structure activity relationship of epilepsy, Lecture notes of Pharmacy

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ANTI-

EPILEPTICS

Shweta Mishra

Assistant

Professor

SAIP Indore

(M.P.)

EPILEPSY  (^) It is a Chronic medical condition produced by sudden changes in the electrical function of the brain.  (^) It is a condition characterized by recurrent episodes of seizures.  (^) Seizure- a paroxysmal abnormal discharge at high frequency from neurons in cerebral cortex.  (^) Convulsions- involuntary, violent, spasmodic contractions of skeletal muscles.  (^) WHO Background

 Approximately 2.5 million people in the U.S. (~1%

general pop)

Cost per patient ranges from $4,272 for persons with

remission after initial diagnosis and treatment to

$138,602 for persons with intractable and frequent

seizures.

NERVE CELL COMMUNICATION

 Neurons communicate between themselves using small molecules called neurotransmitters.  These neurotransmitters modulate and regulate the electrical activity of a given neuron, and tell it when to fire an action potential or when not to.

• Glutamate = excitatory (tells the neuron to fire)

GABA = inhibitory (dampens the neuron firing rate)

 The action potential is an electrical signal that travels down the axon, and is created using sodium ions (Na+), and inhibited by potassium ions (K+).  Usually these processes work synergistically to produce normal behavior and activity.  When dysfunctional, abnormal electrical activity occurs and can produce seizures.

Neurotransmitters

Sodium Ions/Channels

Potassium Ions/Channels

Action Potential (Glutamate, GABA)

PARTIAL (FOCAL) SEIZURES  (^) Excessive electrical activity in one cerebral hemisphere. -Affects only part of the body.  (^) Simple Partial: Person may experience a range of strange or unusual sensations. Confined to single muscle group or limb.

 Motor

 Sensory

 Autonomic

 Key feature : preservation of consciousness.

 (^) Complex Partial :

 Loss of awareness at seizure onset. Person seems

dazed or confused and exhibits meaningless

behaviors like lips smacking or hand wringing

 Typically originate in frontal or temporal lobes (e.g.

Temporal lobe epilepsy)

GENERALIZED SEIZURES  (^) Excessive electrical activity in both cerebral hemispheres.  (^) Usually originates in the thalamus or brainstem.  (^) Affects the consciousness whole body.  (^) Loss of is common.

MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS Antiepileptics inhibit the neuronal discharge or its spread in one or more of the following ways : (1) Enhancing GABA synaptic transmission: barbiturates, benzodiazepines, gabapentin, levetiracetam, tiagabine, vigabatrin, topiramate, valproate; the result is increased permeability to chloride ion, which reduces neuronal excitability. Valproate and topiramate block GABA transaminase and tiagabine blocks reuptake of GABA. (2) Reducing cell membrane permeability to voltage-dependent sodium channels: carbamazepine, lamotrigine, oxcarbazepine, phenytoin, topiramate, valproate. (3) Reducing cell membrane permeability to calcium T-channels: valproate, ethosuximide; the result is diminishing of the generation of action potential. (4) Inhibiting excitory neurotransmitter glutamate: lamotrigine.

 (^) Common structure of Anti-convulsant

STRUCTURE ACTIVITY RELATIONSHIP:

1. R and R’ should both be hydrocarbon radical.

2. If both R and R’ are lower alkyls, the compounds are active against

absence seizures (petit mal) and not active against generalized tonic-

clonic (grandmal) or partial seizures.

3. If one of the hydrocarbon substituents is an aryl group activity tends to

be directed towards generalized tonic clonic and partial seizures and

not anti-absence activity.

4. A conformational analysis of the aryl containing anti-generalized tonic-

clonic agents indicates the conformational arrangement of the

hydrophobic group is important.

O N O R' R R'' R'' NH O Barbiturate NH Hydantoin R'' O CH 2 Oxazolidinediones Succinimides

BARBITURATES:  (^) Sedative- hypnotic barbiturates display anticonvulsant properties, only phenobarbital & mephobarbital found to display enough anti-convulsant selectivity for use as antiepileptics.  (^) Both these agents are effectiveagainst generalized tonic-clonic and partial seizure. NH NH O O O C 2 H 5 C 6 H 5 Phenobarbitone NH N C 6 H 5 C 2 H 5 CH 3 O O O Methyl Phenobarbitone