Anticonvulsants - Bloom Flashcards
Describe two general strategies to treat seizures, and three basic mechanisms which they may employ.
Decrease rates of neuronal discharge or suppress its propagation.
This can be accomplished by alteration of membranae function, inhibition of excitatory signaling, or potentiation of inhibitory signaling.
Phenytoin is one of the earliest anticonvulsants.
Describe its mechanism of action and indication.
What about its pharmacokinetics?
Mechanism: Use-dependent sodium channel blockade.
Indication: Tonic-clonic seizures as well as partial seizures.
Pharmacokinetics: Highly protein bound and hepatically metabolized (note: CYP inducer!). Follows zero-order kinetics at high levels.
Despite being prototypical, phenytoin has fallen out of favor as an anticonvulsant. Describe the side effects that have contributed to this.
CYP inducer; causes many drug interactions.
Many CNS dose-dependent effects such as nausea, sedation, ataxia, nystagmus & diplopia.
Non dose-dependent effects such as gingival hyperplasia, hirsutism, hypersensitivity, and birth defects (cardiac, palatal)
What is Fosphenytoin?
What is Oxycarbazepine?
Fosphenytoin is a water-soluble phenytoin prodrug for status epilepticus (IV administration).
Oxycarbazepine is a carbamazepine analog with a better side effect profile and less enzyme induction.
Carbamazepine
What is its mechanism of action?
Clinical uses?
Carbamazepine
Like phenytoin, causes use-dependent sodium channel blockade.
Drug of choice for partial seizures (NOT absence)
Carbamazepine has a number of side effects and problematic pharmacokinetic considerations. What are they?
Dose-related SE: Diplopia, ataxia, GI upset, drowsiness.
Non dose-related SE: Dyscrasias, spina bifida.
Kinetics: Unpredictable absorption profile, plus CYP induction (like phenytoin)
Ethosuximide
Mechanism of action & indication?
Kinetics?
Side effects & toxicity?
Ethosuximide
Blocks T-Type calcium channels, for absence seizures.
Not protein bound, yet has long half-life (liver metabolized). Good oral absorption.
GI upset, lethargy.
Valproic Acid
Mechanism of action?
Indications?
Valproic Acid
Several; blocks repetitive neuronal firing, blocks T-type calcium currents, and increases GABA.
For absence, tonic-clonic, partial, as well as myoclonic seizures.
Valproic Acid
Kinetics?
Side effects?
Valproic Acid
Plasma protein bound, also a CYP inhibitor
Dose-dependent SE: GI upset, weight gain & hair loss.
Non-dose dependent SE: Hepatotoxicity, spina bifida.
Felbamate
Mechanism of action?
Indication?
Side effects?
Felbamate
NMDA antagonist, also potentiates GABA.
Partial seizures, last-choice.
Aplastic anemia and hepatotoxicity.
Gabapentin
Mechanism of action?
Indication?
Kinetics?
Gabapentin
GABA analog (yet not an agonist; role unclear)
Partial & tonic-clonic seizures, as well as neuropathic pain and ALS.
No protein binding and no liver metabolism (excreted unchanged)
Pregabalin
Mechanism of action?
Indication?
Side effects?
Pregabalin
GABA analog (like gabapentin), also blocks calcium currents.
Partial seizure, neuropathic pain (from several sources)
Very limited abuse potential.
Lamotrigine
Mechanism of action?
Indication?
Side effects?
Lamotrigine
Blocks repetitive action potential (Na?)
Tonic-clonic/absence seizures, also bipolar disorder.
Can cause rash (Stevens-Johnson syndrome!)
Topiramate
Mechanism of action?
Indication?
Side effects?
Topiramate
Antagonizes kainate/AMPA glutamate receptors, may block use-dependent sodium currents.
Partial seizures (adjunctive), migraine prophylaxis.
Fatigue, nausea, confusion, weight loss (marketed!)
Tiagabine
Mechanism of action?
Indication?
Side effects?
Tiagabine
Inhibits GAT-1 transporter (increases synaptic GABA)
Complex and partial seizures (adjunctive)
Dizziness, tremor, somnolence.
Levetriacetam
Mechanism of action?
Indication?
Side effects?
Levetriacetam
Unknown!
Partial, myoclonic, and tonic-clonic (adjunctive)
Dizziness, asthenia, somnolence.
Zonisamide
Mechanism of action?
Indication?
Side effects?
Zonisamide
Blocks sodium and calcium currents.
Partial seizures (adjunctive)
Ataxia, anorexia, nervousness, fatigue, speech impairment
Vigabatrin
Mechanism of action?
Indication?
Side effects?
Vigabatrin
Irreversibly inhibits GABA metabolism.
Complex partial seizures & infantile spasms (adjunctive)
Possible pemanent effects on vision.
Clobazam
Mechanism of action?
Indication?
Clobazam
Blocks sodium and calcium currents, as well as carbonic anhydrase.
Lennox gastaut epilepsy.
Lacosamide
Mechanism of action?
Indication?
Lacosamide
Enhances slow inactivation phase of sodium channels.
Partial seizures (adjunctive)
Perampanel
Mechanism of action?
Indication?
Kinetics?
Perampanel
AMPA antagonist.
Seizures, unclear which.
Interacts with CYP inducers…
Ezogabine
Mechanism of action?
Indication?
Side effects?
Ezogabine
Potassium channel facilitator (hyperpolarizing)
Partial seizures (adjunctive)
Retinal, vision, and skin abnormalities (permanent?)
Rufinamide
Mechanism of action?
Indication?
Rufinamide
Prolongs inactive phase of sodium channels.
Lennox-gastaut epilepsy.
Recap
Name four anticonvulsants that affect CYP activity.
Phenytoin, carbamazepine, oxycarbazepine all induce CYPs.
Valproic acid inhibits CYPs.
Recap
Name 3 anticonvulsants specifically indicated for absence seizures.
Ethosuximide, Lamotrigine, Valproic acid
What is the functional difference between NMDA and AMPA blockade?
Name some drugs that do each of these functions.
AMPA blockade appears to prevent aberrant discharge, while NMDA blockade merely shortens it.
NMDA blockers: Felbamate
AMPA blockers: Topiramate, Perampanel
Recap
Name two drugs that are indicated for Lennox-Gastaut epilepsy.
Clobazam, Rufinamide.
Recap
What anticonvulsant is also indicated for migraine?
Which are also indicated for neuropathic pain?
Recap
Topiramate
Gabapentin, Pregabalin
Recap
Name 2 drugs that are known to affect visual function.
Recap
Vigabatrin, Ezogabine.
Recap
What drug is known to cause aplastic anemia?
Which is a D-fructose analog?
Which irreversibly inhibits GABA metabolism?
Which reduces GABA uptake?
Recap
Felbamate
Topiramate
Vigabatrin
Many, but notably Tiagabine.
