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1
Q

Epilepsy

A

• A chronic neurologic disorder manifesting by repeated seizures (fits) which result from paroxysmal uncontrolled discharges of neurons within the CNS (grey matter disease).
• The clinical manifestations range from a major motor
convulsion to a brief period of lack of awareness.
– altered consciousness
– altered motor activity
– altered sensory phenomenon
– unusual behaviour
• Epilepsy usually presents in childhood or adolescence but may occur for the first time at any age.
• 5% population suffer a single sz at some time,
• 0.5-1% of the population have recurrent sz = EPILEPSY

2
Q

Epilepsy - Classification

A

• Partial (Focal seizures)

  • account for 80% of adult epilepsies
  • Simple partial seizures
  • Complex partial seizures
  • Partial seizures secondarily generalised

• Generalised seizures

  • Tonic-Clonic (grand mal)
  • Absence (petit mal)
  • Myoclonic
  • Status
  • Atonic
3
Q

Partial (Focal) Seizures

A

• Seizure begins locally, often resulting from focal structural lesion in the brain, may remain localised or progress to generalised seizures (spread to entire cortex);

  • Simple partial seizures:
    Motor, somatosensory or psychic symptoms; Usually no loss of consciousness

-Complex partial seizures:
Temporal lobe, psychomotor, Loss of consciousness

4
Q

Generalised Seizures

A

• Affect whole brain with loss of consciousness;

-Tonic-Clonic seizures (Grand Mal):
Initial rigid extensor spasm, respiration stops, defecation,
micturition and salivation occur (tonic phase, ~1min), Violent synchronous jerks (clonic phase, 2-4 min)

- Absence seizures (Petit Mal):
Briefly loss of awareness (10-30s)
No loss of posture tone
May occur 100+ times a day
Primarily paediatric problem
Often described as daydream, not paying attention
Usually disappear as child matures
  • Myoclonic: Seizures of a muscle or group of muscles
  • Atonic: Loss of muscle tone / strength

-Status: A condition when consciousness does not return between seizures for more than 30 min.
This state may be life-threatening with the development of pyrexia, deepening coma and circullatory collapse.
Death occurs in 5-10%

5
Q

Pathogenesis

A

• Unbalance of excitatory and inhibitory neurotransmission:
Excitation (too much) Ionic—inward Na+, Ca++ currents
Neurotransmitter—glutamate, aspartate Inhibition (too little) Ionic—inward CI-, outward K+ currents Neurotransmitter—GABA
• Abnormal electrical properties of the affected cells,
causing sudden excessive & asynchronized neuronal
firing;
• May have no obvious stimulus or may be due to trauma,
hypoglycemia, infection

6
Q

Spread of seizure

A

Spread facilitated by repeated firing:

a) ↑ [K+]out→ ↓K+ efflux
b) ↑ [Ca2+] in →↑ neurotransmitter release
c) excitory nt release (glu) promotes further depolarization

inhibition by surrounding GABAergic neurons

Na+ channel refractory period inhibits spread

7
Q

Antiepileptic drugs (AED)

A

• Aim to inhibit the abnormal neuronal discharge
rather than to correct the underlying one

  1. Inhibition of Sodium channel function:
    - carbamazepine
    - phenytoin
  2. Neuronal calcium channel blocker:
    - ethosuximide
  3. Neuronal potassium channel opener:
    - retigabine
  4. Enhancement of GABA action
    i. GABA receptor agonists
    - benzodiazepines
    - barbiturates
    ii. GABA reuptake inhibitor
    - tiagabine
    iii. GABA transaminase inhibitor
    - vigabatrin
  5. Glutamate receptor antagonist:
    - topiramate
  6. Others:
    - valproic acid
    - GABApentin
    - levetiracetam
8
Q

(1). Na+ channel inhibitors • Mechanism

A

– use dependant - inhibit cells that are firing repeatedly
(i.e those involved in seizure)
– bind preferentially to Na+ channel in refractory state
– slow channel return to resting state
– may have additional mechanisms

9
Q

(1). Na+ channel inhibitors • drugs

A

– Carbamazepine
» may also potentiate opening of K+ channels
– Phenytoin
– Lamotrigine

10
Q

(1). Na+ channel inhibitors • indications

A

– Carbamazepine – anticonvulsant, neuralgia, bipolar disease
– phenytoin
» long term (po) and rapid (i.v.) control of epilepsy
» arrhythmia –blocks cardiac Na+ channel
– lamotrigene –epilepsy

11
Q

(1). Na+ channel inhibitors • PK

A

– Carbamazepine
» metabolized by and induces cytP450 3A4 (induces its own metabolism)
» t1/2 falls (65h →20 h) on repeated use & takes 2 weeks to reach new plasma conc
» measurement of plasma conc helpful after 2 weeks
»  may take several months to titrate, may need b.i.d,
– Phenytoin
» also induces its own metabolism by Cyp 3A4
» metabolism is saturable in normal dose range
– small increase in dose can cause large increase in plasma conc
– increase dose slowly
» highly bound to plasma protein
– may be affeced by or affect other drugs bound to plasma protein
– Lamotrigene
» eliminated by glucoronidation and excretion in urine

12
Q

(1). Na+ channel inhibitors • caution

A

– Carbamazepine
» makes myoclonic and absence seizures worse!
» risk of foetal neural tube defects during pregnancy
– Phenytoin
» risk of foetal neural tube defects in pregnancy (folate antagonism)

13
Q

(1). Na+ channel inhibitors • CI

A

– Carbamazepine in patients with AV conduction abnormalities

14
Q

(1). Na+ channel inhibitors • ADR

A

– Carbamazepine
» rash – may be transient but may be intolerable
» blurred vision
» causes ADH secretion and hence water retention
» CNS effects – drowsiness & loss of balance
– Phenytoin
» immediate – CNS effects- tremor, ataxia, lethargy, coma
» after long term therapy-– altered facial features due to collagen deposition, hirsutism, acne, rash, anaemia
– Lamotrigene
» rash (refer to doctor –possible hypersensitivity)
» CNS effects- dizziness, nervousness, tremor, confusion
» GI effects – nausea, vomiting

15
Q
  1. Calcium channel inhibitors • Mechanism
A

– Inhibit “T-type” Ca2+ channel

16
Q
  1. Calcium channel inhibitors • drugs
A

– Ethosuximide

17
Q
  1. Calcium channel inhibitors • indications
A

– Absence seizures: brief interruption of consciousness, blank state
– Not effective against other generalized seizures (thought not to involve T-type Ca2+ channel)

18
Q
  1. Calcium channel inhibitors • pk
A

– Absorption from the gut is almost complete
– Metabolism in the liver is extensive
– Half-life is long at 2-3 days

19
Q
  1. Calcium channel inhibitors • ADR
A

– Nausea, vomiting, anorexia

– Drowsiness, dizziness, ataxia

20
Q

3(i). GABA receptor agonists

A

• Benzodiazepines
– Enhance GABA binding to GABAR
– promote Cl- channel opening frequency

• Drugs
– diazepam
– lorazepam
– midazolam
– clonazepam
21
Q

3(ii). GABA receptor agonists

A
• Barbiturates increase GABA Cl- channel open duration
• not widely used:
– significant sedation
– respiratory depression
– significant hypotension
Phenobarbital
• Affects duration & intensity of seizures
• Rather than seizure threshold
• Well absorbed
• 50% bound to protein
• T1/2: 50-140h
• 25% is excreted unchanged in urine
• The remaining 75% is metabolised by hepatic microsomal enzymes
22
Q
  1. Glutamate receptor antagonist • mechanism
A

– Antagonist activity at AMPA / Kainite glutamate receptor
– Blockade of neuronal sodium channel
– Enhancement of action of GABA at GABAA receptors

23
Q
  1. Glutamate receptor antagonist • drugs
A

– Topiramate

24
Q
  1. Glutamate receptor antagonist • indications
A

– Seizures

– Migraine

25
Q
  1. Glutamate receptor antagonist • pk
A

– Rapidly absorbed orally
– Metabolism in the liver is extensive
– Half-life: 20-30 hours

26
Q
  1. Glutamate receptor antagonist • ADR
A

– CNS effects, impaired concentration, cognitive impairment
– GI upset, nausea, vomiting, anorexia
– Nephrolithiasis

27
Q
  1. Valproate • mechanism
A

– slows Na+ channel recovery
– stimulates GABA synthesis
– inhibits GABA metabolism

28
Q
  1. Valproate •indications
A

– seizures, neuralgia

29
Q
  1. Valproate • pk
A

– Highly plasma protein bound

30
Q
  1. Valproate • caution
A

– pregnancy

– liver toxicity –avoid in patients with liver disease

31
Q
  1. Valproate • ADR
A

– nausea, vomiting ataxia, tremor
– hair loss, oedema, weight gain
– neural tube defects

32
Q
  1. Valproate • drug interactions
A

– displace phenytoin from plasma proteins, & also inhibits its metabolism

33
Q
  1. GABApentin • Mechanism
A

– GABA analogue but mechanism unknown

– but also inhibits Ca+ channels

34
Q
  1. GABApentin • indications
A

– usually in combination with other anticonvulsants to treat partial seizures

35
Q
  1. GABApentin • ADR
A

– CNS: sleepiness, dizziness, fatigue, ataxia

36
Q
  1. GABApentin • CI
A

– pregnancy

37
Q

Principals of Drug Treatment (1) - Use the right drug for the seizure type

A
  • Seizure type
  • Drug of Choice
  • Alternatives
  • Partial simple & Partial complex
  • Carbamazepine, Phenytoin, Valproate
  • Lamotrigine, Gabapentin, Levetiracetam, Topiramate, Tiagabine, Oxcarbazepine, Phenobarbital
  • Generalised tonic clonic seizures
  • Carbamazepine, Phenytoin, Valproate
  • Lamotrigine, Topiramate, Phenobarbital
  • Absence
  • Ethosuximide, Valproate
  • Lamotrigine, Clonazepam
  • Myoclonic & Status seizure
  • Diazepam i.v. or rectally
  • Clonazepam
  • To stabilise mood
  • Carbamazepine, Valproate
38
Q

Principals of Drug Treatment (2)

A

• Use one drug and increase the dose until a therapeutic effect is gained or toxicity appears (maximum tolerated dose) preferably using one anticonvulsant (monotherapy).
“Start low, increase slow“.
• If monotherapy fails use two drugs
– Polytherapy is to be avoided especially as drug interactions occur between major anticonvulsants
– Carbamazepine & phenytoin
» because induce CytP450, other drugs may be affected eg
– warfarin –less effective
– oral contraceptive – may become ineffective
– Lamotrigene
» valproate inhibits glucuronidation, increased plasma conc of lamotrigine
» carbamzepine & phenytoin induce glucoronidation, reduced lamotrigene conc
– Need to adjust dose if these drugs are used in combination!

39
Q

Principals of Drug Treatment (3)

A

• Epileptic drugs & pregnancy
– Most seizures do not adversely affect foetus
– Patients with epilepsy should consult with specialist
– The “older” anti-epileptic drugs are teratogenic (inc carbamzepine, valproate, phenytoin, phenobarbital). Newer drugs – not known.
» some by inhibiting folate metabolism, causing neural tube defects use folate supplements
» Folic acid 5 mg 3 months prior to conception to end of first trimester
– Some antiepileptic levels can be decreased, especially in second and third trimester, but will lead to “breakthrough seizures”.

• Withdrawing AED
– Abrupt cessation may precipitate status epilepsy
– specialist supervision – abrupt withdrawal can cause rebound seizures
– gradual dose reduction over 2-3 months (benzodiazepines and barbiturates – at least 6 months)
– If on more than one AED, withdraw one at a time

40
Q

Epilepsy Treatment

A

70% seizure free with 1 drug
5-10% seizure free with 2 or more drugs
20% intractable epilepsy

-30% will benefit from surgery:

  • Curative procedure (removal of epileptic focus): anteromesial temporal resection; selective amygdalohippocampectomy extensive lesionectomy
    cortical resection. Hemispherectomy

-Palliative procedure (seizure-related risk decrease and improvement of the QOL):
corpus callosotomy
vagal nerve stimulation (VNS)

41
Q

AED

A

Neuronal sodium channel blockers
Neuronal calcium channel blockers
Neuronal potassium channel openers

Enhancement of GABA action
Glutamate receptor antagonist