A Textbook of Clinical Pharmacology and Therapeutics

Table 22.2: Metabolic interactions of anticonvulsants
concentration. The time to approach a plateau plasma concentration
is longer than is predicted from the t 1/2 of a single dose
of the drug.
Phenytoin is extremely insoluble and crystallizes out in
intramuscular injection sites, so this route should never be
used. Intravenous phenytoin is irritant to veins and tissues
because of the high pH. Phenytoin should 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 essential.
If blood pressure falls, administration is temporarily
stopped until the blood pressure has risen to a satisfactory
level. Fosphenytoin, a prodrug of phenytoin can be given
more rapidly, but still requires careful monitoring.
At therapeutic concentrations, 90% of phenytoin is bound
to albumin and to two α-globulins which also bind thyroxine.
In uraemia, displacement of phenytoin from plasma protein
binding results in lower total plasma concentration and a
lower therapeutic range (see Chapter 3).
Phenytoin elimination is impaired in liver disease. This can
lead to increased plasma concentration and toxicity, but is not
reliably predicted by liver function tests. Conversely hypoalbuminaemia
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
Phenobarbital is 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drug for atypical absence, atonic and tonic seizures, but is obsolete.
Rebound seizures may occur on withdrawal. Monitoring
GENERAL PRINCIPLES OF TREATMENT OF EPILEPSY 137
Enzyme-inducing effect of anti-epileptic drugs Drugs that inhibit the metabolism of anticonvulsants
Anti-epileptic drug Drugs whose metabolism
is enhanced
Inhibitor Anticonvulsant
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
Corticosteroids
Erythromycin and clarithromycin Carbamazepine
Anticonvulsants Cimetidine Phenytoin
Isoniazid Carbamazepine, ethosuximide,
phenytoin
Metronidazole Phenytoin
Miconazole, fluconazole Phenytoin
Valproate Lamotrigine
plasma concentrations is less useful than with phenytoin
because tolerance occurs, and the relationship between plasma
concentration and therapeutic and adverse effects is less predictable
than is the case with phenytoin.
Other adverse effects include dependency, rashes, anaphylaxis,
folate deficiency, aplastic anaemia and congenital
abnormalities.
BENZODIAZEPINES
Use
Benzodiazepines (e.g. diazepam, clobazepam and clonazepam)
have anticonvulsant properties in addition to their anxiolytic
and other actions. Tolerance to their anti-epileptic properties
limits chronic use. Clonazepam was introduced specifically as
an anticonvulsant. It is used intravenously in status epilepticus.
Clonazepam has a wide spectrum of activity, having a place
in the management of the motor seizures of childhood, particularly
absences and infantile spasms. It is also useful in complex
partial seizures and myoclonic epilepsy in patients who are
not adequately controlled by phenytoin or carbamazepine.
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 experience
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, dysphoria,
hypotonia and muscle relaxation, increased salivary
secretion and hyperactivity with aggressive behaviour.