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Antiepileptic Drugs

The term epilepsy refers to a group of disorders characterized by excessive excitability of neurons within the CNS. This abnormal activity can produce a variety of symptoms, ranging from brief periods of unconsciousness to violent convulsions.
Seizures are initiated by synchronous, high-frequency discharge from a group of hyperexcitable neurons, called a focus. A focus may result from several causes, including congenital defects, hypoxia at birth, head trauma, and cancer. Seizures result when discharge from a focus spreads to other brain areas, thereby recruiting normal neurons to discharge abnormally along with focus. Seizures may be partial or generalised depending on the location and spread of the abnormal neuronal discharge. If seizure activity invades a very limited part of the brain, a partial or local seizure occurs. In contrast, if seizure activity spreads to a large portion of the brain, a generalized seizure develops . The attack may involve mainly motor, sensory or behavioural phenomena. Unconsciousness occurs when the reticular formation is involved
Types of Seizure:
Two major categories, namely partial and generalised seizures; there is some overlap and many varieties of each.
1. Partial seizures: The discharge begins locally, and often remains localized.Produce relatively simple symptoms without loss of consciousness.
a. Simple partial seizure
b. Complex partial seizures
c. In some patients, partial seizures may evolve secondarily into generalized seizures
2. Generalized Seizures:
Involve the whole brain, including the reticular system, thus producing abnormal electrical activity throughout both hemispheres.
As a rule, generalized seizures produce immediate loss of consciousness.
a. Tonic- clonic (grand mal).
b. Absence seizures (petit mal).
c. Atonic seizures.
d. Myoclonic seizures.
3. Status epilepticus. SE is defined as a seizure that persists for 30 minutes or more. There are several types of SE, including generalized convulsive SE, absence SE, and myoclonic SE.
4. Febrile seizures. Fever-associated seizures are common among children ages 6 months to 5 years. Febrile seizures typically manifest as generalized tonic-clonic convulsions of short duration. Children who experience these seizures are not at high risk of developing epilepsy later in life.


Antiepileptic Drugs:
Current drug therapy is effective in 70-80% of patients.
1. Phenytoin, 2. Carbamazepine, 3. Phenobarbital
4.Valproic acidm, 5. Benzodiazepines (diazepam, lorazepam clonazepam)
6. Ethosuximide.
Mechanism of action:
Current antiepileptic drugs are thought to act mainly by two main mechanisms:
-Reducing electrical excitability of cell membranes, possibly through inhibition of sodium channel.
-Enhancing GABA-mediated synaptic inhibition. This may be achieved by an -enhanced pre- or post- synaptic action of GABA, by inhibiting GABA-transaminase, or by drugs with direct GABA-agonist properties
-A few drugs appear to act by a third mechanism, namely inhibition of T-type calcium channels.
-Newer drugs act by other mechanism, yet to be elucidated.
-Drugs that block excitatory amino acid receptors are effective in animal models, but not yet developed for clinical use.

Phenytoin:

This drug is active against partial and tonic clonic seizures but not absence seizures. It is the oldest antiseizure drug, introduced in 1938.
Pharmacokinetic
Because phentoin is a weak acid, its intestinal absorption is variable and plasma concentration can vary widely. Monitoring is therefore needed.
It is metabolized by the microsomal system and is excreted first in the bile and then in the urine.
Mechanism of action:
1-phenytoin causes selective inhibition of sodium channels. As a result, entry of sodium into neurons is inhibited, and hence action potentials are suppressed. Blockade of sodium entry is limited to neurons that are hyperactive. Therefore, the drug suppresses activity of seizure-generating neurons while leaving healthy neurons unaffected.
(2) Blocking voltage-dependence Ca2+ channel.
(3) Inhibiting calcium-induced secretory processes, including release of hormones and neurotransmitters.
Therapeutic uses:
Epilepsy. Phenytoin can be used to treat all major forms of epilepsy except absence seizures.
Cardiac Dysrrhythmias. Phenytoin is active against certain types of dysrrhythmias. Phenytoin is a second choice drug after lidocaine for treating digoxin induced dysrrhythmias.
Treatment of peripheral neuralgia.
Adverse Effects:
Effects on the CNS. Sedation, Nystagmus, ataxia, diplopia and cognitive impairment
Gingival hyperplasia. Gingival hyperplasia (excessive growth of gum) is characterized by swelling, tenderness, and bleeding of the gums. This effect occurs in about 20% of patients.
Skin rash. Between 2% and 5% of patients develop a morbilliform rash, exfoliative dermatitis or Stevens-Johnson syndrome. If a rash develop phenytoin should be discontinued.
Hepatitis.
5- Other adverse effects.
a. Hirsutism
b. Interference with vitamin D metabolism may cause rickets and osteomalacia.
c. Interference with vitamin K metabolism can lower prothrombin levels, thereby causing bleeding tendencies in newborns.


Phenytoin and Pregnancy.
Phenytoin is a teratogen in animals and humans. In humans, phenytoin can cause cleft palate, heart malformations, and fetal hydantoin syndrome, characterized by growth deficiency, mental deficiency, microcephaly, craniofacial distortion, hypoplasia of the nails and finger. Accordingly, phenytoin should be used during pregnancy only if the benefits of seizure control outweigh the risk to the fetus.

Preparations, dosage and administration.

Preparations: Injectable, and oral ( tablets and suspension). Dosage: 150mg twice daily. Plasma drug levels are often monitered as an aid to dosage determination. The dosage objective is to produce phenytoin levels between 10 and 20 µg/ ml. Levels below 10 µg/ml are too low to control seizure; at levels above 20 µg/ml, signs of toxicity begin to appear (Narrow therapeutic range).
When treatment with phenytoin is discontinued, dosage should be reduced gradually. Abrupt withdrwal may precipitate seizures.

Carbamazepine:

Carbamazepine (Tegretol) is a mainstay of epilepsy therapy. The drug is active against partial seizures and tonic clonic and other types of seizures but not absence seizures.
Mechanism of action.
The mechanism of action of carbamazepine appears to be the same as that of phenytoin.
Therapeutic uses.
1. Epilepsy. Carbamazepine is effective against all types of epilepsy except absence epilepsy.
2. Bipolar disorder (manic-depressive illness). Carbamazepine can provide symptomatic control in patients with bipolar disorder, and is often effective in patients who are refractory to lithium.
3. Trigeminal neuralgia. Neuralgia is a severe, stabbing pain that occurs along the course of a nerve. Carbamazepine can reduce neuralgia associated with the trigeminal nerves. It is the drug of choice for this type neuralgia.
Adverse effects.
1. CNS effects. Nystagmus, blurred vision, diplopia, ataxia, vertigo and headache.
2. Hematologic effects. Carbamazepine can causing bone marrow suppression leading to leukopenia, anemia and thrombocytopenia. Fatal aplastic anemia has occurred during carbamazepine therapy (1 in 200,000).
3. Hyponatremia. Carbamazepine can inhibit renal excretion of water, by promoting secretion of antidiuretic hormone. Periodic monitoring of serum sodium content is recommended.
4. Dermatologic effects. morbilliform rash, photosensitivity reactions, stevens-Johnson syndrome, and exfoliative dermatitis.
Pregnancy.
Carbamazepine may be teratogenic. In humans, the drug is associated with an increased risk of neural tube defect. In mice, it has caused cleft palate, dilated cerebral ventricles, and growth retardation. So carbamazepine should be used in pregnancy if the benefits of seizure control are deemed to outweigh risks to the fetus.
Preparations, dosage and administrations.
Orally as tablets and suspension. Maintenance dosages for adults range from 600 to 1200 mg/day, administered in divided doses.


Phenobarbital.
Phenobarbital, Luminal: Phenobarbital is one of the oldest antiepileptic drugs. Phenobarbital belongs to the barbiturate family.
Mechanism:
(1) Block Ca2+ currents presynaptic membrane and decrease neurotransmitter release.
(2) Prolong the openings of the Cl- channel in postsynaptic membrane and decrease it’s response.
3-Phenobarbital suppresses seizures by potentiating the effects of GABA. Specifically, the drug binds to GABA receptors, causing the receptor to respond more intensely to GABA itself.
Therapeutic Uses.
Epilepsy. Phenobarbital is effective against partial seizures and generalized tonic clonic seizures but not against absence seizures.
Intravenous phenobarbital can be used for generalized convulsive status epilepticus, but lorazepam and phenytoin are preferred.

Valproic acid (Depakene).

The drug is active against absence seizure, tonic-clonic, partial, atonic and myoclonic seizures.
Mechanism of action
Valproic acid appears to act by 3 mechanisms.
1. The drug shares the same mechanism as phenytoin and carbamazepine: suppression of high-frequency neuronal firing through blockade of sodium channels
2. The drug suppresses calcium influx through calcium channels. 3. In addition, it may augment the inhibitory influence of GABA by inhibiting the metabolism of this neurotransmitter.
Clinical uses
1. Valproic acid is regarded as a broad spectrum antiepileptic agent. It affects all types of epilepsy including absence
2. Bipolar disorder. Like carbamazepine, valproic acid provide symptomatic control in patients with bipolar disorder (manic-depressive illness).
3. Migrain. Valproic acid was recently approved for prophylaxis of migrain.
Adverse effects:
1. GIT effects. Nausea, vomiting and indigestion are common, occurring in 16% of patients.
2. Hepatotoxicity. Rarely, valproic acid has been associated with fatal liver failure. Most deaths have occurred within the first few months of therapy. The overall incidence of fatal hepatotoxicity is about 1 in 30,000.
3. Other adverse effects.
a. skin rashes.
b. Weight gain.
c. Hair loss
d. Blood dyscrasias: leukopenia, thrombocytopenia, anemia
Ethosuximide: Is a drug of choice for absence seizurers, the only seizures for which it is indicated. may exacerbate other form Acts by blocking T-type Ca2+-channels
Relatively few unwanted effects, mainly nausea and anorexia
Mental disturbances.
Gabapentin
Gabapentin is an analog of GABA. However, it does not act at GABA receptors nor enhance GABA actions, nor is it converted to GABA. Its precise mechanism of action is not known.
It is approved as adjunct therapy for partial seizures and for treatment of postherpetic neuralgia. Good choice due to limited or no reported pharmacokinetic drug interactions.
Status epilepticus.
Convulsive SE is defined as a continuous series of tonic clonic seizures that lasts for at least 20 to 30 minutes. Generalized convulsive SE is a medical emergency that requires immediate treatment. Ideally, treatment should commence within 5 minutes of seizure onset. An IV benzodiazepine, either lorazepam or diazepam, is used initially. Both drugs can terminate seizures quickly. Diazepam has a short duration of action, and hence must be administered repeatedly. Effects of lorazepam lasts for 12 to 24 hours. Because of its prolonged effects, lorazepam is generally preferred to diazepam
Once seizures have been stopped with a benzodiazepine, phenytoin or phenobarbitone is given for long-term suppression.


Clinical consideration of Antiepileptic Drugs
Tonic-clonic (grand mal) seizures: carbamazepine preferred because of low incidence of side-effects, .
-Partial (focal) seizures: carbamazepine, valproate; clonazepam or phenytoin are alternatives.
-Absence seizures (petit mal): ethosuximide or valproate. Valproate is used when absence seizures coexist with tonic-clonic seizures, since most drugs used for tonic-clonic seizures may worsen absence seizures.
-Myoclonic seizures: valproate or clonazepam.
-Status epilepticus: must be treated as an emergency, with diazepam intravenously.
- Use of single drug is preferred when possible, because of risk of pharmacokinetic interactions

Antipsychotic Agents (Neuroleptic Drugs)

Main indication for these drugs is schizophrenia. Thus they are called antischizophrenic drugs.
Schizophrenia:
Schizophrenia is a chronic psychotic illness characterized by disordered thinking and a reduced ability to comprehend reality.
Symptoms of Scizophrenia:
Symptoms of schizophrenia can be divided into 2 groups:
Positive symptoms: hallucinations, delusions, disordered thinking, combativeness, agitation and paranoia.
Negative symptoms: social withdrawal, emotional withdrawal, lack of motivation, poverty of speech, poor insight, poor judgment and poor self-care.
Drugs: The antipsychotic drugs fall into 2 major groups:
Conventional antipsychotics.
Atypical antipsychotics.
All of the conventional agents block receptors for dopamine in the CNS. As a result, they all can cause serious movement disorders, known as extrapyramidal symptoms. Because of these neurologic side effects, the conventional antipsychotics are known as neuroleptics.
The atypical agents produce only moderate blockade of receptors for dopamine and much stronger blockade of receptors for serotonin. Because dopamine receptor blockade is low, the risk of extrapyramidal reactions is low as well.
Conventional antipsychotic agents relieve positive symptoms more effectively than negative symptoms. In contrast, atypical antipsychotic agents relieve both types of symptoms.


Conventional Antipsychotic Agents
Classification: The conventional antipsychotics can be classified by potency or chemical structure.
Classification by potency:
Low potency: Chlorpromazine, thioridazine.
Medium potency: loxapine, molindone, perphenazine.
High potency: Trifluoperazine, , fluphenazine, haloperidole .
Although the conventional antipsychotics differ from one another in potency, they all have the same ability to relieve symptoms of psycosis.
The term potency refers only to the size of the dose needed to elicit a given response. Example: Haloperidol is more potent than chlorpromazine, mean only that the dose of haloperidol required to relieve psychotic symptoms is smaller than the required dose of chlorpromazine, it do not mean that haloperidol can produce greater effects. When administered in therapeutically equivalent doses, both drugs elicit an equivalent antipsychotic response. Although these agents produce identical antipsychotic effects, they differ significantly in side effects. Example: low potency agents have low extrapyramidal effects, medium potency have moderate extrapyramidal effects and high potency have high extrapyramidal effects.
Low potency drugs cause high sedative effects, medium potency produce moderate sedative effects and high potency agents produce low sedative effects.
Chemical Classification:
1.Phenothiazine group: chlorpromazine, trifluperazine.
2. Thioxanthene: thiothixene.
3. Butyrophenone: haloperidole.
4. Dihydroindolone: molindone
5. Dibenzoxazepine: loxapine . 6. Diphenylbutylpiperadine: pimozide.
Pharmacodinamic
After oral administration: absorption is unaffected by food. These agents readily pass into the brain, bind well to plasma proteins, are metabolized by the cytochrome P450 system in the liver . Fluphenazine decanoate, haloperidol decanoate, and risperidone are slow-release (up to 2 to 4 weeks) injectable formulations administered via deep gluteal IM injection. The neuroleptic drugs produce some tolerance but little physical dependence.
Mechanism of action: Conventional antipsychotic drug suppress symptoms of psychosis by blocking dopamine (D2) receptors in the mesolimbic and mesocortical areas of the brain regions.
Therapeutic uses:
1-Schizophrenia: Schizophrenia is the primary indication for the neuroleptic drugs. These agents effectively suppress symptoms during acute psychotic episodes and when taken chronically can greatly decrease the risk of relapse. Positive symptoms respond better than negative symptoms. Antipsychotic drugs do not alter the underlying pathology of schizophrenia. Hence, treatment is not curative, it offers only symptomatic relief.
2-Bipolar disorder (manic-depressive illness): Antipsychotic drugs are administered with lithium for the treatment of severe symptoms of mania, when lithium starts to act (after 2 to 3 weeks), antipsychotics are then withdrawn gradually.
3-Tourette's syndrome: This rare inherited disorder is characterized by severe motor tics, barking cries, grunts, and outbursts of obscene language, all of which are spontaneous and beyond the control of the patient.
4-Prevention of emesis: Neuroleptics suppress emesis by blocking dopamine receptors in the chemoreceptor trigger zone of the medulla. These drugs can be employed to suppress vomiting associated with cancer of chemotherapy, gastroenteritis, uremia and other conditions.
5-Other applications: neuroleptics can be used for dementia and other organic mental syndromes (psychiatric syndromes resulting from organic cause, such as infection, metabolic disorder, poisoning, and structural injury to the brain). Delusional disorder, and schizoaffective disorder .In addition, they can relive symptoms of Huntington's chorea.
Adverse effects
1-Extrapyramidal symptoms (ES): ES are movement disorders resulting from effects of antipsychotic drugs on the extrapyramidal motor system. Although the exact cause of ES is unclear, blockade of D2 receptors is strongly suspected. Four types of EP symptoms occur. These differ with respect to time of onset. Three of these reactions: acute dystonia, parkinsonism, and akathisia, occur early in therapy. The fourth reaction, tardive dyskinesia, occurs late in therapy. a-Acute dystonia: time of onset a few hours to 5 days. Features: spasm of muscles of tongue, face, neck and back.
b- Parkinsonism: time of onset 5 to 30 days. Features: bradykinesia, tremor, rigidity.
c-Akathisia: time to onset 5-60 days. Features: compulsive, restless movement, symptoms of anxiety and agitation.
d-Tardive dyskinesia: Time of onset months to years. Features: Choreoathetoid movements of lips, tongue, face, jaws, and limbs and sometimes trunk. TD develops in 15% to 20% of patients during long-term therapy
2-Neuroleptic Malignant syndrome: NMS is a rare but serious reaction that carries a 4% risk of mortality. Primary symptoms are rigidity, sudden high fever, sweating, dysrrhythmias and fluctuations in blood pressure, and seizures or coma my develop. Death can result from respiratory failure, cardiovascular collapse, dysrrhythmias, and other causes. Treatment consists of supportive measures, drug therapy and immediate withdrawal of antipsychotic medication. Hyperthermia should be controlled with cooling blankets and antipyretics e.g. aspirin or paracetamol.
3-Anticholinergic effects: Antipsychotic drugs produce varying degrees of muscarinic cholinergic blockade causing dry mouth, blurred vision, photophobia, urinary retention, constipation and tachycardia.
4-Orthostatic hypotension: by blocking alpha 1 adrenergic receptors on blood vessels. Alpha adrenergic blockers prevents compensatory vasoconstriction when the patient stands, hence blood pressure falls. Patients should be informed about sin of hypotension: lightheadedness, dizziness and advised to sit or lie down if these occur.
5-Sedation: sedation is common during the early days of treatment but subsides within a week or so. Neuroleptics induced sedation is thought to result from blockade of histamine 1 receptors in the CNS.
6-Endocrine effects: Antipsychotics increase levels of circulating prolactin by blocking the inhibitory action of dopamine on prolactin release. Elevation of prolactin levels promotes gynecomastia (breast growth) and galactorrhea in up to 57% of women. Up to 97% experience menstrual irregularities. Gynecomastia and galactorrhea can also occur in males.
7-Seizures: Antipsychotics can reduce seizure threshold, thereby increasing the risk of seizure activity. The risk of seizure is greatest in patients with epilepsy and other seizure disorders.
8-Sexual dysfunction: Antipsychotic drugs can cause sexual dysfunction in women and men. The incidence of these effects is 25% to 60%.
9-Dermatologic effects: Dugs in the phenothiazine class can sensitize the skin to ultraviolet light, thereby increasing the risk of severe sunburn. They can also produce pigmentary deposits in the kin, cornea, and lens of the eye.
10-Agranulocytosis: is a rare but serious reaction. Among the conventional antipsychotics, the risk is highest with chlorpromazine and certain other phenothiazines.
Atypical Antipsychotic Agents (Clozapine ; Risperidone ;Olanzapine)
Atypical antipsychotic agents differ from conventional agents in 2 important ways:
Atypical agents cause few or no extrapyramidal symptoms.
Atypical agents can relieve positive and negative symptoms of schizophrenia, whereas benefits of conventional gents are limited largely to positive symptoms.
Atypical agents moderately blocks dopamine receptors and strongly serotonin receptors.