GENERALPRINCIPLES OFTREATMENT OFEPILEPSY 137concentration. The time to approach a plateau plasma concen-
tration is longer than is predicted from the t1/2of a single dose
of the drug.
Phenytoinis extremely insoluble and crystallizes out in
intramuscular injection sites, so this route should never be
used. Intravenous phenytoinis irritant to veins and tissues
because of the high pH. Phenytoinshould be given at rates
of 50 mg/min, because at higher rates of administration
cardiovascular collapse, respiratory arrest and seizures may
occur. Electrocardiographic monitoring with measurement of
blood pressure every minute during administration is essen-
tial. If blood pressure falls, administration is temporarily
stopped until the blood pressure has risen to a satisfactory
level.Fosphenytoin, a prodrug of phenytoincan be given
more rapidly, but still requires careful monitoring.
At therapeutic concentrations, 90% of phenytoinis bound
to albumin and to two α-globulins which also bind thyroxine.
In uraemia, displacement of phenytoinfrom plasma protein
binding results in lower total plasma concentration and a
lower therapeutic range (see Chapter 3).
Phenytoinelimination is impaired in liver disease. This can
lead to increased plasma concentration and toxicity, but is not
reliably predicted by liver function tests. Conversely hypo-
albuminaemia from whatever cause (e.g. cirrhosis or nephrotic
syndrome) can result in low total plasma concentrations, and
reductions in both effective and toxic plasma concentration.
PHENOBARBITAL
Phenobarbitalis an effective drug for tonic and partial seizures,
but is sedative in adults and causes behavioural disturbances
and hyperkinesia in children. It has been used as a second-line
drug for atypical absence, atonic and tonic seizures, but is obso-
lete. Rebound seizures may occur on withdrawal. Monitoring
plasma concentrations is less useful than with phenytoin
because tolerance occurs, and the relationship between plasma
concentration and therapeutic and adverse effects is less pre-
dictable than is the case with phenytoin.
Other adverse effects include dependency, rashes, ana-
phylaxis, folate deficiency, aplastic anaemia and congenital
abnormalities.BENZODIAZEPINES
Use
Benzodiazepines (e.g. diazepam,clobazepamandclonazepam)
have anticonvulsant properties in addition to their anxiolytic
and other actions. Tolerance to their anti-epileptic properties
limits chronic use. Clonazepamwas introduced specifically as
an anticonvulsant. It is used intravenously in status epilepticus.
Clonazepamhas a wide spectrum of activity, having a place
in the management of the motor seizures of childhood, particu-
larly absences and infantile spasms. It is also useful in complex
partial seizures and myoclonic epilepsy in patients who are
not adequately controlled by phenytoinorcarbamazepine.
Oral treatment is usually started with a single dose at night. The
dose is gradually titrated upwards until control is achieved or
adverse effects become unacceptable.Adverse effects
Adverse effects are common and about 50% of patients experi-
ence lethargy, somnolence and dizziness. This is minimized
by starting with a low dose and then gradually increasing it.
Sedation often disappears during chronic treatment. More
serious effects include muscular incoordination, ataxia, dys-
phoria, hypotonia and muscle relaxation, increased salivary
secretion and hyperactivity with aggressive behaviour.Table 22.2:Metabolic interactions of anticonvulsantsEnzyme-inducing effect of anti-epileptic drugs Drugs that inhibit the metabolism of anticonvulsants
Anti-epileptic drug Drugs whose metabolism Inhibitor Anticonvulsant
is enhanced
Carbamazepine Warfarin Amiodarone Phenytoin
Phenobarbitone Oral contraceptives Fluoxetine Phenytoin, carbamazepine
Phenytoin Theophylline Diltiazem, nifedipine Phenytoin
Primidone Ciclosporin Chloramphenicol Phenytoin
Topiramate Some tricyclic antidepressants Disulfiram Phenytoin
Doxycycline Erythromycin and clarithromycin Carbamazepine
Corticosteroids
Anticonvulsants Cimetidine Phenytoin
Isoniazid Carbamazepine, ethosuximide,
phenytoin
Metronidazole Phenytoin
Miconazole, fluconazole Phenytoin
Valproate Lamotrigine