Pharmacology for Anaesthesia and Intensive Care

P1: PSB Printer: Yet To Come
9780521704632c17 CUFX213A/Peck 9780521618168 December 28, 2007 13:44

17 Centralnervous system

Anticonvulsants

Where possible a single agent should be used to treat epilepsy as it avoids the potential

for drug interaction. In addition patients rarely improve with a second agent.

Phenytoin

Uses

Phenytoin has been used widely for many years in the treatment of grand mal and par-

tial seizures, trigeminal neuralgia and ventricular arrhythmias following TCA over-

dose. It may be given orally or intravenously but the dose must be tailored to the

individual patient as wide interpatient variation exists (about 9% of the population

are slow hydroxylators) and blood assays are useful in this regard. It is incompatible

with 5% dextrose, in which it becomes gelatinous. The normal therapeutic level is

10–20μg.ml−^1.

Mechanism of action

The action of phenytoin is probably dependent on its ability to bind to and stabilize

inactivated Na+channels. This prevents the further generation of action potentials

that are central to seizure activity. It may also reduce Ca^2 +entry into neurones,

blocking transmitter release and enhancing the actions of GABA.

Effects


Idiosyncratic – acne, coarsening of facial features, hirsutism, gum hyperplasia,

folate-dependent megaloblastic anaemia, aplastic anaemia, various skin rashes

and peripheral neuropathy.


Dose-related – ataxia, nystagmus, parasthesia, vertigo and slurred speech. Rapid

undiluted intravenous administration is associated with hypotension and heart

block.


Teratogenicity – it causes craniofacial abnormalities, growth retardation, limb and

cardiac defects and mental retardation.


Drug interactions – as phenytoin induces the hepatic mixed function oxidases it

increases the metabolism of warfarin, BDZs and the oral contraceptive pill. Its

metabolism may be inhibited by metronidazole, chloramphenicol and isoniazid

leading to toxic levels. Furthermore phenytoin’s metabolism may be induced by

carbamazepine or alcohol resulting in reduced plasma levels.

Kinetics

The oral bioavailability is approximately 90% and it is highly plasma protein bound

(90%). It undergoes saturable hepatic hydroxylation resulting in zero-order kinetics

just above the therapeutic range. It can induce its own metabolism and that of other

drugs. Its major metabolite is excreted in the urine.