stabilized on corticosteroid therapy may require dosage adjustments if barbiturates are added to or withdrawn from thier dosage regimen. griseofulvin phenobarbital appears to interfere with the absorption of orally administered griseofulvin, thus decreasing its blood level. the effect of the resultant decreased blood levels of griseofulvin on therapeutic response has not been established. however, it would be preferable to avoid concomitant administration of these drugs. doxycycline phenobarbital has been shown to shorten the half-life of doxycycline for as long as 2 weeks after barbiturate therapy is discontinued. this mechanism is probably through the induction of hepatic microsomal enzymes that metabolize the antibiotic. if phenobarbital and doxycycline are administered concurrently, the clinical response to doxycycline should be monitored closely. phenytoin, sodium valproate, valproic acid the effect of barbiturates on the metabolism of phenytoin appears to be variable. some investigators report an accelerating effect, while others report no effect. because the effect of barbiturates on the metabolism of phenytoin is not predictable, phenytoin and barbiturate blood levels should be monitored more frequently if these drugs are given concurrently. sodium valproate and valproic acid appear to decrease barbiturate metabolism; therefore, barbiturate blood levels should be monitored and appropriate dosage adjustments made as indicated. central nervous system depressants the concomitant use of other central nervous system depressants, including other sedatives or hypnotics, antihistamines, tranquilizers or alcohol, may produce additive depressant effects. monoamine oxidase inhibitors (maois) maois prolong the effects of barbiturates probably because metabolism of the barbiturate is inhibited. estradiol, estrone, progesterone and other steroidal hormones pretreatment with or concurrent administration of phenobarbital may decrease the effect of estradiol by increasing its metabolism. there have been reports of patients treated with antiepileptic drugs (e.g., phenobarbital) who became pregnant while taking oral contraceptives. an alternate contraceptive method might be suggested to women taking phenobarbital.

, mephobarbital and metharbital) for the treatment of generalized tonic-clonic and cortical focal seizures. and, in the emergency control of certain acute convulsive episodes, e.g., those associated with status epilepticus, cholera, eclampsia, cerebral hemorrhage, meningitis, tetanus, and toxic reactions to strychnine or local anesthetics. phenobarbital sodium may be administered intramuscularly or intravenously as an anticonvulsant for emergency use. when administered intravenously, it may require 15 or more minutes before reaching peak concentrations in the brain. therefore, injecting phenobarbital sodium until the convulsions stop may cause the brain level to exceed that required to control the convulsions and lead to severe barbiturate-induced depression. phenobarbital is indicated in pediatric patients as an anticonvulsant and as a sedative, including its preoperative and postoperative use.

to the amount required for the interval until the next appointment. abrupt cessation after prolonged use in the dependent person may result in withdrawal symptoms, including delirium, convulsions and possibly death. barbiturates should be withdrawn gradually from any patient known to be taking excessive dosage over long periods of time (see drug abuse and dependence ). dermatologic reactions exfoliative dermatitis and stevens-johnson syndrome, possibly fatal, are rare hypersensitivity reactions to phenobarbital. physicians should be alert to signs which may precede the onset of barbiturate- induced cutaneous lesions, and the drug should be discontinued whenever dermatological reactions occur. intravenous administration too rapid administration may cause severe respiratory depression, apnea, laryngospasm, hypertension or vasodilation with fall in blood pressure. when administered intravenously, it may require 15 or more minutes before reaching peak concentrations in the brain. therefore, injecting phenobarbital sodium until the convulsions stop may cause brain levels to exceed that required to control the convulsions and lead to severe barbiturate-induced depression. acute or chronic pain caution should be exercised when barbiturates are administered to patients with acute or chronic pain, because paradoxical excitement could be induced or important symptoms could be masked. however, the use of barbiturates as sedatives in the postoperative surgical period and as adjuncts to cancer chemotherapy is well established. use in pregnancy barbiturates can cause fetal harm when administered to a pregnant woman. retrospective, case-controlled studies have suggested a connection between the maternal consumption of barbiturates and a higher than expected incidence of fetal abnormalities. phenobarbital may cause major fetal malformations. following oral or parenteral administration, barbiturates readily cross the placental barrier and are distributed throughout fetal tissues with highest concentrations found in the placenta, fetal liver and brain. fetal blood levels approach maternal blood levels following parenteral administration. withdrawal symptoms occur in infants born to mothers who receive barbiturates throughout the last trimester of pregnancy (see drug abuse and dependence ). phenobarbital should be used during pregnancy only when clearly indicated. if phenobarbital is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. use in children phenobarbital has been reported to be associated with cognitive defects in children taking it for complicated febrile seizures. synergistic effects the concomitant use of alcohol or other cns depressants may produce additive cns depressant effects.

ministered with caution and initially in reduced doses. barbiturates should not be administered to patients showing the premonitory signs of hepatic coma. parenteral solutions of barbiturates are highly alkaline. therefore, extreme care should be taken to avoid perivascular extravasation or intraarterial injection. extravascular injection may cause local tissue damage with subsequent necrosis; consequences of intraarterial injection may vary from transient pain to gangrene of the limb. any complaint of pain in the limb warrants stopping the injection.

r impractical. intramuscular injection of the sodium salts of barbiturates should be made deeply into a large muscle and a volume of 5 ml should not be exceeded at any one site because of possible tissue irritation. injection into or near peripheral nerves may result in permanent neurological deficit. after intramuscular injection of a hypnotic dose, the patient's vital signs should be monitored. subcutaneous administration is not recommended (see contraindications ). intravenous administration intravenous injection is restricted to conditions in which other routes are not feasible, either because the patient is unconscious (as in cerebral hemorrhage, eclampsia or status epilepticus), or because the patient resists (as in delirium) or because prompt action is imperative. slow iv injection is essential, and patients should be carefully observed during administration. this requires that blood pressure, respiration and cardiac function be maintained, vital signs be recorded and equipment for resuscitation and artificial ventilation be available. the rate of intravenous injection for adults should not exceed 60 mg/min for phenobarbital sodium. when given intravenously, do not use small veins, such as those on the dorsum of the hand or wrist. preference should be given to a larger vein to minimize the risk of irritation with the possibility of resultant thrombosis. avoid administration into varicose veins because circulation there is retarded. inadvertent injection into or adjacent to an artery has resulted in gangrene requiring amputation of an extremity or a portion thereof. careful technique, including aspiration, is necessary to avoid inadvertent intraarterial injection. (see below.) treatment of adverse effects due to inadvertent error in administration extravasation into subcutaneous tissues causes tissue irritation. this may vary from slight tenderness and redness to necrosis. recommended treatment includes the application of moist heat and the injection of 0.5% procaine solution into the affected area. intraarterial injection of any barbiturate must be avoided. the accidental intraarterial injection of a small amount of the solution may cause spasm and severe pain along the course of the artery. the injection should be terminated if the patient complains of pain or if other indications of accidental intraarterial injection occur, such as a white hand with cyanosed skin or patches of discolored skin and delayed onset of hypnosis. the consequences of intraarterial injection of phenobarbital can vary from transient pain to gangrene. it is not possible to formulate strict rules for management of such accidents. the following procedures have been suggested: 1) release of the tourniquet or restrictive garments to permit dilution of injected drug, 2) relief of arterial spasm by injecting 10 ml of a 1% procaine solution into the artery and, if considered necessary, brachial plexus block, 3) prevention of thrombosis by early anticoagulant therapy and 4) supportive treatment. anticonvulsant use a therapeutic anticonvulsant level of phenobarbital in the serum is 10 to 25 μg/ml. to achieve the blood levels considered therapeutic in children, higher per-kilogram dosages are generally necessary for phenobarbital and most other anticonvulsants. in children and infants, phenobarbital at loading doses of 15 to 20 mg/kg produces blood levels of about 20 μg/ml shortly after administration. in status epilepticus, it is imperative to achieve therapeutic blood levels of a barbiturate (or other anticonvulsants) as rapidly as possible. when administered intravenously, phenobarbital sodium may require 15 minutes or more to attain peak concentrations in the brain. if phenobarbital sodium is injected continuously until the convulsions stop, the brain concentration will continue to rise and can eventually exceed that required to control the seizures. because a barbiturate-induced depression may occur along with a postictal depression once the seizures are controlled, it is important, therefore, to use the minimal amount required and to wait for the anticonvulsant effect to develop before administering a second dose. phenobarbital has been used in the treatment and prophylaxis of febrile seizures. however, it has not been established that prevention of febrile seizures influences the subsequent development of epilepsy. special patient population dosage should be reduced in the elderly or debilitated because these patients may be more sensitive to barbiturates. dosage should be reduced for patients with impaired renal function or hepatic disease. parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

se.

stabilized on corticosteroid therapy may require dosage adjustments if barbiturates are added to or withdrawn from thier dosage regimen. griseofulvin phenobarbital appears to interfere with the absorption of orally administered griseofulvin, thus decreasing its blood level. the effect of the resultant decreased blood levels of griseofulvin on therapeutic response has not been established. however, it would be preferable to avoid concomitant administration of these drugs. doxycycline phenobarbital has been shown to shorten the half-life of doxycycline for as long as 2 weeks after barbiturate therapy is discontinued. this mechanism is probably through the induction of hepatic microsomal enzymes that metabolize the antibiotic. if phenobarbital and doxycycline are administered concurrently, the clinical response to doxycycline should be monitored closely. phenytoin, sodium valproate, valproic acid the effect of barbiturates on the metabolism of phenytoin appears to be variable. some investigators report an accelerating effect, while others report no effect. because the effect of barbiturates on the metabolism of phenytoin is not predictable, phenytoin and barbiturate blood levels should be monitored more frequently if these drugs are given concurrently. sodium valproate and valproic acid appear to decrease barbiturate metabolism; therefore, barbiturate blood levels should be monitored and appropriate dosage adjustments made as indicated. central nervous system depressants the concomitant use of other central nervous system depressants, including other sedatives or hypnotics, antihistamines, tranquilizers or alcohol, may produce additive depressant effects. monoamine oxidase inhibitors (maois) maois prolong the effects of barbiturates probably because metabolism of the barbiturate is inhibited. estradiol, estrone, progesterone and other steroidal hormones pretreatment with or concurrent administration of phenobarbital may decrease the effect of estradiol by increasing its metabolism. there have been reports of patients treated with antiepileptic drugs (e.g., phenobarbital) who became pregnant while taking oral contraceptives. an alternate contraceptive method might be suggested to women taking phenobarbital.

e dose from 3 to 2 doses a day for 1 week). in studies, secobarbital sodium and pentobarbital sodium have been found to lose most of their effectiveness for both inducing and maintaining sleep by the end of 2 weeks of continued drug administration even with the use of multiple doses. the short-, intermediate- and to a lesser degree, long-acting barbiturates have been widely prescribed for treating insomnia. although the clinical literature abounds with claims that the short-acting barbiturates are superior for producing sleep while the intermediate-acting compounds are more effective in maintaining sleep, controlled studies have failed to demonstrate these differential effects. therefore, as sleep medications, the barbiturates are of limited value beyond short-term use. barbiturates have little analgesic action at subanesthetic doses. rather, in subanesthetic doses these drugs may increase the reaction to painful stimuli. all barbiturates exhibit anticonvulsant activity in anesthetic doses. barbiturates are respiratory depressants by virtue of their direct effect on the medullary respiratory center. they diminish and, in high doses, may abolish the sensitivity of the respiratory center to its normal stimulus, carbon dioxide. the degree of respiratory depression is dependent upon dose. with hypnotic doses, respiratory depression produced by barbiturates is similar to that which occurs during physiologic sleep with slight decrease in blood pressure and heart rate. ordinary hypnotic doses of barbiturates have no significant effect on the cardiovascular system. the barbiturates tend to decrease the tonus of the gastrointestinal musculature. they have no direct injurious effect on the normal kidney. severe oliguria or anuria may occur in acute barbiturate poisoning, largely as a result of the marked hypotension. hypnotic doses tend to reduce slightly the metabolic rate in man. body temperature is reduced slightly, owing to lessened activity and to depression of the central temperature-regulatory mechanisms. while anesthetic doses of all barbiturates exert an anticonvulsant effect, phenobarbital has a selective anticonvulsant activity independent of the degree of sedation produced. phenobarbital limits the spread of seizures and raises the seizure threshold in grand mal (generalized tonic-clonic) epilepsy. studies in laboratory animals have shown that barbiturates cause reduction in the tone and contractility of the uterus, ureters and urinary bladder. however, concentrations of the drugs required to produce this effect in humans are not reached with sedative-hypnotic doses. barbiturates do not impair normal hepatic function, but have been shown to induce liver microsomal enzymes, thus increasing and/or altering the metabolism of barbiturates and other drugs. (see precautions, drug interactions .) following iv administration, the onset of action is 5 minutes for phenobarbital sodium. for im administration, the onset of action is slightly slower. maximal cns depression may not occur until 15 minutes or more after iv administration. duration of action, which is related to the rate at which the barbiturates are redistributed throughout the body, varies among persons and in the same person from time to time. no studies have demonstrated that the different routes of administration are equivalent with respect to bioavailability. barbiturates are weak acids that are absorbed and rapidly distributed to all tissues and fluids with high concentrations in the brain, liver and kidneys. lipid solubility of the barbiturates is the dominant factor in their distribution within the body. the more lipid soluble the barbiturate, the more rapidly it penetrates all tissues of the body. barbiturates are bound to plasma and tissue proteins to a varying degree with the degree of binding increasing directly as a function of lipid solubility. phenobarbital has the lowest lipid solubility, lowest plasma binding, lowest brain protein binding, the longest delay in onset of activity and the longest duration of action. its diffusion across the blood-brain barrier and its distribution into other tissues occurs more slowly than with other short-acting barbiturates. fifteen minutes or more may be required for maximal central depression following intravenous administration of phenobarbital. however, with time, phenobarbital distributes into all tissues and fluids. barbiturates are known to cross the placenta. phenobarbital is 20-45% protein bound. in adults, the plasma half-life of phenobarbital is 53 to 118 hours (mean 79 hours) and in children/newborns, the plasma half-life is 60 to 180 hours (mean 110 hours). barbiturates are metabolized primarily by the hepatic microsomal enzyme system, and the metabolic products are excreted in the urine and, less commonly, in the feces. approximately 25 to 50 percent of a dose of phenobarbital is eliminated unchanged in the urine, whereas the amount of other barbiturates excreted unchanged in the urine is negligible. urinary ph and rate of urine flow affect the renal circulation of unchanged phenobarbital, a greater quantity being eliminated in alkaline urine and at increased flow rates. the excretion of unmetabolized, barbiturate is one feature that distinguishes the long-acting category from those belonging to other categories which are almost entirely metabolized. the inactive metabolites of the barbiturates are excreted as conjugates of glucuronic acid.