Anticonvulsants

Question 1

What are the different types of seizures?

Answer 1

Generalised: (originate from whole cerebrum and consciousness always lost)

• Tonic-clonic
• Absence
• Tonic-atonic
• Myoclonic
• Status epilepticus

Partial: (arise in specific often small loci of cortex in one hemisphere)

• Simple - no alteration in consciousness
• Complex - awareness is altered or lost

Question 2

By what is anti-convulsant therapy determined?

Answer 2

• Seizure type

- Pharmacodynamic and pharmacokinetic properties of specific anti-convulsant drugs

Question 3

What is epilepsy?

Answer 3

Neurological condition causing frequent seizures

Question 4

What is a seizure?

Answer 4

Sudden change in behaviour caused by electrical hypersynchronisation of neuronal networks in the cerebral cortex

Question 5

What neurotransmitter is involved in epilepsy?

Answer 5

Glutamate - excitatory

Question 6

What are the main mechanisms of action of drugs used in epilepsy?

Answer 6

1. Interaction with voltage-dependent Na channels
2. Direct or indirect enhancement of GABA transmission
3. Interaction with neuronal Ca channels
4. Blocking receptors for excitatory neurotransmitters

Question 7

What drugs can be used to block voltage-gated Na channels and how do they work? What types of seizures do they treat?

Answer 7

BOTH REDUCE GLUTAMINERGIC NEURONAL ACTIVITY

1. Carbamezepine - partial, tonic-clonic
   - Stabilises inactive state of Na channel –> reduces neuronal activity
   - Fast onset=1h
   - Long half life initially (36+h) decreases w/chronic treatment (20h or less)
   - CYP450 inducer tf many potential interactions with other drugs metabolised by CYP450
   - Normal (first-order) kinetics, usually twice-daily dosage
2. Lamotrigine - tonic-clonic, absence
   - Inactivates Na channels
   - Fast onset=1h
   - Long half life
   - Mostly metabolised by conjugation, apparently this is inhibited by valproate
   - Adverse effects are mostly dose dependent: dizziness, sedation, diplopia

Question 8

Which classes of drugs can be used to inhibit glutaminergic neuronal activity?

Answer 8

1. Voltage-gated Na channel blockers
2. Voltage-gated Ca channel blockers
3. Drugs that effect glutamate exocytosis and receptors

Question 9

What drug can be used to block voltage-gated Ca channels and how does it work? What types of seizures do they treat?

Answer 9

INHIBITS GLUTAMINERGIC NEURONAL ACTIVITY

1. Ethosuximide - absence
   - Long half life = 50h
   - T-type Ca channel antagonist
   - Decrease activity in relay thalamic neurones

Question 10

What drugs affect glutamate exocytosis and receptors and how do they work? What types of seizures do they treat?

Answer 10

INHIBIT GLUTAMINERGIC NEURONAL ACTIVITY

1. Levetiracetam - myoclonic
   - Binds to synaptic vesicle associated protein (SV2A) to prevent glutamate release
   - Fast onset = 1h
   - Medium half-life (6-8h)
   - Renal clearance
   - Adverse effects are dose dependent: sedation, dizziness
2. Topiramase - myoclonic
   - Fast onset = 1h
   - Half life = 20h
   - Inhibits NMDA Rs (glutamate R) + kainate Rs
   - Also affects VGSCs + GABA Rs

Question 11

How can GABA be enhanced?

Answer 11

1. Drugs affecting GABA A receptors - diazepam

2. GABA transaminase inhibitors - sodium valproate

Question 12

How does sodium valproate work?

Answer 12

• Inhibits GABA transaminase to enhance GABA
• Treats all types of epilepsy
• Onset = 1h
• Half life = 12h tf usually twice daily dosage
• Increases GABA mediated inhibition
• Increases GABA, decreases glutamate (b/d product of GABA) –> reduces excitation
• Extensively metabolised but not by CYP450
• Does inhibit some forms of CYP450

Question 13

How does diazepam work?

Answer 13

• Positive allosteric modulator of GABA A receptors
• Increases GABA-mediated inhibition
• Increases activity of GABA binding to channel
• Rectal gel
• Onset = 15 mins
• Half life = 2h
• Used in status epilepticus (emergency)