Seizure Pharmacology Flashcards
Seizure vs convulsion vs epilepsy definition
- excessive neuronal discharge characterized as brief, involuntary, episodic
convulsion: violent involuntary contraction of voluntary muscles
epilepsy: chronic seizure disorder
Mechanism of seizure
Traceable to unstable neuronal membrane (focal epileptogenesis –>initiation).
- Paroxysmal discharges that can recruit and synchronize a large population of cortical neurons or neurons in thalamic region.
- Enhancement of excitatory NT (primarily glutamate) or deficiency of inhibitory NT (primarily GABA) can promote spread or propagation of abnormal activity as can metabolic causes.
Model for Unstable-Excessive Neurotransmission Seizures
- excessive activity in neuron A
- widespread input from its dendrites triggers too much axonal flow, mediated by VSSC [VALPROATE target]
- This overly activates VSCC linked to glut (lamotrigine target)
- Triggering of excessive, chaotic, unpredictable neurotransmission from neuron A to B
- Seizure activity is then detected by postsynaptic NMDA receptors on neuron B
- Subsequent excitation of its own VSSC and so on
Seizures beget seizures
Drugs for partial seizures
Levetiracetam
drugs for tonic-clonic sz
valproate
levetiracetam
lamotrigine
In class:
carbamazepine
(phenytoin)
(valproic acid)
drugs for atonic, myoclonic sx
valproate
levetiracetam
lamotrigine
drugs for absence sz
ethosuximide
valproate/valproic acid
generalized tonic-clonic sz
-id drug w/ MES test
-EEG high amplitude spike 15-40 cycles/sec
-loss of postural control, LOC
-tonic (rigid extension of trunk/limbs)
-clonic (rhythmic contraction of arms and legs)
Mech:
-initiation locally–>loss of GABA inhibitory tone
-propagation due to decreased GABA tone over large area plus increased response to glutamate and Na channel excitation
Generalized absence
- id drugs w/ PTZ test
- usually start in childhood, cease by age 20
- EEG 3cycles/sec
- Normal muscle tone, impaired consciousness w/ staring spells/eye blinks, function normal after sz
- Mech: oscillatory stimulation of thalamic-cortical-circuitry activation of low threshold T-type Ca channels.
Partial seizures
simple partial:
- preserve consciousness
- cortical in origin in restricted region
complex partial:
-loss of or impaired consciousness
Psychomotor involves limbic as well as temporal/frontal cortex (emotional)
Secondary generalized:
-LOC, include other areas/muscle groups
Mech: involves initiation (rather than propagation)–difficult to treat.
Mechanisms of antiseizure drugs
- elevating seizure threshold–>stabilize membrane
- limiting propagation–>reduce synaptic transmission or nerve conduction
- Drugs are more effective in limiting propagation (generalized seizures) than in preventing initiation (partial sz)
Inhibition of Sodium channel function
- block of sustained high frequency repetitive firing of APs that can initiate seizure formation
- Blockade is USE DEPENDENT (ie blocks epileptic foci)
- prolongs the inactivated state of the Na channel and prolongs refractoriness
- phenytoin, carbamazepine, lamotrigine, topiramate
Enhancement of GABA Action
- BDZs and phenobarbital enhance inhibitory effect of GABA (increased opening of Cl channels)
- Vigabatrin inhibits GABA-transaminase (inactivates GABA)–>increase brain GABA lvls
- Valproate also acts partly by this mech
- Tiagabine blocks reputake of GABA
- Gabapentin alters GABA neurochem (metab, release, or reuptake)
Which drugs need GABA to be present vs not?
- Barbiturates/ethanol/GA increases Cl- +/- GABA (decrase glut @ high doses)
- BDZ increases Cl- if GABA present (no anesthesia w/ BDZs)
Decrease in low threshold Ca (T-type) current
oscillatory currents in thalamic neurons are abnormal in absence sz–blocked by ethosuximide
