Anticonvulsants for Pharmacology and Therapeutics

Question 1

What is a seizure?

Answer 1

Seizures are sudden changes in behaviour caused by electrical hypersynchronization of neuronal networks in the cerebral cortex ie UNCOORDINATED rapid firing of neurones in the brain (caused by INCREASE in EXcitatory neurotransmission or DECREASE in INhibitory neurotransmission)

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 can cause seizures after the stroke due to brain damage

Question 5

What proportion of epilepsy is idiopathic?

Answer 5

70%

Question 6

What are absence seizures

Answer 6

brief staring episodes with behavioural arrest (NO JERKY MOVEMENTS etc. its essentially just someone going into a ‘quiet state’ staring at something)

Question 7

Describe the sequence of events in tonic clonic seizures

Answer 7

loss of consciousness
muscle stiffening (hence tonic)
jerking/twitching (hence clonic)
deep sleep 
wakes up (this seizure is what most people see in films etc)

Question 8

What are the main mechanisms of anti-epileptic drugs?

Answer 8

Inhibit Glutamate mediated excitation

• VGSC inhibitor
• VGCC inhibitor
• SV2A inhibitor (synaptic vesicle protein)
• glutamate receptor antagonist

Enhancing GABA mediated inhibition

• benzodiazepines (Positive Allosteric Modulators)
• GABA transaminase inhibitors (stop GABA breakdown)

Question 9

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

Answer 9

Benzodiazepines

Question 10

Name two drugs that inhibit glutamate-mediated excitation.

Answer 10

Presynaptic – levatiracetam

Postsynaptic – parampanel

Question 11

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

Answer 11

Phenytoin
Carbamazepine
Lamotrigine

Question 12

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

Answer 12

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 13

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

Answer 13

SV2A

This is a protein found on the synaptic vesicle membrane

Question 14

What are the two main excitatory receptors?

Answer 14

AMPA and Kainate (Na+/Ca2+ channel)

NMDA

Question 15

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

Answer 15

Gabapentin

Pregabalin

Question 16

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

Answer 16

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

Question 17

What are the main principles of AED therapy?

Answer 17

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 18

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

Answer 18

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 19

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

Answer 19

CYP4502C9 (mainly)

CYP2C19

Question 20

Describe the enzyme kinetics of phenytoin.

Answer 20

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 21

Describe the effects of important AEDs on hepatic enzymes.

Answer 21

Phenytoin and Carbamazepine – hepatic enzyme INDUCERS

Valproate – hepatic enzyme INHIBITORS

Question 22

List some drugs that affect phenytoin metabolism/availability.

Answer 22

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 23

List some of the effects of phenytoin on other drugs.

Answer 23

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

Question 24

State some drugs that induce carbamazepine metabolism.

Answer 24

Phenytoin

Phenobarbital

Question 25

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

Answer 25

Stevens-Johnsons Syndrome

Toxic Epidermal Necrosis

Question 26

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

Answer 26

HLA-B*1502

Question 27

Tonic and atonic seizures definition?

Answer 27

Tonic/atonic seizures: sudden muscle stiffening (tonic)/sudden loss of muscle control (atonic)

(basically tonic clonic seizure but just the muscle elements)

Question 28

What do you call seizures that are ‘briefer’ versions of tonic seizures?

Answer 28

Myoclonic seizures: sudden, brief muscle contractions. Similar to tonic seizures but shorter time period

Question 29

What is the most severe type of seizure

Answer 29

status epilepticus

> 5 min of continuous seizure activity. Can manifest as any one of the 4 mentioned above. This is the most severe type