Antiepileptics I & Ii

DR.UMA KADAM M.B.B.S. MD ASSOCIATE PROFESSOR PHARMACOLOGY SKNMC

Definition
The epilepsies are a group of disorders characterized by chronic recurrent paroxysmal changes in neurologic function caused by abnormalities in the electrical activity of the brain

SELECTED EPILEPSY TERMS Epilepsy: A clinical paroxysmal disorder of recurring seizures Seizure: A transient dysfunction of brain due to an abnormal firing of cerebral neurons, which may or may not have a clinical manifestation.

Myoclonus: A single abrupt shock like extensor movement of a limb. myoclonic seizures. Petit Mal : Used to describe absence seizures as well as atypical absence. Tonic : Sustained contraction of one or more muscle groups, independent of position (i.e. can be flexed, extended, or opisthotonic). Aura: A generic term for a warning. A colloquial term for simple partial seizure. Convulsion: Tonic , clonic or tonic-clonic seizure

Status
A pathological state different from a single seizure by the Epilepticus (a bsence or reduction of inhibitory processes to terminate the seizure).
Applies to any seizure type. The length of time required to differentiate seizure from status is both empirical and practical.
Convulsive, myoclonic status: 10-30 minutes.

Differential diagnosis of seizures
Syncope
Drop attacks
Narcolepsy-Cataplexy
Pseudoseizures
Panic attacks
Hypoglycemia
Migraine

Epidemiology
Incidence:
Developed countries: 40-70 per one lakh
Developing countries: 100-190 per one lakh
Prevalence:
Developed countries: 4-10 per 10,000
Developing countries: 57 per 10,000
Partial seizures with or without generalization is most common

Bimodal age distribution :
< 1 and > 60. Less sharp in developing countries
Common causes : Perinatal disorders associated with cerebral palsy & mental retardation, Head trauma, CNS infections, Stroke, Brain tumors, Alcohol and other drugs
Men affected 1-2.4 times: compared to women

Revised ILAE (International League Against Epilepsy) Seizure Classification I. PARTIAL (FOCAL, LOCAL) SEIZURES A. Simple partial seizures B. Complex partial seizure C. Partial seizures evolving to generalized tonic-clonic convulsions (GTC)

II. GENERALIZED SEIZURES A. 1. Absence seizures 2. Atypical absence B. Myoclonic seizures, Myoclonic jerks (simple or multiple) C. Clonic seizures D. Tonic seizures E. Tonic-clonic seizures F. Atonic seizures (astatic)

III. UNCLASSIFIED EPILEPTIC SEIZURES Includes all seizures that cannot be classified because of inadequate or incomplete data and some that defy classification in hitherto described categories. This includes some neonatal seizures, e.g., rhythmic eye movements, chewing, and swimming movements .

Antiepileptic drug (AED)
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.
Improves quality of life by minimizing seizures.

CLASSIFICATION OF ANTIEPILEPTICS:
B arbiturates: Phenobarbitone
D eoxybarbiturate: Primidone
H ydantoin: Phenytoin
I munostilbene: Carbamazepine
S uccinimide: Ethosuximide
A liphatic carboxylic acid: Valproate
B enzodiazepine: Clonazepam, Diazepam
C yclic GABA- analogue: Gabapentin
P henyltriazine: Lamotrigine
N ewer drugs: Vigabatrin, Topiramate, Tiagabine, Levetiracetam
i i e i a

CLASSIFICATION ON THE BASIS OF CLINICAL USE

History of Antiepileptic Drug Therapy
1857 - Bromides
1912 - Phenobarbitone
1937 - Phenytoin
1944 - Trimethadione
1954 - Primidone
1960 - Ethosuximide

History of AED therapy
1974 – Carbamazepine, Oxcarbazepine
1975 - Clonazepam
1978 - Valproate
1993 - Felbamate, Gabapentin
1995 – Lamotrigine, Levetiracetam
1997 - Topiramate, Tiagabine

Principles of AED Selection
Correct diagnosis of the type of epilepsy influences treatment, prognosis and genetic counseling.
One best drug to fit the fit, fit the patient; Sequential monotherapy
Use the least expensive AED (all things being equal, like efficacy).
Prefer AEDs which can be taken od over bid / tid.
AEDs almost never need qid dosing

Newer is not better, and almost certainly more expensive
Start with one AED and push the dose to clinical toxicity or seizure control.
Withdraw AEDs that are not effective.
Never have a patient on more than three (3) AEDs.
Principles of AED Selection…cont.

Principles of AED Selection…cont.
Don't use combination medications (e.g., phenytoin with phenobarbital).
No proof that multiple AEDs are synergistic in the treatment of epilepsy.
Polypharmacy is expensive, increases side effects and increases the complexity of adjusting AEDs in the refractory patient.

Therapeutic Drug Monitoring Use AED levels to assess: i. Poor clinical control (compliance, metabolism) ii. Dose-related side effect iii. Drug or disease interaction iv. "Routine" levels on controlled, nontoxic patients are not indicated.

Applied Pharmacokinetics of Antiepileptic Drugs (AEDs)

Absorption
Aqueous solubility - Poor aqueous solubility
Impairs absorption from GIT – carbamazepine
Erratic absorption from parenteral (SC, IM) sites - phenytoin
Poor oral bioavailability – phenytoin
Slows time to attain peak plasma levels – carbamazepine
May cause physical drug interactions during IV infusions

Absorption
Lipid solubility – Good lipid solubility
Enhances absorption across membranes
Quicker absorption
Crosses BBB easily – reaches good levels in CSF
Excreted in breast milk, can cross placenta

Mechanism of action of Antiepileptic Drugs

Cellular Mechanisms of Seizure Generation
Excitation (too much)
• Ionic-inward Na + ,Ca ++ currents
• Neurotransmitter: glutamate,
aspartate
Inhibition (too little)
• Ionic-inward Cl; outward K + currents
• Neurotransmitter: GABA
Inhibition Stimulation

AEDs: Molecular and Cellular Mechanisms
Phenytoin, Carbamazepine
• Block voltage-dependent sodium
channels at high firing frequencies

Open Na + Na + Na + Inactivation gate Activation gate Carbamazepine Phenytoin Felbamate Lamotrigine Inactivated channel Blocked channel firing at high frequencies Barbiturates Topiramate Na + Na+ Na+ Na+

Barbiturates
• Prolong GABA-mediated chloride
channel openings
• Some blockade of voltage-
dependent sodium channels
Benzodiazepines
• Increase frequency of GABA-mediated chloride
channel openings

Valproate
May enhance GABA transmission in
specific circuits
Blocks voltage-dependent sodium channels
Blocks T-type calcium currents
Ethosuximide
• Blocks slow, threshold, “transient”
(T-type) calcium channels in
thalamic neurons

Ca ++ Ca ++ Voltage regulated Ca ++ current, low threshold “T” current in thalamus Involved in 3 per second spike and wave rhythm Ca ++ Ethosuximide Valproate Reduction in the flow of Ca ++ through T – type Ca ++ channels in thalamus Ca ++ Ethosuximide:

Newer AEDs: Molecular and cellular Mechanisms
Vigabatrin
• Irreversibly inhibits GABA- transaminase
Tiagabine
• Interferes with GABA re-uptake
Felbamate
• May block voltage-dependent sodium channel at high
firing frequencies
• May modulate NMDA receptor via strychnine
insensitive glycine receptor
Lamotrigine
• Blocks voltage-dependent sodium channels at high
firing frequencies
• May interfere with pathologic glutamate release

Newer AEDs: Molecular and cellular Mechanisms
Topiramate
Blocks voltage-dependent sodium channels at high firing frequencies
Increases frequency at which GABA opens Cl - channels (different site from benzodiazepines)
Antagonizes glutamate actions at receptor subtype
Gabapentin
• May modulate amino acid transport into brain
• May interfere with GABA re-uptake

GABA metabolites Succinic Semialdehyde Gabapentin GT: GABA transaminase SSD:Succinic semialdehyde dehydrogenase GT SSD Vigabatrin Valproate Benzodiazepines Barbiturates Cl - Gabapentin Tiagabine Topiramate

Status Epilepticus-Definition
1. Major motor (convulsive) status
Three(3) seizures uninterrupted by consciousness or a single prolonged seizure greater than 1/2 hour.
2. Spike wave stupor (Absence or Petit mal status) and complex partial (psychomotor) status are prolonged alterations of consciousness verified by EEG as epileptic.

Status epilepticus
It is a medical emergency – requires prompt and aggressive treatment
Therapy should be aimed at:
Rapid termination of status epilepticus
Prevention of seizure recurrence
Treatment of underlying cause

Immediate treatment
1. Secure IV line draw blood for analysis (including anticonvulsant levels).
2. Push 50 cc of 50% Dextrose i.v.,
100mg thiamine i.v.
3. Monitor vital signs.
4. Examine patient.
5. Protect airway, tongue, head, never leave patient alone
6. Intubate all patients if first line drugs fail.

Non-specific
Correct electrolyte imbalance - acidosis lowers seizure threshold, treat with bicarbonate if pH<7.1
Lower fever
Antibiotics/ LP if indicated
If neurologic exam dictates, treatment of underlying cause may proceed concurrently with drug therapy, e.g., neurosurgical decompression.
Hypotension – maintain BP
Status Epilepticus - Definite Treatment

Status Epilepticus-Definitive Treatment
Diazepam - 10mg IV push over 30-60 seconds repeat after 10-15mins upto 30mg (5mg/min) Repeat after 2-4hrs. 100mg/day
i.Good results, easy to administer. (fast acting, short lasting)
ii. If two doses fail to stop status, then further doses probably won't work either.
iii. Side effects -- hypotension, bradycardia, respiratory depression, cardiac arrest, depresses mental status.

OR Lorazepam - 4 mg IV push (2mg/min) may be repeated. i. Fast acting, medium lasting. ii. Respiratory depression only in the extubated patient.

Status Epilepticus-Definite Treatment
b. Phenytoin - 12-20mg/kg IV (slow IV push) (50mg/min) fast and long acting.
i. Presently used concomitantly with a benzodiazepine
ii. Its pH is 12, all i.v. fluids are pH 4-6. Do not add to dextrose drip as it precipitates.
iii. Monitor BP and ECG

IV Valproate - 25 mg/kg IV push, may repeat.
i. Generally not used because of lack of experience. Good results in both major motor and absence status.
ii. fast acting, long acting.
iii. Far less side effects than Diazepam and dilantin especially in unstable cardiac status, hypotension, hepatic failure etc.

Adverse effects of antiepileptics:
Phenytoin: Gum hyperplasia,hirsutism, hypersensitivity, megaloblastic anemia, osteomalacia, hyperglycemia, fetal hydontoin syndrome, dose dependent vestibular & cerebellar toxicity & iv administration causes hypotension & arrhythmias
Carbamazepine: Dose dependent neurotoxicity, hypersensitivity, teratogenic.
Valproate: Well tolerated, however in children below 3 yrs cause fulminant hepatitis, pancreatitis in patients taking other hepatotoxic drugs & with liver disease. In pregnancy if given cause neural tube defects.

Drug interactions- points to consider
Complex – refer to textbooks when possible
May enhance toxicity without a corresponding increase in antiepileptic effect.
Highly variable and unpredictable

Drug interactions- points to consider
Usually caused by hepatic enzyme induction or hepatic enzyme inhibition
Interactions due to displacement from protein binding sites not significant.
TDM advisable with combination therapy

Carbamazepine often lowers plasma concentrations of:
Phenytoin (it may also raise phenytoin concentration)
Valproate
Phenobarbitone/primidone lowers plasma concentrations of:
Phenytoin (it may also raise phenytoin concentration)
Valproate
Carbamazepine
Clonazepam
Ethosuximide(sometimes)
Phenytoin often lowers plasma concentrations of:
valproate
carbamazepine
clonazepam
Ethosuximide and primidone (sometimes)
Often raises plasma concentrations of
Phenobarbitone

Valproate often lowers plasma concentrations of:
An active metabolite of Carbamazepine
Lamotrigine
phenobarbitone, primidone
Phenytoin (but may lower it too)
Sometimes raises plasma concentrations of
Ethosuximide

Thank you

Antiepileptics I & Ii

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