Drug Treatment of Epilepsy Flashcards
What are epileptic seizures?
Episodic high frequency discharges by a localised group of neurons in the brain
- They are not constantly occurring
- There are factors which decreases seizure threshold including stress and sleep deprivation
How do drugs in relation to epilepsy work?
to prevent excessive neurotransmission - whether that be increase excitation or increase inhibiton
Main Excitatory “ON” switch in the brain
Glutamate
Main Inhibitory “OFF” switch in the brain
GABA
Symptoms of Epilepsy depend on…
The area of the brain affected
- Motor Cortex → Convulsions
- Hypothalamus → Peripheral autonomic effects
- Reticular formation (Upper brainstem) → loss of consciousness
Why is determining the correct dosage of anti-epileptics essential?
Over medication can result in sedative effects including memory loss
The primary cause of epilepsy
Idiopathic
What is secondary epilepsy?
a result of brain damage which generally leads to seizures
What are partial seizures?
Also known as Local or Focal
Discharge is localised to one brain region and hemisphere
Can be Simple or Complex
Complex local seizure
Consciousness is affected (often the Temporal lobe)
What are generalised seizures?
Discharge involves both hemispheres and reticular systems - consciousness is affected
Can be differentiated to Absence Seizures or Tonic-Clonic
Absence Seizure
Also known as Petit Mal..
Most common in children: staring
Tonic-Clonic Seizures
Also known as Grand Mal
Tonic phase - muscle spasm, respiration stops, bowel/bladder discharge
Clonic phase - release
Physical signs - violent jerking, unable to stand
Main aims of antiepileptics
to reduce electrical excitability of excitatory neurons (i.e., glutamate) or to increase inhibitory neurotransmission (i.e., GABA)
4 Main Mechanisms of Antiepileptic Drugs
- Use-dependent Na+ channel block
- Ca2+ channel inhibition
- Increase GABA-mediated neural inhibition
- Inhibit glutaminergic
Other approved antiepileptic strategies
Carbonic anhydrase inhibitors
CBD (i.e., think of Dravett’s)
Ketogenic diet
Example of drug which blocks use-dependent Na+ channel
Phenytoin, Carbamazepine, Lamotrigine, Valproate
Example of drug which inhibits Ca2+ channel
Ethosuximide, Gabapentin, (Phenytoin & Valproate as well)
Drugs which inhibit glutaminergic transmission
NMDA/AMPA/mGluR antagonists
Drugs to enhance GABA activation
Phenobarbital, Benzodiazepeines
Drugs which inhibit GABA deaminase
Valproate, Vigabatrin
Inhibit GABA reuptake
Tigabine
Na+ channel blockers stabilise these channels when..
in its inactivate state (i.e., when it is use-dependent!)
The most widely used AED?
Carbamazepine (CBZ)
→ strong inducer of P450 enzymes
→ increases metabolism of phenytoin, warfarin, OCP etc..
Prodrug analog of CBZ
Oxcarbazepine - metabolised in the liver to CBZ
- used as a monotherapy in children, but in adjunct therapy in adults with partial therapy
Less drug interactions as it is less potent on P450
What is generally first line treatment of partial and secondary generalised seizures?
Phenytoin
How is Ca2+ channel inhibition useful in treatment of epilepsy?
Ca2+ activates proteases responsible for vesicle fusion
Which Ca2+ Channels are implicated in periodic discharge observed in partial seizures?
Low threshold T channels
MOA of Ethosuximide
inhibits T type Ca2+ channels (pre & postsynaptic)
Also inhibits Na+/K+ ATPase and GABA deaminase
MOA of gabapentin
NOTHING TO DO WITH GABA
Presynaptic L type Ca2+ channel inhibitor
Decreases release of glutamate and other associated modulators, therefore increasing GABA levels
MOA of Valproate
Increases GABA in the brain
Simulates glutamate decarboxylase, inhibits GABA deaminase and weakly blocks Na+ and Ca2+ channels
MOA of Vigabatrin
irreversibly blocks GABA deaminase, therefore increasing GABA in the brain
- Side effects: Depression and psychotic disturbances
