Pharmacology of Epilepsy (Segars) Flashcards
Membrane depolarization leads to?
1) Enhanced excitatory (glutamate) actions
2) Reduced inhibitor (GABA) function
Where do the anti-epileptic drugs (AED) that block the voltage-gated Na channels bind?
Interior side of voltage Na channel pore
When can AEDs access the pore in voltage-gated Na channels?
When can they not?
1) Activation gate is open
2) Activation gate is closed
What are examples of an AED Na channel blocker?
1) Lamotrigine
2) Carbamazepine (also other -azepine drugs)
3) Phenytoin
4) Topiramate
5) Valproic acid
6) Lacosamide (also other -amide drugs)
The probability of a Na channel blockade is proportional to?
Frequency of voltage Na channel opening and the dose
Lamotrigine, Carbamazepine, Phenytoin, Topiramate, Valproic acid, and Lacosamide have what effect on the state of Na ion channels?
Lacosamide can also have what effect on the state of voltage Na channels?
1) Prolong fast inactivation state of voltage Na channel
2) Enhance slow inactivation of the channel
What is the overall goal of blocking voltage gated Na channels?
Suppress excitatory (glutamate) actions
What are the AMPA receptor antagonists?
1) Topiramate (also a Na channel blocker)
2) Perampanel (has AMPA is name)
What is the overall goal of blocking AMPA receptors?
Suppress glutamate
What is the NMDA receptor antagonist?
Felbamate
What is the overall goal of blocking NMDA receptors?
Suppress glutamate
What channels mediate 3-Hz spike and wave activity in the thalamus?
This is a hallmark of what type of seizure?
1) T-type Ca2+ channels
2) Absence (petit mal) seizures
Antagonists of T-type Ca2+ channels target?
Cortex-thalamus oscillation
What drug is only used for absence seizures?
Ethosuximide
What are the antagonists of T-type Ca2+ channels?
1) Ethosuximide
2) Zonisamide (also a Na channel blocker)
What is the overall goal of blocking T-type Ca2+ channels?
Suppress glutamate
What drugs inhibit Synaptic Vesicle 2A (SV2A) protein?
1) Levetiracetam
2) Brivaracetam
What is the overall goal of blocking Synaptic Vesicle 2A (SV2A) protein?
Suppress glutamate
What drugs block the α2δ subunit of T-type Ca2+ channels?
1) Gabapentin
2) Pregabalin
What is the overall goal of blocking the α2δ subunit of T-type Ca2+ channels?
Suppress glutamate
What drug opens KCNQ K+ channels (pre-/post-synaptic)?
Ezogabine
What is the overall goal of opening the KCNQ K+ channels?
Suppress glutamate
What is the MOA of Topiramate and Perampanel?
AMPA receptor blockers
What is the MOA of Ethosuximide and Zonisamide?
Ca2+ T-type Channel Blockers
What is the MOA of Gabapentin and Pregabalin?
α2δ subunit Ca2+ Channel Blocker
What is the MOA of Carbamazepine, Oxcarbazepine, Eslicarbazepine, Lamotrigine, Phenytoin, Rufinamide, Topiramate, Valproic acid, Lacosamide, and Zonisamide?
Na+ Channel Blockers
What is the MOA of Felbamate?
NMDA Receptor Blockers
What is the MOA of Levetiracetam and Brivaracetam?
Synaptic Vesicle 2A Protein Blockers
What is the MOA of Ezogabine?
K+ Channel Openers
When GABA(A) receptor is unoccupied what happens to the Cl- channel?
When it is occupied?
1) Closed
2) Opened
What drug blocks the reuptake of GABA by blocking GAT-1 (GABA transproter-1)?
Tiagabine
What drugs block the metabolism of GABA by blocking GABA-T (GABA Transaminase)?
1) Vigabatrin (Has GABA-T in name)
2) Valproic acid (also a Na channel blocker)
What drugs increase GABA levels by stimulating GAD (glutamic acid decarboxylase)?
1) Valproic acid
2) Gabapentin (also blocks the α2δ subunit of T-type Ca2+ channels)
3) Pregabalin (also blocks the α2δ subunit of T-type Ca2+ channels)
Tiagabine, Vigabatrin, Valproic acid, Gabapentin, and Pregabalin all act on what side of GABA-ergic Transmission?
Pre-Synaptic
What is the MOA of Vigabatrin and Valproic acid?
GABA promoting agents by GABA-T inhibition
What is the MOA of Tiagabine?
GABA promoting agent by GAT-1 inhibition
What is the MOA of Valproic acid, Gabapentin, and Pregabalin?
GABA promoting agents by GAD stimulation
Barbiturates, Benzodiazepines, and Topiramate all act on what side of GABA-ergic Transmission?
Post-Synaptic
What happens when benzodiazepines bind to a distinct allosteric site?
Potentiate GABA binding causing Cl- channels to open with greater frequency
What happens when barbiturates bind to a distinct allosteric site?
Increases the duration of Cl- channel opening
Between barbiturates and benzodiazepines, which are GABA independent?
This has what effect at high doses?
1) Barbiturates
2) Barbiturates are more lethal
What is a GABA agonist?
Topiramate
What are the GABA promoting agents that work on the post-synaptic side?
1) Barbiturates (Phenobarbital, Primidone)
2) Benzodiazepines (Clonazepam, Clobazam, Lorazepam, Diazepam)
3) Topiramate
What are the multiple MOA of topiramate?
1) Na+ channel blocker
2) AMPA receptor blocker
3) GABA agonist
What are the multiple MOA of Valproic acid?
1) Na+ channel blocker
2) GABA promoting agent by GAD stimulation
3) GABA promoting agent by GABA-T inhibition
What are the broad warning/risk of all AEDs?
1) Abrupt withdrawal of AED may cause status epilepticus
2) Suicidal behavior
Why does phenytoin have many drug-drug interactions?
It is an inducer of CYP-450 enzymes
What is an unique toxicity that can be caused by phenytoin?
Gingival hyperplasia
Chronic administration of carbamazepine, phenytoin, phenobarbital and valproic acid can cause?
Why?
1) Osteoporosis
2) They induce CYP450-dependent vitamin D catabolism
What are unique toxicities that can be caused by Carbamazepine?
1) Leukopenia
2) Neutropenia
3) Thrombocytopenia
Oxcarbazepine which is an analogue of carbamazepine has fewer CNS/Hematological symptoms due to?
Formation of an alternative active metabolite
What is an unique toxicity that can be caused by vigabatrin?
Permanent vision loss
What interaction do the AED inducers have with contraceptives?
Increase clearance of oral hormonal contraceptives which increases risk of unplanned pregnancy
What interaction do the AED inducers have with anticoagulants?
Increase clearance of warfarin which increases risk for thrombosis
What interaction do the AED inducers have with antivirals?
Increase clearance of HIV medications which increases the risk for HIV replication
How do Valproic acid and Lamotrigine increase the accumulation of other drugs?
How do Phenytoin, Carbamazepine & Phenobarbital cause reduction of parent drug?
1) Inhibit UGT
2) Induce UGT
In the treatment of convulsive status epilepticus in adults what is given in the first IV?
What is given in the second IV?
1) Lorazepam
2) Levetiracetam
