L03 Antiepileptics

Question 1

Explain what is a seizure.

Answer 1

Paroxysmal (unpredictable outburst) event due to abnormal, hypersynchronous (i.e. very coordinated fashion) discharge from mass of CNS neurons.

Results in a diverse range of manifestations, ranging from convulsions (observable) to an experience (subjective).

Question 2

A single seizure due to a correctable or avoidable circumstance is indicative of epilepsy. True or false?

Answer 2

False!!

• Epilepsy MUST be CHRONIC in nature, characterised by seizures.
• Single seizure provoked by alcohol, hypoglycaemia, pyrexia or sleep deprivation is NOT necessarily indicative of epilepsy!!

Question 3

What are some factors to determine the risk of recurrent seizures in patients with a Hx of seizure?

Answer 3

Lower risk (30-50%) of recurrent seizures:

• Only had a single seizure previously
• Normal electroencephalogram (EEG)
• Normal brain scan

Higher risk (80%) of recurrent seizures:

• Hx of previous (undiagnosed) recurrent seizures
• Epileptiform EEG
• Abnormal brain scan (e.g. cysts, tumours)

Question 4

How is epilepsy clinically diagnosed?

Answer 4

1) Requires accurate diagnosis from clinical history & examination
- No rush to diagnose as epilepsy is NO trivial matter.
2) Requires appropriate investigations
- Blood tests (LFT, blood chemistry)
- Electroencephalogram (EEG)
- Brain scan (CT/MRI)
3) Determine the risk of recurrent seizures
- High risk of recurrent seizures may require formal diagnosis of epilepsy
- Otherwise, Dr may adopt a more “watch-and-see” approach.

Question 5

Explain the pathophysiology of seizures.

Answer 5

• Excessive synchronous neural depolarisation (“firing”), usually starting from defined regions (foci) & spreading to other regions.
• Due to unbalanced excitatory & inhibitory receptor / ion channel function which favours depolarisation (-70mV to -50mV)
• Results in a dysregulated discharge displayed as epileptiform EEG

Question 6

Describe the etiology of epilepsy.

Answer 6

1) Congential / Hereditary causes
- E.g. loss / deficiency of ion-channels due to genetic mutations
2) Brain injury, scarring or tumour
3) Infections
- E.g. meningitis or encephalitis
4) Blood glucose alterations
- E.g. chronic hypoglycaemia
5) Metabolic disorders
- E.g. adrenal insufficiency leading to hyponatremia

Question 7

What are some differential diagnoses of epilepsy when a patient is presented with a Hx of seizure?

Answer 7

1) Seizure frequency
- Persistent/Recurrent (> 1) episodes is highly indicative of epilepsy

2) Loss of awareness can be also due to:
- Transient cardiac arrhythmia
- Transient ischaemic attacks
- Hypoglycaemia
- Panic attacks

3) Abnormal movements can also be due to:
- Movement disorders in sleep and wake
- Tremor or paroxysmal choreoathetosis or dystonia
- Drop attacks and cataplexy

Question 8

Classify the various types of epilepsy.

Answer 8

1) General seizures (involves loss of awareness affecting the ENTIRE brain i.e. ALL lobes)
- Tonic clonic (Grand mal): Most dramatic archetypal seizure
- Absence (Petit mal): More subtle loss of consciousness before returning to full awareness; may lose track of time while zoned out
- Myoclonic: Involves clonus (repetitive movement of muscles)
- Atonic: Flopping (no muscle tones)

2) Partial seizures (involves ONLY frontal & temporal lobes of brain)
- Simple: Consciousness not impaired
- Complex: Consciousness impaired

3) Status epilepticus
- Life-threatening EMERGENCY
- In continuous, successive seizure episodes w/o break
- i.e. seizure for >= 5 minutes, followed by recovery & subsequently enter into another episode

Question 9

What is the therapeutic rationale behind using antiepileptics?

Answer 9

General MOA:

1) Decrease membrane excitability by altering Na+ & Ca2+ conductance during action potentials
2) Enhance effects of inhibitory GABA neurotransmitters.

However, NOT all compounds are effective against ALL types of seizures!!

Question 10

Which antiepileptic is effective against all types of seizures?

Answer 10

Valproate

Question 11

Which type of seizure is carbamazepine NOT effective against?

Answer 11

Absence / Petit mal seizures

Question 12

Phenytoin is effective against all types of seizures. True or false?

Answer 12

FALSE!!
Phenytoin is ineffective against the treatment of absence / petit mal seizures!
- Only valproate is effective out of the three primary antiepileptic agents!

Question 13

List the first-line antiepileptics used for the Tx of newly diagnosed partial and generalised tonic clonic seizures.

Answer 13

Phenytoin, carbamazepine & valproate

Question 14

Which antiepileptic drug should be selected as the initial Tx for epilepsy? Why so?

Answer 14

Initial Tx: Monotherapy of any one available antiepileptic

• No preference based on MOH CPG due to similar efficacy in newly diagnosed epilepsy.
• Individualised Tx based on seizure type, epilepsy syndrome, co-medications, comorbidities & individual’s lifestyle and preferences
• If ADR develops or unsuccessful Tx, change to another antiepileptic, BUT remain as monotherapy.

Question 15

Routine checking of antiepileptic drug levels should be conducted. True or false?

Answer 15

False!

Routine checking of antiepileptic drug levels w/o a clear indication is NOT required & is NOT cost-effective.

Question 16

Under what conditions should antiepileptic drug levels be monitored?

Answer 16

1) Assessment of adherence to drug Tx for pt. w/ refractory epilepsy
2) Assessment of symptoms due to possible toxicity
3) Titration of phenytoin dose

Question 17

What are some factors that increase the risk of breakthrough seizures?

Answer 17

1) Non-adherence/compliance to antiepileptic medications
2) DDI/FDI which lowers antiepileptic blood levels
3) Alcohol abuse
4) Sleep deprivation
5) Concurrent illness

Question 18

TM is a 35-year-old female who is currently presented to the emergency department due to a seizure experienced earlier in the day. Upon recovery, she mentioned this was her first time experiencing such an episode during Hx taking. TM has never been admitted to the hospital, has normal renal function and has no known drug allergies. Her CT scan & EEG results returned as normal. Should TM be started on first-line antiepileptic?

Answer 18

No! Observe & probe further on possible causes of seizures outside of epilepsy first.

• 60-70% chance that starting antiepileptic Tx is unnecessary due to single seizure episode w/ normal CT scan & EEG results.
• Tx is unlikely to alter long term prognosis & pt may be subjected to unnecessary side effects of medications
• Prevailing smx indicate lower risk of recurrent seizures

Question 19

MT is a 29-year-old newly married female who is recently diagnosed with epilepsy with a history of absence seizures. What is your recommended antiepileptic to MT?

Answer 19

Valproate

- Use lowest dose possible to control seizures.

Question 20

CW is a 27-year-old newly married female who is recently diagnosed with epilepsy with a history of generalised tonic clonic seizures & has expressed an interest to start a family soon in passing. What is your recommended antiepileptic to CM?

Answer 20

Either carbamazepine or valproate.

• Phenytoin is less preferred due to its teratogenic side-effects.
• Decide based on safety & cost-effectiveness
• Use lowest dose possible to control seizures.

Question 21

Explain the mechanism of action of phenytoin.

Answer 21

Blockade of voltage-dependent Na+ channels

Question 22

Explain the mechanism of action of carbamazepine.

Answer 22

Blockade of voltage-dependent Na+ channels

Question 23

Explain the mechanism of action of valproate.

Answer 23

1) Blockade of voltage-dependent Na+ & Ca2+ channels
2) Inhibit GABA transaminase from breaking down GABA, resulting in increased GABA availability as inhibitory neurotransmitters

Question 24

Which antiepileptic agent requires therapeutic dose monitoring due to its saturable kinetics & non-linear dose-PDC relationship?

Answer 24

Phenytoin

- Relatively narrow therapeutic range of 40-100 uM

Question 25

Which patient population is phenytoin contraindicated for in the Tx of epilepsy?

Answer 25

Pregnancy, due to its teratogenicity

Question 26

What rare, adverse side effect should one be concerned about when prescribing carbamazepine for the Tx of epilepsy?

Answer 26

Aplastic anaemia (2 per million per year)
- Results in a complete wipeout of stem cells within the bone marrow -> life-threatening emergency

Question 27

Which class of drugs should you watch out for when dispensing carbamazepine to a patient for the Tx of epilepsy?

Answer 27

CYP450 substrates

• Carbamazepine is a CYP450 autoinducer that accelerates the elimination of other drugs.
• T1/2 of carbamazepine shortens with repeated doses

Question 28

Which class of drugs should you watch out for when dispensing valproate to a patient for the Tx of epilepsy?

Answer 28

Highly plasma protein-bound drugs

- Valproate displaces other antiepileptics & drugs that exhibit high plasma protein binding

Question 29

What are some general side effects of antiepileptics?

Answer 29

Dose-related:

• Drowsiness, confusion, nystagmus (cross-eyed)
• Ataxia (abnormal, uncoordinated movement)
• Slurred speech, nausea
• Unusual behaviour, mental changes, coma

Non-dose-related:

• Hirsutism, acne
• Gingival hyperplasia
• Folate deficiency
• Osteomalacia (bone softening)
• Hypersensitivity reactions (incl. SJS)

Question 30

Which class of drugs may be used as alternatives to first-line antiepileptics for the Tx of epilepsy?

Answer 30

Intermediate-acting benzodiazepine (BZDs):
Clonazepam & lorazepam

Long-acting benzodiazepine (BZDs):
Diazepam

MOA: Enhances GABA binding to GABA-A receptors and potentiates the effects of inhibitory GABA neurotransmitters via allosteric binding to BZD site.

Question 31

Short-acting BZDs (e.g. midazolam) can be used for the chronic treatment of seizures. True or false?

Answer 31

False!
Only intermediate-acting & long-acting BZDs should be used as alternatives.
However, first-line antiepileptics should be used instead when possible (i.e. phenytoin, carbamazepine & valproate)!