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Barbiturates (Systemic)

This monograph includes information on the following:

1) Amobarbital
2) Aprobarbital ^†
3) Butabarbital
4) Mephobarbital
5) Metharbital ^* ^†
6) Pentobarbital
7) Phenobarbital
8) Secobarbital
9) Secobarbital and Amobarbital

VA CLASSIFICATION
Amobarbital Oral
Primary: CN301

Amobarbital Parenteral
Primary: CN301
Secondary: CN400

Aprobarbital Oral
Primary: CN301

Butabarbital Oral
Primary: CN301

Mephobarbital Oral
Primary: CN400

Metharbital Oral
Primary: CN400

Pentobarbital Oral
Primary: CN301

Pentobarbital Parenteral
Primary: CN301
Secondary: CN400

Phenobarbital Oral
Primary: CN301
Secondary: CN400; GA900

Phenobarbital Parenteral
Primary: CN301
Secondary: CN400; GA900

Secobarbital Oral
Primary: CN301

Secobarbital Parenteral
Primary: CN301
Secondary: CN400

Note: Controlled substance classification—

Note: Controlled substances in the U.S. and Canada as follows ^{69} ^{70} ^{90} ^{95} ^{115} ^{117} ^{120}:

Drug	U.S.	Canada
Amobarbital	II	C
Aprobarbital	III
Butabarbital	III	C
Mephobarbital	IV	C
Pentobarbital Oral	II	C
Parenteral	II	C
Rectal	III	C
Phenobarbital	IV	C
Secobarbital Oral	II	C
Parenteral	II
Secobarbital and Amobarbital	II	C

Commonly used brand name(s): Alurate²; Amytal¹; Ancalixir⁷; Barbita⁷; Busodium³; Butalan³; Butisol³; Gemonil⁵; Luminal⁷; Mebaral⁴; Nembutal⁶; Nova Rectal⁶; Novopentobarb⁶; Novosecobarb⁸; Sarisol No. 2³; Seconal⁸; Solfoton⁷; Tuinal⁹.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^*Not commercially available in the U.S.

^†Not commercially available in Canada.

Category:

Sedative-hypnotic—Amobarbital; Aprobarbital; Butabarbital; Pentobarbital; Phenobarbital (parenteral only); Secobarbital;

Anticonvulsant—Amobarbital (parenteral only); Mephobarbital; Metharbital; Pentobarbital (parenteral only); Phenobarbital; Secobarbital (parenteral only);

Antihyperbilirubinemic—Phenobarbital;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Anesthesia, adjunct—Amobarbital, butabarbital, pentobarbital, phenobarbital (parenteral), and secobarbital are indicated for use as preoperative medication to help reduce anxiety and facilitate induction of anesthesia ^{46} ^{51} ^{69} ^{70} ^{92} ^{99a} ^{105} ^{106} ^{108} ^{115} ^{117} ^{119} ^{164}.

Narcoanalysis—Amobarbital (parenteral) may be indicated in narcoanalysis ^{30} ^{46} ^{114}.

Epilepsy, tonic-clonic seizure pattern (treatment) or
Epilepsy, simple partial seizure pattern (treatment)—Phenobarbital ^{55} ^{56} ^{95}, a long-acting barbiturate, is indicated as long-term anticonvulsant therapy for the treatment of generalized tonic-clonic and simple partial (cortical focal) seizures; mephobarbital ^{33} ^{49} ^{50} and metharbital, also long-acting barbiturates, may be indicated as alternatives to phenobarbital ^{84} ^{86} ^{107} ^{117} ^{119}.

Convulsions (treatment)
Seizures (prophylaxis and treatment)
Status epilepticus (treatment) or
Tetanus (treatment adjunct)—Parenteral barbiturates ^{91} ^{114}, especially phenobarbital, are indicated in the emergency treatment of certain acute convulsive episodes such as those associated with status epilepticus, eclampsia, meningitis, and toxic reactions to strychnine. They are also indicated as adjunctive treatment for acute convulsive episodes associated with tetanus. ^{36} ^{51} ^{54} ^{55} ^{56} ^{58} ^{107} ^{117} ^{119}
—Phenobarbital is used in the prophylaxis and treatment of febrile seizures^{55}^{117}^{119} .¹

[Hyperbilirubinemia (prophylaxis and treatment)]¹—Phenobarbital (oral and parenteral) is used in the prevention and treatment of hyperbilirubinemia in neonates. It is used also to lower bilirubin concentrations in patients with congenital nonhemolytic unconjugated hyperbilirubinemia or chronic intrahepatic cholestasis. ^{113}

[Ischemia, cerebral (treatment)]¹or
[Hypertension, cerebral (treatment)]¹—Pentobarbital (parenteral) is used for induction of coma to protect the brain from various states, including ischemia and increased intracranial pressure that follow stroke and head trauma; however, this use is controversial and further studies are needed.

—Amobarbital, aprobarbital, butabarbital, pentobarbital, phenobarbital, secobarbital, and secobarbital and amobarbital have been used for the short-term treatment of insomnia; however, they generally have been replaced by benzodiazepines. If barbiturates are used, they are not recommended for long-term use since they appear to lose their effectiveness in sleep induction and maintenance after 2 weeks or less. ^{28} ^{46} ^{47} ^{48} ^{50} ^{51} ^{52} ^{55} ^{56} ^{57} ^{58} ^{59} ^{60} ^{69} ^{70} ^{73} ^{90} ^{92} ^{95} ^{99a} ^{105} ^{106} ^{107} ^{108} ^{115} ^{116} ^{117} ^{119} ^{120} ^{121} ^{164}

—Amobarbital, aprobarbital, butabarbital, mephobarbital, pentobarbital, phenobarbital, and secobarbital have also been used for routine sedation to relieve anxiety, tension, and apprehension ^{95} ^{105} ^{106} ^{107} ^{108} ^{115} ^{117} ^{164}; however, barbiturates generally have been replaced by benzodiazepines for daytime sedation ^{46} ^{47} ^{48} ^{52} ^{55} ^{56} ^{57} ^{58}.

Unaccepted
Amobarbital (parenteral) has been used as a diagnostic aid in schizophrenia ^{114} but it generally has been replaced by other agents ^{30}.

Amobarbital (parenteral) has also been used in the management of catatonic and negativistic reactions ^{114}; however, phenothiazines generally are more appropriate therapy for catatonic reactions. It has also been used in the management of manic reactions, although benzodiazepines and lithium are usually preferred. ^{30}

[Phenobarbital (oral and parenteral) has been used in the treatment of familial, senile, or essential action tremors; however, it generally has been replaced by other agents, such as benzodiazepines and beta-adrenergic blockers.]

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Table 1. Pharmacology/Pharmacokinetics

Drug	Protein Binding ^* (%)	Half-life (hr)		Onset of Action ^† (min)	Duration of Action ^‡ (hr)	Elimination/ % Excreted Unchanged ^§
Drug	Protein Binding ^* (%)	Range	Mean	Onset of Action ^† (min)	Duration of Action ^‡ (hr)	Elimination/ % Excreted Unchanged ^§
Long-acting				60 or longer	10–12
Mephobarbital ^#		11–67	34			Renal
Metharbital						Renal/2%; 20% excreted as barbital
Phenobarbital	Low to Moderate (20–45)	53–118 ^**	79			Renal/25–50%
Intermediate-acting				45–60	6–8
Amobarbital	Moderate (61)	16–40	25			Renal/<1%
Aprobarbital	Low (20)	14–34	24			Renal/25–50%
Butabarbital	Low (26)	34–42	^††			Renal/<1%
Short-acting				10–15	3–4
Pentobarbital	Moderate to High (60–70)	15–50	^‡‡			Renal/<1%
Secobarbital	Moderate to High (46–70)	15–40	28			Renal/5%

^* Bound to plasma and tissue proteins to a varying degree; binding increases proportionate to lipid solubility ^{49} ^{52} ^{56} ^{57} ^{84} ^{90} ^{92} ^{99a} ^{115} ^{116} ^{117}
^† Following oral administration. Phenobarbital has the slowest, and secobarbital the fastest, onset of action ^{48} ^{49} ^{54} ^{55} ^{56} ^{57}
^‡ Following oral administration. Duration of action is related to the rate at which the barbiturates are redistributed throughout the body and is variable among individuals and in the same individual from time to time. Phenobarbital has the longest, and secobarbital the shortest, duration of action ^{48} ^{49} ^{51} ^{52} ^{54} ^{55} ^{56} ^{57} ^{90} ^{92} ^{117}
^§ Metabolic products are excreted in the urine and, less commonly, in the feces. Inactive metabolites are excreted as conjugates of glucuronic acid. ^{48} ^{49} ^{50} ^{51} ^{52} ^{54} ^{55} ^{56} ^{90} ^{92} ^{99a} ^{117}
Peritoneal dialysis and hemodialysis ^{68} remove phenobarbital from the body; serum phenobarbital concentrations should be determined during and after peritoneal dialysis and hemodialysis ^{68}
^# Activity due mostly to accumulation of phenobarbital
^** Half-life is 60 to 180 hours in children (half-life 48 hours or less for newborns) ^{55} ^{117}
^†† One manufacturer states that the half-life of butabarbital is 100 hours ^{48} ^{65} ^{66} ^{67} ^{68} ^{115} ^{116}
^‡‡ Dose-dependent; the mean half-life of elimination is 50 and 22 hours following a 50- and 100-mg dose, respectively ^{117}

Physicochemical characteristics:
Molecular weight—
    Amobarbital: 226.27
    Amobarbital sodium: 248.26
    Aprobarbital: 210.23
    Butabarbital sodium: 234.23
    Mephobarbital: 246.27
    Metharbital: 198.22
    Pentobarbital: 226.27
    Pentobarbital sodium: 248.26
    Phenobarbital: 232.24
    Phenobarbital sodium: 254.22
    Secobarbital sodium: 260.27

Mechanism of action/Effect:

Barbiturates act as nonselective depressants of the central nervous system (CNS), capable of producing all levels of CNS mood alteration from excitation to mild sedation, hypnosis, and deep coma ^{90} ^{92} ^{99a} ^{116} ^{117} ^{119} ^{120}. In sufficiently high therapeutic doses, barbiturates induce anesthesia. Recent studies have suggested that the sedative-hypnotic and anticonvulsant effects of barbiturates may be related to their ability to enhance and/or mimic the inhibitory synaptic action of gamma-aminobutyric acid (GABA). ^{51} ^{52} ^{55} ^{56} ^{57} ^{58} ^{84} ^{114} ^{115}

Sedative-hypnotic:

Barbiturates depress the sensory cortex, decrease motor activity, alter cerebral function, and produce drowsiness, sedation, and hypnosis ^{99a} ^{116} ^{120}. Although the mechanism of action has not been completely established, the barbiturates appear to have a particular effect ^{26} at the level of the thalamus where they inhibit ascending conduction in the reticular formation, thus interfering with the transmission of impulses to the cortex.

The mechanism of action of pentobarbital in protecting the brain from ischemia and intracranial pressure is not completely understood; however, it is related to pentobarbital's anesthetic action (produced by sufficiently high dosage) and possibly to the depression of neuronal activity and metabolism ^{90}.

Anticonvulsant:

Barbiturates are believed to act by depressing monosynaptic and polysynaptic transmission in the CNS. They also increase the threshold for electrical stimulation of the motor cortex.

Antihyperbilirubinemic:

Phenobarbital lowers serum bilirubin concentrations probably by induction of glucuronyl transferase, the enzyme which conjugates bilirubin.

Other actions/effects:

Barbiturates have little analgesic action at subanesthetic doses and may increase reaction to painful stimuli ^{51} ^{52} ^{53} ^{55} ^{56} ^{57} ^{90} ^{92} ^{95} ^{99a}.

Although phenobarbital, mephobarbital, and metharbital are the only barbiturates effective as anticonvulsants in subhypnotic doses, all of the barbiturates exhibit anticonvulsant activity in anesthetic doses ^{31} ^{51} ^{56} ^{57} ^{90} ^{99a} ^{117} ^{119}.

Barbiturates are respiratory depressants; the degree of respiratory depression is dose-dependent ^{48} ^{49} ^{51} ^{52} ^{53} ^{55} ^{56} ^{57} ^{60} ^{84} ^{90} ^{92} ^{99a} ^{115} ^{116} ^{117} ^{119} ^{120}.

Barbiturates have been shown to reduce the rapid eye movement (REM) phase of sleep or dreaming stage. Also, Stages III and IV sleep (slow-wave sleep, SWS) are decreased. ^{48} ^{51} ^{52} ^{53} ^{55} ^{56} ^{57} ^{60} ^{99a} ^{115} ^{116} ^{117} ^{119} ^{120}

Animal studies have shown that barbiturates cause reduction in the tone and contractility of the uterus, ureters, and urinary bladder; however, concentrations required to produce this effect in humans are not attained with sedative-hypnotic doses ^{49} ^{51} ^{52} ^{53} ^{55} ^{56} ^{90} ^{117} ^{119}.

Barbiturates have been shown to induce liver microsomal enzymes, thereby increasing and altering the metabolism of ^{62} other medications or compounds ^{48} ^{49} ^{50} ^{51} ^{52} ^{53} ^{55} ^{56} ^{57} ^{84} ^{90} ^{92} ^{95} ^{99a} ^{115} ^{117} ^{118} ^{119} ^{120}.

Absorption:

Absorbed in varying degrees following oral, parenteral, or rectal administration ^{48} ^{49} ^{51} ^{52} ^{53} ^{55} ^{57} ^{90} ^{117}.

Barbiturate sodium salts are absorbed more rapidly than the free acids because of rapid dissolution ^{48} ^{51} ^{52} ^{53} ^{57} ^{90} ^{92} ^{116} ^{117} ^{119}.

The rate of absorption is increased if barbiturates are taken well diluted or on an empty stomach ^{48} ^{51} ^{52} ^{53} ^{55} ^{57} ^{115} ^{116} ^{117} ^{119}.

Distribution:

Rapidly distributed to all tissues and fluids with high concentrations in the brain, liver, and kidneys ^{48} ^{49} ^{51} ^{52} ^{53} ^{55} ^{56} ^{57} ^{58} ^{60} ^{84} ^{99a} ^{115} ^{116} ^{117} ^{119} ^{120}.

Lipid solubility is the primary factor in distribution within the body. The more lipid soluble the barbiturate, the more rapidly it penetrates all tissues of the body; phenobarbital has the lowest lipid solubility and secobarbital the highest ^{49} ^{51} ^{52} ^{53} ^{55} ^{56} ^{60} ^{84} ^{90} ^{92} ^{99a} ^{117} ^{119} ^{120}.

Biotransformation:

Hepatic, primarily by the hepatic microsomal enzyme system ^{46} ^{47} ^{48} ^{51} ^{52} ^{53} ^{55} ^{56} ^{59} ^{90} ^{92} ^{95} ^{113} ^{114} ^{115} ^{116} ^{117} ^{119}.

About 75% of a single oral dose of mephobarbital is metabolized to phenobarbital in 24 hours ^{49} ^{84}.

Metharbital is metabolized to barbital ^{50} ^{86}.

Onset of action:

Oral or rectal—Varies from 20 to 60 minutes ^{52} ^{53} ^{55} ^{58}.

Intramuscular—Slightly faster than for oral or rectal ^{52} ^{53} ^{55} ^{58}.

Intravenous—Ranges from almost immediately for pentobarbital sodium to 5 minutes for phenobarbital sodium ^{52} ^{53} ^{55} ^{56} ^{58}.

Therapeutic serum concentration

Anticonvulsant—Phenobarbital: 10 to 40 mcg per mL (43 to 172 micromoles/L) ^{172}.

Note: The optimal blood phenobarbital concentration should be determined by response in seizure control and the appearance of toxic effects.
To achieve blood concentrations considered therapeutic in children, higher-per-kg dosages of phenobarbital and most other anticonvulsants generally are required ^{117} ^{119}.

Time to peak effect:

Phenobarbital—Maximal CNS depression may not occur for 15 minutes or more after intravenous administration of phenobarbital sodium ^{51} ^{55} ^{56} ^{117} ^{119}.

Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to one of the barbiturates may be sensitive to other barbiturates also.

Carcinogenicity/Tumorigenicity/Mutagenicity

For butabarbital and secobarbital—No long-term studies in animals have been done to determine the carcinogenic and mutagenic potential of butabarbital or secobarbital ^{48} ^{58} ^{115} ^{116}.

For pentobarbital—Adequate studies have not been done in humans or animals to determine the carcinogenic potential of pentobarbital ^{51} ^{52} ^{53} ^{90} ^{92}.

For phenobarbital—Studies in animals have shown that phenobarbital is carcinogenic in mice and rats following lifetime administration. It produced benign and malignant liver cell tumors in mice and benign liver cell tumors very late in life in rats. A study in humans did not provide sufficient evidence that phenobarbital is carcinogenic in humans. ^{31} ^{55} ^{56} ^{117} ^{120}

Pregnancy/Reproduction
Fertility—
For butabarbital: No long-term studies in animals have been done to determine the effects of butabarbital on fertility ^{48}.

Pregnancy—
Barbiturates readily cross the placenta following oral or parenteral administration. They are distributed throughout fetal tissues, the highest concentrations being found in the placenta, fetal liver, and brain. ^{84} ^{115} ^{116} ^{120} Following parenteral administration, fetal blood concentration approaches maternal blood concentration ^{48} ^{49} ^{50} ^{51} ^{52} ^{53} ^{55} ^{56} ^{58} ^{60} ^{84} ^{90} ^{92} ^{120}.

Barbiturates have been shown to cause an increased incidence of fetal abnormalities. Risk-benefit must be carefully considered when the medication is required in life-threatening situations or in serious diseases for which other medications cannot be used or are ineffective. ^{31} ^{55} ^{56} ^{57} ^{60} ^{84} ^{90} ^{92} ^{99a} ^{115} ^{116} ^{117} ^{118} ^{119} ^{120} ^{121}

Third trimester: Use of barbiturates throughout the last trimester of pregnancy may cause physical dependence with resulting withdrawal symptoms in the neonate. In infants suffering from long-term exposure in utero, the acute withdrawal syndrome of seizures and hyperirritability has been reported to occur from birth to a delayed onset of up to 14 days. ^{48} ^{51} ^{52} ^{53} ^{55} ^{56} ^{57} ^{60} ^{84} ^{99a} ^{115} ^{116} ^{120}

Use of long-acting barbiturates, especially phenobarbital, as anticonvulsants during pregnancy is reportedly associated with a neonatal coagulation defect that may cause bleeding during the early neonatal period (usually within 24 hours of birth). This coagulation defect is characterized by decreased concentrations of vitamin K–dependent clotting factors and prolongation of the prothrombin time and/or the partial thromboplastin time. Vitamin K should be given to the mother during delivery and to the infant (intramuscularly or subcutaneously) immediately after birth. ^{49} ^{50} ^{51} ^{52} ^{53} ^{56} ^{57} ^{84}

Also, one study in humans has suggested that prenatal exposure to barbiturates may be associated with an increased incidence of brain tumors ^{49} ^{51} ^{52} ^{53} ^{55} ^{56} ^{57} ^{84} ^{90} ^{92} ^{117} ^{119}.

FDA Pregnancy Category D ^{31} ^{55} ^{56} ^{57} ^{60} ^{84} ^{90} ^{92} ^{99a} ^{115} ^{116} ^{117} ^{118} ^{119} ^{120} ^{121}.

Labor and delivery—

Barbiturates in hypnotic doses do not appear to inhibit uterine activity; however, full anesthetic doses of barbiturates decrease the force and frequency of uterine contractions ^{31} ^{48} ^{51} ^{52} ^{53} ^{55} ^{56} ^{60} ^{84} ^{90} ^{92} ^{99a} ^{117} ^{119} ^{120}.

Use of barbiturates during labor may cause respiratory depression in the neonate, especially the premature neonate, because of immature hepatic function ^{30} ^{47} ^{49} ^{51} ^{52} ^{53} ^{55} ^{56} ^{59} ^{60} ^{69} ^{70} ^{84} ^{90} ^{99a} ^{115} ^{116} ^{117} ^{119} ^{120} ^{121}.

If barbiturates are used during labor and delivery, it is recommended that resuscitation equipment be readily available ^{31} ^{51} ^{52} ^{53} ^{55} ^{56} ^{60} ^{84} ^{90} ^{92} ^{99a} ^{115} ^{116} ^{117} ^{119} ^{120}.

Breast-feeding

Barbiturates are distributed into breast milk; use by nursing mothers may cause CNS depression in the infant ^{48} ^{49} ^{51} ^{52} ^{53} ^{55} ^{56} ^{59} ^{84} ^{99a} ^{115} ^{116} ^{117} ^{119} ^{120}.

Pediatrics

Some children may react to barbiturates with paradoxical excitement.

Geriatrics

Geriatric patients may react to usual doses of barbiturates with excitement, confusion, or mental depression ^{28} ^{29} ^{46} ^{47} ^{48} ^{49} ^{53} ^{55} ^{56} ^{57} ^{58} ^{59} ^{69} ^{70} ^{84} ^{90} ^{92} ^{95} ^{99a} ^{114} ^{115} ^{117} ^{118} ^{119} ^{120} ^{121}.

The risk of barbiturate-induced hypothermia may be increased in elderly patients, especially with high doses or in acute overdose of barbiturates.

In addition, elderly patients are more likely to have age-related hepatic or renal function impairment, which may require a reduction of dosage in patients receiving a barbiturate ^{84} ^{90} ^{95} ^{99a} ^{115} ^{116} ^{120}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Acetaminophen    (therapeutic effects of acetaminophen may be decreased when the medication is used concurrently in patients receiving chronic barbiturate therapy because of increased metabolism resulting from induction of hepatic microsomal enzymes; also, risk of hepatotoxicity with single toxic doses or prolonged use of high doses of acetaminophen may be increased in alcoholics or in patients regularly using hepatic enzyme inducers such as barbiturates ^{45} ^{122} ^{179} ^{180} ^{182})

Addictive medications, other, especially CNS depressants with habituating potential    (prolonged concurrent use may increase the risk of habituation; caution is recommended ^{45})

» Adrenocorticoids, glucocorticoid and mineralocorticoid^{28}^{29}^{31}^{45}^{48}^{49}^{51}^{54}^{55}^{59}^{84}^{90}^{92}^{95}^{99a}^{114}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{122}^{123}^{124}^{179}^{180} or
Chloramphenicol^{172}^{174}^{175}^{179}^{180} or
» Corticotropin^{45}^{48}^{49}^{51}^{52}^{53}^{54}^{55}^{57}^{59}^{60}^{124} or
Cyclosporine^{125}^{180} or
Dacarbazine^{126} or
Digitalis glycosides^{120}^{127}^{179}^{180} or
Metronidazole^{172}^{173}^{176}^{177}^{178}^{179}^{180} or
Quinidine^{129}^{179}^{180}    (effects may be decreased when these medications are used concurrently with barbiturates, especially phenobarbital, because of enhanced metabolism resulting from induction of hepatic microsomal enzymes; dosage adjustment of these medications, with the exception of digoxin, may be necessary ^{28} ^{29} ^{45} ^{46} ^{69} ^{70} ^{95} ^{114} ^{115} ^{123} ^{124})

» Alcohol^{84}^{90}^{92}^{99a}^{115}^{116}^{117}^{118}^{119}^{120}^{121}^{179}^{180} or
» CNS depression–producing medications, other (See Appendix II )    (concurrent use may increase the CNS depressant effects of either these medications or barbiturates; caution is recommended and dosage of one or both agents should be reduced ^{28} ^{29} ^{31} ^{45} ^{46} ^{47} ^{48} ^{49} ^{51} ^{52} ^{53} ^{54} ^{55} ^{56} ^{57} ^{58} ^{59} ^{60} ^{69} ^{70} ^{90} ^{92} ^{95} ^{114} ^{115} ^{116} ^{121} ^{179} ^{180})

Amphetamines^{130}    (concurrent use may cause a delay in the intestinal absorption of phenobarbital ^{45} ^{130})

Anesthetics, halogenated hydrocarbon^{131}^{180}    (chronic use of barbiturates prior to enflurane, halothane, or methoxyflurane anesthesia may increase anesthetic metabolism leading to increased risk of hepatotoxicity ^{45} ^{131})

    (chronic use of barbiturates prior to methoxyflurane anesthesia may increase formation of nephrotoxic metabolites leading to increased risk of nephrotoxicity ^{45} ^{131})

» Anticoagulants, coumarin- or indandione-derivative^{132}^{179}^{180}    (effects may be decreased when these medications are used concurrently with barbiturates because of increased metabolism resulting from induction of hepatic microsomal enzymes; also, bleeding may result when the barbiturate is discontinued ^{62}; periodic prothrombin-time determinations may be required to determine if dosage adjustments of anticoagulants are necessary ^{28} ^{29} ^{45} ^{46} ^{47} ^{48} ^{49} ^{50} ^{51} ^{52} ^{53} ^{54} ^{55} ^{57} ^{60} ^{69} ^{70} ^{90} ^{92} ^{95} ^{99a} ^{114} ^{115} ^{116} ^{117} ^{118} ^{119} ^{120} ^{121} ^{132})

Anticonvulsants, hydantoin^{133}^{179}^{180}    (concurrent use with barbiturates appears to produce variable and unpredictable effects on the metabolism of hydantoin anticonvulsants; blood concentrations of hydantoin anticonvulsants should be closely monitored when these medications are used concurrently ^{31} ^{45} ^{48} ^{49} ^{51} ^{52} ^{53} ^{55} ^{60} ^{84} ^{90} ^{92} ^{115} ^{116} ^{117} ^{119} ^{120} ^{133})

Anticonvulsants, succinimide or^{61}^{134}
» Carbamazepine^{166}^{179}^{180}    (concurrent use with barbiturates may result in increased metabolism, leading to decreased serum concentrations and reduced elimination half-lives of carbamazepine or succinimide anticonvulsants because of induction of hepatic microsomal enzyme activity; monitoring of serum concentrations as a guide to dosage is recommended, especially when carbamazepine or a succinimide anticonvulsant is added to or withdrawn from an existing regimen ^{45} ^{61} ^{62} ^{63} ^{134} ^{166})

Antidepressants, tricyclic^{135}^{179}^{180}    (effects of tricyclic antidepressants may be decreased when these medications are used concurrently with barbiturates, especially phenobarbital, because of increased metabolism resulting from induction of hepatic microsomal enzymes ^{45} ^{135})

Calcium channel blocking agents^{137}^{179}^{180}    (caution is advised during titration of calcium channel blocker dosage for those patients taking medication known to promote hypotension, such as barbiturate preanesthetics, since the combination may result in excessive hypotension ^{45} ^{137})

Carbonic anhydrase inhibitors^{138}    (osteopenia induced by barbiturates, especially phenobarbital, may be enhanced when carbonic anhydrase inhibitors are used concurrently; it is recommended that patients receiving concurrent therapy be monitored for early signs of osteopenia and that the carbonic anhydrase inhibitor be discontinued and appropriate treatment initiated if necessary ^{45} ^{138})

» Contraceptives, estrogen-containing, oral^{31}^{139}    (concurrent use with barbiturates, especially phenobarbital, may result in reduced contraceptive reliability because of accelerated estrogen metabolism caused by induction of hepatic microsomal enzymes; use of a nonhormonal method of birth control or a progestin-only oral contraceptive may be necessary ^{45} ^{48} ^{49} ^{51} ^{52} ^{53} ^{55} ^{60} ^{84} ^{90} ^{92} ^{115} ^{116} ^{117} ^{119} ^{120} ^{139} ^{179} ^{180} ^{181})

Cyclophosphamide^{140}^{179}    (concurrent use with barbiturates, especially phenobarbital, may induce microsomal metabolism to increase formation of alkylating metabolites of cyclophosphamide, thereby reducing the half-life and increasing the leukopenic activity of cyclophosphamide ^{140})

Disopyramide^{141}    (concurrent use with barbiturates, especially phenobarbital, may reduce serum disopyramide to ineffective concentrations; therefore, monitoring of its serum concentrations is necessary during concurrent therapy ^{141})

» Divalproex sodium^{144} or
» Valproic acid^{144}^{179}^{180}    (concurrent use may decrease the metabolism of barbiturates, resulting in increased serum ^{62} concentrations, which may lead to increased CNS depression and neurological toxicity; barbiturate serum ^{62} concentrations should be monitored to determine if dosage adjustment is necessary when these medications are used concurrently; also, the half-life of valproic acid may be decreased and dosage adjustment may be necessary ^{48} ^{49} ^{51} ^{52} ^{53} ^{60} ^{84} ^{90} ^{92} ^{115} ^{116} ^{117} ^{119} ^{120})

    (in addition, phenobarbital may enhance valproic acid hepatotoxicity, presumably through the formation of hepatotoxic valproate metabolites ^{62} ^{64})

Doxycycline^{145}^{179}^{180}    (half-life of doxycycline may be shortened when this medication is used concurrently with barbiturates, especially phenobarbital, probably because of increased metabolism resulting from induction of hepatic microsomal enzymes; this effect may continue for up to 2 weeks after barbiturate therapy is discontinued; adjustment of doxycycline dosage during and after therapy or substitution of another tetracycline may be necessary ^{31} ^{48} ^{49} ^{51} ^{52} ^{53} ^{55} ^{60} ^{84} ^{90} ^{92} ^{115} ^{116} ^{117} ^{119} ^{120} ^{145})

Fenoprofen^{146}^{180}    (concurrent use with phenobarbital may decrease the elimination half-life of fenoprofen, possibly because of increased metabolism resulting from induction of hepatic microsomal enzyme activity; fenoprofen dosage adjustment may be required ^{146})

Griseofulvin^{148}^{179}^{180}    (absorption may be decreased when this medication is used concurrently with barbiturates, especially phenobarbital, resulting in decreased serum concentrations; although the effect of decreased serum ^{62} concentrations on therapeutic response has not been established, concurrent use preferably should be avoided ^{31} ^{48} ^{49} ^{51} ^{52} ^{53} ^{55} ^{84} ^{90} ^{92} ^{115} ^{116} ^{117} ^{119} ^{120} ^{148})

Guanadrel^{142} or
Guanethidine^{143}    (concurrent use with barbiturates may aggravate orthostatic hypotension ^{142} ^{143})

Haloperidol^{149}^{180}    (concurrent use with barbiturate anticonvulsants may cause a change in the pattern and/or frequency of epileptiform seizures; dosage adjustments of anticonvulsants may be necessary; serum concentrations of haloperidol may be significantly reduced ^{149})

Hypothermia-producing medications, other (See Appendix II )    (concurrent use with barbiturates in high doses or acute overdose may increase the risk of hypothermia)

Ketamine^{150}    (concurrent use of ketamine, especially in high doses or when rapidly administered, with barbiturate preanesthetics may increase the risk of hypotension and/or respiratory depression ^{150})

Leucovorin^{151}    (large doses may counteract the anticonvulsant effects of barbiturate anticonvulsants ^{151})

Levothyroxine^{152}    (concurrent use of barbiturates may increase hepatic degradation of levothyroxine, which may result in increased requirements; dosage adjustment may be necessary ^{45} ^{152})

Loxapine^{153} or
Phenothiazines^{154}^{179}^{180} or
Thioxanthenes^{155}    (may lower the seizure threshold; dosage adjustment of barbiturate anticonvulsants may be necessary ^{153} ^{154} ^{155})

    (concurrent use of chlorpromazine with phenobarbital has been shown to increase the metabolism ^{62} of chlorpromazine; therefore, phenobarbital may decrease serum concentrations of phenothiazines when used concurrently ^{24} ^{154} ^{179})

Maprotiline^{156}    (in addition to possibly enhancing CNS depressant effects, concurrent use of maprotiline may lower the convulsive threshold, at high doses, and decrease the effects of barbiturate anticonvulsants ^{156})

Methylphenidate^{157}    (concurrent use may increase serum concentrations of barbiturate anticonvulsants, especially phenobarbital, because of metabolism inhibition, possibly resulting in toxicity; dosage adjustment of the barbiturate anticonvulsant may be necessary ^{157})

Mexiletine^{158}    (concurrent use with barbiturates may accelerate metabolism and result in decreased plasma concentrations of mexiletine; plasma concentrations of mexiletine should be monitored during concurrent use to ensure efficacy is maintained ^{27} ^{158})

Monoamine oxidase (MAO) inhibitors, including furazolidone, pargyline, and procarbazine^{159}^{179}^{180}    (concurrent use may prolong the CNS depressant effects of barbiturates, probably because metabolism of the barbiturate is inhibited ^{48} ^{49} ^{51} ^{52} ^{53} ^{55} ^{57} ^{84} ^{90} ^{92} ^{99a} ^{115} ^{116} ^{159})

    (concurrent use with barbiturate anticonvulsants may cause a change in the pattern of epileptiform seizures; dosage adjustment of the barbiturate anticonvulsant may be necessary ^{31} ^{159})

Phenylbutazone^{147}^{179}^{180}    (concurrent use may decrease the efficacy of barbiturates by inducing hepatic microsomal enzymes and increasing their metabolism; also, hepatic enzyme inducers such as barbiturates may increase phenylbutazone metabolism and decrease its half-life ^{45} ^{147})

Posterior pituitary^{160}    (concurrent use with barbiturates may increase the risk of cardiac arrhythmias and coronary insufficiency ^{160})

Primidone^{161}^{179}    (although concurrent use with barbiturate anticonvulsants is rarely indicated, since primidone is metabolized to phenobarbital ^{62}, it may cause a change in the pattern of epileptiform seizures because of altered medication metabolism and also increase the sedative effect of either primidone or the barbiturate anticonvulsant ^{62}; decreases in primidone dosage may be necessary ^{161})

Rifampin^{170}^{179}^{180}    (concurrent use with rifampin may enhance the metabolism of hexobarbital by induction of hepatic microsomal enzymes, resulting in lower serum concentrations; there are conflicting data on rifampin's effect on phenobarbital; dosage adjustment may be required)

Vitamin D^{162}    (effects may be reduced by barbiturates, especially phenobarbital, because of accelerated metabolism by hepatic microsomal enzyme induction; vitamin D supplementation may be required in patients on long-term barbiturate anticonvulsant therapy to prevent osteomalacia, although rickets is rare ^{49} ^{84} ^{162})

Xanthines, such as^{163}^{179}^{180} :
Aminophylline
Caffeine
Oxtriphylline
Theophylline    (concurrent use with barbiturates, especially phenobarbital, may increase metabolism of the xanthines [except dyphylline] by induction of hepatic microsomal enzymes, resulting in increased theophylline clearance; also, concurrent use may antagonize hypnotic effects of barbiturates ^{45} ^{163})

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Cyanocobalamin Co 57    (absorption of radioactive cyanocobalamin may be impaired by concurrent use of barbiturate anticonvulsants, especially phenobarbital)

Metyrapone test    (increased metabolism of metyrapone by an hepatic enzyme inducer such as a barbiturate may decrease the response to metyrapone ^{169})

Phentolamine test    (barbiturates may cause a false-positive phentolamine test; it is recommended that all medications be withdrawn at least 24 hours, preferably 48 to 72 hours, prior to a phentolamine test)

With physiology/laboratory test values
Bilirubin, serum    (concentrations may be decreased in neonates, in patients with congenital nonhemolytic unconjugated hyperbilirubinemia, and in epileptics; this effect is presumably due to induction of glucuronyl transferase, the enzyme responsible for the conjugation of bilirubin)

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problem exists:
» Porphyria, acute intermittent or variegata, or history of    (barbiturates may aggravate symptoms by inducing enzymes responsible for porphyrin synthesis ^{28} ^{29} ^{46} ^{47} ^{48} ^{49} ^{50} ^{51} ^{52} ^{53} ^{54} ^{55} ^{56} ^{57} ^{58} ^{59} ^{60} ^{69} ^{70} ^{84} ^{90} ^{91} ^{92} ^{95} ^{99a} ^{114} ^{115} ^{116} ^{117} ^{118} ^{119} ^{120} ^{121})

Risk-benefit should be considered when the following medical problems exist
Anemia, severe    (may be complicated by barbiturate-induced respiratory depression, especially with phenobarbital)

Asthma, history of    (hypersensitivity reactions such as bronchospasm more likely to occur in these patients ^{28} ^{29} ^{47} ^{48})

Diabetes mellitus, especially with phenobarbital
» Drug abuse or dependence, history of    (predisposition of patient to habituation and dependence ^{28} ^{29} ^{46} ^{47} ^{51} ^{54} ^{56} ^{57} ^{58} ^{69} ^{70} ^{95} ^{99a} ^{114} ^{115} ^{116} ^{118} ^{120} ^{121})

» Hepatic coma, premonitory signs of, or
Hepatic function impairment    (barbiturates metabolized in liver; medication should be administered with caution and, initially, in reduced dosage ^{28} ^{29} ^{46} ^{47} ^{48} ^{49} ^{50} ^{51} ^{52} ^{53} ^{54} ^{55} ^{56} ^{57} ^{58} ^{59} ^{60} ^{69} ^{70} ^{90} ^{92} ^{95} ^{99a} ^{114} ^{115} ^{116} ^{117} ^{118} ^{119} ^{120} ^{121})

Hyperkinesis    (condition may be exacerbated)

Hyperthyroidism    (symptoms may be exacerbated because barbiturates displace thyroxine from plasma proteins)

Hypoadrenalism, borderline    (systemic effects of exogenous hydrocortisone and endogenous cortisol may be diminished by barbiturates ^{28} ^{29} ^{46} ^{47} ^{59} ^{69} ^{70} ^{95} ^{99a} ^{114} ^{118} ^{121})

Mental depression and/or
Suicidal tendencies    (condition may be exacerbated, especially in elderly patients ^{48} ^{49} ^{54} ^{57} ^{59} ^{69} ^{70} ^{90} ^{95} ^{115} ^{116} ^{118} ^{120} ^{121})

» Pain, acute or chronic    (paradoxical excitement may be induced or important symptoms may be masked ^{28} ^{29} ^{46} ^{47} ^{48} ^{49} ^{50} ^{51} ^{52} ^{53} ^{54} ^{55} ^{56} ^{57} ^{58} ^{59} ^{69} ^{70} ^{84} ^{90} ^{92} ^{95} ^{99a} ^{114} ^{115} ^{116} ^{117} ^{118} ^{121})

Renal function impairment, especially with intermediate- and long-acting barbiturates    (barbiturates excreted primarily by kidneys; dosage reduction may be necessary ^{84} ^{116} ^{120})

» Respiratory disease involving dyspnea or obstruction, particularly status asthmaticus    (serious ventilatory depression may occur ^{28} ^{29} ^{46} ^{47} ^{48} ^{49} ^{52} ^{53} ^{57} ^{58} ^{69} ^{70} ^{84} ^{95} ^{99a} ^{114} ^{118} ^{121})

» Sensitivity to barbiturate prescribed    (in patients sensitive to barbiturates, severe hepatic damage can occur from ordinary doses and is usually associated with dermatitis and involvement of parenchymatous organs ^{69} ^{70} ^{90} ^{92} ^{95} ^{99a} ^{114} ^{115} ^{116} ^{117} ^{118} ^{119} ^{120} ^{121})

Caution should be used also in debilitated patients because they may react to usual doses with marked excitement, mental depression, and confusion^{69}^{70}^{84}^{90}^{92}^{95}^{99a}^{115}^{116}^{117}^{118}^{119}^{120}^{121}
For parenteral dosage forms only:
Cardiac disease    (adverse circulatory reactions may occur with intravenous administration, especially with too-rapid administration)

Hypertension    (hypotension may occur with intravenous administration, especially in these patients; slow administration usually prevents this occurrence)

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Folate concentrations, serum    (determinations recommended periodically because of increased folate requirements of patients on long-term anticonvulsant therapy with phenobarbital and possibly mephobarbital ^{171})

Hematopoietic function and
Hepatic function and
Renal function    (determinations recommended at periodic intervals during prolonged barbiturate therapy ^{31} ^{48} ^{49} ^{51} ^{52} ^{53} ^{55} ^{57} ^{60} ^{84} ^{90} ^{92} ^{99a} ^{115} ^{116} ^{117} ^{119} ^{120})

Barbital concentrations, serum    (determinations recommended when clinically indicated during metharbital therapy)

Phenobarbital concentrations, serum    (determinations recommended as clinically indicated when phenobarbital or mephobarbital is used as an anticonvulsant)

Side/Adverse Effects

Note: Exfoliative dermatitis and Stevens-Johnson syndrome, possibly fatal, may occur rarely as hypersensitivity reactions to barbiturates. If dermatologic reactions occur, the barbiturate should be discontinued.
Severe respiratory depression, apnea, laryngospasm, bronchospasm, or hypertension may occur with intravenous administration of barbiturates, especially if administered too rapidly ^{30} ^{47} ^{55} ^{58} ^{114} ^{117} ^{119}.
Prolonged barbiturate therapy may result in osteopenia or rickets ^{49}.
Barbiturate dependence may occur, especially following prolonged use of high doses. The characteristics of dependence include: a strong desire or need to continue taking the barbiturate; a tendency to increase the dose; a psychological dependence on the effects of the medication; and a physical dependence on the effects of the medication requiring its presence for maintenance of homeostasis and resulting in an abstinence syndrome when the barbiturate is discontinued. Symptoms of withdrawal are related to the pharmacokinetics of the specific barbiturate and can be severe and may even cause death. ^{48} ^{55} ^{57} ^{84} ^{90} ^{92} ^{116} ^{117} ^{119} ^{120}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent

Sensitivity to barbiturates (confusion)—especially in geriatric or debilitated patients^{84}^{90}^{92}^{115}^{116}

mental depression —especially in geriatric or debilitated patients

paradoxical reaction (unusual excitement)—especially in children or geriatric or debilitated patients^{28}^{29}^{46}^{47}^{84}^{90}^{92}^{95}^{115}^{116}

Incidence rare

Agranulocytosis (sore throat and/or fever)

allergic reaction (skin rash or hives; swelling of eyelids, face, or lips; wheezing or tightness in chest)—especially in patients who have asthma, urticaria, angioedema, and similar conditions

exfoliative dermatitis (fever; red, thickened, or scaly skin)

hallucinations

hypotension or megaloblastic anemia (unusual tiredness or weakness)—with chronic barbiturate use

Stevens-Johnson syndrome (bleeding sores on lips; chest pain; muscle or joint pain; painful sores, ulcers, or white spots in mouth; skin rash or hives; sore throat or fever)^{95}

thrombocytopenia (unusual bleeding or bruising)

thrombophlebitis (soreness, redness, swelling, or pain at injection site)—for parenteral dosage forms only

With prolonged or chronic use

Hepatic damage (yellow eyes or skin)

osteopenia or rickets (bone pain, tenderness, or aching; loss of appetite; muscle weakness; unusual weight loss)

^{46}^{47}^{48}^{49}^{50}^{51}^{52}^{53}^{54}^{55}^{56}^{57}^{58}^{59}^{60}

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent

Clumsiness or unsteadiness

dizziness or lightheadedness

drowsiness

``hangover'' effect

Incidence less frequent

Anxiety or nervousness

constipation

feeling faint

headache

irritability

nausea or vomiting

nightmares or trouble in sleeping

^{46}^{47}^{48}^{49}^{50}^{51}^{52}^{53}^{54}^{55}^{56}^{57}^{58}^{59}^{60}^{69}^{70}^{84}^{90}^{92}^{95}^{115}^{116}^{118}

Those indicating possible barbiturate withdrawal and need for medical attention if they occur after medication is discontinued
Minor symptoms
—may occur within 8 to 12 hours and usually occur in the following sequence:
Anxiety or restlessness

muscle twitching

trembling of hands

weakness

dizziness

vision problems

nausea

vomiting

trouble in sleeping, increased dreaming, or nightmares

orthostatic hypotension (feeling faint; lightheadedness)

Major symptoms
—may occur within 16 hours and last up to 5 days
Convulsions

hallucinations
^{69}^{70}^{84}^{90}^{92}^{95}^{115}^{121}

Note: Intensity of withdrawal symptoms gradually declines over a period of approximately 15 days ^{90} ^{92} ^{115}.

^{46}^{47}^{48}^{49}^{50}^{51}^{52}^{53}^{54}^{55}^{56}^{57}^{58}^{59}^{60}^{84}^{90}^{92}^{99a}^{115}^{116}^{121}
^{69}^{70}^{84}^{90}^{92}^{95}^{99a}^{114}^{115}^{116}^{117}^{118}^{119}^{120}^{121}

Overdose
For specific information on the agents used in the management of barbiturate overdose, see:
   • Charcoal, Activated (Oral-Local) monograph; and/or
   • Ipecac (Oral-Local) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute

Confusion, severe

decrease in or loss of reflexes ^{40}

drowsiness, severe

fever ^{40}

hypothermia ( low body temperature)^{40}

shortness of breath or slow or troubled breathing

slow heartbeat

slurred speech

staggering

unusual movements of the eyes

weakness, severe
^{46}^{47}^{48}^{49}^{50}^{51}^{52}^{53}^{54}^{55}^{56}^{57}^{58}^{59}^{60}^{69}^{70}^{95}^{99a}^{114}^{115}^{116}^{117}^{118}^{119}^{120}^{121}

Note: In acute barbiturate overdosage, CNS and respiratory depression may progress to Cheyne-Stokes respiration, areflexia, slight constriction of the pupils (in severe toxicity, pupils may be dilated), oliguria, tachycardia, lowered body temperature, and coma. Typical shock syndrome (apnea, circulatory collapse, respiratory arrest, and death) may occur. ^{55} ^{57} ^{115} ^{116} ^{117} ^{119}
In extreme barbiturate overdosage, all electrical activity in the brain may cease. In this case an electroencephalogram (EEG) may be ``flat,"" but this does not necessarily indicate clinical death since, unless hypoxic damage occurs, this effect is fully reversible. ^{48} ^{55} ^{57} ^{84} ^{90} ^{92} ^{95} ^{115} ^{116} ^{117} ^{119}
Complications in barbiturate overdosage such as pneumonia, pulmonary edema, cardiac arrhythmias, congestive heart failure, and renal failure may occur ^{55} ^{57} ^{84} ^{90} ^{92} ^{95} ^{115} ^{117} ^{119}.
In acute overdosage, the blood barbiturate concentration for some of the barbiturates relative to the degree of CNS depression in nontolerant persons is as follows:

Table 2. General Dosing Information

Drug	Onset/Duration of Action	Barbiturate Blood Concentrations (mcg/mL) Categories of Degree of CNS Depression ^*
Drug	Onset/Duration of Action	(1)	(2)	(3)	(4)	(5)
Pentobarbital	Fast/short	£2	0.5–3	10–15	12–25	15–40
Secobarbital	Fast/short	£2	0.5–5	10–15	15–25	15–40
Amobarbital	Intermediate/	£3	2–10	30–40	30–60	40–80
	intermediate		</

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