VA Class:CN301

VA Class:CN202

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AHFS Class:

• Barbiturates 28:24.04

Associated Monographs

• Amobarbital

• Pentobarbital

• Phenobarbital

Barbiturates are substituted pyrimidine derivatives of barbituric acid that cause CNS depression and are used as sedatives, hypnotics, anxiolytics, anesthetics, or anticonvulsants.

Insomnia and Anxiety

Barbiturates are used principally as hypnotics in the short-term treatment of insomnia, and preoperatively to relieve anxiety and provide sedation. In the treatment of insomnia, the duration of barbiturate therapy should be limited to 2 weeks, since the drugs appear to lose their efficacy for sleep induction and maintenance after this period of time. If retreatment is necessary, it should be undertaken only upon further evaluation of the patient and drug-free intervals of 1-2 weeks. Alternative nondrug therapies should be attempted for the treatment of chronic insomnia. Barbiturates also have been used for routine sedation and to relieve anxiety and provide sedation in patients with alcohol withdrawal syndrome. Although barbiturates are now infrequently used for routine sedation, it has never been conclusively demonstrated that other anxiolytic agents are more effective than barbiturates for the management of mild to moderate anxiety. However, some clinicians believe that there are few clinical situations in which oral barbiturates provide an advantage in safety or efficacy over nonbarbiturate sedatives and hypnotics.

Anesthesia

Methohexital, thiamylal (no longer commercially available in the US), and thiopental (no longer commercially available in the US) are used IV principally as basal or general anesthetics; methohexital also is used IM or rectally for induction of general anesthesia in children. In addition, pentobarbital (rectal preparations are no longer commercially available in the US) and secobarbital (parenteral and rectal preparations are no longer commercially available in the US) may be used parenterally or rectally as basal anesthetics. For information about use of barbiturates in anesthesia, see Methohexital 28:04.04.

Other Uses

Mephobarbital (no longer commercially available in the US), metharbital (no longer commercially available in the US), and phenobarbital are useful anticonvulsants. (See 28:12.04.) Methohexital, thiamylal, and thiopental may be used in the management of acute seizure episodes. Amobarbital, pentobarbital, secobarbital, and thiopental may be used IM or IV to control status epilepticus or acute seizure episodes resulting from meningitis, poisons, eclampsia, alcohol withdrawal, tetanus, chorea, or administration of local or inhalation anesthetics.

Barbiturates also have been used parenterally to control acute episodes of agitated behavior in psychoses, although the drugs have little value in long-term management of psychoses. Barbiturates, especially amobarbital and thiopental have also been used parenterally in narcoanalysis and narcotherapy; amobarbital also has been used as a diagnostic aid in schizophrenia.

Barbiturates often have been used in combination with analgesics, but it has never been convincingly demonstrated that the combination of an analgesic with a sedative dose of a barbiturate increases the analgesic effect. Since sedative doses of the drugs may alleviate anxiety associated with pain, they may be of value in decreasing pain in some patients.

For information on the use of barbiturates for the management of seizure disorders, see the Anticonvulsants General Statement 28:12.

Administration

Although most of the barbiturates are administered orally, some barbiturates may be administered rectally, subcutaneously, IM, and/or IV.

Dosage

In general, the smallest effective dose should be used. Dosage must be individualized for each patient. Dosage should be reduced in geriatric or debilitated patients and in patients with impaired hepatic function. Because of their higher metabolic rate, children may tolerate comparatively larger doses than adults. Barbiturates should be withdrawn slowly to avoid the possibility of precipitating withdrawal symptoms.

In the treatment of insomnia, consideration should be given to intermittent rather than to daily administration; with daily administration, duration of therapy should be limited to 2 weeks. To prevent rebound in rapid eye movement (REM) sleep, withdrawal of a single therapeutic dose over 5 or 6 days (e.g., decreasing dosage from 3 to 2 doses daily for 1 week) has been recommended when barbiturates are discontinued following prolonged use.

Nervous System Effects

Adverse effects of barbiturates may include drowsiness, lethargy, vertigo, headache, severe CNS depression, mental depression, and myalgic, neuralgic, or arthralgic pain. Residual sedation or “hangover” occurs frequently following hypnotic doses, and subtle distortion of mood, impaired judgment, and impaired motor skills may persist for many hours. Some patients, particularly those with severe pain, experience paradoxical excitement and/or euphoria, restlessness, or delirium, and, therefore, barbiturates should not be administered in the presence of uncontrolled pain. Phenobarbital frequently produces paradoxical excitement and hyperactivity in children or exacerbates existing hyperactivity. Geriatric patients may react to usual doses of barbiturates with excitement, confusion, or depression. Many patients experience increased dreaming, nightmares, or increased insomnia when hypnotic doses of barbiturates are discontinued. There is a potential risk of complex sleep-related behaviors such as sleep-driving (i.e., driving while not fully awake after ingesting a sedative-hypnotic drug, with no memory of the event), making phone calls, or preparing and eating food while asleep in patients receiving butabarbital or secobarbital.109

Sensitivity Reactions

Hypersensitivity reactions to barbiturates include urticaria, angioedema, morbilliform or scarlatiniform rash, fever, serum sickness, erythema multiforme, or Stevens-Johnson syndrome. Hypersensitivity reactions are most likely to occur in patients with asthma, urticaria, or angioedema. Rarely, photosensitivity reactions have been reported. Phenobarbital, metharbital, and mephobarbital appear to cause rashes more frequently than do other barbiturates. Exfoliative dermatitis, which may be accompanied by hepatitis and jaundice, has occurred rarely and has resulted in a few fatalities. Rarely, cutaneous reactions have preceded the development of barbiturate-induced systemic lupus erythematosus. Adverse cutaneous reactions may proceed to an irreversible stage even though the medication has been discontinued, because barbiturates are slowly metabolized and excreted. There also is a potential risk of anaphylaxis in patients receiving butabarbital or secobarbital.109 Anaphylaxis and angioedema may occur as early as with the first dose of the drug.109

Other Adverse Effects

Adverse GI effects of barbiturates include nausea, vomiting, diarrhea, and constipation. A few cases of agranulocytosis, thrombocytopenic purpura, and megaloblastic anemia have been attributed to barbiturate administration.

Barbiturates may elevate blood ammonia. Animal studies indicate that thiopental impairs the ability of the liver to metabolize ammonia. For this reason, it has been suggested that barbiturate administration be avoided in patients with ammonia intoxication.

IV administration of barbiturates may produce severe respiratory depression, apnea, laryngospasm, bronchospasm, coughing, and vasodilation and hypotension, especially if administered too rapidly. IV administration may cause thrombophlebitis, pain at the injection site, or injury to adjacent nerves. Intra-arterial injection or extravasation of sodium salts of barbiturates can produce tissue necrosis.

Precautions and Contraindications

Patients should be warned that barbiturates may impair their ability to perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery or driving a motor vehicle). There also is a potential risk of complex sleep-related behaviors such as sleep-driving (i.e., driving while not fully awake after ingesting a sedative-hypnotic drug, with no memory of the event), making phone calls, or preparing and eating food while asleep in patients receiving butabarbital or secobarbital.109 Barbiturates should be used with caution in patients with acute or chronic pain, since paradoxical excitement may occur or important symptoms might be masked. Barbiturates should be used cautiously, if at all, in patients who are mentally depressed, have suicidal tendencies, or a history of drug abuse. Aprobarbital, barbital, mephobarbital, and phenobarbital should be avoided or used only with extreme caution in patients with nephritis or renal insufficiency. Hepatic disease is not usually a contraindication to barbiturate administration; however, those drugs that are metabolized in the liver should be used with caution and in reduced dosage in patients with impaired liver function.

Physicians should be alert to the signs, including high fever, severe headache, stomatitis, conjunctivitis, rhinitis, urethritis or balanitis, which may precede the onset of barbiturate-induced cutaneous lesions. Because skin eruptions can precede potentially fatal reactions, barbiturates should be discontinued whenever dermatologic reactions occur.

Blood counts should be determined prior to and periodically during long-term therapy with barbiturates. In addition, patients should be instructed to report immediately symptoms such as sore throat, fever, easy bruising, petechiae, epistaxis, or other signs of infection or bleeding tendency which may be indications of hematologic toxicity. Barbiturates should be discontinued if blood dyscrasias occur.

Barbiturates should be administered parenterally only with caution to patients with hypertension, hypotension, or pulmonary or cardiovascular disease. The drugs also should be administered with caution to patients in whom the hypnotic effect may be prolonged or intensified such as those with shock or uremia or who have recently received another respiratory depressant. IV administration should be reserved for emergency treatment of acute seizures or for anesthesia.

Barbiturates are contraindicated in patients with bronchopneumonia or other severe pulmonary insufficiency, as well as in patients with known hypersensitivity to any of the barbiturates. The drugs may exacerbate acute intermittent porphyria or porphyria variegata and are contraindicated in patients with a history of porphyria.

Pediatric Precautions

FDA warns that repeated or prolonged use of general anesthetics and sedation drugs in children younger than 3 years of age or during the third trimester of pregnancy may affect brain development.750,753 Animal studies in multiple species, including nonhuman primates, have demonstrated that use for longer than 3 hours of anesthetic and sedation drugs that block N -methyl-d-aspartic acid (NMDA) receptors and/or potentiate γ-aminobutyric acid (GABA) activity leads to widespread neuronal and oligodendrocyte cell loss and alterations in synaptic morphology and neurogenesis in the brain, resulting in long-term deficits in cognition and behavior.750,751,752,753 Across animal species, vulnerability to these neurodevelopmental changes occurs during the period of rapid brain growth or synaptogenesis; this period is thought to correlate with the third trimester of pregnancy through the first year of life in humans, but may extend to approximately 3 years of age.750 The clinical relevance of these animal findings to humans is not known.750

While some published evidence suggests that similar deficits in cognition and behavior may occur in children following repeated or prolonged exposure to anesthesia early in life, other studies have found no association between pediatric anesthesia exposure and long-term adverse neurodevelopmental outcomes.750,752 Most studies to date have had substantial limitations, and it is not clear whether the adverse neurodevelopmental outcomes observed in children were related to the drug or to other factors (e.g., surgery, underlying illness).750 There is some clinical evidence that a single, relatively brief exposure to general anesthesia in generally healthy children is unlikely to cause clinically detectable deficits in global cognitive function or serious behavioral disorders;750,751,752 however, further research is needed to fully characterize the effects of exposure to general anesthetics in early life, particularly for prolonged or repeated exposures and in more vulnerable populations (e.g., less healthy children).750

Results from an observational study (the Pediatric Anesthesia Neurodevelopment Assessment [PANDA] study) and preliminary results from an ongoing multicenter, randomized trial (the General Anesthesia Compared to Spinal Anesthesia [GAS] trial) provide some evidence that a single, relatively brief exposure to general anesthesia in generally healthy children is unlikely to cause clinically detectable deficits in global cognitive function or serious behavioral disorders.750,751,752 The PANDA study compared global cognitive function (as measured by intelligence quotient [IQ] score) of children 8-15 years of age who had a single anesthesia exposure for elective inguinal hernia surgery before the age of 3 years with that of a biologically related sibling who had no anesthesia exposure before the age of 3 years.750,752 All of the children had a gestational age at birth of at least 36 weeks, and sibling pairs were within 3 years of being the same age.750,752 Children who underwent the elective procedure were mostly males (90%) and generally healthy.750,752 The mean duration of anesthesia was 84 minutes; 16% of those receiving anesthesia had exposures exceeding 2 hours.750 The study found no substantial difference in IQ score between children who had a single anesthesia exposure before the age of 3 years and their siblings who had not.750,752 The GAS trial was designed to compare neurodevelopmental outcomes in children who received general anesthesia with those in children who received awake regional (caudal and/or spinal) anesthesia for inguinal herniorrhaphy before they reached a postmenstrual age of 60 weeks (with a gestational age at birth of more than 26 weeks); the primary outcome was the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale IQ at 5 years of age.750,751 In an interim analysis at the age of 2 years, no difference in composite cognitive score (as measured by the Bayley Scales of Infant and Toddler Development III) was detected between children who had received sevoflurane anesthesia of less than 1 hour's duration (median duration: 54 minutes) compared with those who had received awake regional anesthesia.750,751

Anesthetic and sedation drugs are an essential component of care for children and pregnant women who require surgery or other procedures that cannot be delayed;750,753 no specific general anesthetic or sedation drug has been shown to be less likely to cause neurocognitive deficits than any other such drug.750 Pending further accumulation of data in humans from well-designed studies, decisions regarding the timing of elective procedures requiring anesthesia should take into consideration both the benefits of the procedure and the potential risks.750 When procedures requiring the use of general anesthetics or sedation drugs are considered for young children or pregnant women, clinicians should discuss with the patient, parent, or caregiver the benefits, risks (including potential risk of adverse neurodevelopmental effects), and appropriate timing and duration of the procedure.750,753 FDA states that procedures that are considered medically necessary should not be delayed or avoided.750,753

Carcinogenicity

Phenobarbital sodium is carcinogenic in mice and rats following lifetime administration; in mice, the drug produced benign and malignant liver cell tumors and, in rats, benign liver cell tumors very late in life. In one long-term epidemiologic study of patients treated with anticonvulsants, including phenobarbital, there was a higher than usual incidence of hepatic carcinoma; however, some of the patients had previously received thorium dioxide, a contrast medium known to produce hepatic carcinomas, and the study did not provide sufficient evidence that phenobarbital is carcinogenic in humans. One retrospective, case-control study has suggested an association between prenatal exposure to barbiturates and an increased incidence of brain tumors.

Pregnancy and Lactation

Pregnancy

Barbiturates can cause fetal harm when administered to pregnant women. Retrospective, case-controlled studies have suggested an association between maternal ingestion of barbiturates and a higher than expected incidence of fetal abnormalities. If a barbiturate is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.

Based on animal data, repeated or prolonged use of general anesthetics and sedation drugs during the third trimester of pregnancy may result in adverse neurodevelopmental effects in the fetus.750,753 The clinical relevance of these animal findings to humans is not known; the potential risk of adverse neurodevelopmental effects should be considered and discussed with pregnant women undergoing procedures requiring general anesthetics and sedation drugs.750 (See Cautions: Pediatric Precautions.)

Barbiturates have caused postpartum hemorrhage and hemorrhagic disease in neonates. The drug-induced hemorrhagic disease of the neonate is similar to that resulting from vitamin K deficiency and is readily reversible with vitamin K therapy. Neonates born to women who receive barbiturates throughout the last trimester of pregnancy may show withdrawal symptoms. (See Chronic Toxicity: Manifestations.) Neonates whose mothers have received barbiturates during labor should be closely observed for signs of respiratory depression, and treatment for barbiturate overdosage should be instituted if necessary. (See Acute Toxicity: Treatment.) Premature neonates are particularly susceptible to the depressant effects of barbiturates, and the drugs should be administered with caution when delivery of a premature neonate is anticipated.

Lactation

Because barbiturates are distributed into the milk of nursing women, nursing should be discontinued if nursing infants of barbiturate-treated women exhibit signs of toxicity.

Concurrent administration of numerous drugs with barbiturates has been reported to affect either the patient's response to the barbiturates or to the other drugs. Most of the reported drug interactions relate to phenobarbital, but the possibility of similar interaction with other barbiturates should be considered.

In addition to the interactions listed, many other drugs have been reported to alter the response to barbiturates and/or have their responses altered by barbiturates; however, in most instances the clinical importance of these interactions has not been established. Since documentation for these interactions may be forthcoming and additional clinically important interactions may be established, caution should be observed when any drug is added to or deleted from any therapeutic regimen which contains a barbiturate, giving consideration to the possible need for dosage adjustment.

CNS Depressants

Barbiturates may be additive with or may potentiate the action of other CNS depressants including other sedatives or hypnotics, antihistamines, tranquilizers, and alcohol.

Anticoagulants

Barbiturates, especially phenobarbital, may decrease absorption of dicumarol from the GI tract. In addition, phenobarbital and possibly other barbiturates may induce hepatic microsomal enzymes resulting in increased metabolism of coumarin anticoagulants and decreased anticoagulant response. Patients maintained on both barbiturates and a coumarin anticoagulant have a risk of hemorrhage if the barbiturate is discontinued and the dosage of the anticoagulant is not adjusted. Barbiturate therapy should not be initiated or discontinued in patients receiving oral anticoagulants without careful attention to the possible need for adjusting anticoagulant dosage.

Corticosteroids

Phenobarbital, secobarbital, and butabarbital appear to increase the metabolism of corticosteroids, probably by induction of hepatic microsomal enzymes. In addition, animal data indicate that barbiturates may interfere with pituitary corticotropin production.

Patients with asthma who were receiving prednisone have experienced exacerbation of asthma when phenobarbital therapy was initiated and reversal of exacerbation when phenobarbital was discontinued. Asthmatics receiving corticosteroids should be closely monitored when barbiturate therapy is begun. The possibility that this interaction may occur in other patients receiving corticosteroids and barbiturates should also be considered.

Antidepressants

Barbiturates may potentiate adverse effects (e.g., respiratory depression) induced by toxic doses of tricyclic antidepressants (e.g., amitriptyline, imipramine). With therapeutic doses of tricyclic antidepressants, barbiturates appear to stimulate metabolism and decrease blood concentrations of the antidepressants; however, the clinical importance of this effect has not been established.

It appears that monoamine oxidase inhibitors (MAOs) may inhibit the metabolism of barbiturates which may result in prolonged barbiturate effects and may require reduction of barbiturate dosage.

Griseofulvin

Phenobarbital may decrease blood griseofulvin concentrations, probably by impairing griseofulvin absorption. Although the effects of these decreased concentrations of griseofulvin on therapeutic response have not been established, it is recommended to avoid concomitant administration of these drugs pending accumulation of further information. If concomitant therapy is necessary, it has been suggested that absorption of griseofulvin may be improved when the drug is administered in 3 daily divided doses. Blood griseofulvin concentrations should be monitored and dosage increased if necessary.

Doxycycline

Phenobarbital may decrease the half-life of doxycycline by inducing hepatic microsomal enzymes that metabolize the antibiotic. Concomitant administration of doxycycline and barbiturates should be avoided if possible. If concomitant therapy is necessary, doxycycline may be administered at 12-hour intervals and/or doxycycline concentrations should be closely monitored.

Oral Contraceptives

Pretreatment with or concurrent administration of phenobarbital in patients receiving oral contraceptives may decrease the effectiveness of oral contraceptives. There have been reports of women receiving anticonvulsants (e.g., phenobarbital) who became pregnant while receiving oral contraceptives. Phenobarbital may enhance the metabolism of both the estrogenic and progestinic components of oral contraceptives, presumably by induction of hepatic microsomal enzymes. Because of the risk of contraceptive failure during concomitant use of oral contraceptives and phenobarbital (or mephobarbital), it has been suggested that alternate methods of contraception be considered in patients receiving phenobarbital.

Anticonvulsants

For information of the interactions of barbiturates with other anticonvulsants, see Drug Interactions in the Anticonvulsants General Statement 28:12.

Other Drugs

Phenobarbital may enhance the metabolism of digitoxin (no longer commercially available in the US), presumably by induction of hepatic microsomal enzymes, resulting in decreased plasma digitoxin concentrations and half-life. Patients receiving digitoxin and phenobarbital should be observed for possible underdigitalization, and digitoxin dosage should be increased if necessary.

Concurrent administration of disulfiram with barbiturates may result in inhibition of metabolism of the barbiturates and an increased incidence of barbiturate toxic effects.

Ketamine anesthesia following administration of a barbiturate for preoperative anxiety and sedation has been reported to produce profound respiratory depression.

Laboratory Test Interferences

Barbiturates may increase the retention of sulfobromophthalein and give elevated readings and should not be administered during the 24 hours preceding the test.

Acute Toxicity

Pathogenesis

The toxic dose of barbiturates varies considerably but, in general, a severe reaction is likely to occur when the amount ingested is more than 10 times the usual oral hypnotic dose. Potentially lethal blood concentrations are those in excess of 80 mcg/mL for phenobarbital, 50 mcg/mL for amobarbital or butabarbital, and approximately 30 mcg/mL for secobarbital or pentobarbital; however, some patients have survived much higher blood concentrations.

Manifestations

Overdosage of barbiturates produces CNS depression ranging from sleep to profound coma to death; respiratory depression which may progress to Cheyne-Stokes respiration, central hypoventilation, and cyanosis; cold, clammy skin and/or hypothermia or later fever, areflexia, tachycardia, hypotension, loss of peripheral vascular resistance,100 muscular hyperactivity (twitching to convulsive-like movements)100 seizures,100 allergic reactions,100 and decreased urine formation. Pupils usually are slightly constricted but may be dilated in severe poisoning. Patients with severe overdosage often experience typical shock syndrome; apnea, circulatory collapse with loss of peripheral vascular tone,100 cardiac arrest,100 respiratory arrest, and death may occur. Complications such as pneumonia, pulmonary edema, or renal failure may also prove fatal. Other complications which may occur are congestive heart failure, cardiac arrhythmias, and urinary tract infections. Some patients have bullous cutaneous lesions which heal slowly. Sweat gland necrosis may also occur.

Treatment

One manufacturer states in case of barbiturate overdosage a poison center should be contacted to receive the most current information on the treatment of such overdosage.100 That manufacturer also states that the possibility of multiple drug overdosage, drug interactions, and unusual pharmacokinetics of concomitantly used drugs also should be considered.100 Treatment of overdosage is mainly supportive including maintenance of an adequate airway and assisted respiration and oxygen administration if needed. Resuscitative measures should be initiated promptly.100 Standard treatment for shock should be administered if necessary. Management of hypotension may include administration of IV fluids, elevation of the lower extremities, and/or use of vasopressor or inotropic agents.100 For seizures, IV diazepam and phenytoin may be used; in case of refractory seizures, general anesthesia and paralysis induced by a neuromuscular blocking agent may be necessary.100 Activated charcoal is an effective barbiturate absorbent when administered within 30 minutes following ingestion of the drugs. Gastric lavage or gastric aspiration is not recommended unless there is evidence that the drug has been ingested recently (within 4 hours); care should be taken to prevent pulmonary aspiration of gastric contents. Multiple-dose, nasogastric administration of activated charcoal has been used effectively to treat phenobarbital overdose; activated charcoal enhances elimination of the drug and shortens the duration of coma. The patient's vital signs, fluid intake, blood gases,100 and serum electrolytes100 should be monitored closely. Analeptic drugs should not be administered because they may produce paroxysmal cerebral activity which may result in generalized seizures. In addition, it has been demonstrated that analeptics are incapable of stimulating respiration and exerting an arousal effect in patients with severe barbiturate poisoning and profound CNS depression. If renal function is normal, forced diuresis may be of benefit. In addition, alkalinization of the urine increases renal excretion of phenobarbital, aprobarbital, and mephobarbital which is metabolized to phenobarbital. Peritoneal dialysis or hemodialysis may be useful in severe barbiturate intoxication and/or if the patient is anuric or in shock.

Chronic Toxicity

Pathogenesis

At usual therapeutic dosage, administration of barbiturates may be continued for years without difficulty. Tolerance, psychological dependence, and physical dependence may occur, however, particularly following prolonged use of high doses of barbiturates. Daily administration of 600-800 mg of amobarbital, butabarbital, pentobarbital, or secobarbital for approximately 8 weeks will produce some degree of physical dependence. The average daily dose ingested by those psychologically and physically dependent on barbiturates is usually about 1.5 g; however, the acute toxic dose remains the same for barbiturate-dependent individuals as for those who are not barbiturate dependent.

Manifestations

Symptoms of barbiturate dependence are similar to those of chronic alcoholism, but can be more severe than those associated with alcohol or opiate abstinence syndrome and may result in fatalities. Withdrawal symptoms (which usually appear after 8-12 hours of abstinence) may vary from mild, consisting only of weakness, anxiety, muscle twitches, insomnia, nausea, vomiting, postural hypotension, and/or weight loss, to more severe hallucinations, delirium, and seizures. Seizures, clinically indistinguishable from tonic-clonic (grand mal) seizures, may occur as early as 16 hours after the last dose of barbiturate or may be delayed for as long as 5 days. Some fatalities resulting from cardiovascular collapse have occurred.

Neonates born to women who receive barbiturates throughout the last trimester of pregnancy may show withdrawal symptoms from 1-14 days after birth. Withdrawal symptoms, which resemble congenital opiate withdrawal symptoms, include hyperactivity, restlessness, disturbed sleep, tremor, and hyperreflexia.

Treatment

Treatment of barbiturate dependence consists of cautious and gradual withdrawal of the drug. A stabilizing dose is established (usually pentobarbital is administered at 6-hour intervals) which is then reduced by no more than 100 mg per day. If withdrawal symptoms reappear, the dosage should be maintained or slightly increased until such symptoms disappear. Severely dependent patients usually can be withdrawn from barbiturates in 14-21 days. Alternatively, barbiturate-dependent patients can be withdrawn using phenobarbital. A 30-mg dose of phenobarbital is administered orally for each 100- to 200-mg dose of barbiturate that the patient has been taking daily. The total daily dose of phenobarbital is administered in 3 or 4 divided doses. If the patient shows signs of withdrawal on the first day, a loading dose of 100-200 mg phenobarbital may be administered IM in addition to the oral dose. After stabilization on phenobarbital, the total daily dose of phenobarbital is decreased by 30 mg daily.

Neonates physically dependent on barbiturates may be given phenobarbital orally in a dosage of 3-10 mg/kg daily. After barbiturate withdrawal symptoms are relieved, dosage of phenobarbital should be gradually decreased and withdrawn completely over a 2-week period.

Pharmacology

The exact mechanism(s) by which barbiturates exert their effect on the CNS, has not been fully elucidated.103,104,105,106 However, it is believed that such effects are related, at least partially, to the drugs' ability to enhance the activity of γ-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the CNS,104,105,106,107,108 by altering inhibitory synaptic transmissions that are mediated by GABA_A receptors.105,106,108

Although the drugs act throughout the CNS, a site of particular sensitivity is the polysynaptic midbrain reticular formation which is concerned with the arousal mechanism. Barbiturates induce an imbalance in central inhibitory and facilitatory mechanisms influencing the cerebral cortex and the reticular formation. The significance of the effect of barbiturates on neurotransmitters is unclear. It appears that the drugs decrease the excitability of both presynaptic and postsynaptic membranes. It has not been determined which of the various actions of barbiturates at cellular and synaptic levels are responsible for their sedative and hypnotic effects.

Barbiturates are capable of producing all levels of CNS depression—from mild sedation to hypnosis to deep coma to death. The degree of depression depends upon dosage, route of administration, and pharmacokinetics of the particular barbiturate. In addition, the patient's age, physical or emotional state, and/or the concurrent use of other drugs may alter the response.

Relatively low doses of the barbiturates depress the sensory cortex, decrease motor activity, and produce sedation and drowsiness. In some patients, however, drowsiness may be preceded by a period of transient elation, confusion, euphoria, or excitement, especially after subhypnotic doses of aprobarbital, pentobarbital, or secobarbital. Phenobarbital frequently produces paradoxical excitement and hyperactivity in children or exacerbates existing hyperactivity. Geriatric patients may react to usual doses of barbiturates with excitement, confusion, or depression, probably as a result of the drugs' depressant effects on inhibitory centers of the cerebral cortex. Larger doses distort judgment, cloud perception, suppress motor activity, and produce drowsiness and sleep. Still larger doses induce anesthesia. Barbiturate-induced sleep differs from physiologic sleep. Barbiturates reduce the rapid eye movement (REM) or dreaming stage of sleep. Stages III and IV sleep are also decreased. Although tolerance develops to the REM-suppressant effects during chronic administration, REM rebound occurs when the drugs are withdrawn, and the patient may experience markedly increased dreaming, nightmares, and/or insomnia.

Barbiturates have no analgesic action and may increase the reaction to painful stimuli at subanesthetic doses. All barbiturates exhibit anticonvulsant activity, but only phenobarbital, metharbital, and mephobarbital are effective anticonvulsants in subhypnotic doses.

In usual hypnotic doses, barbiturates depress respiration similar to that occurring in natural sleep. With larger doses, however, the drugs markedly decrease the rate, depth, and volume of respiration, probably through a direct action on medullary centers. Rapid IV administration of these drugs may produce respiratory depression and transient hypotension.

Reduction of tone and motility of the GI tract following sedative doses of the barbiturates is largely caused by their central depressant action rather than by any direct effects on the GI tract. In toxic doses, the drugs depress transmission of impulses in autonomic ganglia. Although barbiturates decrease oxygen consumption of all tissues, hypnotic doses have no measurable effect on the basal metabolic rate.

Barbiturates have no direct effects on renal function, although severe renal impairment may occur in acute barbiturate poisoning as a result of marked hypotension. (See Acute Toxicity: Manifestations.) Hepatic function is not adversely affected by barbiturates, but the drugs, particularly phenobarbital, induce hepatic microsomal enzymes and thus may alter the metabolism of other drugs. (See Drug Interactions.) Deep barbiturate anesthesia may prolong labor by decreasing the force and frequency of uterine contractions, although hypnotic doses have no effect on uterine activity.

Barbiturates lower serum bilirubin concentrations in neonates and patients with congenital nonhemolytic unconjugated hyperbilirubinemia, presumably by induction of glucuronyl transferase, the enzyme that conjugates bilirubin.

Pharmacokinetics

Absorption

Barbiturates are absorbed in varying degrees following oral, rectal, or IM administration. The sodium salts are more rapidly absorbed by all routes of administration than are the acids. The rate of oral absorption is increased when the sodium salt is ingested as a dilute solution or taken on an empty stomach. Alcohol also enhances the rate of absorption, possibly by increasing blood flow through the gastric mucosa.

Following oral or rectal administration, the onset of action varies from 10-30 minutes for amobarbital, aprobarbital, butabarbital, pentobarbital, and secobarbital and from 20-60 minutes for metharbital, mephobarbital, and phenobarbital. IM administration results in a slightly faster onset of action. Following IV administration of the sodium salts of amobarbital, pentobarbital, phenobarbital, or secobarbital, the onset of action ranges from almost immediately for methohexital, pentobarbital, and thiopental to 5 minutes for phenobarbital. Maximum effects of thiopental or pentobarbital are achieved within about 1 minute while as much as 30 minutes may be required with administration of phenobarbital.

The duration of sedative effects of all the barbiturates is usually 3-6 hours following IV administration and 6-8 hours when the drugs are administered by other routes. There appears to be very little difference in duration of hypnotic action among barbiturates used orally as hypnotics. Therefore, most authorities now believe that barbiturates should be classified according to their intended pharmacologic action (i.e., sedative-hypnotic barbiturates and anesthetic barbiturates [methohexital, thiamylal, thiopental]), rather than as long-acting (mephobarbital, metharbital, and phenobarbital), intermediate-acting (amobarbital and butabarbital), short-acting (aprobarbital, pentobarbital, and secobarbital), and ultrashort-acting (methohexital, thiopental).

Distribution

Following absorption or IV injection, barbiturates are rapidly distributed to all tissues and fluids with high concentrations in brain and liver. Lipid solubility of the barbiturates is the dominant factor in their distribution in the body. Barbiturates suitable for clinical use as anesthetics are those that are most lipid soluble and most rapidly penetrate all tissues of the body. These highly lipid-soluble drugs (e.g., thiopental) penetrate the blood-brain barrier rapidly, and their rate of entry into the brain is limited only by the rate of cerebral blood flow. Less lipophilic barbiturates (e.g., phenobarbital) penetrate and leave the brain more slowly and thus have a slower onset and longer duration of action. Plasma concentrations fall rapidly as highly lipid soluble drugs are distributed into total body water and tissue binding sites including fat and the high concentrations of the drugs in the brain decline. Termination of the anesthetic effects of these barbiturates depends more upon redistribution than metabolism; metabolism and excretion are more important in the termination of the other effects of the sedative-hypnotic barbiturates.

Barbiturates readily cross the placenta, and fetal blood concentrations approach maternal blood concentrations within a few minutes following parenteral administration of the drugs. During chronic oral administration, barbiturates are distributed throughout fetal tissues in concentrations slightly lower than those in the mother. The drugs are distributed into milk in concentrations much lower than those in plasma.

Individual barbiturates differ in their degree of plasma protein binding. In general, the more lipid soluble the barbiturate, the more the drug is bound to plasma protein; thiopental (the most lipid soluble barbiturate) is 65% bound to plasma proteins. Tissue proteins also bind barbiturates. Some studies indicate that sulfonamides and barbiturates compete for the same binding sites.

Elimination

The plasma half-life of the barbiturates ranges from 1.5-22 hours for methohexital and thiopental to 2-6 days for phenobarbital.

Barbiturates are slowly metabolized, chiefly by hepatic microsomal enzymes. Phenobarbital and probably other barbiturates induce hepatic microsomal enzymes and thus may accelerate metabolism of other concomitantly administered drugs metabolized by these enzymes. (See Drug Interactions.) There is no conclusive evidence that barbiturates accelerate their own metabolism.

Approximately 25-50% of a dose of phenobarbital or aprobarbital is excreted unchanged in the urine. The amount of the other barbiturates excreted unchanged is negligible. The inactive metabolites of the barbiturates are conjugated with glucuronic acid and excreted in the urine. Trace amounts of the drugs and/or their metabolites are also excreted in feces and sweat.

Orally administered activated charcoal has been shown to enhance the elimination of phenobarbital. Following IV administration of phenobarbital in healthy adults in one study, orally administered activated charcoal decreased the mean serum half-life of phenobarbital and increased mean total body and nonrenal clearances of the drug.

Chemistry and Stability

Chemistry

Amobarbital, aprobarbital (no longer commercially available in the US), butabarbital, mephobarbital (no longer commercially available in the US), pentobarbital, phenobarbital, and secobarbital are used as sedatives and/or hypnotics. Methohexital, thiamylal (no longer commercially available in the US), and thiopental (no longer commercially available in the US) are used as anesthetics. Butalbital is commercially available only in combination products. Barbiturates and their sodium salts are subject to control under the Federal Controlled Substances Act of 1970.

Barbiturates are substituted pyrimidine derivatives. The basic structure common to these drugs is barbituric acid (condensation of malonic acid and urea), a substance that has no CNS activity. Replacing the 2 hydrogens at position 5 with alkyl, alkenyl, and/or aryl groups produces compounds with CNS activity. Other variations of this structure include replacement of the oxygen at the 2-position with a sulfur atom (thiobarbiturates) or the replacement of the hydrogen at the N -1 position with a methyl group ( N -methyl barbiturates).

Generally, barbiturates occur as colorless, crystalline solids and are insoluble in water, soluble in alcohol, and very soluble in nonpolar solvents.

Stability

Sodium salts of all barbiturates are very soluble in water, forming unstable alkaline solutions. Stable solutions of sodium salts of barbiturates in polyethylene glycol or propylene glycol may be prepared, and these vehicles are frequently used as solvents in commercially available injections. Solutions for injection should not be used if they contain a precipitate.

Only references cited for selected revisions after 1984 are available electronically.

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