CNS-ANTICONVULSANTS-PART-VI-Contd..

ANTICONVULSANTS-Contd..

4.Primidone (Mysoline)

It is chemically related to barbiturates and also it works very similar to phenobarbital.

Primidone is used in adults as an alternative medicine to treat grand mal and partial seizures.

It can be given orally

Primidone is metabolized in the liver to little phenobarbital with a compound of phenyl ethyl melon amide (PEMA) as a major metabolite.

Primidone is mostly excreted in the urine as unchanged(53%) along with its metabolites PEMA (43%) and a little phenobarbital(4%).

Side Effects

Very similar to phenobarbital

1.Sedation

2.Ataxia

3.Nausea

4.Vomiting 

5.Drowsiness

5.Valproic Acid (Depakene)

It is medically used as a sodium salt.

It is the drug of choice in the treatments of myoclonic and absences seizures.

It is also used to relieve migraine and bipolar psychoses.

Mechanism

Works by prolonging the inactive state of Na+(sodium) channels and increasing the cerebral GABA concentration.

It can be given orally and it is well absorbed thereby.

After absorption 90% of the drug is bound to plasma proteins.

Metabolism

Extensively metabolized in the liver by the CYP-450 system and hence care and dosage adjustment should be considered if taken along with any medicine which affects the CYP-450 system either by induction or suppression.

This drug anyhow is not an inducer of the CYP-450 system.

Excreted in the urine as its metabolites (97%) with a little unchanged.

Side Effects

1.Liver damage

2.Nausea and Vomiting

3.Ataxia

4.Tremor

5.Lethargy

Use in Pregnancy and Lactation

Safety is not well established.

If taken during the first trimester there are high possibilities of neural tube damages.

6.Ethosuximide

It is the drug of choice for absences (Petit mal)

Chemically it is a succinimide derivative.

Mechanism

It is a calcium channel inhibitor and inhibits the influx of Ca++ into T-type channels of thalamic neurons and thereby it regulates abnormal electrical conduction in the brain.

Metabolism and Kinetics

The drug is well absorbed orally.

It is mostly metabolized in the liver by CYP-450 system

It is not inducing the enzyme

Side Effects

1.Dizziness

2.Agitation

3.Nausea

4.Vomiting

5.Diarrhea

6.Mental confusion

7.Liver damage

6.Kidney damage

Blood dyscrasias-Leukopenia, Aplastic anemia, and thrombocytopenia in sensitive patients

7.Allergic skin reactions-Stevens-Jonson syndrome

7.Benzodiazepines

Benzodiazepines are already presented in last posts (Anti-anxiety drugs) well in details however here we see some of them used as anticonvulsants.

1.Diazepam (Valium)

2.Clonazepam

3.Clorazepate

Therapeutics

Diazepam can be given as an intravenous injection in the emergency situation of Status Epilepticus.

Clonazepam can be used in treating myoclonic seizures in children

Clorazepate may be used for partial seizures (simple or complex) in combination with phenytoin or carbamazepine.

Side Effects

Even though the side effects are mild but we should take care of the following effects:-

1.Drowsiness

2.Respiratory depression

3.Cardiac depression.

8.Gabapentin

Gabapentin is chemically a GABA derivative.

It is used to treat partial seizures both simple and complex.

It is acting by increasing GABA secretion in the CNS.

It is excreted unchanged in the urine.

Side Effects

1.Ataxia

2.Somnolence

3.Fatigue

9.Lamotrigene

It is used to treat partial seizures in adults in combination with other drugs.

Mechanism

It is acting by blocking voltage dependant active sodium channels and thereby preventing the sustained firing of action potentials.

The drug is metabolized in the liver

Side Effects

1.Dizziness

2.Blurred vision

3.Rash

4.Urinary retention

5.BPH.

CNS-PAR-VI-ANTICONVULSANTS-Contd..

ANTICONVULSANTS

Seizures can be controlled if not completely treated by various drugs known as Anticonvulsants mentioned below.

1.Phenytoin (Dilantin)

2.Carbamazepine

3.Phenobarbital

4.Pirimidone

5.Valproic Acid

6.Ethosuximide

7.Benzodiazepine

8.Gabapentin

9.Lamotrigine

1.Phenytoin (Dilantin)

Phenytoin is used in treating tonic/clonic seizures and partial seizures. Chemically it is a hydantoin derivative.

Phenytoin is not effective in treating Absences.

Used in treating Status Epilepticus by intravenous route as an adjunct with diazepam.

Phenytoin is acting by blocking voltage-gated sodium channels and thereby prevent the neurons to get depolarized sufficiently to excite an action potential.

Kinetics and Route

Phenytoin can be administered either by intravenous and oral routes.

Since the absorption through the GI system is slow the oral route may have a longer gestation period to reach the required effects pharmacodynamically.

In contrast the intravenous route is rapid and reaches the required effect within minutes and lasts for 24 hours.

Phenytoin is metabolized in the liver by hydroxylation by the endometrial CYP-450 enzymes such as CYP-3A4 and CYP-2-C19. Watch for toxicity if these two enzymes induced by phenytoin get consumed completely.

Side Effects

1.Gingival Hyperplasia-A major toxicity in which there is a painful enlargement of teeth gum. Folic acid supplementation is recommended

2. Megaloblastic Anemia-Because phenytoin interferes with folic acid metabolism. Folic acid supplementation is required.

3.Hirsutism-Unwanted growth of hair.

4.Diminished deep tendon reflexes in the extremities.

5.Stevens-Jonson Syndrome-Severe skin rashes with cell necrosis with fever and usually a life-threatening reaction.

6.CNS depression

7.Endocrine reactions-Diabetes Insipidus(Watery Urine), Hyperglycemia, glycosuria, and osteomalacia(bone weakness)

Drugs Interactions

The following three drugs are competing with phenytoin for the enzyme CYP-450 successfully, by decreasing its metabolism and thereby increasing its plasma concentration.

1.Chloramphenicol-Anti typhoid

2.Isoniazid-Anti T.B.

3.Cimetidine.-Antihistamine to reduce hyperacidity

Dosage adjustment should be necessary when giving Phenytoin concomitantly with the above drugs.

Carbamazepine by inducing rapid metabolism of phenytoin decreases its plasma concentration. Dosage adjustment of phenytoin is important accordingly if given along with carbamazepine.

Use in Pregnancy and Lactation

Phenytoin is a teratogenic drug as it can cross into the placenta and milk and hence it should not be given during pregnancy and lactation as serious reactions such as prenatal growth deficiencies, congenital malfunctions such as the cleft palate and heart malfunctions may occur.

2.Carbamazepine (Tegretol)

Carbamazepine is a neuroleptic drug that can be used as an antipsychotic agent and to relieve neuropathic pain.

Carbamazepine is effective as well as phenytoin and valproic acid in the treatment of grand mal and petit mal as a drug of choice but not in treating absence seizures and myoclonic seizures.

Mechanism of Action

Very similar to phenytoin

Metabolism and Kinetics

Similar to phenytoin but given orally only 

metabolized by the CYP-450 hepatic enzyme system similar to phenytoin but successfully compete with it.

Drug Interactions

The following drugs are competing successfully for CYP-450 enzyme with greater affinity than carbamazepine and hence they increase the carbamazepine plasma level by inhibiting its metabolism.

1.Erythromycin-Antibiotic

2.Isoniazid-Anti-T.B.

3.Propoxyphene-A pain killer

4.Verapamil-Calcium Channel Blocker for B.P

5.Cimetidine-A histamine H-2 receptor blocker used for reducing acid secretion in the stomach.

Hence dosage should be adjusted accordingly.

Side Effects

1. Acutely can cause respiratory depression and coma

2.Liver toxicity-Require frequent liver tests.

3.Aplastic anemia-Lack of blood cells formation due to bone marrow and erythropoietic stem cells damage

4.Agranulocytosis-A deficiency of granulocytes in the blood.

5.Drowsiness

6.Ataxia-Loss of full control of body movements.

7.Nystagmus-Involuntary movements of eyeballs.

3Phenobarbital (Luminol)

Chemically phenobarbital is a barbituric acid derivative.

Mechanism

Phenobarbital enhances the action of GABA at its receptors and thereby inhibiting the neuronal excitation.

Uses

1.Drug of choice for treating febrile seizures.

2.Used to treat grand mal in children

3.Partial seizures

Metabolism and Kinetics

Absorbed well by the oral route. Three fourth of the drug is metabolized in the liver.

It is a potent inducer of the CYP-450 enzyme in the liver.

Care should be taken when given along with any drug metabolized by or inducing this enzyme.

The metabolites are excreted in the urine.

Side Effects

1.Sedation

2.Nystagmus

3.Psychotic reactions

4.Allergic reactions such as serious Stevens-Jonson syndrome

5. Overdosage may result in respiratory depression, coma, and death.

Will be continued.....