Screening of Anticonvulsant Drugs

Lab #5

Outlines

Brief overview on epilepsy Anticonvulsant drugs Methods of screening of anticonvulsants

Epilepsy

• Epilepsy: disorder of brain function characterized by a periodic and unpredictable occurrence of seizures

• Seizure: transient alteration of behavior due to disordered and rhythmic firing of population of brain neurons

• Convulsion: The major motor manifestations of a seizure (rhythmic jerking of the limbs)

Pathophysiology of Epilepsy

High frequency discharge of impulses by interconnected cerebral neurons

Starts locally then spread

Enhancement of excitatory transmission

Reduction of inhibitory transmission

Causes of Epilepsy

• Neurological diseases• Medical trauma as stroke • Infection• Head injury• Neoplasm of brain

• Heredity

Types of Epilepsy

Partial (small area in brain, no loss of consciousness)

Generalized (spread over larger area of brain, e.g. tonic-clonic, absence seizure)

Status epilepticus (convulsions without cessation)

Anticonvulsant Drugs

Drugs that enhance GABA action: phenobarbital, benzodiazepines, vigabatrin, tiagabine

Drugs that inhibit sodium channels function: phenytoin, carbamazepine, valproate, lamotrigine

Drugs that inhibit calcium channels function: ethosuximide

Screening Methods For Anticonvulsants

Principle

The ability of anticonvulsant drug to partially or completely antagonize

siezure induced either chemically or electrically

Screening Methods For Anticonvulsants

Supramaximal electroshock: tonic-clonic, mice, repetitive shocks (high freq.) , diff. doses IP inj.

Psychomotor electroshock: low freq., absence, mice

Leptazol seizure method: mice, SQ pentylentetrazol (100 mg/kg)

PD50

Protective dose 50: the dose that is required to abolish seizure in 50% of animal

Comparison of drug effectiveness

Screening Methods For Anticonvulsants

Strychnine-induced seizure: tonic Picrotoxine-induced seizure: clonic

Tonic vs Clonic

Clonic convulsion Tonic convulsion -Produced by ↑dose of medullary stimulants-Asymmetric -Coordinated -Spontaneous -Intermittent-Removed by decapitation

-Produced by ↑dose of spinal cord stimulants-Symmetric-Non-coordinated -Reflex in origin -Continuous-Removed by pithing

Lab work

Drug injected Onset of convulsion

Number of convulsion/1min

Strychnine Or picrotoxine

25 mg/kg phenobarb.

50 mg/kg phenobarb.

75 mg/kg phenobarb.

Chart

The dose response curve of phenobarbital (the effect of different doses on the no. of convulsions per 1 min.)

Dose (mg/kg)

no

. of

con

vuls

ion

s/1

min