Anti-epileptics Flashcards by Sara Johnson

Which 2 drugs are selective fast-acting Na channel blockers?

Phenytoin, Carbamazepine

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Which 3 drugs are fast-acting Na channel blockers with additional MOA?

Lamotrigine, Topiramate, Valproic acid

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Which drug is a T type Ca channel blocker?

Ethosuximide

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Which drug is a presynptic alpha2-delta subunit Ca channel modulator?

Gabapentin

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Which drug is a synaptic transmission modulator?

Levetiracetam

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Which drug can be used to treat gen status epilepticus?

Phenytoin

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Which two drugs can be used to treat gen absence?

valproic acid, ethosuximide

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Which type of seizure is not sensitive to Na channel blockers?

absence (too slow)

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What event triggers seizures and how? How do AED’s work against this mechanism?

Paroxysmal depolarizing shift: long lasting local depolarization that moves neuron close to threshold for Na channel activation
the fast Na dependent AP’s sitting on top of PDS can propagate to other regions of the brain —- AED’s prevent spread in this manner, but do not act against the trigger PDS

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Which drug is preferred in treating TC seizures, and essential for SE treatment after acute phase?

Phenytoin (good for SE because it’s injectable)

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What is the main pathway for metabolism of phenytoin?

CYP2C9 oxidation – glucoronic conjugation = hepatic metabolism

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Unique pharmacokinetics of phenytoin?

Non-linear because therapeutic concentrations exceed drug’s Km

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What are 2 ways phenytoin can affect metabolism of other drugs?

CYP2C9 inducer

- extensively bound to plasma proteins (valproic acid)

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Advantages of phenytoin prodrug Fosphenytoin?

more water soluble
better tolerated (injection suspension of phenytoin is basic and irritating)
rapidly converted to phenytoin in blood

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What 3 drug classes are associated with gingival overgrowth? Why?

phenytoin > cyclosporine (immuneodepressant) > nifedipine (Ca channel blocker)
increase secretion/effect of inflammatory cytokines –> increase in fibroblast secreted ECM in gingiva

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Along with sulfa AB’s, what drug is commonly associated with Stevens’Johnson syndrome?

Phenytoin

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What are 4 severe and 3 common AE’s associated with phenytoin?

Cardiac arrhythmias/inhibition
hypersensitivity (genetics, Asian)
teratogenic to fetal heart
decreased bone mineral density
Lethargy, CNS depression, ataxia, nystagmus – DOSE DEPENDENT

3 uses of carbamazepine? Why not SE?

long term TC treatment
bipolar, neuropathic pain
not available as injectable
CAN AGGRAVATE ABSENCE

Metabolism and potentiation drug interactions of carbamazepine? Unique qualities of metabolism?

metab by multiple CYP450 (3A4)
induces CYP2C19 and 3A4
first order kinetics, AUTOINDUCTION (must titrate over time)

Which AED is most clearly associated with decreased bone mineral density? MOA?

Carbamazepine (also phenytoin)
secondary hyperparathyroidism due to induction of CYP24 that inactivates calcotriol (low calcitriol, low serum Ca levels, parathyroid mobilized in response to release Ca from bones)

Two black box warnings associated with Carbamazepine?

hypersensitivity (toxic epidermal necrolysis, Stevens Johnson)
agranulocytosis/aplastic anemia (rare, but pot. fatal)

MOA and uses of Lamotrigine?

fast Na channel blocker, weak Ca blocker

- adjunct in TC Tx (alternative for absence due to Ca effects)

Metabolism of lamotrigine? Drug interactions?

CYP450
Phenytoin, carbamazepine induce elimination
valproic acid inhibits elimination

Black box warning and other AE’s associated with Lamotrigine? Black box target population?

hypersensitivity (most common in children)
aseptic meningitis due to rare drug irritation
teratogen – BUT LOWER risk than other Na blockers
CNS effects (no sig sedation)

MOA and uses of valproic acid?

- fast Na blocker, weak Ca blocker (VERY weak enhancement of GABA transmission) - BROADEST RANGE - absence - most useful for complicated epilepsy syndromes w/ multiple seizure types - migraine prophylaxis - bipolar

Double anti-epileptic mechanism of valproic acid?

- decreases neuronal hypersensitivity primarily by inhibiting neuronal excitation (like others) - GABA enhanced transmission makes minor contribution by enhancing neuronal inhibition

Elimination mechanisms for valproic acid?

- hepatic conjugation AND oxidation - conjugation is most important - VPA can also be burned via mito/ER oxidation

Two drug interactions associated with valproic acid?

- phenytoin/carbamazepine induce hepatic glucoronyltransferase - BOTH phenytoin and VPA are extensively bound to plasma proteins ---- competition can lead to increased blood levels of free phenytoin (non-linear pharmacokinetics)

Two black box warnings associated with VPA?

- teratogenicity (HIGH NTD's, cognitive) | - hepatotox/pancreatitis (more common in children)

Topiramate MOA and uses?

- fast Na blocker with supplemental mech (poorly understood, complex: augment activation of GABAa receptors, antagonize glut kainate receptors-- also carbonic anhydrase inhibition = metab acidosis) - BROAD: TC, partial (focal), migraines

4 AE's associated with topiramate?

- CNS sedation, cog effects (more common in adults) - metab acidosis (renal carbonic anhydrase inhibition) - teratogenicity (cleft lip, palate) - weigh loss

How does renal carbonic anhydrase inhibition associated with topiramate cause metab acidosis?

- CA inhibition decreases renal bicarb reabsorption | - loss of bicard can induce metab acidosis

Elimination and drug interactions of Topiramate?

- renal - hyperammonemia with VPA - other CA inhibitors = metab acidosis

MOA and use of Ethosuximide?

- T type Ca blocker | - ONLY absence

Cellular targets of ethosuximide?

- T-type Ca channels on thalamic relay neurons that regularly produce PDS - absence seizures generated by thalamocortical and corticothalamic excitatory pathways that cyclically stimulate each other and cause 3Hz spike and wave EEG absence pattern

Metabolism of ethosuximide?

- mostly CYP3A4 (but no induction issues) | - some renal

3 AE's associated with ethosuximide?

- GI distress = common - bone marrow depression - hypersensitivity

MOA and uses of gabapentin?

- presynaptic alpha-2 delta Ca channel modulator (binds alpha2delta subunits and prevents incorporation into P/Q type Ca channels which are found in pre-syn nerve terminals and are closely linked to exocytosis and neurotransmission) - adjunct for refractory partial seizures - neuropathic pain

Elimination and absorption of gabapentin?

- RENAL (fewer interactions bc not hepatic) | - oral bioavailability limited at HIGH doses due to SATURATION of GI uptake transporters (spread doses throughout day)

MOA and uses of Levetiracetam?

- synaptic transmission modulator (binds to synaptic vesicle protein 2 and DECREASES synaptic vesicle release for a variety of NT's) - partial or generalized seizures - adjunct to other AED's

Elimination of levetiracetam?

RENAL (no interactions)

AE's associated with levetiracetam?

- reversible, less severe - weakness, fatigue, asthenia - BEHAVIORAL problems