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P A R T 4
Drugs acting on the central and peripheral nervous systems
DRUGS FOR TREATING GENERALISED
SEIZURES
Drugs typically used to treat generalised seizures stabil
ise the nerve membranes by blocking channels in the
cell membrane or altering receptor sites. Because they
work generally on the CNS, sedation and other CNS
effects often result. Various drugs are used to treat gen
eralised seizures, including hydantoins, barbiturates,
barbiturate-like drugs, benzodiazepines and succini
mides. These drugs affect the entire brain and reduce
the chance of sudden electrical outburst. Associated
adverse effects are often related to total brain stabilisa
tion (Figure 23.2).
Absence seizures, another type of generalised
seizure, may require drugs that are different from
those used to treat or prevent other types of generalised
seizures. The succinimides and drugs that modulate the
inhibitory neurotransmitter gamma-aminobutyric acid
(GABA) are most frequently used (see Table 23.2).
H
ydantoins
The currently available hydantoin in Australia and New
Zealand is phenytoin (
Dilantin
). Because hydantoins are
generally less sedating than many other antiepileptics,
phenytoin may be the drug of choice for people who are
not willing to tolerate sedation and drowsiness. It does
have significant adverse effects; thus, less toxic drugs,
such as benzodiazepines, have replaced it in many
situations.
Therapeutic actions and indications
Phenytoin stabilises nerve membranes throughout the
CNS directly by influencing ionic channels in the cell
membrane, thereby decreasing excitability and hyper
excitability to stimulation. By decreasing conduction
through nerve pathways, it reduces the tonic–clonic,
muscular and emotional responses to stimulation. See
Table 23.2 for usual indications.
Pharmacokinetics
Phenytoin is well absorbed from the GI tract, metabo
lised in the liver and excreted in the urine. Therapeutic
serum phenytoin levels range from 10 to 20 mcg/mL.
In general the reported plasma half-life of phenytoin
averages 22 hours, with a range of 7 to 42 hours. Steady
state therapeutic levels are achieved at least 7 to 10 days
(5 to 7 half-lives) after initiation of therapy with rec
ommended doses of 300 mg/day. Conventionally, with
drugs following linear kinetics the half-life is used to
determine the dose rate, drug accumulation and the time
to reach steady state. Phenytoin, however, demonstrates
non-linear kinetics and therefore the half-life is affected
by the degree of absorption, saturation of metabolic
pathways, dose and the degree of metabolic enzyme
induction. This results in considerable inter- and intra-in
dividual variability in phenytoin pharmacokinetics.
As phenytoin is highly protein bound, free phenytoin
levels may be altered in people whose protein binding
characteristics differ from normal. Protein binding may
be lower in neonates and hyperbilirubinaemic infants; it
may also be altered in people with hypoalbuminaemia,
uraemia or acute trauma and in pregnancy. Phenytoin is
available in oral (also available in paediatric formulation
e.g. syrup) and parenteral forms.
Barbiturates depress
conduction in
brainstem and cortex Cortex
Limbic
system
RAS
Cerebellum
GABA
Sodiumvalproate
GABA effects,
and decreases
electrical activity
Zolpidem
affects serotonin
levels in RAS
Mechanisms
not understood:
levetiracetam
Hydantoins
stabilise
nerve membranes
Acetazolamide,
zonisamide
alter Na
+
and Ca
+
channels
Carbamazepine,
gabapentin,
lamotrigine,
oxcarbazepine,
pregabalin,
tiagabine and
topiramate
increase GABA
activity and block
Na
+
and Ca
+
channels
to stop APs
Cell firing inhibited,
leading to stabilisation
Benzodiazepines
GABA effects,
to inhibit neuron firing
FIGURE 23.2
Sites of action of drugs used to treat various types of
epilepsy. AP, action potential; GABA, gamma-aminobutyric acid;
RAS, reticular activating system.
