ANTISEIZURES DRUGS

GMM

Case Study
A 19yrs old man has had 8yrs h/o recurrent
episodes of loss of conscious activity that lasts for seconds to mins. Sometimes he has 100lapses/day. He regains awareness very quickly. No motor symptom or confusion. CNS exam is normal. Which of the following drugs would be most effective for this patients problems?

A) Phenytoin B) Carbarmazepine C) Sodium valproate D) Phenobarbital

Definitions
seizure, excessive discharges neurons.
Epilepsy unprovoked recurrent seizures.

Classification
1. Partial seizures a. Simple partial seizures (with motor, sensory, autonomic, or psychic signs) b. Complex partial seizures c. Partial seizures with secondary generalization 2. Primarily generalized seizures a. Absence (petit mal) b. Tonic-clonic (grand mal) c. Tonic d. Atonic e. Myoclonic 3. Unclassified seizures a. Neonatal seizures b. Infantile spasms

Mechanisms of Seizure initiation and propagation

initiation phase The initiation phase (1) high-frequency =influx of extracellular (Ca2+), &(Na+) (2) hypersynchronization.

Mechanisms of Seizure initiation and propagation

Propagation Phase,

Dysfunction inhibitory neurons. (1) increase extracellular K+, Ca2+ in presynaptic terminals,
enhanced neurotransmitter release (3) Depolarization-i (NMDA)

Basic Pharmacology of antiseizure drugs

Chemistry clasification Antiseizure barbiturates, hydantoins, oxazolidinediones, succinimides, and acetylureas. Structure These groups have in common a heterocyclic ring structure with a variety of substituents (Draw).

Basic Pharmacology of antiseizure drugs

Pharmacokinetics Absorption: 100% Distribution: poor plasma proteins. Metabolism: hepatic. Excretion: liver

Basic Pharmacology of antiseizure drugs

Pharmacodynamics to total body water. Plasma clearance slow; May inducers of hepatic microsomal enzyme activity.

The antiseizure Drugs 1) Phenytoin , 2) Carbamazepine, 3) Valproate, 4) The barbiturates. Newer drugs lamotrigine, levetiracetam, gabapentin, oxcarbazepine, pregabalin, topiramate, vigabatrin, and zonisamide

Basic Pharmacology of Antiseizure drugs

PHENYTOIN

oldest nonsedative antiseizure drug.

diphenylhydantoin.

Chemistry hydantoin .

Structure (Draw)

PHENYTOIN
Mode of action conductance, Alters Na+, K+, and Ca2+ Glutamate, neurotransmitters norepinephrine, acetylcholine, (GABA).

PHENYTOIN

Pharmacokinetics

Absorption
dependent on formulation. GIT peak 3hrs-12hrs. I.M (Fosphenytoin, a more soluble phosphate prodrug of phenytoin).

PHENYTOIN
Distribution

highly bound proteins. decreases uremia/hypoalbuminemia. Pass bbb

PHENYTOIN
Metabolism

inactive metabolites. low levels first-order kinetics. t1/2 , average of 24 hrs. 57 days to reach steady-state. dose-dependent.

Excretion

urine.

PHENYTOIN
Clinical use tonic-clonic. Therapeutic Levels, therapeutic plasma 10 -20 mcg/mL. Dosage Adults, P.O. 300 mg/d. Increased by 2530 mg. In children, 5 mg/kg/d Formulations

PHENYTOIN
Drug interactions 90% bound proteins, can b misdisplaced

PHENYTOIN
Side effects/Toxicity CNS: Nystagmus, loss of smooth pursuit movements, Diplopia. Sedation, Skin:, hypersensitivity MSS: Osteomalacia Heamatological: megaloblastic anemia. Agranulocytosis. Others: Gingival hyperplasia, Lymphadenopathy,, fever and rash.

CARBAMAZEPINE
Chemistry and Structure A tricyclic compound. Mode of action =phenytoin.

CARBAMAZEPINE
Pharmacokinetics

Absorption

varies with patients. Peak 68 hours administration. after meals

Distribution

Slow; 70% bound; no displacement T1/2 ,36 hours.

CARBAMAZEPINE
Clinical Use partial seizures and generalized tonicclonic seizures. Trigeminal neuralgia Mania (bipolar disorder).

CARBAMAZEPINE
Dosage, formulations and Therapeutic levels, Carbamazepine is available only in oral form. In children, 1525 mg/kg/d. In adults, 1 g -2 g/day . The therapeutic level is usually 48 mcg/mL (trough level). Drug interactions Increases metabolism of other drugs, eg, primidone, phenytoin, ethosuximide, valproic acid, and clonazepam. Valproic acid may inhibit carbamazepine clearance

CARBAMAZEPINE
Side effects CNS: Diplopia and ataxia, Unsteadiness, Drowsiness GIT. Mild Heamatological: aplastic anemia and agranulocytosis, Leukopenia Skin: Erythematous skin rash Others: Hyponatremia and water intoxication.

VALPROIC ACID & SODIUM VALPROATE

Chemistry and Structure carboxylic acids that have antiseizure activity. (Draw). Mode of action Mechanism of action of valproic acid remains speculative. Its action against partial seizures may be a consequence of effect on Na+ currents. Blockade of NMDA receptor-mediated excitation may also be important.

VALPROIC ACID & SODIUM VALPROATE

Clinical Use/Indications Absence seizures. Generalized tonic-clonic attacks. Myoclonic seizures. Atonic attacks partial seizures. Bipolar disorder

VALPROIC ACID & SODIUM VALPROATE

Side effects GIT: Nausea (Commonest), vomiting,

abdominal pain and heartburn. gradually CNS: Sedation, fine tremor. Others: Weight gain, increased appetite, and hair loss, idiosyncratic hepatotoxicity, spina bifida,

Summary
Answer

C) Sodium valproate