a pharmacological approach

1. ANTIEPILEPTIC DRUGS
PART 2
PBL 2

2. OBJECTIVES
To know pharmacology of
Antiepileptic drugs :
• Aliphatic carboxylic acids
• Benzodiazepine
• Phenyltriazine
• Cyclic GABA analogues
• Newer drugs

3. SEIZURE AND EPILEPSY
# Seizure (L. Sacire – to take possession of)
A paroxysmal event due to abnormal
excessive or synchronous neuronal activity
# Epilepsy
Two or more unprovoked seizures

4. Seizures
A shift in the normal balance of
excitation and inhibition
within CNS

6. Approach

7. Blocking the initiation or spread of seizure
by
modifying ions channels or neurotransmitters
“They suppress the seizures but do not cure the disorders “

10. Refractory period
High discharge
frequency
Inhibited while
low/normal discharge
unaffected.
(By prolonging of
inactivated state of
voltage
Sensitive Na+
channel)

11. Class of drugs Drugs
Barbiturates Phenobarbitone
Deoxybarbiturate Primidone
Hydantoin Phenytoin, fosphenytoin
Iminostilbene Carbamazepine
Succinimide Ethosuximide
Aliphatic carboxylic acid Valproic acid
Benzodiazepine Clonazepam , Lorazepam, clobazam
Phenyltriazine Lamotrigine
Cyclic GABA analogue Gabapentine
Newer drugs Topiramate, Zonisamide, levetiracetam

13. PHARMACOKINETICS
Anti-epileptic
drug
Protein Half life (Hr) Active
metabolites
Major organ
elimination
Valproic acid High (90%) 10-15 various liver
Clonazepam High (85%) 24 liver
Diazepam High (99%) 30-60 oxazepam liver
Lamotrigine Low 16-24 Liver
Gabapentin Low 6 kidney
Topiramate Low 21 Various
Zonisamide Low 63 Liver

14. ALIPHATIC CARBOXYLIC ACID
Valproic acid ( sodium valproate)
- Choice for absence seizure
MOA : multiple mechanism
1. Phenytoin like elongation of Na+ inactivation
2. Weak attenuation of CA++ mediated T current
3. Augmentation of GABA release by inhibiting its degredation
(GABA-T) & probably by increasing its synthesis from glutamic
acid

15. ADR :
• Anorexia, loose motion, heart burn – common but mild
• Alopecia, curling of hair, weight gain and increased bleeding tendency
Drug interaction :
• Incr. Plasma phenobarbitone and lamotrigine - by metabolism
inhibition
• Phenytion toxicity- displacement from protein bound and decr. Of
metabolism
• Clonazepam + valproate – contraindicated – may cause absence status
• Valproate + Carbamazepine – Fetal Abnormalities

16. BENZODIAZEPINE
Clonazepam
• Potentiate GABA action
• Inhibit spread of seizures
• Primarily used in absence seizure
Diazepam
• Rapid development of tolerance to antiepileptic effect and sedative
effect
• First line drug for Emergency control for convulsions

17. PHENYLTRIAZINE
Lamotrigine
• Broad Spectrum anti-seizures efficacy
MOA :
• Prolongation of Na+ channel inactivation and suppression of high
frequency firing
• Direct blockage of voltage sensitive NA+ channel – stabilizes
presynaptic membrane – prevent release of excitatory
neurotransmitter (mainly Aspartate & Glutamate)

18. ADR :
• sleepiness , dizziness diplopia, ataxia and vomiting
• Rash – severe reaction esp. in children – Withdrawal of
drug

19. CYCLIC GABA ANALOGUES
Gabapentin
• Enhances GABA release
• Add on drug
• ADR- mild sedation, tiredness, dizziness
Pregabalin
• Similar to Gabapentin
• Particularly used for neuropathic pain ( diabetic neuropathy, postherpetic
neuralgia)

20. NEWER DRUGS
Topiramate
 Weak carbonic anhydrase inhibitors
Broad Spectrum Anti-convulasant activity
Prophylaxis of migraine
MOA : Multiple
• Phenytoin like elongation of Na+ inactivation
• GABA potentiation by a postsynaptic effect
• Antagonism of certain glutamate receptor
• Neuronal hyperpolarization
ADR
• Impairment of
attention
• Sedation
• Ataxia
• poor memory
• Weight loss
• Paresthesia
• Renal stone

21. Levetiracetam
Mechanism of action: Unknown
Uses:
• Suppress kindled seizures
• Adjuvant and monotherapy in refractory partial seizures
• Add-on drug in CPS, GTCS and myoclonic epilepsy
• Plasma half life: 6-8 hours
• Adverse effects:
• Sleepiness
• Dizziness, weakness
• Impaired driving

22. PRINCIPLE OF ANTI-CONVALESCENT THERAPY
 Increase dose of suitable single agent until desire effect is
achieved or toxicity prevents
A second drug may be added if maximal doses of initial
drug fail.
Abrupt discontinuation of an anticonvulsant may induce
status epilepticus – always taper doses
Counsel patient about the possible Adverse effects of drugs

24. REFERENCES
1. Essentials of medical pharmacology, kd tripathi, 7e
2. Elsevier's integrated pharmacology
3. Lippincott illustrated pharmacology
4. Harrison’s principle of internal medicine,19e

25. •Thank you