Anticonvulsants for Pharmacology and Therapeutics Flashcards
What is an epileptic seizure?
Manifestation of an abnormal or excessive synchronised discharge of a set of cerebral neurones
What is epilepsy?
A tendency to recurrent, unprovoked seizures
What are the two main types of epilepsy?
Partial/Focal – the excess discharge is localised to one area of the brain
Generalised – the synchronised discharge affects all brain areas
When are the two peaks in incidence of epilepsy and what are they usually caused by?
Young adults – where genetic predispositions begin to manifest
Later years – when patients start getting brain injuries e.g. stroke
What proportion of epilepsy is idiopathic?
70%
What is a key characteristic of absence seizures?
3 Hz brain activity
What are the possible harms that can be done to the patient by giving anti-epileptic drug therapy?
Psychosocial consequences (illness status etc.) Idiosynchratic and dose-related
State some factors influencing the decision to treat.
Number of seizures at presentation
Seizure type and severity
Cause of seizure
What are the main mechanisms of anti-epileptic drugs?
Enhancing GABA-mediated inhibition
Inhibiting glutamate-mediated excitation
Na+ channel blockade (blocking nerve conduction)
Calcium channel blockade
Give an example of a group of drugs that enhance GABA-mediated inhibition.
Benzodiazepines
Name two drugs that inhibit glutamate-mediated excitation.
Presynaptic – levatiracetam
Postsynaptic – parampanel
Name three drugs that exert their effect as AEDs by blocking action potentials (Na+ channel blockade).
Phenytoin
Carbamazepine
Lamotrigine
What is the main mechanism of current anti-epileptic drugs?
Sodium channel blockade
It causes use-dependency blockade meaning that it only blocks the nerve conduction when the neurones are firing excessively (i.e. during a seizure) and so the drugs inhibit seizures without affecting normal cognitive function
What does Levatiracetam bind to in order to inhibit glutamate release?
SV2A
This is a protein found on the synaptic vesicle membrane
What are the two main excitatory receptors?
AMPA and Kainate (Na+/Ca2+ channel)
NMDA
Name two important drugs that block the presynaptic calcium channel, hence preventing neurotransmitter exocytosis.
Gabapentin
Pregabalin
Describe the difference in terms of the old and new anti-epileptics in terms of efficacy and pharmacokinetics.
The new ones are no more effective than the old ones at preventing seizures but they have better pharmacokinetics and are better tolerated
What are the main principles of AED therapy?
Discuss risks and benefits with the patient
One AED where possible
Therapeutic drug monitoring is of little use
Never withdraw drugs suddenly (could cause status epilepticus)
Make one change at a time
Consider drug interactions
Why is drug monitoring of little use with most AEDs? What is the exception?
Because of the blood-brain barrier, the amount of drug in the blood has little relationship with the amount in the brain
Exception – phenytoin
What are the two main enzymes that are responsible for metabolizing phenytoin?
CYP4502C9 (mainly)
CYP2C19
Describe the enzyme kinetics of phenytoin.
They are saturable
So once the enzymes get saturated, there is a large increase in plasma concentration of the drug for every small increase in dose
Describe the effects of important AEDs on hepatic enzymes.
Phenytoin and Carbamazepine – hepatic enzyme INDUCERS
Valproate – hepatic enzyme INHIBITORS
List some drugs that affect phenytoin metabolism/availability.
Amiodarone and isoniazid INHIBIT phenytoin metabolism
Aspirin displaces phenytoin from plasma protein binding thus increasing the amount of free phenytoin
Valproate displaces phenytoin from plasma protein binding and it INHIBITS phenytoin metabolism
Generally speaking, avoid using valproate and phenytoin together
List some of the effects of phenytoin on other drugs.
Warfarin – increased metabolism of warfarin
Increased clearance of lamotrigine, corticosteroids, cyclosporin
Decreased effectiveness of the oral contraceptive pill
State some drugs that induce carbamazepine metabolism.
Phenytoin
Phenobarbital
What are the two most severe forms of allergic reaction to AEDs?
Stevens-Johnsons Syndrome
Toxic Epidermal Necrosis
What polymorphism confers increased risk of getting these severe allergic reactions?
HLA-B*1502
