360
P A R T 4
Drugs acting on the central and peripheral nervous systems
Pharmacokinetics
Diazepam is available in oral, rectal and parenteral
forms. Diazepam has a biphasic elimination curve,
the terminal half-life being 1–2 days. It is extensively
protein-bound. Diazepam is metabolised in the liver
and the following active metabolites are produced:
desmethyldiazepam, methyloxazepam, oxazepam and
temazepam. The metabolites are then eliminated by
the kidneys in either their free or conjugated form. The
half-life of diazepam is prolonged in individuals with
kidney or liver disease. Diazepam and its active metab
olites show significant accumulation during multiple
dosage regimens. Steady state plasma concentrations are
attained in 5 days to 2 weeks, as some of its metabolites
take several days to weeks to be eliminated.
Clonazepam, on the other hand, is quickly and
almost completely absorbed after oral administration.
Peak plasma concentrations are reached in most cases
within 1–4 hours after an oral dose. The absorption
half-life is around 25 minutes. Bioavailability is 90%
after oral administration. The mean elimination half-life
is 30–40 hours. The elimination half-life and clearance
values in neonates are of the same order of magnitude as
those reported for adults.
Clonazepam is now available in liquid form, making
it a good choice for people who have difficulty swallow
ing capsules or tablets. These agents are well absorbed
from the GI tract, metabolised in the liver and excreted
in the urine. They have a long half-life of 18–50 hours.
Contraindications and cautions
Contraindications for benzodiazepines are the same as
those discussed for phenytoin.
Adverse effects
The most common adverse effects associated with
benzodiazepines 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. Benzodiaze
pines may be associated with physical dependence and
withdrawal syndrome. In infants and young children
clonazepam may cause increased production of saliva
and bronchial secretions. Therefore special attention
must be paid to maintaining patency of the airways.
The dosage of clonazepam must be carefully adjusted
to individual requirements in people: with pre-existing
disease of the respiratory system (e.g. chronic obstruc
tive pulmonary disease); with pre-existing disease of the
liver; undergoing treatment with other centrally acting
medications or anticonvulsant (antiepileptic) agents (see
Clinincally important drug–drug interactions). Like
all medicines of this type, clonazepam may, depending
on dosage, administration and individual susceptibil
ity, modify the person’s reactions (e.g. driving ability,
behaviour in traffic).
Clinically important drug–drug interactions
Because the risk of CNS depression is increased when
benzodiazepines 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.
Prototype summary: Diazepam
Indications:
Management of anxiety disorders; acute
alcohol withdrawal; muscle relaxant; treatment
of tetanus; adjunct in status epilepticus and severe
recurrent convulsive seizures; preoperative relief
of anxiety and tension; management of epilepsy
in people who require intermittent use to control
bouts of increased seizure activity.
Actions:
Acts in the limbic system and reticular
formation; potentiates the effects of GABA; has
little effect on cortical function.
Pharmacokinetics:
Route Onset
Peak
Duration
Oral
30–60 mins 1–2 hours
3 hours
IM 15–30 mins 30–45 mins 3 hours
IV 1–5 mins
30 mins
15–60 mins
Rectal Rapid
1.5 hours
3 hours
T
1/2
:
20 to 80 hours; metabolised in the liver,
excreted in the urine.
Adverse effects:
Drowsiness, sedation, depression,
lethargy, apathy, fatigue, disorientation,
bradycardia, tachycardia, paradoxical excitatory
reactions, constipation, diarrhoea, incontinence,
urinary retention, drug dependence with
withdrawal syndrome.
S
uccinimides
The currently available succinimide is ethosuximide
(
Zarontin
). Ethosuximide is most frequently used to
treat absence seizures, a form of generalised seizure.
Therapeutic actions and indications
Although the exact mechanism of action is not under
stood, ethosuximide suppresses the abnormal electrical
activity in the brain that is associated with absence
seizures. The action may be related to activity in inhib
itory neural pathways in the brain (see Figure 23.2).
