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

Objective

Definition of Seizures Classification of seizure Mechanism of seizure initiation Basic Pharmacology of antiseizure drugs Pharmacology of the major antseizure drug

Definitions
A seizure is a paroxysmal event due to
abnormal, excessive discharges from an aggregate of CNS neurons. person has unprovoked recurrent seizures due to a chronic, underlying process.

Epilepsy describes a condition in which a

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

Seizure activity has a seizure initiation phase and a seizure
propagation phase.
initiation phase The initiation phase is characterized by two concurrent events in an aggregate of neurons: (1) high-frequency bursts of action potentials and (2) hypersynchronization. The bursting activity is caused by a relatively long-lasting depolarization of the neuronal membrane due to influx of extracellular calcium (Ca2+), which leads to the opening of voltagedependent sodium (Na+) channels, influx of Na+, and generation of repetitive action potentials. This is followed by a hyperpolarizing afterpotential mediated by aminobutyric acid (GABA) receptors or potassium (K+) channels, depending on the cell type. The synchronized bursts from a sufficient number of neurons result in a so-called spike discharge on the EEG.

Mechanisms of Seizure initiation and propagation

Propagation Phase,

Normally, the spread of bursting activity is prevented by intact

hyperpolarization and a region of surrounding inhibition created by inhibitory neurons. With sufficient activation there is a recruitment of surrounding neurons via a number of mechanisms. (1) An increase in extracellular K+, which blunts hyperpolarization and depolarizes neighboring neurons; (2) Accumulation of Ca2+ in presynaptic terminals, leading to enhanced neurotransmitter release. (3) Depolarization-induced activation of the N-methyl-D-aspartate (NMDA) subtype of the excitatory amino acid receptor, which causes Ca2+ influx and neuronal activation. The recruitment of a sufficient number of neurons leads to a loss of the surrounding inhibition and propagation of seizure activity into contiguous areas via local cortical connections, and to more distant areas via long commissural pathways such as the corpus callosum

Basic Pharmacology of antiseizure drugs

Chemistry Most Antiseizure drugs can be classified into five very similar chemical groups: 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: Absorption is usually good, with 80 100% of the dose reaching the circulation Distribution: Most antiseizure drugs are not highly bound to plasma proteins. Metabolism: Antiseizure drugs are cleared chiefly by hepatic mechanisms. Excretion: Many are converted to active metabolites that are also cleared by the liver

Basic Pharmacology of antiseizure drugs

Pharmacodynamics These drugs are predominantly distributed into total body water. Plasma clearance is relatively slow; many anticonvulsants are therefore considered to be medium- to long-acting. Some have half-lives longer than 12 hours. Many are potent 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

Phenytoin is the oldest nonsedative

antiseizure drug. It was known for decades as diphenylhydantoin.

Chemistry Phenytoin is a diphenyl-substituted

hydantoin .

Structure (Draw)

PHENYTOIN
Mode of action Alters Na+, K+, and Ca2+ conductance, Alters membrane potentials, Alters the concentrations of amino acids eg Glutamate, Alters the neurotransmitters norepinephrine, acetylcholine, and Gamma- Aminobutyric acid (GABA). NB: At therapeutic concentrations, the major action of phenytoin is to block sodium channels and inhibit the generation of rapidly repetitive action potentials.

PHENYTOIN
Pharmacokinetics Absorption Absorption is highly dependent on the formulation.

Particle size and pharmaceutical additives affect both the rate and the extent of absorption. Absorption from the GIT is nearly complete in most patients, time to peak ranges 3hrs-12hrs. I.M is unpredictable, and some drug precipitation in the muscle occurs; this route of administration is not recommended for phenytoin. (Fosphenytoin, a more soluble phosphate prodrug of phenytoin, is well absorbed after intramuscular administration).

PHENYTOIN
Distribution

Phenytoin is highly bound to plasma

proteins. The total plasma level decreases with uremia or hypoalbuminemia. Correlation of free levels with clinical states remains uncertain. Drug concentration in cerebrospinal fluid is proportionate to the free plasma level..

PHENYTOIN
Metabolism Excretion

Phenytoin is metabolized to inactive metabolites.

The metabolites are excreted in the urine. Only a very small proportion of phenytoin is excreted

unchanged. The elimination is dose-dependent. At very low blood levels,metabolism follows first-order kinetics. The t1/2 , 12 hrs to 36 hrs, average of 24 hrs. At low blood levels, it takes 57 days to reach steadystate blood levels after every dosage change;

PHENYTOIN
Clinical use Phenytoin is effective against partial seizures and generalized tonic-clonic seizures. Therapeutic Levels, The therapeutic plasma level is between 10 -20 mcg/mL. A loading dose can be given either P.O or I.V. Dosage In Adults, P.O. 300 mg/d. Increased by 2530 mg. In children, 5 mg/kg/d Formulations

PHENYTOIN
Drug interactions Primarily related to protein binding or to metabolism.

Since phenytoin is 90% bound to plasma

proteins, other highly bound drugs, such as phenylbutazone and sulfonamides, can displace phenytoin from its binding site.

Phenytoin has been shown to induce microsomal

enzymes responsible for the metabolism of a number of drugs.

PHENYTOIN
Side effects/Toxicity CNS: Nystagmus, loss of smooth extraocular pursuit movements, Diplopia and ataxia. Sedation, mild peripheral neuropathy. Skin: Hirsutism, coarsening of facial features, hypersensitivity MSS: Osteomalacia due to abnormalities of vitamin D metabolism Heamatological: Low folate levels and megaloblastic anemia. Agranulocytosis. Others: Gingival hyperplasia, Lymphadenopathy, Idiosyncratic reactions, fever and rash.

CARBAMAZEPINE
Chemistry and Structure A tricyclic compound, closely related to imipramine and other antidepressants.

The ureide moiety (NCONH2) present in the

heterocyclic ring of most antiseizure drugs is also present in carbamazepine (Draw structure).

Mode of action The mechanism of action of carbamazepine appears to be similar to that of phenytoin.

CARBAMAZEPINE
Pharmacokinetics

Absorption

The rate of absorption of carbamazepine varies widely

among patients. Peak Levels are usually achieved 68 hours after administration. Slowing absorption by giving the drug after meals helps the patient tolerate larger total daily doses.

Distribution

Distribution is slow. The drug is 70% bound to plasma

proteins; no displacement of other drugs from protein binding sites has been observed. T1/2 ,36 hours observed in subjects following an initial single dose decreases to as short as 812 hours in subjects receiving continuous therapy.

CARBAMAZEPINE
Clinical Use Both partial seizures and generalized tonic-clonic 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 Almost exclusively related to the drug's enzymeinducing properties . Increases rate of 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 gastrointestinal upsets Heamatological: Idiosyncratic blood dyscrasias eg aplastic anemia and agranulocytosis, Mild and persistent Leukopenia Skin: Erythematous skin rash Others: Hyponatremia and water intoxication.

VALPROIC ACID & SODIUM VALPROATE

Chemistry and Structure Valproic acid is one of a series of fatty 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. Other uses: Bipolar disorder and migraine prophylaxis

VALPROIC ACID & SODIUM VALPROATE

Side effects GIT: Nausea (Commonest), vomiting,

abdominal pain and heartburn. The drug should be started gradually to avoid these symptoms.

CNS: Sedation, fine tremor. Others: Weight gain, increased appetite, and
hair loss, idiosyncratic hepatotoxicity, Idiosyncratic thrombocytopenia, spina bifida,

Questions
Questions

Summary
Answer

C) Sodium valproate