Anticonvulsant – Sedative-Hypnotic
Pharmacology: Barbiturates are nonselective central nervous system (CNS) depressants, capable of producing all degrees of depression from mild sedation and hypnosis to general anaesthesia, deep coma and death. The extent of CNS depression varies with the route of administration, dose and pharmacokinetic characteristics of the particular barbiturate. Patient specific factors such as age, physical or emotional state and the concomitant use of other drugs will also affect response.
The mechanism of action of barbiturates is not completely known. They may act by enhancing and/or mimicking the synaptic action of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter. The sedative-hypnotic action of barbiturates may be due to an inhibition of conduction in the reticular formation resulting in a decrease in the number of impulses reaching the cerebral cortex.
Anticonvulsant activity may result from a reduction in CNS synaptic transmission and an increase in the threshold for electrical stimulation of the motor cortex. Phenobarbital is the only barbiturate with anticonvulsant activity at subhypnotic doses.
The therapeutic index of barbiturates is narrow. Amounts needed to relieve anxiety and those causing general CNS depression are not greatly different. Therefore, the use of barbiturates as anxiolytics is almost always accompanied by some degree of impairment of cognitive function. Supratherapeutic doses lead to marked impairment of mental and motor faculties i.e. distortion of judgment, clouding of perception, slurring of speech and ataxia. In some patients however, (especially children and the elderly), drowsiness may be paradoxically preceded by transient euphoria, elation, excitement and confusion.
Pharmacokinetics: After oral administration, absorption is usually rapid and relatively complete. The sodium salts undergo rapid dissolution and are absorbed more quickly than their corresponding free acids. The rate of absorption is increased when the barbiturate is formulated as a liquid, when the stomach is empty and when alcohol is ingested concurrently. The onset of action following rectal administration is similar to that following oral administration. After i.v. administration, the onset of action is immediate for amobarbital and pentobarbital and within 5 minutes for phenobarbital. The onset of action following i.m. administration is slightly faster than when the drugs are administered orally or rectally.
Once absorbed the barbiturates are rapidly distributed to all tissues and fluids. High concentrations appear in the brain, liver and kidneys. Secobarbital has the highest degree of lipid solubility and thus the fastest distribution, phenobarbital is the least lipid soluble and has the slowest distribution. Barbiturates readily cross the placenta and are excreted into breast milk. If administered i.v., fetal blood concentrations are approximately equal to maternal serum concentration; if administered orally fetal concentrations are less than maternal levels.
Barbiturates are slowly metabolized and/or conjugated in the liver and then excreted renally. Amobarbital, butabarbital, pentobarbital and secobarbital are almost completely metabolized. Due to its lower lipid solubility, phenobarbital is not metabolized as extensively and almost 25% is excreted unchanged in the urine. Metabolic elimination is influenced by age (being slower in the elderly and infants), chronic liver disease and other drugs.
Indications: Barbiturates are indicated as hypnotics in the treatment of insomnia and as sedatives in other conditions including use as preanesthetics in surgery or to relieve the symptoms of anxiety or tension resulting from emotional, physical or situational stress. They are indicated in certain cases of increased intracranial pressure and in the treatment of prolonged status epilepticus which is refractory to standard treatment.
Phenobarbital is indicated for the control of generalized tonic-clonic and complex partial seizures.
Contraindications: Not to be administered to patients who are known to be hypersensitive to barbituric acid derivatives. Patients with porphyria, severe respiratory depression or pulmonary insufficiency, renal impairment, hepatic impairment, sleep apnea, suicidal potential, alcoholism or drug dependence. Not to be used in the presence of uncontrolled pain as paradoxical excitement may be produced. Barbiturates should not be administered to elderly patients who exhibit nocturnal confusion or restlessness from sedative hypnotic drugs or to persons who are known to be, or are likely to become, dependent on sedative hypnotic medications.
Precautions: Prolonged use of barbiturates, even in therapeutic dosages, may result in psychologic and physiologic dependence. Patients may escalate dosage without medical advice. Withdrawal symptoms may occur following abrupt termination of hypnotic doses causing nightmares or insomnia, sweating, irritability, tremor, weight loss, anorexia or after chronic use of large doses, resulting in delirium, seizures, or death. Withdrawal should be cautious and gradual.
Rarely, rickets and osteomalacia have been reported following prolonged usage of barbiturates due to increased metabolism of vitamin D.
Barbiturates should be used with caution in patients with impaired liver function or in patients with a history of drug dependence or abuse. Caution is essential when the drug is administered in the presence of any respiratory difficulty. Special care should be taken when barbiturates are administered to patients in whom the hypnotic effect may be prolonged or intensified, as in those suffering from shock, hepatic dysfunction, uremia, or after recent administration of other respiratory depressants.
Since barbiturates are potent CNS depressants, i.v. administration should not be attempted without adequate provisions for supporting respiration and circulation. Rapid injection can cause cardiovascular collapse. Slow administration will usually prevent this occurrence but may cause apnea, laryngospasm, coughing, or other respiratory difficulties.
I.M. injection should not exceed a volume of 5 mL at any one site because of possible tissue damage.
Barbiturate solutions are highly alkaline. Extreme care should be exercised to avoid extravasation or intra-arterial injection. Extravascular injection may cause local tissue damage with subsequent necrosis. The consequences of intra-arterial injection may vary from transient pain along the course of the artery to gangrene of the limb. Signs of accidental injection by this route include, in addition to pain, delayed onset of hypnosis, pallor and cyanosis of the extremity and patchy discoloration of the skin. Any complaint of pain in the limb warrants stopping the injection.
Hypotension may result from i.v. administration of the drug, particularly in patients with hypertension. Slow administration will usually prevent this occurrence.
Solutions which appear cloudy or in which a precipitate has formed should not be used.
Occupational Hazards: Barbiturates may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a vehicle or operating machinery. The concomitant use of alcohol or other CNS depressants may have an additive effect. Patients should be warned accordingly. The incidence of fractures due to falls may be increased, particularly in the elderly. Following use of barbiturates in office procedures, warn patients against operating motor vehicles for the remainder of the day.
Drug Interactions : Most drug interactions have been documented with phenobarbital, however they are likely applicable to other barbiturates as well. The barbiturates are inducers of hepatic microsomal enzymes, and are capable of increasing the clearance of many hepatically metabolized drugs. This can result in two concerns: i) decrease in or loss of effectiveness of other drugs during barbiturate use; ii) increase in effect and even frank toxicity on discontinuation of the barbiturate.
When adding or deleting any barbiturate to or from the patient’s therapeutic regimen, pharmacotherapy must be monitored closely as dosage adjustment may be necessary.
Anticonvulsants: Phenytoin: When phenobarbital is used with phenytoin, concentrations of either or both drugs may be increased, decreased or unchanged. While phenobarbital may induce the metabolism of phenytoin, it may also decrease it because both drugs compete for the same metabolic pathway. Plasma concentrations of both drugs should be monitored when any change in the therapeutic regimen occurs. Valproic Acid: Concomitant administration of valproic acid and phenobarbital usually results in increased levels of phenobarbital and resultant oversedation. There have been case reports of progression of CNS depression to coma. Plasma concentrations of both drugs should be monitored when any change in the therapeutic regimen occurs. Carbamazepine: When phenobarbital and carbamazepine are used together, the metabolism of carbamazepine is usually accelerated and plasma concentrations may be decreased. The clinical significance of this interaction is not known. Plasma concentrations of both drugs should be monitored when any change in the therapeutic regimen occurs.
Antidepressants, MAO Inhibitors: MAO inhibitors may inhibit barbiturate metabolism, resulting in increased CNS depressant effects. A reduction in barbiturate dosage may be required.
Antidepressants, Tricyclic: Barbiturates may increase metabolism of tricyclic antidepressants resulting in lack of effect. Plasma tricyclic concentrations should be monitored if possible, especially if the patient is not responding to standard dosages of antidepressant. The use of both drugs concomitantly may result in additive respiratory depressant effects.
CNS Depressants: Alcohol, benzodiazepines, other sedatives and hypnotics, antihistamines etc. when used concurrently with a barbiturate may result in excessive CNS depressant effects.
Corticosteroids: Barbiturates may increase the metabolism of corticosteroids. There have been several reports of exacerbation of asthma and other conditions when barbiturates were added to regimens containing corticosteroids.
Oral Anticoagulants: Metabolism of coumarin anticoagulants may be accelerated, resulting in decreased anticoagulant response. Correspondingly, if the barbiturate is discontinued from a stabilized dosage, the hypoprothrombinemic response may be greatly increased potentially resulting in hemorrhagic complications. Prothrombin times should be monitored closely when barbiturates are added to or deleted from a regimen that includes oral anticoagulants.
Oral Contraceptives: Barbiturates may accelerate the metabolism of both the estrogenic and progestagenic components of the contraceptive, resulting in decreased effectiveness which may or may not be signalled by breakthrough bleeding. There have been reports of pregnancy resulting from this combination. If the barbiturate is necessary it would be advisable to use some other form of contraception.
Miscellaneous: Barbiturates have been reported to increase the metabolism and correspondingly reduce the effectiveness of the following: griseofulvin, digitoxin and doxycycline. When ketamine is used for anesthesia following preoperative administration of a barbiturate, profound respiratory depression may result.
Pregnancy: Barbiturates readily cross the placental barrier.
Amobarbital: Amobarbital use during the first trimester has been associated with cardiovascular malformations, genitourinary malformations, inguinal hernia and club foot. This drug should be avoided in women of childbearing potential and particularly during early pregnancy.
Butabarbital, Pentobarbital and Secobarbital: The safe use of these drugs during pregnancy has not been established.
Phenobarbital: The great majority of mothers on antiepileptic medication deliver normal infants. It is important to note that antiepileptic drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.
In addition to reports of increased incidence of congenital malformations such as cleft lip/palate and heart malformations in children of women receiving phenobarbital and other antiepileptic drugs, there have been reports of fetal hydantoin syndrome. This consists of prenatal growth deficiency, microcephaly and mental deficiency in children born to mothers who have received barbiturates, phenytoin, alcohol or trimethadione. However, these features are all inter-related and are frequently associated with intrauterine growth retardation from other causes.
The prescribing physician should weigh these considerations in treating or counseling epileptic women of childbearing potential.
The serum level of anticonvulsants may decline during pregnancy requiring adjustments in dosage. Postpartum restoration of the original dosage will probably be indicated.
Neonatal coagulation defects have been reported within the first 24 hours in babies born to epileptic mothers receiving phenobarbital and/or phenytoin. Vitamin K has been shown to prevent or correct this defect and has been recommended to be given to the mother before delivery and to the neonate after birth.
Barbiturate withdrawal has occurred in newborns who were exposed to the drug in utero and may be characterized by hypotonia, irritability and vomiting.
Lactation: Breast milk concentrations are 35 to 50% maternal serum concentrations. Breast-fed infants should be observed for excessive drowsiness, feeding problems, rash or other adverse effects. If any of these occur, breast feeding should be discontinued. When breast-feeding is discontinued there exists a potential for withdrawal symptoms in infants. Barbiturates are eliminated slowly in neonates and the drug may accumulate. If possible serum concentrations in the infant may be monitored.
Adverse Effects: CNS: Drowsiness is frequent especially at initiation of therapy and may persist throughout the next day after hypnotic doses. Mild impairment of concentration, judgment, memory, and fine motor skills may occur. Disturbances of sleep, dizziness, vertigo, headache and depression may occur. Patients with uncontrolled pain may experience paradoxical euphoria, elation, excitement and confusion. In children, hyperactivity is not uncommon; behavioral disturbances and cognitive impairment may occur. Geriatric patients may experience excitation, confusion or depression.
Cardiovascular: Hypotension may be observed with i.v. administration and is generally related to the rate of administration (see Precautions).
Respiratory: respiratory depression (see Precautions).
Hypersensitivity: Facial edema, skin rash (1 to 2%) may be purpuric, vesicular or erythematous. Exfoliative dermatitis and erythema multiforme are rare. Hypersensitivity reactions have a greater tendency to occur in patients with a history of asthma, urticaria or angioedema.
Hepatic: Severe allergic reactions may result in jaundice due to degenerative changes in the liver. Toxic hepatitis is rare.
Hematologic: megaloblastic anemia (responds to folic acid therapy). Agranulocytosis and thrombocytopenia are rare.
Metabolic: Barbiturates may increase vitamin D requirements, possibly by increasing vitamin D metabolism via enzyme induction. Rarely, rickets and osteomalacia have been reported following prolonged use of barbiturates.
Gastrointestinal: nausea, vomiting, diarrhea and constipation.
Miscellaneous: Exacerbation of porphyria, pain at the injection site, withdrawal (see Precautions).
Overdose: Symptoms: Acute overdosage with barbiturates primarily involves the CNS and the cardiovascular system. Mild overdose resembles alcohol intoxication. Drowsiness, confusion, stupor, respiratory depression, ataxia, sluggish or absent reflexes, early hypothermia, late fever, cardiovascular depression with hypotension, renal failure, cardiac arrhythmias, pulmonary edema, aspiration pneumonia, bullae over pressure points and decreased gastrointestinal motility are all possible symptoms. Severe overdose may progress to shock, coma and death.
Doses that can result in toxicity vary widely between patients. A severe and potentially lethal dose (after acute intoxication) is about 10 times the usual hypnotic dose of amobarbital, pentobarbital and secobarbital (1 to 3 g). The lethal dose of phenobarbital is believed to be 5 g.
Chronic ingestion of barbiturates results in the development of tolerance and large doses can be ingested without overt toxicity. Serious toxicity can result at lower barbiturate levels if combined with alcohol or other CNS depressant drugs.
Treatment: Support hemodynamic and respiratory functions and monitor for pulmonary complications. If the drug has been ingested recently (within 4 hours), empty stomach. Take precautions to avoid aspiration. Administer activated charcoal and a cathartic. Charcoal may be repeated for ingestions involving phenobarbital. Administer i.v. fluids to correct hypovolemia, maintain blood pressure and body temperature. If renal and cardiac function are satisfactory and the patient is hydrated, forced diuresis and i.v. sodium bicarbonate may be used to enhance urinary excretion of phenobarbital. This will only result in a maximum increased elimination of 25% as this is the amount excreted unchanged in the urine. Urinary alkalinization is not indicated for amobarbital, pentobarbital and secobarbital. In the event of renal failure, hemodialysis should be instituted.
CNS stimulants are not indicated. They are not antidotes; mortality rates were much higher when CNS stimulants were used formerly in barbiturate overdose.
Dosage: The general use of barbiturates as sedatives or hypnotics has for the most part, been supplanted by other less toxic drugs (i.e., benzodiazepines). Decreased dosage is recommended in geriatrics or older individuals and in patients with decreased renal or hepatic function. For more information on pediatric dosages, consult specialized pediatric references. The barbiturates can be given orally or by deep i.m. or slow i.v. injection.
Amobarbital: Oral: Hypnotic: 65 to 200 mg at bedtime.
Sedative: 50 to 300 mg daily in divided doses. Children, 2 mg/kg 3 times a day.
Pre-operative: 200 mg 1 to 2 hours prior to surgery. Children, 2 to 6 mg/kg up to a maximum of 100 mg 1 to 2 hours prior to surgery.
Parenteral: Hypnotic: 65 to 200 mg daily i.v. or i.m. Children, 2 to 3 mg/kg i.m.
Sedative: 30 to 50 mg i.v. or i.m. 2 or 3 times a day.
Anticonvulsant: 65 to 500 mg i.v.
The rate of i.v. administration in adults should not exceed 100 mg/minute. The maximum i.m. dose is 500 mg and the maximum i.v. dose is 1 g.
Butabarbital: Oral: Hypnotic: 50 to 100 mg at bedtime.
Sedative: 15 to 30 mg 3 or 4 times a day. Children, 2 mg/kg 3 times a day.
Pentobarbital: Oral: Hypnotic: 100 mg at bedtime.
Sedative: 20 mg 3 or 4 times a day. Children, 2 to 6 mg/kg/day.
Pre-operative: 100 mg 30 minutes prior to surgery. Children, 2 to 6 mg/kg to a maximum of 100 mg per dose.
Parenteral: Hypnotic: 150 to 200 mg i.m. or 100 mg i.v. with additional doses if necessary at 1 minute intervals to a maximum daily dose of 500 mg. Children, 2 to 6 mg/kg i.m. to a maximum of 100 mg per dose or 50 mg i.v. with additional doses if necessary at 1 minute intervals.
Pre-operative: 150 to 200 mg i.m. prior to surgery. Children, 2 to 6 mg/kg i.m. to a maximum of 100 mg per dose.
Anticonvulsant: 100 mg i.v. with additional doses if necessary at 1 minute intervals to a maximum daily dose of 500 mg. Children, 50 mg i.v. with additional doses if necessary at 1 minute intervals.
Rectal: Hypnotic: 120 to 200 mg. Children, under 4 years, 3 to 6 mg/kg; over 4 years, 1.5 to 3 mg/kg/dose.
Phenobarbital: Oral: Hypnotic: 100 to 320 mg at bedtime.
Sedative: 30 to 120 mg daily in 2 or 3 divided doses. Children, 2 mg/kg 3 times a day.
Anticonvulsant: 60 to 250 mg daily in a single dose or in divided doses. Maximum daily dose should not exceed 600 mg. Children, 1 to 6 mg/kg/day in a single dose or in divided doses.
Parenteral: Hypnotic: 100 to 325 mg i.v. or i.m.
Sedative: 30 to 120 mg i.v. or i.m. daily in 2 or 3 divided doses.
Pre-operative: 130 to 200 mg 1 to 2 hours prior to surgery. Children, 1 to 3 mg/kg 1 to 2 hours prior to surgery.
Anticonvulsant: 100 to 320 mg i.v. with additional doses if necessary to a maximum daily dose of 600 mg. Children, 1 to 6 mg/kg/day.
Status epilepticus: 10 to 20 mg/kg by slow i.v. injection. Repeat if necessary at 20 minute intervals, until the seizure is controlled or a total dose of 1 to 2 g is given. Children, 10 to 20 mg/kg by slow i.v. injection. Repeat if necessary at a dose of 5 to 10 mg/kg every 20 minutes, until the seizure is controlled or a total dose of 40 mg/kg is given.
The rate of i.v. administration should not exceed 60 mg/minute.
Secobarbital: Oral: Hypnotic: 100 mg at bedtime.
Sedative: 30 to 50 mg 3 or 4 times a day. Children, 2 mg/kg 3 times a day.
Pre-operative: 200 to 300 mg 1 to 2 hours prior to surgery. Children, 2 to 6 mg/kg to a maximum of 100 mg, 1 to 2 hours prior to surgery.
Parenteral: Hypnotic: 100 to 200 mg i.m. or 50 to 250 mg i.v. Children, 3 to 5 mg/kg to a maximum of 100 mg.
The reader is referred to individual product monographs for more specific prescribing information.
BARBITURATES Amobarbital Butabarbital Pentobarbital Phenobarbital Secobarbital Anticonvulsant – Sedative-Hypnotic