2. Antiepileptic Drugs
Seizure: An abnormal and excessive excitation and
synchronization of a population of cortical
neurons
Epilepsy: a disease characterized by spontaneous
recurrent seizures
Antiepileptic drugs: Drugs which decrease the
frequency and/or severity of
seizures in epileptic patients
3. Etiology of epilepsy
Epilepsy can affect anyone at any age, but most
commonly
– Children,
– Teenage years and early 20s
– Elderly
1- idiopathic or primary epilepsy
- Most cases of epilepsy are idiopathic
- May be due to an inherited abnormality of the CNS
2- Symptomatic or secondary epilepsy
- As a result of: head injury, hypoglycemia, brain tumors,
meningeal infection, alcohol withdrawal
4.
5. Classification of seizures:
According to the EEG patterns and the cerebral
neurons involved the seizures are classified into:
I- partial seizures (focal)
- They involve only a portion of the brain
- Symptoms depend on the site of the neuronal
discharge
- Partial seizures can become secondarily
generalized
6. Simple partial:
- Occur at any age
- The patient does not lose consciousness
- Abnormal activity of a single limb or muscle
group (clonic movements)
- There may be sensory symptoms too.
7. Complex partial
• Local onset, then spreads
- Impairment or loss of consciousness
- Clinical manifestations vary with site of origin and
degree of spread
– Presence of aura
– Automatisms, Motor dysfunction e.g. chewing
movements, lip smacking, post-ictal confusion
Temporal lobe epilepsy most common
- Sensory hallucinations (smell or taste)
- Speech disturbances (if dominant hemisphere)
8. Secondarily Generalized
Seizures
• Begins focally, with or without focal neurological
symptoms
• Variable symmetry, intensity, and duration of tonic
(stiffening) and clonic (jerking) phases
• Typical duration up to 1-2 minutes
• Postictal confusion and somnolence
9. II- Generalized seizures
• Both hemispheres are widely involved from the
outset.
• Present in 40% of all epileptic Syndromes.
They may be convulsive or non-convulsive
Absence seizures (petit mal epilepsy)
- Occur mainly in children till puberty
- Brief abrupt loss of consciousness
- Staring, rapid eye blinking for few seconds with
impaired awareness then return to full function
- Characteristic EEG pattern
10. Myclonic seizures
- Sudden brief involuntary muscle contractions
(shock-like Jerks of trunk, neck & limbs)
- Occur at any age usually around puberty or
early adulthood. Consciousness is not impaired
11. Tonic-Clonic seizures (Grand mal epilepsy)
- Seizures are preceded by a warning sign (aura)
in the form of a sound, smell or taste
-The patient then passes into coma, followed by
tonic convulsions (muscle rigidity & cyanosis)
which slows over 60-120 sec
- Post-ictal symptoms include confusion,
exhaustion and the patient often falls asleep
- Seizures consist of tonic-clonic convulsions
12. Generalized Tonic-Clonic Seizures
Major convulsions, usually with two phases:
1) Tonic phase: muscles will suddenly tense up, causing
the person to fall to the ground if they are standing.
2) Clonic phase: muscles will start to contract and relax
rapidly, causing convulsions
13. Atonic seizures: sudden loss of postural tone;
most often in children but may be seen in
adults
Febrile seizures
-They occur in young children with illness
accompanied by high fever
14. Status epilepticus
- Two or more seizures lasting for a total of 30
minutes or longer without recovery of full
consciousness between them.
- Life threatening and requires emergency Rx
15. Diagnosis of epilepsy
- Based on clinical description (eye witness)
- Blood tests to exclude metabolic causes
- EEG to test the electrical activity of the
brain
- CT scan or MRI scan
16. Antiepileptic Drug
• Goal
– to maximize seizure control
– To minimize drug side effects
– to improve the patient’s quality of life
• A drug which decreases the frequency and/or
severity of seizures in people with epilepsy
• Treats the symptom of seizures, not the underlying
epileptic condition
• Currently no “anti-epileptogenic” drugs available
17. Therapy Has Improved Significantly
• “Give the sick person some blood from a
pregnant donkey to drink; or steep linen in it, dry
it, pour alcohol onto it and administer this”.
– Formey, Versuch einer medizinischen
Topographie von Berlin 1796, p. 193
• In our country: ......
18. Current Pharmacotherapy
• Just under 60% of all people with epilepsy can
become seizure free with drug therapy
• In another 20% the seizures can be drastically
reduced
• ~ 20% epileptic patients, seizures are refractory to
currently available AEDs
• Antiepileptic therapy must be continued for at
least 2 years after the last attack
19. Management of epilepsy
• Drug choice is based on
• Classification of seizures,
• Patient’s age,
• Health,
• lifestyle &
• characteristics of the drug (cost & drug interactions)
• Initially : 1st line drug (monotherapy) until
seizures are controlled or toxicity occurs.
• If ineffective, switch to another AED or add a 2nd
drug (combination therapy).
22. Targets for AEDs
• Increase inhibitory neurotransmitter system - GABA
• Decrease excitatory neurotransmitter system—
glutamate
• Block voltage-gated inward positive currents— Na+
or Ca++
• Increase outward positive current—K+
• Many AEDs —act via multiple mechanisms
23. Mechanism of action of antiepileptic drugs:
Blockade of Na+ channels:
• phenytoin, oxcarbazepine, carbamazepine,
lamotrigine, felbamate, topiramate, Zonisamide
Blockade of Ca+ channels:
• ethosuximide, Valproic acid, lamotrigine
Enhancement of GABAergic transmission:
• valproic acid, benzodiazepines, topiramate,
phenobarbitone, primidone, felbamate, gabapentin
Interference with glutamate transmission:
• felbamate, topiramate
24. Epilepsy—Glutamate
• The brain’s major excitatory neurotransmitter
• Two groups of glutamate receptors
– Ionotropic—fast synaptic transmission
• Gated Ca++ and Gated Na+ channels
– Metabotropic—slow synaptic transmission
• Regulation of second messengers (cAMP and
Inositol)
• Modulation of synaptic activity
• Modulation of glutamate receptors
– Glycine, polyamine sites, Zinc, redox site
26. Epilepsy—GABA
• Major inhibitory neurotransmitter in the CNS
• Two types of receptors
– GABAA—post-synaptic, specific recognition sites,
CI- channel
– GABAB —presynaptic autoreceptors, also
postsynaptic, mediated by K+ currents
28. Na+ Channels as AED Targets
• Neurons fire at high frequencies during seizures
• Action potential generation is dependent on Na+
channels
• Use-dependent or time-dependent Na+ channel
blockers reduce high frequency firing without
affecting physiological firing
29. Ca2+ Channels as Targets
• General Ca2+ channel blockers have not proven to
be effective AEDs.
• Absence seizures are caused by oscillations
between thalamus and cortex that are generated in
thalamus by T-type (transient) Ca2+ currents
30. What about K+ channels?
• K+ channels have important inhibitory control over
neuronal firing in CNS—repolarizes membrane to
end action potentials
• K+ channel agonists would decrease
hyperexcitability in brain
• So far, the only AED with known actions on K+
channels is valproate
• Retiagabine is a novel AED in clinical trials that acts
on a specific type of voltage-dependent K+ channel
(M-channel)
31. Regulation of Neurotransmitter
release
• Several AED have actions that result in the
regulation of neurotransmitter release from the
presynaptic terminal, such as lamotrigine, in
addition to their noted action on ion channels or
receptors.
• Levetiracetam appears to have as its primary action
the regulation of neurotransmitter release by
binding to the synaptic vesicle protein SV2A
32. Side effect issues
• Sedation - especially with barbiturates
• Cosmetic - phenytoin
• Weight gain – valproic acid, gabapentin
• Weight loss - topiramate
• Reproductive function – valproic acid
• Cognitive - topiramate
• Behavioral – felbamate, leviteracetam
• Allergic - many
33. Antiepileptic drugs
1- Phenytoin
- The oldest non-sedative antiepileptic drug.
- Well absorbed orally, not given IM => Tissue
necrosis
- Extensively bound to plasma albumin 90%.
- Metabolized by the liver microsomal enzymes
- The metabolism of the drug follows saturation, or
zero order kinetics i.e. small increase in a daily
dose can produce large increase in the plasma
concentration drug toxicity
34. Antiepileptic action:
- Blocks voltage-gated Na+ channels in the inactive
state slowing its return to resting state
- At very high concentration it can block voltage-gated
Ca+ channels
Therapeutic uses:
- Generalized tonic-clonic convulsions
- Partial seizures, status epilepticus
Adverse effects:
- Vertigo, ataxia, nystagmus, confusion, diplopia
- Gingival hyperplasia, hirsutism
- Megaloblastic anaemia, skin rash, teratogenic effects
- hepatitis, hypoprothrombinemia & haemorrhage
35. Drug interactions:
- Phenytoin is a hepatic microsomal enzyme inducer
leading to induction of its own metabolism & the
metabolism of concomitantly used drugs e.g oral
contraceptives, oral anticoagulants, other
antiepileptics, digitoxin
- Enzyme inducers increase phenytoin metabolism
decreasing its plasma levels
- Enzyme inhibitors increase the plasma levels of
phenytoin
- Interacts with other highly protein-bound drugs
36. 2- Fosphenytoin:
- A prodrug rapidly converted to phenytoin in
the body high levels within minutes.
- Given IV or IM, similar toxicites to phenytoin
3- Carbamazepine
- Chemically related to TCAs
- Slowly absorbed after oral administration,
70% bound to plasma proteins
- It induces its own metabolism & has an active
metabolite.
37. Antiepileptic action
Similar to phenytoin, carbamazepine blocks Na+
channels preventing the generation of repititive
action potentials in the epileptic focus
Therapeutic uses:
- partial seizures with or without secondary
generalization
- Generalized tonic-clonic convulsions
- Treatment of trigeminal neuralgia & bipolar
disease
- Shouldn’t be used in absence seizures
38. Adverse effects:
- Vertigo, dizziness, ataxia, diplopia
- Allergic reactions: lymphadenopathy, rash
- Bone marrow depression (aplastic anemia,
agranulocytosis).
- Hyponatremia especially in the elderly
Drug interactions:
- Carbamazepine is a powerful enzyme inducer
increasing the metabolism of other drugs e.g.
phenytoin, oral contraceptives, oral anticoagulants
- Enzyme inhibitors inhibit the metabolism of
carbamazepine
39. 4- Oxcarbazepine
- Closely related to carbamazepine and used in
children & adults with partial seizures.
- Oxcarbazepine is a prodrug that is rapidly reduced
to 10-monohydroxy metabolite (MHD) which
blocks the sodium channels
- It is a less potent enzyme inducer than
carbamazepine
• Sedating but otherwise less toxic than Carbamazapi
ne
40. 5- Lamotrigine
• Blocks sodium channels & high voltage dependent
calcium channels
Effective in:
• partial seizures, generalized seizures, absence seizures
& Lennox-Gastaut syndrome
Also approved for use in bipolar disorder
• Well tolerated by the elderly with partial seizures
• Rapid titration to high serum concentrations can
cause a rash which may progress to life threatening
reaction
• Dosage must be reduced when valproate is added to
the therapy
41. 6- Felbamate
- It has multiple proposed mechanisms
- blocking voltage-dependent Na channels
- Weak activity against NMDA receptors
- Blocking calcium channels
- Potentiation of GABA actions
- Used in refractory epilepsies due to the risk of
aplastic anemia & hepatic failure
- Restricted for use only in extreme refractory
epilepsy
- It induces drugs metabolized by CYP3A4 and
inhibits drugs metabolized by CYP2C19
42. 7- Topiramate
• Broad spectrum of antiseizure activity
• Blocks voltage-dependent sodium channels
• Increases the frequency of Cl- channel opening by
binding to GABAA receptor
• Reduces the high-voltage calcium currents
• It is a carbonic anhydrase inhibitor and may act at
glutamate (NMDA) sites
- Used in partial and primary generalized seizures and
also in migraine
- Very long half-life (20h)
Adverse effects :
• Renal stones, hyperthermia, paresthesias & weight
loss
43. 8- Divalproex
• A combination of Na valproate & valproic acid.
• Proposed mechanisms include:
- inhibition of GABA transaminase which is responsible
for degradation of GABA
- Blockade of the sodium & calcium channels
• Used in partial & primary generalized seizures
• Adverse effects include hepatotoxicity, ataxia, weight
gain, teratogenicity
• Valproate inhibits the metabolism of other
antiepileptics
• > 90% bound to plasma proteins, so cause significant
interactions with other highly protein bound drugs
44. 9- Ethosuximide:
• Effective in treating only absence seizures
• Not effective in other seizure types therefore its
use is limited
• It blocks T-type calcium channels
- Adverse effects
• Anorexia, nausea, vomiting, cramps,
agranulocytosis, hypersensitivity reactions
45. 10- Phenobarbitone:
• It enhances the inhibitory effects of GABA (increases
the duration of opening of Cl channels leading to
hyperpolarization and neuronal inhibition)
• Used in
- Status epilepticus IV , febrile convulsions
- patients with refractory epilepsy
- (partial or generalized seizures)
• Potent enzyme inducer level of other drugs
• Toxic effects: sedation, nystagmus & ataxia,
osteomalacia, folate deficiency and vitamin K
deficiency
46. 11- Benzodiazepines
• They bind to GABA inhibitory receptors to reduce
firing rate
• Diazepam is used IV in status epilepticus
• Lorazepam & diazepam are used as adjunctive
therapy in myoclonic, partial and generalized tonic-
clonic seizures
12- Gabapentin
• Analog of GABA but doesn’t work through the GABA
pathway (mechanism not known)
• Used as adjunctive therapy in partial seizures
• Well tolerated by the elderly due to mild adverse
effects & no pharmacokinetic drug interactions
47. 13- Tiagabine
- Blocks GABA uptake into presynaptic neurons
- Used in patients with partial epilepy
14- primidone (metabolized to phenobarbitone)
• Its pharmacological properties, uses and side
effects are similar to phenobarbitone.
• Used in patients with refractory epilepsy
15- Levetiracetam
- Used as adjunct therapy of partial, myoclonic
and tonic-clonic seizures in adults & children
- Doesn’t affect the pharmacokinetics of other
antiepileptic drugs
48. 16- Zonisamide
- Sulfonamide derivative with a broad spectrum
of actions
- Blocks voltage-gated Na channels & T-type Ca
currents
- Also has a limited carbonic anhydrase activity
- Used in partial epilepsy
- May cause renal stones, oligohidrosis ,
hyperthermia
49. Antiepileptic therapy in pregnancy
- Therapy shouldn’t be stopped during pregnancy
- Only one drug should be prescribed at the lowest
effective dose, if possible.
- Antiepileptic drugs e.g. phenytoin, barbiturates &
valproate increase the risk of congenital defects
when given during the first trimester
- All women should be on high doses of folic acid
prior to conception & during the first trimester
- Newborns of mothers receiving phenobarbitone,
or phenytoin may develop hypoprothrombinemia
serious haemorrhage prevented by Vit K
50. Vagal nerve stimulation
• Is effective in treatment of partial seizures in
patients who are:
- Refractory to multiple drugs
- Sensitive to the adverse effects of antiepileptics
- Having difficulty to follow medication schedule
-The vagal nerve stimulator generates an electrical
pulse to stimulate the nerve and prevent the
abnormal activity of the brain
Patients activate the stimulator when they expect
a seizure
