ANTI-EPILEPTIC

DRUGS
Dr Ayesha Jamil
• Epilepsy is not a single entity

• An assortment of different seizure types and syndromes originating from several mechanisms
that have in common the sudden, excessive, and synchronous discharge of cerebral neurons.

• Resulting in a variety of events, including loss of consciousness, abnormal movements, atypical

or odd behavior, or distorted perceptions that are of limited duration but recur if untreated.
• In most cases, epilepsy has no identifiable cause. Focal areas that are functionally abnormal may
be triggered into activity by changes in any of a variety of environmental factors, including
• Alteration in blood gases,
• Ph,electrolytes,
• Blood glucose level,
• Sleep deprivation,
• Alcohol intake,
• And stress.
 TYPES OF EPILEPSY
• Idiopathic epilepsy:

• When no specific anatomic cause for the seizure, such as trauma or neoplasm, is evident, a patient may
be diagnosed with idiopathic or cryptogenic (primary) epilepsy. These seizures may result from an
inherited abnormality in the central nervous system (CNS).

• Symptomatic epilepsy:

• A number of causes, such as illicit drug use, tumors, head injury, hypoglycemia, meningeal infection, or
rapid withdrawal of alcohol from an alcoholic, can precipitate seizures. When two or more seizures occur,
then the patient may be diagnosed with symptomatic (secondary) epilepsy.
 CLASSIFICATION OF SEIZURES
• Seizures have been classified into two broad groups: partial (or focal), and generalized

• Simple partial:

• These seizures are caused by a group of hyperactive neurons exhibiting abnormal electrical

Activity, which are confined to a single locus in the brain. The electrical discharge does not spread, and the patient does not lose
consciousness. The patient often exhibits abnormal activity of a single limb or muscle group that is controlled by the region of the brain
experiencing the disturbance.

Complex partial:

• These seizures exhibit complex sensory hallucinations, mental 2. Distortion, and loss of consciousness. Motor dysfunction may involve
chewing movements, diarrhea, and/or urination. Consciousness is altered. Simple partial seizure activity may spread and become complex
and then spread to a secondarily generalized convulsion. Partial seizures may occur at any age.
 CLASSIFICATION

• Hyadantoin: Phenytoin

• Barbiturates: Phenobarbitone

• Iminostilbenes: Carbamezapine & Oxcarbazepine

• Succinamides: Ethosuximide

• Benzodiazepines: Diazepam, Lorazepam,clonazepam.

• Carboxylic Acid Derivatives: Valproic Aid

• Others: Vigabatrin, Lamotrigine, Gabapentin,lacosamide, Levitiracetam,felbamate, Topiramate.

• Tonic-clonic:
• Absence:
• Myoclonic:
• Febrile seizures:
• Status epilepticus:
 carbamezapine,
lamotrigine
Valproic acid
Phenytoin, felbamate Levtiracetam
Lacosamide , topiramate
SV2A

lamotrigine, valproate,
GAD
ethosuxamide
α2δ Valproic acid
pregabaline topiramate,
Gabapentine felbate felbamate
ethosuxamide,
Tiagabine felbamate

vagabatrine
valproate
benzo
Barb
 MECHANISM OF ACTION OF
ANTIEPILEPTIC DRUGS
• Drugs that are effective in seizure reduction accomplish this by a variety of mechanisms,
including
• Blockade of voltage-gated channels (Na+ or Ca2+),
• Enhancement of inhibitory GABAergic impulses,
• Or interference with excitatory glutamate transmission.
• Some antiepileptic drugs appear to have multiple targets.
 BENZODIAZEPINES

• Benzodiazepines bind to GABA inhibitory receptors to reduce firing rate.

• Diazepam, and lorazepam are most often used as an adjunctive therapy for myoclonic as well as
for partial and generalized tonic-clonic seizures.
CARBAMAZEPINE (SODIUM CHANNEL
BLOCKER)
• Carbamazepine reduces the propagation of abnormal impulses in the brain
by blocking sodium
Channels, thereby inhibiting the generation of repetitive action potentials in
the epileptic focus and preventing their spread.

Indications:
 Partial seizures

• Generalized tonic-clonic seizures

• Trigeminal neuralgia
• Bipolar disorder
CARBAMAZEPINE (SODIUM CHANNEL
BLOCKER)
• Pharmacokinetics :
• Absorption : slow and erratic
• It induces its own drug metabolism and has an active metabolite.
• It is a substrate for
• CYP3A4 with minor metabolism by CYP1A2 and CYC2C8.
• The epoxide metabolite accounts for 25 percent of the dose, is active, and can be inhibited by drugs
that inhibit udp glucouronosyltransferase (ugt), leading to toxicity.
• Carbamazepine is an inducer of the isozyme families CYP1A2, CYP2C, AND CYP3A and UGT
enzymes
• Which may increase the clearance and reduce the efficacy of drugs that are metabolized by these
 CARBAMAZEPINE (SODIUM CHANNEL
BLOCKER)

• ADVERSE EFFECTS
• Hyponatremia may be noted in some patients, especially the elderly.
• Epoxide metabolite of the drug has been implicated in causing Blood Dyscrasias

• A characteristic Rash may develop

• Sedation, drowsiness, vertigo, ataxia, diplopia, blurring of vision, nausea, vomiting and mental confusion.
• Bone marrow suppression with neutropenia, aplastic anemia.
• Chronic therapy may cause water retention due to release of ADH.
 PHENYTOIN
• It’s one of the most commonly used anti-epileptic.
• Mechanism of action:

• It stabilizes the neuronal discharge.

• It delays the recovery from inactive state of Na+ Channel.

• This in turn leads to decrease of hyper-excitable neuronal discharges.

• At high doses it also blocks the calcium channels.

• It reduces glutamate levels

• It increases responses to GABA.

 Pharmacokinetics Of Phenytoin

• Slowly absorbed from the GI tract.

• Well distributed through out the body.
• Completely metabolized in the liver by hydroxylation and glucuronide conjugation.

• When given in lower concentration that is less than 10mcg/ml it follows 1 st order kinetics.(t1/2=10—
24hrs)
• When the dose exceeds this level the enzymes responsible for the metabolism are saturated and then
it starts following 2nd order kinetics. (t1/2=60 hrs)

• It is an enzyme inducer so it increases rate of metabolism the drugs these specific enzymes.
 Indications and side effects
• Generlized tonic –clonic seizures.
• Partial seizures
• Trigeminal neuralgia.
• Arrhythmias
• Status epilepticus.
 Side effects of phenytoin at therapeutic
concentrations
• Side effects are dose dependent.
• At therapeutic dose:
• Hypertrophy and hyperplasia of gums
• Hypersensitivity reactions(rash, neutopenia,and sometimes even hepatic necrosis)
• Hirsutism,
• Hypeglycemia due to decreased release of insulin.
• Osteomalacia due to increased metabolism of Vitamin D.
• Hypocalcemia due to decreased absorption of calcium from the gut.
• Feotal Hydantoin syndrome: cleft lip or palate,digital hypoplasia.
 Side Effects of phenytoin at high doses
• CVS: hypotension and cardiac arrhythmias, extravasation of drug leading to tissue necrosis.
• CNS: vertigo, ataxia,tremors, headache and psychological disturbances.
• GIT: nausea vomiting and dyspepsia.(can be minimized if taken with food.)
SV2A
 DIVALPROEX

• PHARMACOKINETICS :
• Valproate inhibits metabolism of the CYP2C9, UGT and epoxide hydrolase systems.
• Valproate is bound to albumin (greater than 90 percent), which can cause significant
interactions with other highly protein bound drugs.
• Adverse effects:
• GIT: nausea, vomiting, anorexia and abdominal discomfort.
• CNS: sedation, ataxia and tremors.
• Skin rashes, alopecia and curling of hair, weight gain.
• Fulminant hepatitis have also been reported.
• Due to teratogenic effects is contraindicated in pregnancy,
 ETHOSUXIMIDE
• MOA:
• Blocks the propagation of abnormal electrical activity by blocking the t-type calcium
channels.
• Indications:
• It’s only used in the treatment of primary generalized seizures.

• Adverse effects:
• Nausea, vomiting and anorexia.
• Headache, hiccups, eosinophilia, neutropenia, thrombocytopenia and BMS.
 FELBEMATE

• MOA:

I. Blocks the voltage-dependent sodium channels.

II. Competing with the glycine-coagonist binding site on the n-methyl-d-aspartate (NMDA) glutamate
receptor,
III. Blocks the AMPA-R receptors
Full range is
IV. Blocking calcium channels, and
effected
V. Potentiation of GABA actions.
It is an inhibitor of drugs metabolized by CYP2C19 and beta-oxidation.
• It is reserved for use in refractory epilepsies (particularly LENNOX-GASTAUT SYNDROME)because of the
risk of aplastic anemia (about 1:4000) and hepatic failure
 GAPAPENTENE

• It’s an analogue of GABA.

• It does not act at GABA receptors nor enhance GABA actions, nor is it converted to GABA.

• Indications:

• Simple partial seizures

• Complex partial seizures

Gabapentin has been shown to be well tolerated by the elderly population with partial seizures due to
the relatively mild adverse effects and a good choice due to limited or no reported pharmacokinetic drug
interactions.
 LAMOTRIGINE
• MOA: blocks sodium channels as well as high voltage-“dependent calcium channels

• It also blocks the voltage gated NA+ channels.

• Indications: partial seizures,

• Generalized seizures,

• Typical absence seizures,

• And the LENNOX-GASTAUT syndrome.

Plasma t1/2 =24-35hrs. Enzyme inducers like carbamazepine and phenytoin decrease it’s t1/2
 OXCARBAZEPINE

• It’s is a prodrug that is rapidly reduced to the 10-monohydroxy (MHD) metabolite

• MOA:
• MHD blocks sodium channels preventing the spread of the abnormal discharge.
• Modulation of calcium channels is also a hypothesis.
• Indications:
• It is approved for use in adults and children with partial onset seizures.
PHENOBARBITAL
• The primary mechanism of action is the enhancement of inhibitory effects of GABA-MEDIATED
neurons.
• Mainly recommended to be used in status epilepticus.
 Weight Cognitive
loss impairment

hirsuitism

Visual
disturbance

Weight gain

lymphadenopathy

Visual disturbances
Curling of hair
Weight gain
 Treatment of status Epilepticus

If seizures
continue
Diazepam (10 mg I/V) Watch B.P and
Step 1 Or Resp rate
Lorazepam 0.1 mg/kg
If seizures
continue
Phenytoin 20mg/kg Monitor
Step 2
I/v cardiac rhythm
If seizures
continue

Step 3 Phenenobarbitone
Watch for resp
10-15mg/kg i/v
depression
G.A (Thiopentone Or Propofol)
https://www.youtube.com/watch?v=xFUHE9gX6W8