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58 Cards in this Set
- Front
- Back
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What is most significant factor in choosing one antiepileptic drug over another?
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Beneficial effects on comorbid conditions
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What is the most predictable attribute of one antiepileptic drug over another
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Drug interactions
Effectiveness is most unpredictable b/c drug trials are usually pt populations for severe, refractory epilepsy, unlike Abx which kill bugs regardless of who has them. ADEs are variable response |
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Seizure vs Epilepsy
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Seizure - clinical manifestation of an abnormal, HYPERSYNCHRONIZED, discharge (usually REPETITIVE) in a population of cortical excitatory neurons
Epilepsy: A tendency toward recurrent seizures (at least 2) UNPROVOKED by acute systemic or neurologic insults Seizures are NOT an overload or storm but highly synchronized reponses People can get a single seizure from flashing lights, infection, tumor etc. which is provoked |
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RMP of a neuron and processes making it less negative and more negative
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Normal RMP is negative
Excitatory processes - make potential less negative or more positive (depolarize) - inward sodium or calcium current Inhibitory processes - make the neuron more negative or hyperpolarized - inward chloride or outward potassium current |
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2 potential ways ADEs can affect membrane potential
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Directly affect a specific ion channel
Indirectly affect channel by influencing synthesis, metabolism, or function of NTs or receptors controlling channel |
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Major excitatory NT, inhibitory NT
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Excitatory - glutamate
Inhibitory - GABA |
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MOA potentials of ADEs: Anti-excitatory vs Pro-inhibitory
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Anti-excitatory - Na+ channel blockers/modulators (most common), Ca++ channel blockers/modulators, Glutamate antagonism (minor)
Proinhibitory - Increase GABA mediated Cl- influx via (increased opening time and frequency of channels, decreased GABA reuptake, inhibition of GABA transaminase) OR increased K efflux |
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Physiology of Voltage-Gated Sodium Channels (4 stages) and drug types affecting them
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Resting State - closed
Open State - during depolarization (local anesthetics keep here so no AP can propagate) Inactivated state-fast - "ball and chain" with ball inside channel blocking during repolarization. Very fast (within ms) restoration to resting state to allow another AP. - Classic AED target Inactivated state-slow - ONLY activated under continuous depolarization cycles. Takes longer for gate to reopen and allow an AP. (New VIMPAT dugs for AED) Most common path is from open to fast inactivated state but if continually depolarized can go to slow inactivated state |
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Why must antiepileptic drugs act on inactivated state
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Want to keep cell from depolarizing again too fast. If kept in open (like local anesthetics) no AP can fire and person would die
They just SLOW down the cycle to allow normal inhibitory brain fxn to take over |
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2 Types of GABA receptors in CNS and role
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GABAa - Postsynaptic FAST inhibition, specific recognition sites, mediated by Cl- current
GABAb - post synaptic SLOW inhibition, Presynaptic reduction in Ca++ influx, mediated by K+ efflux GABAa is one most used in ADE |
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2 Types of Glutamate receptors in CNS and role
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Major EXCITATORY NT in CNS
Ionotropic - FAST synaptic transmission. AMPA, NMDA Metabotropic - SLOW synaptic transmission, G protein linked, intrinsic and synaptic cellular activity Ionotropic is more important for treatment |
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NMDA receptor, modulators
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Glutamate fast synaptic transmission receptor
Excitatory Conducts Na+ and Ca++ to depolarize and promote AP Modulated by glycine, zinc, redox site, polyamine site |
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MOA relation to impact on effectiveness or response to a drug
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NONE, same mechanisms may have vastly different results
SO just b/c an epilepsy pt has a certain channel mutation does not mean that should guide which drug to use. Also not clear if two of same type of drugs are redundant or helpful or harmful |
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Phenytoin MOA, ASE
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Blocks voltage dependent Na channels at high firing frequencies
ASE: Hirsutism, acne, coarsness of facial features, cerebellar atrophy, peripheral neuropathy, osteomalacea CEREBELLAR ATROPHY and PERIPHERAL NEUROPATHY are irreversible |
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Carbamazeipine MOA, ASE
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MOA: blocks voltage dependent sodium channels at high firing frequencies
ASE: RARE RARE aplastic anemia, toxic hepatitis, SJS |
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ASE common to most ADEs
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sedation, dizziness, ataxia
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Drug that can cause irreversible cerebellar atrophy and peripheral neuropathy
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Phenytoin
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Barbituates MOA, ASE
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MOA: increases DURATION of GABA mediated chloride channel opening.
ASE: memory problems, SOFT TISSUE CHANGES (Dupuytren's contracture, frozen shoulder, fibromas, thickening of heel/knuckle pads) |
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Benzodiazepines MOA, ASE
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MOA: Increase FREQUENCY of GABA-mediated chloride channel opening
ASE: DEPENDENCE, tolerance, WITHDRAWAL Used for an acute attack in the ER |
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Drug causing dependence and withdrawal
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Benzodiazepines
NOT for daily use, just an acute attack |
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Ethosuximide MOA, ASE
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MOA: blocks low threshold "transient" (T-type) calcium channels in thalamic neurons
ONLY useful for absence epilepsy |
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Valproate MOA, ASE
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MOA: enhance GABA transmission in specific circuits, blocks voltage dependent sodium channels, modulates T-type calcium channels
ASE: hepatic failure, BIRTH DEFECTS Used for migraine and bipolar disorder |
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Which medication is for absence epilepsy
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Ethosuximide
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Drug with many mechanisms to block epilepsy
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Valproate: enhances GABA transmission in some circuits, blocks voltage dependent Na+ channels, modulates T-type calcium channels
Used for migraine and bipolar disorder Zonisamide: blocks voltage-dependent sodium channels and T-type calcium channels, mild carbonic anhydrase inhibitors Useful for migraines Gabapentin: Blocks Ca++ channels, enhances H current, suppresses presynaptic vesicle release, suppresses NMDA receptor at glycine site Used for Neuropathic pain and migraine Topiramate: locks voltage dependent Na+ channels at high frequency, increases frequency at which GABA opens Cl- channels, antagonizes glutamate action at AMPA/kainate receptor, inhibits carbonic anydrase Used for migraines |
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Felbamate MOA, ASE
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MOA: Blocks voltage-dependent sodium channels with high firing frequencies, modulates NMDA and GABA receptors
ASE: 1/4500 fatal aplastic anemia or hepatic failure |
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Drug most likely to lead to aplastic anemia
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Felbamate
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Gabapentin MOA, ASE
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MOA: Blocks calcium channels, enhances H current (determines RMP, regulates hyperpolarization), suppresses presynaptic vesicle release, suppresses NMDA receptor at glycine site
LOOKS LIKE GABA BUT NOT GABAergic USED FOR NEUROPATHIC PAIN |
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Last resort epilepsy drug
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Felbamate, can cause fatal aplastic anemia
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Medication that looks like GABA molecularly
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Gabapentin, NOT GABAergic
Blocks Ca++ channels, enhances H current, suppresses presynaptic vesicle release, suppresses NMDA receptor at glycine site |
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Drug used for neuropathic pain and migraine
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Gabapentin
Not much use in epilepsy Pregabalin - fibromyalgia |
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Lamotrigine MOA, ASE
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MOA: blocks voltage dependent sodium channels at high firing frequencies, enhances H current, modulates kainate receptors
ASE: Stevens Johnson risk if titrated quickly |
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Which drug must be titrated slowly
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Lamotrigine
SJS risk |
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Zonisamide MOA, ASE
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MOA: blocks voltage-dependent sodium channels and T-type calcium channels, mild carbonic anhydrase inhibitors
LONG HALF LIFE ONCE A DAY DOSING Useful for migraines |
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Drug that can be dosed once per day
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Zonisamide
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Topiramate MOA, ASE
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MOA: blocks voltage dependent Na+ channels at high frequency, increases frequency at which GABA opens Cl- channels, antagonizes glutamate action at AMPA/kainate receptor, inhibits carbonic anydrase
ASE: Fatigue, concentration difficulty, word finding difficulty, weight loss, parasthesia Used for migraines |
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Drug causing concentration difficulty
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Topiramate
word finding difficulty |
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Tiagabine MOA, ASE
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MOA: interferes with GABA re-uptake
ASE: 3 times a day dosing so poor adherence |
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Drug with poorest adherence
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Tiagabine - needs 3/day
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Levetiracetam MOA, ASE
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MOA: biding of reversible saturable specific binding site SV2a (synaptic vesicle protein) and reverses GABA and glycine inhibition
MOST COMMON PROSCRIBED IN US |
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Most common prescribed ADE in US
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Levetiracetam
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Oxcarbazepine MOA, ASE
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MOA: blocks voltage dependent sodium channels at high frequency
ASE: HYPONATREMIA |
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Pregabalin MOA, ASE
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MOA: increases glutamic acid decarboxylase (high GABA)
USED FOR NEUROPATHIC PAIN and fibromyalgia |
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Lacosamide MOA, ASE
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MOA: enchances SLOW INACTIVATION of voltage gated sodium channels
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Only drug that works to enhance slow inactivation of voltage gated sodium channels
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Lacosamide
Sedation and cognitive changes not significantly worse than placebo |
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Rufinamide Use
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MOA: unclear, may stabilize in inactive state sodium channel
USED FOR Lennox-Gastaut Syndrome |
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Drug for Lennox-Gastaut Syndrome
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Rufinamide
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Vigabatrin MOA, ASE
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MOA: irreversibly inhibits GABA transaminase
ASE: 30% chance of irreversible peripheral vision loss, mild and only if use chronically |
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Drug with potential of irreversible peripheral vision loss
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Vigabatrin, from chronic use
Uses in Lennox-Gastaut |
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Major P450 inducers and inhibitors
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Inducers - Phenobarbital, Phenytoin, Carbamazepine
Inhibitors - Valproic acid IF taking WARFARIN, antivirals then will have more/less in circulation inhibitors take effect earlier |
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ADEs with NO drug interactions
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Gabapentin, Levetiracetam, Pregabalin, Lacosamide
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Drug for infantile spasms
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Vigabatrin
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Good drug for partial onset seizure
Good one for generalized seizure (His bolded stuff) |
Partial onset - LACOSAMIDE
Generalized - Vigabatrin (infantile spasms), Rufinamide (Lennox-Gastaut) |
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Dose-related ASE vs idiosynchratic vs beneficial side effects and predictability for ADEs
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Predictability
Dose-related>Beneficial>Idiosynchratic Dose-related - CNS symptoms Idiosyncratic - rash usually but can be SKIN, LIVER, BLOOD Beneficial - weight loss, headache cure, mood stabilization, no neuropathic pain |
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Drug if want weight loss too
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Topamax
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Drugs if want to help reduce headaches
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Topamax, Zonegran, Depakote
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Drug to use if have had problems with drug interactions
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Keppra (LEVETIRACETIM)
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Main situation to avoid
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Dilantin and Phenobarbitol
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What to avoid if on coumadin
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dilantin, phenobarbitol, tegretol
Anything inducing CYP450 - phenytoin |
