobarbital is given as a 5 to 15 mg/kg IV loading dose followed by a continuous infusion of 0.5 to 5 mg/kg/hour. It is important to recognize that continuous infusion dosing of pentobarbital is titrated to EEG (Neurocritical Care Society guidelines).[14]

• Butalbital: Butalbital is used with aspirin/acetaminophen/caffeine for migraine and tension headaches. American academy of neurology doesn't endorse its use for a long time due to the risk of dependence and medication overuse headaches.[13]

• Primidone: The usual starting dose of primidone is 100 to 125 mg at bedtime for seizure control in treatment-naive patients. The regular maintenance beyond ten days is 250 mg three times a day. The total daily dose of primidone should not exceed 2000 mg. Primidone is also used to treat essential tremors; the suggested starting dose is 25 mg daily, increasing by 25 or 50 mg per month as tolerated.[39]

• Amobarbital: The sedative dose of amobarbital is 30 mg to 50 mg, given 2 or 3 times daily. The hypnotic dose is 65 mg to 200 mg at bedtime. Amobarbital is a DEA-scheduled II substance, and agents with better safety profiles should be used due to misuse potential.[40]

Use in Specific Patient Populations

• Patients with Renal Impairment: No dose adjustment has been provided for methohexital. The use of thiopental is relatively contraindicated in renal disease. Dose reduction is recommended in phenobarbital. Nephrotoxicity is reported with an overdose of phenobarbital.[41]

• Patients with Hepatic Impairment: No dose adjustment has been provided for methohexital. As phenobarbital undergoes extensive hepatic metabolism, dose reduction is advised.[42]

• Pregnancy Considerations: The placental transfer occurs within 1 minute of administration.[20] Neonatal depression may occur if thiopental is used as an induction agent for cesarean section. Methohexital can also cross the placental barrier. For general anesthesia, drugs other than methohexital are recommended by ACOG (American College of Obstetricians and Gynecologists).[43] The use of phenobarbitone is associated with major malformations. Antiepileptic agents, lamotrigine and levetiracetam, are preferred during pregnancy.[44][45]

• Breastfeeding Considerations: Clinical data on the effects of phenobarbital indicates that there is inter and intrapatient variability of excretion in breast milk. Phenobarbital can cause drowsiness in infants, especially when used with other sedating drugs. In a series of breastfeeding infants, for each mg/kg of phenobarbital taken by mothers, the infant's serum concentration increased by 2 to 5 mg/L. Several case reports exist of infant sedation occurring in mothers treated with phenobarbital.[46] Consequently, monitor the infant for drowsiness, and weight gain, especially in younger, exclusively breastfed infants. If there is excessive sedation, discontinuation of breastfeeding is suggested.[46] Concerning the short-acting IV barbiturates, mothers who received methohexital were found in breastmilk at the highest concentrations 1 to 2 hours after an IV dose and undetectable 24 to 48 hours after an IV dose.[47] For thiopental, when used for induction of anesthesia for cesarean section, the highest concentration of thiopental in breast milk was in the first nursing after anesthesia, about 0.9 mg/L.[48] Breastfeeding can be resumed as soon as the mother has recovered sufficiently from general anesthesia. However, if a combination of drugs is used during the procedure, follow the standard operating procedure considering the elimination half-life of each agent.[48]

Adverse Effects

For women taking phenobarbital as monotherapy, the drug correlates with congenital defects in exposed infants.[5]

When given in IV anesthetics, barbiturates will produce a reduction in blood pressure and an increase in heart rate. Respiratory depression and apnea may occur.[20]

Thiopental and thiamylal have been shown to release histamine, while methohexital and pentobarbital have minimal histamine release.[49]

Extravasation of thiopental (a vesicant) may cause severe tissue necrosis. If extravasation occurs, treatment measures include hyaluronidase and phentolamine.[50] Case reports of successful treatment also include the topical application of a eutectic mixture of local anesthetics (EMLA) and the local injection of lidocaine.[51]

Barbiturates such as butalbital can lead to withdrawal symptoms, including seizures. The recommended risk mitigation strategy is to taper off barbituates gradually under supervision.[52]

Hepatotoxicity: Barbiturates can cause allergic reactions and skin rashes associated with mild liver injury. Phenobarbital is predominantly linked with drug-induced liver injury. Phenobarbital-induced serious adverse drug reactions are DRESS (Drug reaction with eosinophilia and systemic symptoms), Stevens-Johnson syndrome, and toxic epidermal necrolysis.[53]

Drug-drug Interactions 

• Phenobarbital is known to be an inducer of the cytochrome enzyme system, specifically the CYP1A2, 2B6, 2C9, and 3A4/5 isozymes that will reduce the efficacy of warfarin, steroids, psychoactive drugs, and immunosuppressants.
• Phenobarbital will also lower the plasma concentrations of other antiepileptic drugs, such as lamotrigine, oxcarbazepine, phenytoin, tiagabine, and valproate.[54]
• Contraceptive failure can occur when systemic hormonal contraception drugs are administered with enzyme inducers like phenobarbital.[55]
• Phenobarbital is a strong CYP3A4 inducer; avoid combination with hepatitis C drugs paritaprevir/ritonavir, ombitasvir, and dasabuvir.[56]
• Primidone is also a CYP3A4 inducer; combination with apremilast should be avoided.[57]
• Barbiturates combined with other CNS depressants like benzodiazepines and opioids can cause oversedation and severe respiratory depression.[58][59]

Contraindications

Absolute contraindications for any barbiturate include status asthmaticus and acute and intermittent variegate porphyria.[20] Hypersensitivity to barbiturates or excipients is a contraindication to their use. Hypersensitivity reactions, including anaphylaxis, have been reported. Barbiturates can trigger hypersensitivity reactions by direct histamine release or IgE-mediated mechanisms.[60]

Monitoring

Monitoring for Misuse: Due to the abuse potential of barbiturates, restricted access started with the passage of the Federal Comprehensive Drug Abuse and Control Act of 1970. Barbiturates are classified as Schedule II-IV based on their abuse potential.[61]

Evaluation and monitoring for anesthesia: Preanesthetic evaluation is required when barbiturates are used for general anesthesia. RCRI (Revised Cardiac Risk Index for Pre-Operative Risk) can estimate the risk of cardiac complications after noncardiac surgery.[62] During anesthesia American Society of Anesthesiologists (ASA) guidelines recommend monitoring oxygenation, ventilation, circulation, and temperature. (Standards for Basic Anesthetic Monitoring). According to the American Society of Anesthesiologists Task Force on postanesthetic care, mental status, patient temperature, pain, nausea/vomiting, and volume status should be monitored.[63]

Development of Tolerance and Dependence: Tolerance is a gradual loss of effectiveness such that the dose has to be increased to maintain the same effect.[23] This effect is partly explained by enzyme induction in the liver. Animal models have demonstrated tolerance. Withdrawal symptoms may occur: nervousness, tremor, agitation, and hypotension may develop 2 to 8 days after the abrupt discontinuation of barbiturates. Additionally, the patient may develop delirium or grand mal seizures.[23] Phenobarbital has a narrow therapeutic range of 10 to 30 mg/L, with 80 mg/L reported as being fatal.[64] A Cochrane review found no clear evidence of a benefit to routine serum monitoring drug concentrations for antiepileptic drugs. Dose titration to control seizures was found to be effective.[65]

Toxicity

Acute barbiturate toxicity may result from an intentional or unintentional overdose. Barbiturates have a history of abuse; New York City Health Department data showed 8469 cases of barbiturate poisoning in the period between 1957 through 1963.[66]  Overdosage of phenobarbital symptoms includes CNS depression, respiratory failure, and hemodynamic instability. No antidote exists. Treatment of an overdose includes supportive care and urinary alkalinization.[64] 

A systematic review demonstrates the efficacy of multiple-dose activated charcoal for phenobarbital and primidone overdose. Haemodialysis and haemoperfusion may be considered in patients having life-threatening barbiturate toxicity.[67] Extracorporeal clearance with dialysis can augment drug elimination in cases of severe butalbital overdose.[68] During recovery, patients with chronic barbiturate misuse can present with seizures and autonomic instability.[52]

Enhancing Healthcare Team Outcomes

Barbiturates have historically been a widely prescribed class of drugs in outpatient and inpatient settings. Barbiturates are controlled substances; thus, all DEA prescription requirements must be met. The prescription drug monitoring program(PDMP) can identify potential misuse and abuse.[69] Benzodiazepines have largely replaced them when used for anti-anxiety or insomnia. IV anesthetic uses of barbiturates are minimal for two reasons:

• After 2011, major manufacturers no longer produced thiopental or methohexital
• the preferred routine IV anesthetic induction agent has become propofol due to its availability, rapid onset, and offset

Phenobarbital continues to be used as a second-line antiepileptic drug in the US and has frequent use in low-resource countries as a first-line drug due to its low cost. All healthcare workers, including physicians, and nurse practitioners who prescribe these agents, must be fully aware of the adverse drug reactions, misuse, drug-drug interactions, and the potential to develop physical dependence. When barbiturates are used in anesthesia, supervision by anesthetics and certified registered nurse anesthetists (CRNAs) is necessary. Movement disorder specialists should oversee the use of primidone for essential tremors. Given the potential for severe adverse events, including death, a pharmacist should verify the dosing and perform a thorough medication reconciliation to ensure no drug interactions, particularly additive CNS depressing effects.

The healthcare team must know how to resuscitate the patient in case of an overdose; MICU-level care and consultation with a critical care physician are often required. A toxicologist should be consulted in case of severe overdose. A psychiatrist should be consulted once the patient has recovered in case of an overdose. Prescribing barbiturates and follow-up monitoring requires an interprofessional team approach, including clinicians (MD, DO, NP, PA), specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient outcomes related to barbiturate therapy. [Level 5]