1. Epilepsy, Seizure, Convulsion
2. Causes & Pathophysiology of Epilepsy
3. Classification and Choice of antiepileptics
4. Antiepileptics Mechanism of action of , Adverse effects, Drug interactions, General guidelines for use.
5. Recommendation to Antiepileptics and pregnancy according to RCOG 2016, SIGN 2017 guidelines
6. Treatment of status epilepticus according to American Epilepsy Society 2016 guidelines
2. 1. Categorize the major classes of antiepileptic drugs.
2. Identify the molecular mechanism of action of antiepileptic drugs.
3. Select the proper antiepileptic drug for each type of epilepsy
4. Predict the most serious adverse effects of antiepileptic drugs.
5. Link drug-drug interactions with specific observable and major adverse
effects antiepileptic drugs.
6. Provide proper management of epilepsy in pregnant woman.
7. Decide the appropriate antiepileptic drug used in the management of
status epilepticus.
3. • Epilepsy is 3rd common neurologic
disorder after cerebrovascular &
Alzheimer's disease.
• Epilepsy affects ≈ 50 million people
worldwide (WHO, 2019).
• About 10 % of G population have one
seizure in their lifetime.
• Epilepsy Rate: 4 - 10 per 1000 people
Epilepsy
N LANCET, 2019
4. What is the difference between
Epilepsy, Seizure and Convulsion?
5. What is Epilepsy?
(≥ 2 unprovoked seizures with 24 hours apart)
Epileptic Seizure:
Abnormal Excessive neuronal
electrical Activity in the Brain
→ Sudden onset and offset,
transient recurrent neurological
symptoms and/or signs
6. • The site of origin of the abnormal neuronal firing determines
the symptoms that are produced.
• e.g. if the motor cortex is involved, the patient may experience
abnormal movements (motor seizure) …………..
7. • The most common site of origin of seizures or Abnormal
electrical activity is Temporal Lobe and Frontal Lobe.
Frontal Lobe
Temporal Lobe
8. Mesial Temporal Lobe or Frontal limbic → Psychotic Seizures, DD …..
(Insula, Gut Brain)
9. What is Convulsion?
Convulsion is an abnormal, involuntary contraction of
the muscles most typically seen with certain seizure
disorders (Motor Seizure).
10. Causes of Epilepsy
A] Primary: “Idiopathic”
(inherited genetic abnormality in CNS)
B] Secondary:
➢ Trauma
➢ Tumors
➢ Toxin & Drugs → insulin (hypoglycemia) – Cocaine - TCAs –
antipsychotics – Li+.……
➢ Infection e.g. Meningitis, encephalitis …
➢ Vascular e.g. Cerebrovascular disorders , stroke.
➢ Fever in Children e.g. Febrile Convulsion
13. Pathophysiology of Epilepsy
➢ ↑↑Excitatory
Neurotransmitter
“Glutamate”
➢ ↓ ↓ Inhibitory
Neurotransmitter
“GABA”
➢ ↑ Neuronal Ca & Na →
Depolarization & action
Potential
14.
15. Mechanism of Antiepileptic Drugs
Act on brain
transmitters
1) ↑ GABA
Phenobarbital
BZDs
2) ↓ Glutamate
Topiramate
↓ membrane ion
permeability
1) Block Na
channels
Carbamazepine
Phenytoin
2) Block Ca
channels
Ethosuximide
Most antiepileptic drugs act by more than one mechanism:
17. 1. Blockade of Na+ Channels repetitive firing of neurons
• Phenytoin – carbamazepine – valproate.- Topiramate - Lamotrigine.
2. Blockade of T- type Ca++ Channels in thalamus brain rhythmic
activity (effective in absence seizures) Ethosuximide., Valproate.
3. Blockade of presynaptic voltage gated Ca++ Channels ↓glutamate release
• Lamotrigine., Gabapentin – pregabalin.
4. Binding to vesicle protein VS2A modify release of glutamate
• Levetiracetam.
5. NMDA & AMPA glutamate receptor antagonists Valproate & Topiramate
6. Effects on GABA
i. Facilitate GABAAction: phenobarbital –benzodiazepines –topiramate.
ii. GABA Level: inhibits breakdown by transaminase: Vigabatrin.
↑turnover via ↑GAD by Valproate & Gabapentin
18. Classification of Antiepileptic drugs
I. Classic agents (major or older agents)
• Phenytoin (Prototype)
• Carbamazepine
• Valproate (Valproic acid)
• Ethosuximide.
• Phenobarbital e.g. Phenobarbital.
• Benzodiazepines e.g. Clonazepam, Midazolam.
II. Newer agents
• Lamotrigine
• Levetiracetam
• Topiramate – gabapentin- pregabalin.
19. Broad spectrum of antiseizure activity.
➢Valproic acid,
➢Lamotrigine
➢Levetricetam
have Multiple mechanisms of action (act on brain transmitters and reduce
neuronal Ca & Na) → they have Broad Spectrum antiseizure activity and can
indicated in both generalized and partial epilepsy
20. Divalproex = sodium valproate + valproic acid that
is converted to valproate ion when it reaches the GIT
tract. It improves GIT tolerance of Valproic acid.
21. Proper Choice of Antiepileptic
Proper Diagnosis
Electroencephalogram EEG EEG is Good +ve
22. Partial Tonic- clonic Absence Myoclonic
First line
• Carbamazepine
• Lamotrigine
• Valproate.
• Lamotrigine.
• Ethosuximide.
• Valproate
• Valproate.
Alternatives
• Levetiracetam
• Valproate
• Oxcarbazepine
• Carbamazepine
• Oxcarbazepine
• Levetiracetam
• Lamotrigine. • Levetiracetam
• Topiramate.
Choice of Antiepileptic Drugs in Different Types of Epilepsy
Valproate is preferred to ethosuximide if tonic- clonic or myoclonic seizures coexist.
23. AEDs that may worsen seizures sub-types
Absence Seizures
Phenytoin
Carbamazepine& Oxc
Myoclonic Seizures
Phenytoin
Carbamazepine& Oxc
Gabapentin
Pregabalin
Lamotrigine not preferred
Levetiracetam not used
Gabapentin
Pregabalin
Phenobarbital not preferred
24. • Due to sedation & tolerance, Phenobarbital & BZD are
used mainly in acute fits & in status epilepticus.
• Phenobarbital (in tonic-clonic & partial) &
• Clonazepam (in absence & myoclonic) are used as 2nd
line or adjuncts to other agents.
25. Phenytoin
• Limit use bec: cosmetic disturbances & pharmacokinetics.
a. Irregular bioavailability (→use one formula from a single manufacturer).
b. Saturation kinetics (serum conc. may to toxic levels → monitor serum level).
c. CYP inducer→ Drug interactions with other antiepileptics.
• Use: -in partial & generalized Tonic-Clonic
- in status epilepticus (& Fosphenytoin)
• Not used in absence and myoclonic seizure
(exacerbate it). Also, carbamazepine
26. Fosphenytoin
Prodrug phenytoin used in status epilepticus (1.5 mg = 1 mg phenytoin)
❑Advantages over phenytoin:
given IM or IV , Less Phlebitis, less cardiotoxicity (hypotension &arrhythmia)
Better Bioavailability (faster infusion & Not PPT)
(BUT, More expensive)
(100% Bioavailability)
27. • Oxcarbazepine is analog of carbamazepine with same
mechanism and indications
• Less potency BUT
• Less side effects (enzyme induction & blood dyscrasias)
28. Adverse Effects & Precautions of Anti-epileptics
Phenytoin Carbamazepine Valproate
Hypersensitivity Skin rash stop drug
GIT Disturbances N. V - epigastric pain (>> valproic acid) give small dose after meals.
Neurological
Disturbances
(specially in toxic
doses)
• Nystagmus, diplopia.
• Ataxia&Drowsiness.
• Learning in children.
• Diplopia.
• Ataxia.
• Drowsiness.
• Fine hand tremors.
• Ataxia.
• Less sedative.
Hepatic CYP450
(monotherapy is
preferred)
Enzyme inducer
• Metabolism of other
antiepileptics.
• Osteomalacia:
vitD metabolism (→
vit D & Ca2+
supplements ).
Enzyme inducer
• Metabolism of
antiepileptics ,
warfarin & Oral
contraceptive pills
&other drugs.
Enzyme inhibitor
• Metabolism of
antiepileptics &
other drugs.
33. Ethosuximide: “Narrow Spectrum, only for Absence”
(Safest): BUT ? (not so effective)
Side effects:
• GIT upset,
• Skin rash,
• Dizziness, drowsiness, headache.
34. Specific adverse effects of newer antiepileptics
• Lamotrigine
• Levetiracetam
• Gabapentin /Pregabalin
• Topiramate
Newer agents are generally better tolerated with fewer drug interactions than the older agents.
35. Lamotrigine: (Broad Except Myoclonus)
Rash or fatal dermatitis (Stevens Johnson syndrome),
hypersensitivity
Lamotrigine Drug interaction
1. Valproate inhibits its metabolism (need to ↓its dose to 50%)
2. Oral contraceptive pills and Carbamazepine increase its metabolism
(need to ↑ its dose to control seizures)
40. Pharmacokinetic changes in the elderly that may affect
and need dose adjustment:
i. ↓ Clearance e.g. Carbamazepine, Lamotrigine.
ii. ↓Protein binding if hypoalbuminemic e.g. Phenytoin,
Valproic acid.
Carbamazepine, Lamotrigine, Levetiracetam and gabapentin are preferred in elderly
42. General guidelines for antiepileptic drug therapy
1. Proper diagnosis
2. Monotherapy is preferred (avoid drug interaction)
3. Start therapy with a small dose & a single drug and
gradually dose. Then, gradually substitute or add another drug.
4. Long treatment: for 2 years if epileptic fits are absent.
5. Gradual withdrawal: over 6 months (avoid status epilepticus
or relapse).
8. Periodic monitoring of serum level of drugs
43. Uses of Antiepileptics
1. Epilepsy
2. Mood stabilizers in bipolar depression
Lamotrigine – valproate – carbamazepine.
3. Neuropathic pain
Carbamazepine- gabapentin - pregabalin.
4. Migraine: Valproate - topiramate.
5. Antiarrhythmic:
Phenytoin. (IB, in VA …)
45. Preconceptual: “RCOG 2016 &SIGN 2015”.
1. Folate at 5 mg/d ↓ teratogenic risk (before and after pregnancy).
2. Attempt to reach monotherapy
3. Taper dosages of AEDs to the lowest possible dose
4. In women who have not had a seizure for 2-5 years,
attempt complete withdrawal of pharmacotherapy
5. Try to replace AEDs by Carbamazepine and
Lamotrigine, Levetiracetam (the lowest rates of birth defects)
6. Vitamin K 10 mg oral in 3rd trimester to ↓ Newborn postpartum hemorrhage
46. -Pregnancy metabolism of anti-epileptics
and also hemodilution adjust dose
according to plasma level.
48. [Prolonged or repeated tonic-clonic seizures]
➢ Active part of a tonic-clonic seizure ≥ 5 minutes
➢ Repeated seizures within ≤ 30 minutes.
without recovering consciousness from the first one.
Convulsive Status Epilepticus
N.B. Most seizures are brief, lasting less than 5 minutes
Most tonic-clonic seizures end normally in 1 to 2 minutes
TIME is BRAIN
49. Why Status Epilepticus??
1. Withdrawal or Low level of Antiepileptic drug (Most common)
2. Metabolic (glucose, Ca, Mg, Na….)
3. Trauma
4. Stroke
5. Hypoxia
6. Drug or Alcohol overdose or Withdrawal e.g. Tramadol
50. Status Epilepticus is FATAL (≈25%)
1. Hyperthermia,
2. Brain Damage (Hypoxia, Metabolic)
3. Pulmonary Edema & Resp. Failure
4. Cardiac Arrhythmias &CV Collapse
5. Renal Failure (Myoglobinuria & dehydration)
6. Acidosis (Lactic a ↑) The main cause of DEATH
51. Management of Status Epilepticus:
(Step I: ABCDE)
(Step II: drugs are given IV)
1. BZD Midazolam (IM) or diazepam (IV or rectal) or
Lorazepam (IV) → for rapid control.
2. Fosphenytoin or phenytoin → long-acting, to maintain control.
3. Phenobarbital →2nd choice to phenytoin.
4. IV antiepileptics (Valproate, Levetiracetam)
5. IV or inhalation anesthesia → in resistant cases.