Anticonvulsants for Pharmacology and Therapeutics

Question 1

What is an epileptic seizure?

Answer 1

Manifestation of an abnormal or excessive synchronised discharge of a set of cerebral neurones

Question 2

What is epilepsy?

Answer 2

A tendency to recurrent, unprovoked seizures

Question 3

What are the two main types of epilepsy?

Answer 3

Partial/Focal – the excess discharge is localised to one area of the brain
Generalised – the synchronised discharge affects all brain areas

Question 4

When are the two peaks in incidence of epilepsy and what are they usually caused by?

Answer 4

Young adults – where genetic predispositions begin to manifest
Later years – when patients start getting brain injuries e.g. stroke

Question 5

What proportion of epilepsy is idiopathic?

Answer 5

70%

Question 6

What is a key characteristic of absence seizures?

Answer 6

3 Hz brain activity

Question 7

What are the possible harms that can be done to the patient by giving anti-epileptic drug therapy?

Answer 7

Psychosocial consequences (illness status etc.) 
Idiosynchratic and dose-related

Question 8

State some factors influencing the decision to treat.

Answer 8

Number of seizures at presentation
Seizure type and severity
Cause of seizure

Question 9

What are the main mechanisms of anti-epileptic drugs?

Answer 9

Enhancing GABA-mediated inhibition
Inhibiting glutamate-mediated excitation
Na+ channel blockade (blocking nerve conduction)
Calcium channel blockade

Question 10

Give an example of a group of drugs that enhance GABA-mediated inhibition.

Answer 10

Benzodiazepines

Question 11

Name two drugs that inhibit glutamate-mediated excitation.

Answer 11

Presynaptic – levatiracetam

Postsynaptic – parampanel

Question 12

Name three drugs that exert their effect as AEDs by blocking action potentials (Na+ channel blockade).

Answer 12

Phenytoin
Carbamazepine
Lamotrigine

Question 13

What is the main mechanism of current anti-epileptic drugs?

Answer 13

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

Question 14

What does Levatiracetam bind to in order to inhibit glutamate release?

Answer 14

SV2A

This is a protein found on the synaptic vesicle membrane

Question 15

What are the two main excitatory receptors?

Answer 15

AMPA and Kainate (Na+/Ca2+ channel)

NMDA

Question 16

Name two important drugs that block the presynaptic calcium channel, hence preventing neurotransmitter exocytosis.

Answer 16

Gabapentin

Pregabalin

Question 17

Describe the difference in terms of the old and new anti-epileptics in terms of efficacy and pharmacokinetics.

Answer 17

The new ones are no more effective than the old ones at preventing seizures but they have better pharmacokinetics and are better tolerated

Question 18

What are the main principles of AED therapy?

Answer 18

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

Question 19

Why is drug monitoring of little use with most AEDs? What is the exception?

Answer 19

Because of the blood-brain barrier, the amount of drug in the blood has little relationship with the amount in the brain
Exception – phenytoin

Question 20

What are the two main enzymes that are responsible for metabolizing phenytoin?

Answer 20

CYP4502C9 (mainly)

CYP2C19

Question 21

Describe the enzyme kinetics of phenytoin.

Answer 21

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

Question 22

Describe the effects of important AEDs on hepatic enzymes.

Answer 22

Phenytoin and Carbamazepine – hepatic enzyme INDUCERS

Valproate – hepatic enzyme INHIBITORS

Question 23

List some drugs that affect phenytoin metabolism/availability.

Answer 23

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

Question 24

List some of the effects of phenytoin on other drugs.

Answer 24

Warfarin – increased metabolism of warfarin
Increased clearance of lamotrigine, corticosteroids, cyclosporin
Decreased effectiveness of the oral contraceptive pill

Question 25

State some drugs that induce carbamazepine metabolism.

Answer 25

Phenytoin

Phenobarbital

Question 26

What are the two most severe forms of allergic reaction to AEDs?

Answer 26

Stevens-Johnsons Syndrome

Toxic Epidermal Necrosis

Question 27

What polymorphism confers increased risk of getting these severe allergic reactions?

Answer 27

HLA-B*1502