Pharmacology of Antiepileptic agents with

Antiepileptic drugs
paroxysmal cerebral dysrhythmia
 disturbance of consciousness (seizures)
 with or without characteristic body movements (convulsions)
These are group of disorders of CNS characterized by
Epilepsy
It is a Chronic medical condition produced by sudden changes in the electrical
function of the brain.
Sreenu Thalla
Associate Professor
Department of Pharmacology

Classification
1. Barbiturate – Phenobarbitone
2. Deoxybarbiturate – Primidone
3. Hydantoin – Phenytoin, Fosphenytoin
4. Iminostilbene – Carbamazepine, Oxcarbazepine
5. Succinimide – Ethosuximide
6. Aliphatic carboxylic acid – Valproic acid, Divalproex
7. Benzodiazepenes – Clonazepam, Diazepam, Lorazepam, Clobazepam
8. Phenyltriazene – Lamotrigine
9. Cyclic GABA analogue – Gabapentin
10. Newer drugs – Vigabatrin, Topiramate,Tiagabine, Zonisamide, Levetiracetam

Drugs
Seizure disorder
Carbamazepine or
Valproate or
Phenytoin or
Phenobarbital
Tonic-clonic(Grand mal)
Drug of Choice
Topiramte
Lamotrigine (as adjunct or alone)
Gabapentin (as adjunct)
Alternatives:
Carbamazepine or Topiramte or
Phenytoin or
Valproate
Partial (simple or complex)
Drug of choice
Phenobarbital
Lamotringine (as adjunct or alone)
Gabapentin (as adjunct )
Alternatives:
TREATMENT

Valproate or
Ethosuximide
Absence ( petit mal)
Drug of choice
Clonazepam
Lamotrigine
Alternatives:
Valproate
Myoclonic, Atonic
Drug of choice
Clonazepam
Alternatives:
Diazepam, i.v.
or Phenytoin, i.v. or Vaproate
Status Epilepticus
Drug of choice
Phenobarbital, i.v
Alternatives:
Diazepam, rectal*
Diazepam ,i.v
Valproate
Febrile Seizures
* Preferred

Mechanism of action
• Current antiepileptic drugs are thought to act mainly by three main mechanisms:
 Reducing electrical excitability of cell membranes, mainly through use-
dependent block of sodium channels
 Enhancing GABA-mediated synaptic inhibition; this may be achieved by an
enhanced postsynaptic action of GABA, by inhibiting GABA transaminase, or
by drugs with direct GABA agonist properties
 Inhibiting T-type calcium channels (important in controlling absence seizures).
• Newer drugs act by other mechanisms yet to be elucidated.
• Drugs that block glutamate receptors are effective in animal models but are unsuitable
for clinical use

 Phenytoin is the most important member of the hydantoin group of compounds,
which are structurally related to the barbiturates.
 It is highly effective in reducing the intensity and duration of electrically induced
convulsions in mice, although ineffective against PTZ-induced convulsions.
 Despite its many side effects and unpredictable pharmacokinetic behaviour,
Phenytoin is widely used, being effective against various forms of partial and
generalised seizures, although not against absence seizures, which may even get worse.
PHENYTOIN
Mechanism of Action
 Membrane stabilization by blocking Na+ & Ca+2 influx into the neuronal axon.
Or
 Inhibits the release of excitatory amino acids via inhibition of Ca+2 influx

 Well absorbed when given orally, however, it is also available as iv. (for emergency)
80-90% protein bound
Induces liver enzymes (Very Important)
Metabolized by the liver to inactive metabolite
Metabolism shows saturation kinetics and hence t ½ increases as the dose increased
Excreted in urine as glucuronide conjugate
Plasma t ½ approx. 20 hours
Pharmacokinetics
.
Pharmacokinetic Interactions
Inhibitors of liver enzymes elevate its plasma levels e.g. Chloramphenicol, INH
Inducers of liver enzymes reduce its plasma levels e.g. Carbamazipine; Rifampicin.

Side effects
Ataxia, headache, but not sedation.
 Marked confusion with intellectual deterioration occurs
 Hyperplasia of the gums often develops gradually, as does hirsutism
 Megaloblastic anaemia (Decreased RBC production)
 Hypersensitivity reactions, mainly rashes, are quite common.
 Severe idiosyncratic (unexpected sensitivity) reactions, including hepatitis
 Skin reactions and neoplastic lymphocyte disorders
Clinical Uses
• Used for partial Seizures & generalized tonic-clonic seizures.
• But not effective for absence Seizures

Carbamazepine
 One of the most widely used antiepileptic drugs, is chemically derived from the tricyclic
antidepressant drugs
 Was found in a routine screening test to inhibit electrically-evoked seizures in mice.
 Pharmacologically and clinically, its actions resemble those of Phenytoin although it
appears to be particularly effective in treating complex partial seizures (e.g. psychomotor
epilepsy).
 It is also used to treat other conditions, such as neuropathic pain and manic-depressive
illness
Pharmacokinetics
Carbamazepine is well absorbed.
Its plasma half-life is about 30 hours when it is given as a single dose.
A slow-release preparation is used for patients who experience transient side effects
coinciding with plasma concentration peaks

Adverse effects
 Drowsiness , dizziness and ataxia to more severe mental and motor disturbances.
 It can also cause variety of gastrointestinal and cardiovascular side effects.
 The incidence and severity of these effects is relatively low.
 Severe bone marrow depression, causing neutropenia (low levels of neutrohills)
 Hypersensitivity reaction can occur but are very rare.
 Treatment is usually started with a low dose, which is built up gradually to
avoid dose-related toxicity

Phenobarbital
Mechanism of Action
 Increases the inhibitory neurotransmitters (e.g: GABA ) and decreasing the excitatory
transmission.
 Also, it also prolongs the opening of Cl- channels.
Pharmacokinetics
 Well absorbed, and about 50% of the drug in the blood is bound to plasma albumin.
 It is eliminated slowly from the plasma (half-life, 50-140 hours).
 About 25% is excreted unchanged in the urine.

Clinical uses
Used in adults because of sedation.
For some years, it was widely used in children, including as prophylaxis following febrile
convulsions in infancy.
 It can cause behavioural disturbances and hyperkinesia, and is now seldom used at all in
newly diagnosed patients
Adverse effects
 Some degree of tolerance to the sedative effect seems to occur.
 Cognition and motor performance show impairment even after long-term treatment.
 Megaloblastic anaemia , mild hypersensitivity reactions
 Osteomalacia (softening of bones).
 It must not be given to patients with porphyria (distubance of metabolism).
 In overdose, Phenobarbital produces coma and respiratory and circulatory failure, as do
all barbiturates

Ethosuximide
 Which belongs to the succinimide class, is another drug developed empirically by
modifying the barbituric acid ring structure.
 Pharmacologically and clinically, however, it is different from the drugs so far
discussed, in that it is active against PTZ-induced convulsions in animals and against
absence seizures in humans, with little or no effect on other types of epilepsy.
 It supplanted Trimethadione, the first drug found to be effective in absence seizures,
which had major side effects.
 Ethosuximide is used clinically for its selective effect on absence seizures.
Mechanism of action
The main effect described is inhibition of T-type calcium channels, which may
play a role in generating the 3/second firing rhythm in thalamic relay neurons that is
characteristic of absence seizures.

Pharmacokinetics
• Ethosuximide is well absorbed, and metabolised and excreted much like Phenobarbital,
with a plasma half-life of about 50 hours
Side effects
 Nausea and anorexia, sometimes lethargy and dizziness, and it is said to precipitate
tonic-clonic seizures in susceptible patients.
 Very rarely, it can cause severe hypersensitivity reactions.

Sodium Valproate
• It is a simple monocarboxylic acid, chemically unrelated to any other class of
antiepileptic drug
• In 1963 it was discovered quite accidentally to have anticonvulsant properties in mice.
• It inhibits most kinds of experimentally induced convulsions and is effective in many
kinds of epilepsy, being particularly useful in certain types of infantile epilepsy.
•Like Carbamazepine,Valproate is also used in psychiatric conditions such as bipolar
depressive illness

Mechanism
 It causes a significant increase in the GABA content of the brain and is a weak
inhibitor of two enzyme systems that inactivate GABA, namely GABA transaminase
and succinic semialdehyde dehydrogenase, but in vitro studies suggest that these effects
would be very slight at clinical dosage.
 Other more potent inhibitors of these enzymes (e.g. vigabatrin) also increase GABA
content and have an anticonvulsant effect in experimental animals.
 There is some evidence that it enhances the action of GABA by a postsynaptic
action, but no clear evidence that it affects inhibitory synaptic responses.
 It also inhibits sodium channels, but less so than Phenytoin

Unwanted effects
 It causes thinning and curling of the hair in about 10% of patients.
 The most serious side effect is hepatotoxicity.
 An increase in serum glutamic oxaloacetic transaminase, which signals liver damage of
some degree, commonly occurs, but proven cases of valproate-induced hepatitis are rare.
The few cases of fatal hepatitis in valproate-treated patients may well have been caused
by other factors.
 Valproate is teratogenic, causing spina bifida and other neural tube defects.
Pharmacokinetics
Valproate is well absorbed orally and excreted, mainly as the glucuronide, in
the urine, the plasma half-life being about 15 hours.

NEWER ANTIEPILEPTIC DRUGS
Vigabatrin
 The first 'designer drug' in the epilepsy field, is a vinyl-substituted analogue of GABA.
 Designed as an inhibitor of the GABA-metabolising enzyme GABA transaminase.
 Extremely specific for this enzyme and works by forming an irreversible covalent bond.
 In animal studies, vigabatrin increases the GABA content of the brain and also increases
the stimulation-evoked release of GABA, implying that GABA transaminase inhibition can
increase the releasable pool of GABA and effectively enhance inhibitory transmission.
 In humans, vigabatrin increases the content of GABA in the cerebrospinal fluid.
 Although its plasma half-life is short, it produces a long-lasting effect because the enzyme
is blocked irreversibly, and the drug can be given by mouth once daily.

 Evidence of neurotoxicity was found in animals but has not been found in humans,
removing one of the main question marks hanging over this drug.
 The main drawback of vigabatrin is the occurrence of depression, and occasionally
psychotic disturbances, in a minority of patients; otherwise, it is relatively free from side
effects.
 Vigabatrin has been reported to be effective in a substantial proportion of patients
resistant to the established drugs, and may represent an important therapeutic advance

Levetiracetam
 Developed as an analogue of piracetam, a drug used to improve cognitive function, and
discovered by accident to have antiepileptic activity in animal models.
 Unusually, it lacks activity in conventional models such as electroshock and PTZ tests,
but is effective in the kindling model. It has little or no effect on known targets (ion
channels and GABA-related mechanisms), and its mechanism of action is unknown.
 It is excreted unchanged in the urine.

Gabapentin
 Designed as a simple analogue of GABA that would be sufficiently lipid-soluble to
penetrate the blood-brain barrier.
 It turned out to be an effective anticonvulsant in several animal models but,
surprisingly, not by acting on GABA receptors.
 Its main site of action appears to be on T-type calcium channel function, by binding to
a particular channel subunit (α2δ), and it inhibits the release of various neurotransmitters
and modulators, but the details remain unclear.
 The side effects of Gabapentin (mainly sedation and ataxia) are less severe than with
many antiepileptic drugs.
 The absorption of Gabapentin from the intestine depends on the amino acid carrier
system and shows the property of saturability, which means that increasing the dose does
not proportionately increase the amount absorbed.
 This makes Gabapentin relatively safe and free of side effects associated with
overdosing.

Pharmacokinetics
 Its plasma half-life is about 6 hours, requiring dosing two to three times daily. It is
excreted unchanged in the urine and is free of interactions with other drugs.
 These drugs are excreted unchanged in the urine, and so must be used with care in
patients whose renal function is impaired.
Uses
 It has limited efficacy when used on its own, so is used mainly as add-on therapy.
 It is also used as an analgesic to treat neuropathic pain.
 A recently introduced follow-up drug, Pregabalin is more potent than Gabapentin but
otherwise very similar.

Clinical uses
• Cardiac dysrhythmias - phenytoin
• Bipolar disorder - valproate, carbamazepine, oxcarbazepine,lamotrigine topiramate
• Migraine prophylaxis - valproate, gabapentin
• Anxiety disorders - gabapentin
• Neuropathic pain - gabapentin , carbamazepine, lamotrigine
• Tonic-clonic (grand mal) seizures: carbamazepine, phenytoin, valproate
• Use of a single drug is preferred, when possible, to avoid pharmacokinetic interactions
newer agents include vigabatrin, lamotrigine, felbamate, gabapentin
• Partial (focal) seizures: carbamazepine,valproate,alternatives are clonazepam or
phenytoin.

•Absence seizures (petit mal): ethosuximide or valproate
• valproate is used when absence seizures coexist with tonic-clonic seizures, because
most other drugs used for tonic-clonic seizures can worsen absence seizures.
• Myoclonic seizures: diazepam intravenously or (in absence of accessible veins) rectally.
• Neuropathic pain: for example carbamazepine, gabapentin.
• To stabilise mood in mono- or bipolar affective disorder (as an alternative to lithium):
for example carbamazepine, valproate

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