Epilepsy and antiepileptic drugs

Epilepsy: is a very common chronic disorder characterized by recurrent seizures. Seizure: excessive discharge of cortical neuron
Convulsion: involuntary contraction of voluntary muscles Patients may have epilepsy or seizure disorders without convulsions
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Any Seizure Result From

Types Of Ion Channels

Ion Channels

Voltage-gated Channels
Na+ & ca ++ depolarize the cell membrane (E)
K+ hyperpolarize the cell membrane (I)

Ligand -gated channels

Glutamate (E) GABA (I)

Types of s (focal) Primary

International Classification Of Seizures

a. Partial focal : In which the discharge involves one part of the cortex. 1.Simple: consciousness is preserved 2.Complex: consciousness is impaired

b. Generalized In which the discharge involves the whole cortex 1. Tonic-Clonic: Grandmal seizures
Tonic: abrupt loss of consciousness (less than 1 min) Clonic: jerking of body muscles with lip or tongue biting, fecal & urinary incontinence

2. Absence or petit mal: altering of consciousness lasting 10-30 seconds, onset of this type occurs from ages 3-16 years 3. Myoclonic: Single or Multiple muscle jerk

c. Status epilepticus:

Series of seizures without recovery of consciousness between attacks It is life threatening emergency

Febrile seizures Young child (3 months to 5 years) frequently develop seizures with illness accompanied by high fever Treatment: acute case Diazepam rectally Diagnosis of specific seizure type is important for prescribing the most appropriate antiseizure drug Treatment may involve combination of drugs

Generalized tonic clonic seizures (grand mal seizures)

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Generalized Seizure (Absence or Petit Mal )

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ATONIC SEIZURE

Aim of Treatment
a: Complete suppression of fits and if not possible. b: Reduction of fit frequency as much as possible, with minimum and tolerable ADRs.

The management of patients with epilepsy is focused on 3 main goals:

Improve Quality Of Life

Goals
Avoiding Side Effects Controlling Seizures

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Etiology of epilepsy Some seizures arise secondary to other conditions. However, in most cases, the cause of the seizure is unknown. 1. Primary (idiopathic) seizures have no identifiable cause.

2.Secondary seizures (symptomatic or acquires seizures) occur secondary to an identifiable cause. * Intracranial neoplasms. * Infectious diseases, such as meningitis, influenza, * High fever (in children) * Head trauma. * Metabolic disorders, such as hypoglycemia and hypocalcemia. * Alcohol or drug withdrawal.

Clinical evaluation
History includes an evaluation of the seizure, including interviews of the patients family

Laboratory test may also identify an underlying etiology

Neurological imaging studies

EEG studies measure the electrical activity of the brain. - An EEG is useful for classifying the seizure, but the EEG by itself cannot rule seizures in or out, as there are patients with normal EEGs who have seizure disorders.

Therapy Principles of drug therapy Seizure control.

Approximately 50% of epileptics achieve complete seizure control through drug therapy. In another 25% drugs reduce the frequency of seizures. Epileptics generally require continuous drug therapy for at least 4 seizure-free years before the drug can be discontinued.

Antiepileptics are indicated when there is two or more seizures occurred in short interval An initial therapeutic aim is to use only one drug (monotherapy)

Treatment:
Before any drug treatment is instituted, remedial causes of the seizure activity should be excluded. A single primary drug that is most appropriate for the seizure type must be selected. If there is more than one appropriate primary drug, age, sex, and compliance of the patient must be considered

Treatment
Additional therapy. If seizures recur after the maximal tolerated dose is reached; a second drug is added at a low dose. The dose of the second drug is increased until a therapeutic level is reached. The first drug is maintained until the optimal dose of the second drug is determined; then the first drug is discontinued gradually to avoid triggering seizure activity.

The sudden withdrawal of drugs should be avoided withdrawal may be considered after seizure- free period of 2-3 or more years

MOA of antiepleptic drugs:

inhibitory tone by facilitation of GABA-mediated hyperpolarization-barbiturates, benzodiazepines axonal conduction by preventing Na' influx through fast Na channels-carbamazepine, phenytoin; also, at high doses, barbiturates and valproic acid

presynaptic ca2 + influx through type-T channels in thalamic neurons-ethosuximide and valproic acid

Pharmacology of antiepileptic drug

DRUG THAT BLOCK VOLTAGEDEPENDENT SODIUM CHANNELS

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Anti-epileptic drugs

Phenytoin
MOA: blocks voltage gated sodium channels in neuronal membrane Clinical uses: partial seizures & generalized tonic-clonic seizures

It has narrow therapeutic index

Phenytoin
the relation between the dose & plasma concentration is not linear. Has high drug Interactions. Induction of dug metabolizing enzymes

 S/Es

1. 2. 3. 4.

CNS: ataxia, diplopia, nystagmus Gingival hyperplasia Hairsutism Teratogenic effect (not given during pregnancy) 5. Abnormalities of vitamin D catabolism 6. folate levels megaloblastic anemia

Gingival hyperplasia

 Carbamazepine MOA: blocks sodium channels Uses: as phenytoin & for Trigeminal Neuralgia & Rx of mania
Similarities between phenytoin & carbamazepine:

Both are liver enzyme inducers Both enhance catabolism of vitamin D Both cause megaloblastic anemia but more with phenytoin Both are not used in absence seizures
S/Es

CNS: ataxia, diplopia

 Valproic acid
MOA

Interfere with sodium channels at high doses Can potentiate the inhibitory effect of GABA
Therapeutic uses

Generalized Tonic-Clonic, partial & can be used in absence seizure

S/Es

Alopecia (hair loss) Teratogenicity Liver damage

 Ethosuximide
MOA: act by blocking T-calcium channel The main drug used to treat absence seizures S/Es: nausea & anorexia

Phenobarbital
clinical use: the same as phenytoin, for TonicClonic seizures

 Benzodiazepines 1. Diazepam: given I.V. to treat status epilepticus 2. Clonazepam

Drugs Used in Seizure Disorders

Tonic-Clonic & Partial Seizure

Absence Seizure

Myoclonic

Carbamazepine Phenytoin Valproic acid phenobarbital

Ethosuximide Valproic acid Clonazepam

Clonazepam Valproic acid

Management of status epilepticus

1.Establish airway, oxygenate, recovery position 2. Establish IV access and give IV lorazepam 2-4mg (IV diazepam 5-10mg alternative; Buccal midazolam 10mg preferred over rectal diazepam)
3. Check blood for: glucose, urea and electrolytes, Calcium, anticonvulsant levels, and arterial blood gas and pH.

4.If seizures continue, administer intravenous phenobarbital or phenytoin as second-line treatment

5. In sever status epilepticus especially that not respond to these meausres, general anesthesia and neuromuscular blocker and artificial respiration.