ANTIEPILEPTIC AGENTS Flashcards
epilepsy
condition characterized by seizures, in unpredictable manner, not associated with stimulus
seizure
episode of disordered, synchronized, rhythmic firing of brain neurons
causes of epileptic seizures
birth/ perinatal injuries blood clots head trauma metabolic disturbances drug/alcohol withdrawal neoplasia infection genetic hyperthermia in children visual stimuli
describe partial seizures
- COMPLEX PARTIAL (most frequent)
- partial consciousness with/without autonomic movements - SIMPLE PARTIAL
- conscious state not affected
- localised speech/sensory/motor defects
describe general seizures
- GRAND MAL
- loss of consciousness + rigid paralysis (TONIC state)
- rhythmic jerking movement of limbs (CLONIC state) - PETIT MAL (absence seizure)
- person suddenly exhibits a blank stare + unaware of surroundings
describe the effects of seizures on electroencephalographs
tonic - disorder (+) amplitdue
clonic - strokes of high rhythmic activity
petit mal - very rhythmic (+) amplitude
partial - distinctive - only effecting certain parts of brain
best treatment = detect whilst undergoing seizure
what does a PET scan do
measure areas of high metabolism
Kindling model
repeated electrical stimulation of amygdaloid nuclei = induce state where spontaneous seizures can occur
Kainate model
KAINATE + NMDA (agonists of glutamate receptors)
= produce spontaneous seizures and PAROXYSMAL DEPOLARISING SHIFT (PDS)
- suggesting overstimulation of glutamate receptors trigger seizures
what can induce PDS
penicilin
NMDA
Evidence that seizures can be induced by a deficit in INHIBITORY AMINO ACID NT
. GAGA receptor antagonists can induce seizures in animal model system
. drugs that have anti-seizure activities
= enhance activity of GABA (benzodiazepines)
OR
= inhibit GABA degradative pathways
= GABA reuptake inhibitors
3 mechanisms of anti-epileptics
- enhancement of GABA binding to receptor
- inhibition of Na+ channel
- inhibition of Ca2+ channel
primary antiepileptic drugs
- PHENYTOIN
- CARBAMAZEPINE
- VALPROATE
- ETHOSUXIMIDE
- BENZODIAZEPINES
- BARBITUATES
PHENYTOIN
Voltage-gated Na+ channel blocker -binds to inactive channels
•Grand mal and partial; not effective in petit mal
Treats status epilepticus
- Drug interactions: Competes for the metabolism of other drugs including oral anticoagulants
- Side effects: dizziness, nystagmus*, ataxia^, mental confusion, gingival hyperplasia, hirsutism, birth defects
where does PHENYTOIN bind
Phenytoin preferentially binds to the inactivation gate of Na2+ channels when they are in the closed position
CARBAMAZEPINE
- Derivative of Tricyclic Antidepressants
- Voltage-gated Na+ channel blocker + accentuation of adenosine-based inhibition of neuron firing
- Grand mal and partial; not effective in petit mal
• Side effects: drowsiness, dizziness, blurred vision,
ataxia, bone marrow depression (granulocytopenia
and/or aplastic anemia), birth defects
VALPROATE
- Voltage-gated Na+ channel blocker
- Works on all types of epilepsy, including petit mal
• Side effects: Nausea, vomiting, lethargy, hair
loss, teratogenic, hepatotoxicity
ETHOSUXIMIDE
• Derived from barbiturate structure
- Inhibition of T-type (thalamic) calcium channels
- Only useful for PETIT mal // worsen grand mal seizures
• Side effects: nausea, vomiting, anorexia, drowsiness, persistent hiccups
BENZODIAZEPINES and BARBITUATES
• bind to GABAA receptors = affinity of GABA for the receptor is enhanced
- Effective against all types (except petit mal)
- Epilepsy is only condition, other than GE, for which barbituates have a legitimate clinical use
• Sedation, general CNS suppression are problems, along with dependence + withdrawal
Other Antiepileptic Drugs
• Vigabatrin-a GABA analogue
= Irreversible inhibitor of GABA transaminase in astrocytes
- Lamotrigine = voltage-gated Na+ channel blocker
- Gabapentin = cyclic analogue of GABA - blocks Ca2+ channels in Dorsal Horn of SC = inhibits NMDA R and increases actions of CNS adrenergic neurons
