C H A P T E R 2 3
Antiseizure agents
359
Pharmacokinetics
Phenobarbitone, which is available in oral and parenteral
forms, is well absorbed from the GI tract, metabolised
in the liver and excreted in the urine. This drug has
very low lipid solubility, giving it a slow onset and a very
long duration of activity. The plasma half-life is 90 to
100 hours in adults, and 65 to 70 hours in children, but
is greatly prolonged in neonates. The therapeutic serum
level range is 15 to 40 mcg/mL.
Primidone, available only as an oral agent, is well
absorbed from the GI tract, metabolised in the liver to
phenobarbitone metabolites and excreted in the urine.
It tends to have a longer half-life than phenobarbitone.
The therapeutic serum levels are 5 to 12 mcg/mL. Bar
biturates readily cross the placenta and, if administered
IV, fetal blood concentrations are approximately equal
to maternal serum concentrations. Phenobarbitone is
excreted into breast milk.
Contraindications and cautions
Contraindications and cautions for barbiturates are the
same as those discussed for hydantoins. Phenobarbi
tone should not be administered to elderly people who
exhibit nocturnal confusion or restlessness from sedative
hypnotic drugs or to persons who are known to be, or
are likely to become, dependent on sedative hypnotic
medications.
Adverse effects
The most common adverse effects associated with
barbiturates relate to CNS depression and its effects
on body function: depression, confusion, drowsiness,
lethargy, fatigue, constipation, dry mouth, anorexia,
cardiac arrhythmias and changes in blood pressure,
urinary retention and loss of libido. Because barbitu
rates and barbiturate-like drugs depress nerve function,
they can produce sedation, hypnosis, anaesthesia and
deep coma. The degree of depression is dose related. At
doses below those needed to cause hypnosis, these drugs
block seizure activity.
In addition, phenobarbitone may be associated with
physical dependence and withdrawal syndrome. The
drug has also been linked to severe dermatological reac
tions and the development of drug tolerance related to
changes in drug metabolism over time.
Clinically important drug–drug interactions
Because the risk of CNS depression is increased when
barbiturates are taken with alcohol, people should be
advised not to drink alcohol while they are taking these
agents. Always consult a drug reference before any drug
is added or withdrawn from a therapeutic regimen that
involves any of these agents.
B
enzodiazepines
Some benzodiazepines are used as antiepileptic agents.
These include clonazepam (
Rivotril
,
Paxam
[in New
Zealand]) and diazepam (
Valium
).
Therapeutic actions and indications
The benzodiazepines may potentiate the effects of
GABA, an inhibitory neurotransmitter that stabilises
nerve cell membranes. These drugs, which appear to act
primarily in the limbic system and the RAS, also cause
muscle relaxation and relieve anxiety without affecting
cortical functioning substantially. The benzodiazepines
stabilise nerve membranes throughout the CNS to
decrease excitability and hyperexcitability to stimula
tion. By decreasing conduction through nerve pathways,
they reduce the tonic–clonic, muscular and emotional
responses to stimulation. In general, these drugs have
limited toxicity and are well tolerated by most people.
(See Chapter 20 for the use of benzodiazepines as
sedatives and anxiolytics.) See Table 23.2 for usual indi
cations for each of these agents. Clonazepam may lose
its effectiveness within 3 months (affected individuals
may respond to dose adjustment).
Prototype summary: Phenobarbitone
Indications:
Long-term treatment of generalised
tonic–clonic and cortical focal seizures; emergency
control of certain acute convulsive episodes
(status epilepticus, tetanus, eclampsia, meningitis);
anticonvulsant treatment of generalised tonic–
clonic seizures and focal seizures (parenteral).
Actions:
General CNS depressant; inhibits impulse
conduction in the ascending RAS; depresses the
cerebral cortex; alters cerebellar function; depresses
motor output; and can produce excitation, sedation,
hypnosis, anaesthesia and deep coma.
Pharmacokinetics:
Route
Onset
Duration
Oral
30–60 mins
10–16 hours
IM, SC
10–30 mins
4–6 hours
IV
5 mins
4–6 hours
T
1/2
:
79 hours; metabolised in the liver, excreted in
the urine.
Adverse effects:
Somnolence, insomnia, vertigo,
nightmares, lethargy, nervousness, hallucinations,
insomnia, anxiety, dizziness, bradycardia,
hypotension, syncope, nausea, vomiting,
constipation, diarrhoea, hypoventilation,
respiratory depression, tissue necrosis at injection
site, withdrawal syndrome.
