Barbiturates (Phenobarbital and other Barbiturates)

Phenobarbital (phenobarbitone) is seldom used nowadays as a first option because of its toxicity profile.

• It is effective for tonic-clonic generalised seizures and partial seizures but may be sedative in adults and cause behavioural disturbances and hyperkinesia in children.
• It may be tried for atypical absence, atonic, and tonic seizures.
• Rebound seizures may be a problem on withdrawal.
• Monitoring plasma concentrations is less useful than with other drugs because tolerance occurs.
• Primidone is largely converted to phenobarbital and this is probably responsible for its antiepileptic action.

Indications¹

• Phenobarbital is an established treatment for partial and tonic-clonic seizures but is seldom used nowadays as a first option because of its toxicity profile.
• Phenobarbital is a drug of choice for the treatment of established status epilepticus. It is highly effective, has a rapid onset of action, and prolonged anticonvulsant effects. Acute tolerance to the antiepileptic effect is unusual in contrast to the benzodiazepines and seizures do not tend to recur once controlled.

Contraindications

• Porphyria

Cautions

• Elderly
• Debilitated
• Children
• Hepatic impairment (may precipitate coma)
• Severe renal impairment
• Respiratory depression (avoid if severe)
• Pregnancy (possible congenital malformations with first trimester use and may cause vitamin K deficiency and risk of neonatal bleeding if given in third trimester) and breast-feeding (risk of drowsiness in baby)
• Avoid sudden withdrawal

Important interactions

• Phenobarbitone is an enzyme inducer and can accelerate the metabolism of many lipid-soluble drugs.

Common problems

• The major problem in the clinical use of phenobarbitone is its effect on cognition, mood and behaviour. It can produce fatigue, listlessness and tiredness in adults and insomnia, hyperactivity and aggression in children, and paradoxical excitement, restlessness and confusion in the elderly. Subtle impairment of memory, mood and learning capacity can occur.
• Depression may be a consequence of long-term administration.
• Arthritic changes, frozen shoulder, allergic skin reactions, megaloblastic anaemia (responsive to folic acid) and Dupuytren's contracture can also be associated problems.
• Tolerance develops to the deleterious cognitive effects of the drug but also to its efficacy in some patients.
• In the treatment of status epilepticus, the main disadvantages of phenobarbitone are its potential to cause sedation, respiratory depression and hypotension. However these effects are usually slight except at high levels and its safety is well established.

Initiation

• To minimise sedation, a low dose should be started (30 mg in adolescents and adults), which can be increased gradually (15-30 mg incremental steps) according to clinical requirements.
• Status:
  • The usual recommended adult intravenous loading dose of phenobarbitone is 10 mg/kg (doses of up to 20 mg/kg have been used and recommended), given at a rate of 100 mg/minute (i.e. a total of about 700 mg in seven minutes).
  • This should be followed by daily maintenance doses of 1-4 mg/kg. In neonates, initial phenobarbitone loading doses of between 12 and 20 mg/kg have been recommended to produce therapeutic levels, with subsequent supplementation of 3-4 mg/kg per day, to a maximum dose of 40 mg/kg.
  • In older children, loading doses of between 5 and 20 mg/kg are recommended and maintenance doses of 1-4 mg/kg, although much higher doses have been safely given.
  • After loading, maintenance doses can be given by the oral, intravenous, or intramuscular route.

Monitoring

Although routine drug level monitoring of phenobarbitone is of limited value, monitoring can be useful for improving compliance, confirming the clinical diagnosis of toxicity, and minimising the effects of drug interactions.

• The value of measuring phenobarbitone levels is limited, as the concentration associated with optimal seizure control varies considerably. In addition, the development of tolerance to its CNS side effects makes the toxic threshold imprecise.
• An unexpectedly low or high concentration may help to make the correct clinical decision in an individual patient.
• The usefulness of monitoring phenobarbitone has been limited by the fact that inter-patient variability in the plasma phenobarbitone-efficacy/toxicity inter-relationship is rather large.
• Because of its long elimination half-life, sampling time in relation to dose is not critical, therefore sampling at trough is not an absolute requirement.
• For therapeutic purposes phenobarbital and phenobarbital sodium may be considered equivalent in effect. Plasma concentration for optimum response 15-40 mg/litre (60-180 micromol/litre). The blood level at which toxicity with phenobarbitone appears is not well defined, but adverse neurological effects (nystagmus, ataxia and lethargy) are usually only seen with blood levels above 100 mmol/L. Many other side effects, including behavioural problems, are unrelated to blood levels.
• Many studies have reported excellent correlation between saliva and plasma free phenobarbitone concentrations.

Primidone is metabolised to two pharmacologically active metabolites, phenobarbitone and phenylethylmalonamide. Primidone is not as well tolerated as phenobarbitone. There is therefore nothing to recommend it over phenobarbitone for patients in whom treatment with a barbiturate is contemplated.

• Indications:
  • All forms of epilepsy except absence seizures.
  • Essential tremor.
• A small starting dose of primidone with gradual increase in dose over several weeks is essential.
• Because the metabolism of primidone results in the production of phenobarbitone, if monitoring is indicated, it is usually only recommended that phenobarbitone be monitored.
• Monitoring of primidone along with phenobarbitone may be useful for assessing short-term drug non-compliance. At steady-state the typical ratio of phenobarbitone to primidone is about 3:1. If a patient has generally been non-compliant but remembers to take the medication for the previous few days, the primidone level will reflect steady-state, but the phenobarbitone level will be low because of it's long half-life. If a patient has recently stopped taking primidone, the phenobarbitone level will remain measurable for several days after the primidone level is no longer detectable.
• Primidone concentrations in plasma and saliva correlate well and therefore monitoring of primidone in saliva can be useful.