Pharmacology of Anticonvulsants (Epilepsy)

Question 1

What are the core drugs used to treat Epilepsy?

Answer 1

Lamotrigine
Sodium Valproate
Diazepam
Levetiracetam

Question 2

What is the primary mechanism of action of Lamotrigine?

Answer 2

Blocks voltage gated Na+ channels preventing Na+ influx. Prevents depolarisation of glutamatergic neurones and reduces glutamate excitotoxicity

Question 3

What is the drug target of Lamotrigine?

Answer 3

Voltage gated Na+ channels

Question 4

What are the main side effects of Lamotrigine?

Answer 4

Common: Rash, drowsiness
Less common but serious: Steven-Johnson’s syndrome, suicidal thoughts

Question 5

How should you introduce Lamotrigine to a patient?

Answer 5

Introducing lamotrigine gradually is one of the keys to reducing the frequency and severity of allergic skin reactions.

Question 6

What is the primary mechanism of action of sodium valproate?

Answer 6

Inhibition of GABA transaminase prevents the breakdown of GABA. This increases GABA concentrations directly in the synapse presynaptically and also indirectly prolongs GABA in the synapse due to the fact that extraneuronal metanolism of GABA is slowed which also slows GABA removal from the synapse.

Question 7

What is the drug target of sodium valproate?

Answer 7

GABA transaminase

Question 8

What are the main side effects of Sodium Valproate?

Answer 8

Common: Stomach pain and diarrhoea, drowsiness, weight gain, hair loss
Serious: hepatotoxicity, teratogenicity, pancreatitis

Question 9

What effect does Sodium Valproate have on other drugs?

Answer 9

Broad CYP enzyme inhibitor - increases serum concentration of many co-administered drugs

Question 10

What is the primary mechanism of action of Diazepam?

Answer 10

Increases choride ion influx in response to GABA binding at the GABA A receptor. Increased chloride ion influx associated with hyperpolarisation of excitatory neurones.

Question 11

What is the drug target of Diazepam?

Answer 11

Benzodiazepine site on the GABA A receptor

Question 12

What are the main side effects of Diazepam?

Answer 12

Common: Drowsiness, respiratory depression (if i.v. or at high dose)
Uncommon but serious: Haemolytic anaemia, jaundice

Question 13

Can Diazepam used long-term? Why?

Answer 13

No: Main reason that diazepam is not used for long term suppression of seizures is due to the development of tolerance.
Diazepam is a Schedule 4 controlled drug - addiction prone individuals more likely to become dependent on diazepam.

Question 14

What is the primary mechanism of action of Levetiracetam?

Answer 14

Inhibition of the synaptic vesicle protein SV2A. It inhibits this protein and prevents vesicle exocytosis. A reduction in glutamate secretion is reduces glutamate excitotoxicity

Question 15

What is the drug target of Levetiracetam?

Answer 15

Synaptic vesicle protein SV2A

Question 16

What are the main side effects of Levetiracetam?

Answer 16

Common: dizziness, somnolence, fatigue and headache

Question 17

What are some benefits of Levetiracetam?

Answer 17

The metabolism of levetiracetam has no effect on the cytochrome P450 enzyme system so it is favorable in terms of no drug–drug interactions.

Question 18

What is “the seven steps” approach to prescribing treatment?

Answer 18

1. Identify the patient’s problem
2. Specify the therapeutic objective
3. Select a drug on the basis of comparative efficacy, safety, cost and suitability
4. Discuss choice of medication with patient (and carer) and make a shared decision about treatment
5. Write a correct prescription
6. Counsel the patient on appropriate use of the medicine
7. Make appropriate arrangements for follow up (Monitor/stop the treatment)

Question 19

What 2 things affect the type of treatment patients receive for epilepsy?

Answer 19

Treatment dependent on type of seizure and individual patient

Question 20

Why is there a difference in treatment between men (and post-menopausal women) and women of child-bearing potential for the drug prescribed?

Answer 20

Drugs can have effects on a fetus:
“Valproate” causes:
- Neural tube defects
- Decreased IQ
- Autism
(after in utero exposure)

Question 21

How can Lamotrigine affect the combined oral contraceptive pill (COC)?

Answer 21

COC appears to have an impact on lamotrigine blood levels – coadministration leads to a reduced level of lamotrigine in the blood.
- REDUCED SEIZURE CONTROL
*COC may reduce lamotrigine absorbtion so less gets into the blood in the first place
*COC may enhance lamotrigine metabolism and so more is cleared from the blood
*COC may enhance lamotrigine excretion and thus enhance clearance from the blood

Lamotrigine does not appear to have an impact on blood ethinyl estradiol levels.
-NO CONTRACEPTIVE FAILURE

Question 22

Why does the combined oral contraceptive (COC) pill affect the levels of Lamotrigine in our blood?

Answer 22

(COC appears to have an impact on lamotrigine blood levels – coadministration leads to a reduced level of lamotrigine in the blood.)

There is an enzyme “uridine diphosphate glucuronic acid (UDPGA)” that converts Lamotrigine into its inactive form, Lamotrigine N2-glucuronide (LTG-Gluc)

The COC pill induces this enzyme; less active lamotrigine

Question 23

How would you tackle the issue of reduced Lamotrigine, if prescribing it to a patient on the COC pill?

Answer 23

COC= combined oral contraceptive pill
1. Increase dose of lamotrigine
2. Change contraception

Question 24

What is a common issue with AED’s?

Answer 24

AED= anti-epileptic drugs
- Drug-drug interactions are common
- Frequently involve drug-induced changes in liver metabolism
- Antiepileptic drugs commonly interfere with metabolism of other drugs (incl COC)