34. Anticonvulsants Flashcards
What is epilepsy and how is it classified?
Epilepsy is a chronic disease
resulting from
paroxysmal, episodic, abnormal and spontaneous discharge
of electrical activity in the brain.
It can be classified as
follows:
GENERALISED
Involve both cerebral hemispheres. Consciousness
is impaired.
Tonic-clonic (Grand mal) Tonic Myoclonic Absence (Petit mal) Akinetic
PARTIAL
(also called FOCAL)
Occurs in one region of the brain.
Further subdivided into:
SIMPLE PARTIAL
Consciousness preserved.
Confined to one brain region,
often temporal lobe or hippocampus.
Symptoms depend on origin, e.g. extreme emotion, hallucinations (auditory, altered visual perception, olfactory), déjà-vu, etc. Patients remember the event.
COMPLEX PARTIAL
Consciousness impaired.
Confined to one brain region,
most commonly the temporal
lobe.
Patient may still be able
to communicate very simply or
follow simple instructions,
and occasionally continue complex tasks, e.g. driving. Seizures cause automatisms (stereotyped movements),
e.g. lip smacking, chewing, picking or noises, e.g. moaning, stereotyped speech. Usually last 30 s − 2 min.
No memory of event.
A simple partial seizure may progress
to become complex. They may both become
generalised. A simple seizure is called an
‘aura’ when it precedes another seizure.
Which drugs are available to treat epilepsy and how do they work?
There are a wide variety of anticonvulsants available, but their mechanisms of action can be divided into two main groups:
1 > Drugs enhancing GABA- mediated inhibition – benzodiazepines, barbiturates, sodium valproate and vigabatrin.
2
> Drugs modulating sodium flux in nerves –
phenytoin and carbamazepine.
This latter group of drugs exert
their effect by binding to
inactivated fast Na+ channels,
reducing the flux of Na+ into cells
and stabilising their membranes.
Ca2+ and K+ efflux are also reduced.
Their anticonvulsant effect is probably
achieved by preventing the repetitive opening
and closing of fast Na+ channels,
so that the sodium current is reduced
until it no longer provokes an action potential.
Drugs enhancing GABA-mediated inhibition:
Drugs enhancing GABA-mediated inhibition:
1 > Benzodiazepines, e.g. diazepam (see spider diagrams, Chapter 37, ‘Miscellaneous drugs’, benzodiazepines).
Benzodiazepines (BDZ) appear to have
their own specific receptors,
which are closely coupled to the GABAA receptor.
When a BDZ binds it facilitates the
binding of GABA to its
respective receptor.
BDZs exert their effect by increasing
the frequency of opening
of the GABAA channels.
There are two types of BDZ receptor:
• BDZ1 found in the spinal cord
and cerebellum.
Stimulation causes anxiolysis.
• BDZ2 found in the
spinal cord,
hippocampus
and cerebral cortex.
Stimulation causes sedation
and has an anticonvulsant effect.
Other non BZD Gaba
2 > Barbiturates, e.g. phenobarbitone Barbiturates increase the duration of opening of the GABAA chloride channel when stimulated.
3
> Sodium valproate –
refer to the spider diagram
4
> Vigabatrin:
This reversibly inhibits GABA transaminase,
the enzyme that breaks down GABA.
Drugs modulating sodium flux in nerves:
> Phenytoin –
refer to spider diagram
> Carbamazepine –
refer to the spider diagram
How would you anaesthetise a patient with epilepsy?
Pre-operative assessment:
Pre-operative assessment:
Take a full and
through anaesthetic history,
paying close attention to the following:
> History of the epileptic activity
> Underlying pathology or lesion causing the seizures
> Type, frequency and duration
of the seizures and when the last one occurred
> Occupation and driving status
> Drug history.
It is important that the patient receives
their medication in a timely manner.
If they are nil by mouth for any prolonged period,
appropriate medication should be given by an alternative route,
e.g. rectally or intravenously.
This should be discussed with a neurologist.
Anaesthetic for Epileptic patients
Pre-operative care:
> Induce anaesthesia using thiopentone.
> Avoid ketamine and etomidate
as they can lower the seizure threshold.
> Anticonvulsants induce liver
enzyme activity
and
therefore the patient may need
increased doses of
anaesthetic agents and muscle relaxants.
> Avoid hypoxia and hypercapnia
throughout the procedure as
these states can lower the seizure threshold.
> Avoid tramadol as this
can lower seizure thresholds.
Propofol is said to cause epileptiform movements,
but it has not been shown to
produce epileptiform activity on the EEG.
In some units it is used in the treatment
of status epilepticus and
so it is probably safe for
routine use in patients with epilepsy.
Describe the GABA receptor.
GABA (gamma amino-butyric acid)
is the main inhibitory
neurotransmitter in the CNS.
The activation of the GABA receptor
causes increased
flux of chloride
or
potassium ions
into the cell and causes hyperpolarisation
of the membrane,
therefore stabilising the synapse.
There are two GABA receptor subtypes:
> GABAA:
A ligand-gated chloride ion channel,
with five receptor subunits
(2α, 2β, γ) arranged
around the ion channel.
These are found on the post-synaptic membrane.
> GABAB:
A G-protein-coupled receptor.
Stimulation of GABAB causes increased
potassium conductance.
These are found on both the
pre- and postsynaptic membranes.
Baclofen acts via these receptors.
PHENYTOIN
Dose
Range
MOA
Uses
PHENYTOIN
Anticonvulsant
Class 1b antiarrhythmic
- Capsules: 25/50/100/300 mg
- Syrup: 6 mg/mL
- Solution: 50 mg/mL
DOSE
• Loading: 15 mg/kg for treatment of seizure
- Maintenance: 100 mg 8 hourly
- Oral dose: 200–600 mg daily
- Therapeutic range: 10–20 mg/L
MOA
1 • Binds to inactivated fast Na+ channels
reducing Flux of Na+ into cells
and stabilising the membrane
2 • Ca2+ and K+ efflux also reduced
3 • Anticonvulsant effect probably achieved by
preventing repetitive opening and closing of fast
Na+ channels,
so that the sodium current is
reduced until it no longer provokes
an action potential
USES
• Treatment and prophylaxis of tonic-clonic seizures
• Trigeminal neuralgia
• Antiarrhythmic (Class 1b) used to treat ventricular
arrhythmias of tricyclic and digoxin overdose
PHENYTOIN
ADME
METABOLISM
AND EXCRETION
• Hepatic metabolism
• Exhibits zero order kinetics just above
therapeutic range so care should be taken
with dosing so as not to cause toxicity
• 80% renally excreted
• Potent liver enzyme inducer, so check for
drug interactions
• Increases the required dose of
aminosteroid muscle relaxants by 80%
• May decrease MAC of volatiles
ABSORPTION/
DISTRIBUTION
- Oral bioavailability 90%
- Protein binding 90%
- VD 0.5 L/kg
PHENYTOIN
Effects
CVS 2
Idiosyncratic 9
Concentration 7
Major concern x4
EFFECTS
CVS
• Class 1b shortens refractory period of
cardiac muscle.
Rapid injection can cause heart block,
VF and asystole
CNS
• Antiepileptic
SIDE-EFFECTS
Idiosyncratic:
- Hirsuitism
- Coarse facies
- Acne
- Gum hyperplasia
- Megaloblastic anaemia
- Aplastic anaemia
- Rashes
- SLE
- Peripheral neuropathy
Concentration-dependent:
- Nausea and vomiting
- Tremor
- Ataxia
- Nystagmus
- Vertigo
- Drowsiness
Teratogenicity: • Craniofacial abnormalities • Limb abnormalities • Cardiac abnormalities • Growth retardation
SODIUM VALPROATE
Dose
MOA 3
Uses 3
SODIUM VALPROATE
Anticonvulsant
- Tablets: 100/200/500 mg
- Syrup: 40 mg/mL
- Powder: 400 mg ampoules for dissolution in water
DOSE
- 600–2500 mg/day in 2 divided doses
- Therapeutic range 40–100 mg/L
MOA
• Inhibits succinic semialdehyde dehydrogenase
and so increases brain levels of GABA
• It may have some stabilising
effect on sodium channels
• May mimic the action of
GABA at postsynaptic receptors
USES
• Treatment of epilepsy,
especially generalised seizures
and infantile spasms
- Chronic pain
- Mood stabiliser in mental illness
SODIUM VALPROATE
adme
ABSORPTION/ DISTRIBUTION
- Oral bioavailability almost 100%
- Protein binding 90%
- VD 0.1–0.4 L/kg
- t½ 8–20 hours
METABOLISM
AND EXCRETION
• Hepatic metabolism
• Small amout excreted in urine, unchanged
SODIUM VALPROATE
Effects
cns 2
gi 3
Other 3
Haem 2
EFFECTS
CNS
• Antiepileptic
• Drowsiness
GI
• Hepatic dysfunction
(contraindicated in
liver disease. Monitor
LFTs with chronic use)
- Pancreatitis
- Nausea and vomiting
OTHER
- Hair loss
- Weight gain
- Oedema
HAEMATOLOGICAL
• Thrombocytopenia and ↓ aggregation
(check platelet function
prior to regional/ neuroaxial blockade)
• Impaired clotting reported
CARBAMAZEPINE
CARBAMAZEPINE
Anticonvulsant
- Tablets: 100/200/400 mg
- Suppositories: 125/250 mg
- Syrup: 20 mg/mL white
DOSE
• 100–1600 mg/day
MOA
• Binds to inactivated fast Na+ channels
reducing flux of Na+ into cells
and stabilising the membrane
• Ca2+ and K+ efflux also reduced
• Anticonvulsant effect probably
achieved by preventing repetitive
opening and closing of fast Na+ channels,
so that the sodium current is
reduced until it no longer provokes
an action potential
