Anticonvulsants Flashcards
What is a seizure?
a failure of conscious intent to control brain function
What are convulsions?
failure to inhibit motor output
what are absence seizures?
inability to generate motor output
What causes seizures?
idiopathic of secondary to various conditions
What should you treat with seizures?
the cause, whenever possible
When is chronic pharmacological treatment warranted?
if seizures are of unknown cause and recurring (epilepsy) or in the aftermath of a known cause
what are the three stages of seizures?
focal discharge (paroxysmal depolarization), spread, termination
What does spread of seizures depend on and what can inhibit a seizure?
action potentials (sodium channels) and release of excitatory transmitters (glutamate, calcium channels). it is prevented by inhibitory neurotransmitters (GABA)
Do anti-seizure drugs stop the cause of seizures?
no, just suppress the spread
How to anti-seizure drugs suppress the spread of abnormal electrical activity (4)?
1) block AP’s (sodium channel block)
2) increase inhibitory tone of brain (increase GABA transmission)
3) reduce NT release (calcium channel block)
4) reduce excitatory neurotransmission (decrease glutamate neurotransmission)
What determines drug choice?
classification of seizures
What are the two types of partial seizures and what distinguishes them?
Simple partial: key feature is preservation of consciousness
Complex partial: localized onset followed by widespread discharges (usually bilateral). confused behavior, impairment of consciousness. most arise from temporal lobe, almost always involve the limbic system
What are the two types of generalized seizures and what distinguishes them?
Tonic-clonic (Grand mal): major convulsions (tonic spasms then clonic jerking). prolonged depression of all central functions after seizures
Absence (petit mal): sudden onset, abrupt cessation. brief LOC, sometimes with motor involvement. occurs in childhood and often disappears during maturation. may be frequent. characteristic 3 Hz spike and wave EEG
What are the three points about animal models?
1) some models may relate to epilepsy if the animals have spontaneous recurrent seizures (seizure prone genetic strain, “kindles” animals.
2) most models related better to acute seizures, either partial or general
3) animal models are most useful for screening for new drugs or testing drug combos
What are the 10 anticonvulsants to know?
Phenytoin, Carbamazepine, Lamotrigine, Topiramate, Valproic acid, Phenobarbital, Diazepam (Lorazepam), Gabapentin, Tiagabine, Ethosuximide
Which drugs block Na channels?
phenytoin, carbamazepine, lamotrigine
Which drugs enhance GABA neurotransmission?
valproic acid (decrease GABA turnover), phenobarbital and benzodiazepines increase GABAa receptor activation
Which drugs block Ca channels?
Lamotrigine, valproic acid, ethosuximide
Which drugs work against simple partial seizures (6)?
phenytoin, caramazepine, lamotrigine, valproic acid, phenobarbital, benzodiazepines
Which drugs work against grand mal seizures (6)?
phenytoin, carbamazepine, lamotrigine, valproic acid, phenobarbital, benzodiazepines
Which drugs work against petit mal seizures?
lamotrigine, valproic acid, ethosuximide
Which drugs work against all three types of seizures?
lamotrigine, valproic acid
Which drug only works against petit mal seizures?
ethosuximide
What are the main sodium channel blockers?
phenytoin, carbamazepine, lamotrigine
what are the sodium channel blockers effective against?
partial seizures and generalized tonic clonic (grand mal)
do anticonvulsants affect normal APs?
no, just inhibit high frequency seizure acitivties
What are the side effects of sodium channel blockers?
nystagmus, diplopia, ataxia
What are the GABA neurotransmission enchancing drugs effective against?
partial seizures and grand mal
What are the GABAa receptor modulators (postsynaptic)?
barbiturates (phenobarbital) and benzos (diazepam, lorazepam)
What are the drugs that increase synaptic GABA levels (presynaptic)?
valproic acid, tiagabine, gabapentin
What are the calcium channel blockers and what do they inhibit?
ethosuximide and valproic acid: inhibit T type channels that are responsible for absence seizures (petit mal)
lamotrigine: inhibits another type of calcium channel
What are the drugs that decrease glutamate neurotransmission?
valproic acid, topiramate, and lamotrigine
What are general considerations for drug therapy in epilepsy (5)?
1) anti-seizure drugs only provide symptomatic relief (no cure) and efficacy varies.
2) many drugs have narrow therapeutic indexes (adverse effects)
3) careful monitoring of blood drug concentrations is important
4) reduction in dosage should be gradual to avoid seizure recurrence
5) multiple drug therapies are common
Why are multiple drug therapies used?
may allow a primary agent to be used at a lower dosages if side effects are limiting. best combos use drugs with diff mechanisms
What is another general consideration?
drug interaction is common with other anticonvulsants and other drugs (Warfarin)
Which drugs induce cytochrome P450 enzymes and therefore increase metabolism of each other?
cabamazepine, phenytoin, phenobarbital
Which drug inhibits some CYP enzymes and therefore increases the plasma concentration of phenytoin, carbamazepine, and phenobarbital?
valproic acid
Which two drugs are high protein binding?
phenytoin, valproic acid
Which condition is Ethosuximide contraindicated for?
other types of seizures (not petit-mal) and vice-versa
which two types of seizures can be confused?
absence or petit mal and partial seizures
What is status epilepticus?
one continueous seizures or recurrent seizures without regaining consciousness for greater than 30 min. it is life threatening
What do you treat status epilepticus with?
IV lorazepam or diazepam
Which drugs appear to increase the likelihood of birth defects?
phenytoin, carbamazepine, valproic acid, topiramate
how do you treat a pregnant women with epilepsy?
withdraw drugs at least 6 months before pregnancy or monotherapy with carful drug monitoring to keep the blood concentraion in low therapeutic ranges (usually safer than untreated epilepsy)
Phenytoin (5)
- prolongs inactivated state of sodium channels
- acute toxicities: nystagmus, ataxia, diplopia
- long-term side effects: gingival hyperplasia, hirsutism, teratogen
- very low therapeutic indix
- highly variable and dose-dependent phamacokinetics: zero order! be careful in increasing dose!
Carbamazepine (5)
- similar structure and mech as phenytoin
- considered the drug of choice for partial seizures and grand mal
- induces microsomal CYP enzymes
- diplopia and ataxia, also skin rash. aplastic anemia and agranulocytosis but rare
- also used for pain control
Phenobarbital (4)
- enhances GABA mediated Cl influx
- induces microsomal enzymes
- long plasma half-life: easy to maintain constant blood level
- less sedating than other barbs, but frequently causes sedation
Benzodiazepines (2)
- used for status epilepticus: IV lorazepam of diazepam
2. not used for long-term therapies
Ethosuximide (3)
- blocks T type calcium channels
- pure petit mal drug (absence) and lacks hepatotoxicity of valproate (drug of choice!)
- gastric distress
Valproic Acid (7)
- first drug effective vs. both absence and tonic-clonic (grand mal and petit mal)
- discovered by accident
- blocks sodium channels and T type calcium channels and increases synaptic GABA concentration by inhibiting GABA turnover
- hepatotoxicity
- reducses serum protein binding of some drugs, e.g. phenytoin
- inhibits CYP enzymes: increases plasma concentration of phenobarbital and phenytoin
- teratogen: spina bifida
Gabapentin (4)
- structurally similar to GABA, but has no effect on GABA receptors
- appears to increase GABA transmission (don’t know how)
- well tolerated
- not metabolized by liver: no known drug interaction
Lamotrigine (3)
- mech: blocks sodium channels, inhibits calcium channels, inhibits glutamate release
- broader spectrum: even absence
- diplopia, SKIN RASH
Topiramate (3)
- mech: inhibits sodium channels, modulates GABAa receptors, blocks glutamate receptors
- broad spectrum: even absence
- also useful for preventing migraines
Tiagabine (2)
- blocks reuptake of GABA into nerve terminals and glia by inhibiting GABA transporter, GAT-1
- mild side effects
