Anticonvulsant Drugs

ANTIEPLEPTICS 2019ا.د.غادة Anticonvulsants

Epilepsy
is a common neurological abnormality Epilepsy is a chronic, usually life-long disorder characterized by recurrent seizures or convulsions and usually, episodes of unconsciousness and/or amnesia affecting about 1% of the human population And Approximately 10% of the population will have at least one seizure in their lifetime.


Epilepsy is originating from several mechanisms that have in common the sudden and excessive discharge of cerebral neurons. This abnormal electrical activity may result in a variety of events, including loss of consciousness, abnormal movements, atypical or odd behavior. The site of origin of the abnormal neuronal firing determines the symptoms that are produced.


Medications are the most widely used mode of treatment for patients with epilepsy. In general, seizures can be controlled with one medication in approximately 75% of patients. Patients may require more than one medication in order to optimize seizure control, and some patients may never obtain total seizure control..

What is seizure

Seizures are finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons.

Types of seizures

classified as: general and focal seizures. seizures with or without loss of consciousness.


Genetic epilepsy These seizures result from an inherited abnormality in the central nervous system (CNS). Some genetic mutations have been identified in epilepsy syndromes. Obtaining a detailed family history may provide important information for assessing the possibility of a genetic link to seizures.
The causes of seizures


Structural/metabolic epilepsy A number of causes, such as illicit drug use :Toxic manifestation of the action of central nervous system (CNS) stimulants and certain other drugs. tumor, head injury, hypoglycemia, uremia,or pyridoxine deficiency. meningeal infection, and the rapid withdrawal of alcohol from an alcoholic, can precipitate seizures.

In cases when the cause of a seizure can be determined and corrected, medication may not be necessary. For example, a seizure that is caused by a drug reaction is not epilepsy and does not require chronic therapy. In other situations, antiepilepsy medications may be needed when the primary cause of the seizures cannot be corrected.

Unknown cause When no specific anatomic cause for the seizure, such as trauma or neoplasm, is evident, a patient may be diagnosed with seizures where the underlying cause is unknown. Most cases of epilepsy are due to an unknown cause. Childhood fevers, Seizures often occur in hyperthermia (febrile seizures are very common in infants).

Antiepileptics drugs

Neuronal site of action of Antiepileptics


1- BenzodiazepinesBenzodiazepines bind to GABA inhibitory receptors to reduce firing rate. Diazepam given intravenously and Diazepam is also available for rectal administration to avoid prolonged generalized tonic–clonic seizures when oral administration is not possible.Diazepam and Lorazepam, is the drug of choice in the acute treatment of status epilepticus.

Toxcicty

Sedative properties, drowsiness, somnolence, and fatigue. Higher dosage ataxia, dizziness and behavior changes. Respiratory depression and cardiac depression may occur when given intravenously in acute treatment .

2- Phenytoin

Discovered in 1938

Phenytoin Therapeutic uses

partial seizures with complex symptoms.Generalized tonic–clonic seizures.

Mechanism of Action

blocks voltage-gated sodium channels by selectively binding to the channel in the inactive state and slowing its rate of recovery. This lead to limit the spread of electrical excitation by inhibiting sustained high-frequency firing of neurons.

Pharmacokinetic

phenytoin absorption is slow but usually complete. Phenytoin is highly bound (about 90%) to plasma proteins. It displays zero-order (or saturation) kinetics in its metabolism

Adverse effects of phenytoin

usually result from over dosage. 1- Nystagmus , ataxia, vertigo, and diplopia 2- Higher doses lead to altered levels of consciousness and cognitive changes. 3- Megaloplastic anemia occur because drug interferes with Vit B12 metabolism and hepatic necrosis.

4- Idiosyncratic reactions may be seen shortly after therapy has begun: Skin rashes are most common. Exfoliative dermatitis or toxic epidermal necrolysis

5- Gingival hyperplasia occurs in up to 50% of patients.

6 - Thickening of subcutaneous tissue, coarsening of facial features, and enlargement of lips and nose , are often seen in patients receiving long-term phenytoin. 7 - phenytoin is Teratogenic in humans, but the mechanism is not clear. Although phenytoin is advantageous due to its low cost, the actual cost of therapy may be much higher, considering the potential for serious toxicity and adverse effects.



Drug Interaction
Coadministration of the following drugs can result in elevations of plasma phenytoin levels in most patients: Cimetidine, Chloramphenicol (inhibition of microsomal responsible for phenytoin metabolism ). Phenytoin often causes a decline in plasma Carbamazepine levels if these two drugs are given together.(phenytoin induce the P-450).

Carbamazepine

Is a tricyclic compound Closely related to Imipramine and other antidepressants.

Carbamazepine Mechanism of Action

Carbamazepine, like phenytoin, blocks sodium channels at therapeutic concentrations and inhibits high-frequency repetitive firing in neurons . It also acts presynaptically to decrease synaptic transmission.

Carbamazepine Clinical Uses:

Drug of choice for both partial seizures and generalized tonic-clonic seizures( not sedative). It can be used with phenytoin in many patients who are difficult to control. Very effective in Trigeminal neuralgia and other neuropathic pain. useful in mania (bipolar disorder).

Carbamazepine Adverse Effects

dose-related: diplopia and ataxia. mild gastrointestinal upsets. Unsteadiness. idiosyncratic blood dyscrasias including fatal cases of a plastic anemia and agranulocytosis 5. The mild and persistent leukopenia. 6. The most common idiosyncratic reaction is an erythematous skin rash.

Drug Interactions

It induce the enzymes that metabolize other anticonvulsant drugs, including phenytoin, phenobarbital, valproic acid, Clonazepam.A common drug–drug interaction is between carbamazepine and the macrolide antibiotics erythromycin

3- Phenobarbital Is the oldest of the currently available anti seizure drugs (sedative effects). Mechanism of action
Phenobarbital binds to an allosteric regulatory site on the GABA A receptor. Phenobarbital also blocks excitatory responses induced by glutamate .

Clinical uses

Treatment of partial seizures and generalized tonic-clonic seizures, and for every seizure type, especially when attacks are difficult to control. The drugs of choice for seizures only in infants

4-Valproic acid

Sodium valproate, also used as the free acid, valproic acid, was found to have antiseizure properties Mechanism of action reduces the propagation of abnormal electrical discharge in the brain. It may enhance GABA action at inhibitory synapses.

Clinical uses

Treatment of myoclonic seizures. The drug diminishes absence seizures but is a second choice because of its hepatotoxic potential. Reduces the incidence and severity of tonic-clonic seizures

toxicity

Nausea and vomiting. Sedation, ataxia, and tremor. Hepatic toxicity may cause a rise in hepatic enzymes in plasma, which should be monitored frequently. Rash and alopecia may occur. Bleeding times may increase because of both thrombocytopenia and an inhibition of platelet aggregation.

5- Gabapentin

Gabapentin is an amino acid, an analog of GABA, that is effective against partial seizures. Its mechanism is not known The drug also binds to the voltage-sensitive Ca2+ channels.

Clinical uses : 1-Gabapentin is effective as an adjunct against partial seizures and generalized tonic-clonic seizures. 2- treatment of neuropathic pain 3- now indicated for post herpetic neuralgia in adults . Adverse effects : somnolence, dizziness, ataxia, headache, and tremor.