PPt is made by pharmacology lecturer according to Lippincott Illustrated Reviews, 6th edition.

1. Drugs for Epilepsy
Lippincott, chapter 12

2. Definitions

4. Classification of Seizures

6. Drug selection
Therapeutic strategies for
managing
newly diagnosed epilepsy

8. Mechanism of anti-seizure drugs
Drugs reduce seizures through such mechanisms as:
• blocking voltage-gated channels (Na+ or Ca2+),
• enhancing inhibitory γ-aminobutyric acid (GABA)-ergic
impulses
• interfering with excitatory glutamate transmission.
• Antiepilepsy medications suppress seizures but do not
“cure” or “prevent” epilepsy.

9. Mechanism of anti-seizure drugs

10. Older Drugs
• Barbiturates
• Hydantoins
• Oxazolidinediones
• Succinimides
• Acetylureas

11. New Drugs
• Eslicarbazepine
• Felbamat
• Gabapentin
• Lacosamide
• Lamotrigin
• Levetiracetam
• Oxcarbazepine
• Perampanel
• Pregabalin
• Retigabine
• Rufinamide
• Stiripentol
• Tiagabine
• Topiramate
• Vigabatrin
• Zonisamide

13. Pharmacokinetics
• Orally active
• Enter the CNS
• Phenytoin, tiagabine, and valproic acid –
highly bound to plasma proteins
• Cleared chiefly by hepatic mechanisms
• Half-life – medium or long
• Older antiseizure drugs are potent inducers of
hepatic microsomal enzyme activity

14. Adverse
affects

15. Drugs Used in Partial and Generalized
Tonic-Clonic Seizures
• Older drus
– phenytoin (and congeners), carbamazepine,
valproate, and the barbiturates
• Newer drugs
– eslicarbazepine, lamotrigine, levetiracetam,
gabapentin, oxcarbazepine, pregabalin, retigabine,
topiramate, vigabatrin, lacosamide, and
zonisamide

16. Phenytoin
• Mechanism of Action:
– It alters Na+, K+, and
Ca²⁺conductance
– neurotransmitters: NE, Ach,
and GABA
• Decreases the synaptic release
of glutamate and enhances the
release of GABA
• Block Na⁺ channels and inhibit
the generation of rapidly
repetitive action potentials

17. Clinical Uses of Phenytoin
 Is effective against:
– partial seizures and
– generalized tonic-clonic seizures - either primary
or secondary to another seizure type

18. Pharmacokinetics of Phenytoin (Dilantin)
• Fosphenytoin, is available for parenteral use
– a more soluble phosphate prodrug of phenytoin, is well
absorbed after I/M
• 90% bound to plasma proteins
• Metabolism follows
– first-order kinetics at very low doses
– zero order kinetics at therapeutic doses
• accumulates in brain, liver, muscle, and fat
• Half-life - average 24 hrs
• It takes 5–7 days to reach steady-state
• Slow-release extended-action formulation can be given in a single
daily dosage

19. Pharmacokinetics of phenytoin
(continued)
• Drug interactions: Phenylbutazone and sulfonamides
can displace phenytoin from plasma protein binding site
• Phenytoin induces microsomal enzymes  increases
metabolism of carbamazepin
• Autostimulation of its own metabolism - insignificant
• Phenytoin related drugs: Ethotoin, Mephenytoin (active
metabolite – nirvanol)

20. Adverse Effects of Phenytoin
• Nystagmus
• Peripheral neuropathy
• Diplopia, ataxia – dose-dependent
• Sedation –at very high levels
• Gingival hyperplasia and hirsutism
• Coarsening of facial features
• Abnormalities of vitamin D metabolism - osteomalacia
• osteoporosis
• Idiosyncratic reactions – rare,
• Hypersensitivity reactions, skin exfoliative lesions

21. Carbamazepine
• Drug of choice for both partial
seizures and generalized tonic-
clonic seizures
• Other clinical uses of
carbamazepin:
– bipolar depression
– trigeminal neuralgia
• Drug of choice for treatment of
epilepcy in pregnant women
• Related drugs:
– oxcarbazepine
– Eslicarbazepine

22. Pharmacokinetics of Carbamazepine
• Peak levels are usually achieved 6–8 hours after
administration
• 70% bound to plasma proteins
• Volume of distribution is roughly 1 L/kg
• Extended-release preparations permit twice-daily dosing for
most patients
• Half-life of 36 hrs, 8– 12 hours in subjects receiving
continuous therapy
• Induces microsomal enzymes, needs dose adjustment
• Increases rate of metabolism of other drugs: primidone,
phenytoin, ethosuximide, valproic acid, and clonazepam

23. Carbamazepine Toxicity
• Dose-dependent
– Diplopia and ataxia
– Mild gastrointestinal upsets, unsteadiness, and, at
much higher doses - drowsiness
• Idiosyncratic
– blood dyscrasias including fatal cases of aplastic
anemia and agranulocytosis
– Mild and persistent leukopenia
– Erythematous skin rash

24. Phenobarbital (Barbiturate)
• Suppresses Na+ conductance
• Block some Ca2+ currents
(L-type and N-type)
• Enhances the GABA receptor-mediated
current
• Decrease release of glutamate
• Blocks of AMPA responses
Clinical use:
• partial seizures and
generalized tonic-clonic seizures
• Absence, atonic attacks and infantile
spasms may worsen due to
phenobarbital treatment
• Related drug – primidone, is
metabolized to phenobarbital

25. Newer Drugs

26. Vigabatrin
• Mechanism:
– inhibitor of GABA aminotransferase (GABA-T)
• Clinical use:
– partial seizures and infantile spasms – refractory to
other treatments
• Typical toxicities:
– drowsiness, dizziness, and weight gain
• Prolonged use:
– in 30–50% of patients – irreversible damage to retina
– visual field defects

27. Lamotrigine
• Mechanism:
– blockade of Na+ channels, voltage-
gated Ca2+ channels, particularly the
N- and P/Q-type
– decreases the synaptic release of
glutamate
• Clinical uses:
– partial seizures, absence and
myoclonic seizures in children,
Lennox-Gastaut syndrome
• Adverse effects
– dizziness, headache, diplopia, nausea,
somnolence, and skin rash
(hypersensitivity reaction)
– life-threatening dermatitis will
develop in 1–2% of pediatric patients

28. Felbamate
• Mechanism
– block NMDA receptor, potentiate GABA receptor
• Drug interaction
– increases plasma phenytoin and valproic acid levels
but decreases levels of carbamazepine
• Clinical use:
– partial seizures, Lennox-Gastaut syndrome
– Third-line drug for refractory cases
• Adverse effects:
– Aplastic anemia, severe hepatitis

29. Levetiracetam
• Mechanism
– modifies the synaptic release of glutamate and GABA
– inhibits N-type Ca²⁺channels
• Clinical uses
– primary generalized tonic-clonic seizures
– myoclonic seizures of juvenile myoclonic epilepsy
• Adverse effects
– somnolence, asthenia, ataxia, and dizziness
• No drug interactions

30. Gabapentin and Pregabalin
 Mechanism:
Analogs of GABA, do not act
directly on GABA receptors,
block voltage-gated N-type
Ca2+ channels decrease in
the synaptic release of
glutamate
 Adverse effects:
somnolence, dizziness, ataxia,
headache, and tremor
 Clinical uses of Gabapentin
 partial seizures and generalized
tonic-clonic seizures
 neuropathic pain
 postherpetic neuralgia
 Clinical uses of Pregabalin
 neuropathic pain(painful
diabetic peripheral neuropathy,
postherpetic neuralgia)
 Fibromyalgia
 generalized anxiety disorder

31. Tiagabine
• Mechanism:
– inhibition of GABA uptake
• Clinical use:
– partial seizures
• Pharmacikinetics:
– highly protein bound, food decreases the peak plasma
concentration, oxidized in the liver by CYP3A.
– Elimination - feces (60–65%)
• Adverse events:
– nervousness, dizziness, tremor, difficulty in concentrating,
and depression. Psychosis occurs rare.
– Excessive confusion, somnolence, or ataxia may require
discontinuation

32. Topiramate
• Mechanism:
– blocking of voltage-gated
Na+ channels , (L-type)
Ca2+ channels,
– potentiates the inhibitory
effect of GABA
• Clinical use:
– partial and generalized
tonic-clonic seizures,
Lennox-Gastaut syndrome,
infantile spasms, absence
seizures
– migraine headaches
• Adverse effects:
– somnolence, fatigue,
dizziness, cognitive slowing,
paresthesias, nervousness,
and confusion
– Acute myopia and glaucoma
may require prompt drug
withdrawal
– Urolithiasis
• Drug interactions:
– affect topiramate level
– Birth control pills may be less
effective

33. Zonisamide
• Mechanism
– blocks Na+ channel, T-type
voltage-gated Ca²⁺ channels
• Clinical use
– partial and generalized tonic-
clonic seizures, infantile
spasms, myoclonias
• Adverse effects
– drowsiness, cognitive
impairment and potentially
serious skin rashes
• Zonisamide does not interact
with other antiseizure drugs

34. Ethosuccimide (Zarotonin)
• Ethosuximide and valproate are
– the drugs of choice for absence seizures
• In thalamic neurons reduces Ca²⁺currents
- the low-threshold (T-type) current
• Promotes inwardly rectifying K+ channels
• not protein-bound
• half-life of approximately 40 hours
• twice-a-day dosage is common

35. Ethosuccimide Toxicity
• Drug interactions
– valproic acid decreases ethosuximide clearance
• Dose-related adverse effects of ethosuximide:
– gastric distress, including pain, nausea, and vomiting
– transient lethargy or fatigue
much less commonly:
– headache, dizziness, hiccup, and euphoria
• Idiosyncratic effects – extremely rare

36. Valproic Acid & Sodium Valproate
Mechanism of action: Valproate
blocks:
 Na⁺current, NMDA receptors,
 increases levels of GABA
Pharmacokinetics:
 Bioavailability > 80%.
 90% bound to plasma proteins
 Half-life - 9 to 18 hrs
 20% of the drug is excreted as a
direct conjugate of valproate

37. Valproate -Drug Interactions
• Drug Interactions
– displaces phenytoin from plasma proteins
– Inhibits liver ezymes
– inhibition of phenobarbital metabolism; levels of the
barbiturate rises steeply, causing stupor or coma
– Valproate can dramatically decrease the clearance of
lamotrigine

38. Valproate - Toxicity
• Toxicity – very popular drug, severe adverse effects are
rare
• Dose-related toxicity:
– nausea, vomiting, and other gastrointestinal complaints
such as abdominal pain and heartburn
• Sedation is uncommon with valproate alone but
– may be striking when valproate is added to phenobarbital
• Idiosyncratic toxicity
– fatal hepatotoxicity
– Careful monitoring of liver function is recommended when
starting the drug
– thrombocytopenia

39. Valproate - Clinical Uses
• Broad-spectrum
• Very effective against absence seizures
• Effective in
– tonic-clonic seizures
– myoclonic seizures
– atonic attacks
• I/V valproate - status epilepticus
• Other uses:
– bipolar disorder and
– migraine prophylaxis

42. Partial Seizures
• Simple partial seizure
– 60-90 sec
– patient is completely aware
of the attack
• Secondarily generalized attack
– immediately precedes a
generalized tonic-clonic
(grand mal) seizures
• Complex partial seizures
– widespread – bilateral
– involves limbic system
– starts from temporal lobes
– automatism – motor
behaviour
– alteration of consciousness
– lasts 30-120 seconds
– feel tired

43. Generalized Seizures
• Generalized tonic-clonic (grand mal)
• Absence (petit mal) seizure
• Myoclonic jerking
• Atonic seizures
• Infantile spasms

44. Treatment Strategy
• Most newer drugs have
– a broader spectrum of activity
– well tolerated
• The drugs used for generalized tonic-clonic
seizures are the same as for partial seizures

45. Treatment Strategy
Three drugs are effective
against absence seizures
 Ethosuximide
 Valproate
 Clonazepam

46. Treatment Strategy
• Specific myoclonic syndromes are
usually treated with valproate
• Others:
– clonazepam, nitrazepam
– Zonisamide and levetiracetam
• Juvenile myoclonic epilepsy
– valproate is the drug of choice
• Alternative:
– lamotrigine and topiramate

47. Treatment Strategy
• Infantaile spasms
– intramuscular corticotropin
– repository corticotropin for
injection
– clonazepam or nitrazepam
– Vigabatrin

48. Corticotropin

49. Treatment Strategy
Status Epilepticus I/V drugs:
– diazepam or lorazepam
– phenytoin
– phenobarbital
– intubation and ventilation
– general anesthesia

50. Other Uses of Antiepileptic Drugs
• Valproate:
– Migrane prophylaxis
– bipolar disorder
• Carbamazepin:
– bipolar depression
– trigeminal neuralgia
• Gabapentin
– neuropathic pain
– postherpetic neuralgia
• Pregabalin
– neuropathic pain(painful
diabetic peripheral
neuropathy, postherpetic
neuralgia)
– fibromyalgia
– generalized anxiety disorder

51. Adverse Effects
• Hepatotoxicity
– felbamat, valproate
• Anemias
– Carbamazepin, felbamat
• Weight gain
– Valproate
• Weight loss
– Topiramat, zonisamide
• Steven-Jonson syndrome
– Lamotrigine,
– carbamazepin,
– zonisamide

52. Teratogenicity
• Phenytoin
– Fetal hydantoin syndrome
(dilantin syndrome)
• Valproate (antifolate drug)
– Spina bifida
– Fetal valproate syndrome

53. Fetal hydantoin (Dilantin) syndrome

54. Fetal Valproate Syndrome

56. Spina Bifida(Valproate )