15) Anti-Seizure Flashcards
Epilepsy
- Group of chronic syndromes that involve the recurrence of seizures (ie, limited periods of abnormal discharge of cerebral neurons)
Seizure
- Occurs when a burst of electrical impulses in thebrain escape their normal limits
- Spread to neighboring areas and create an uncontrolled storm of electrical activity
- Electrical impulses can be transmitted to the muscles, causingtwitches or convulsions
Sodium channel blockade MOA
- Block voltage-gated sodium channels in neuronal membranes
- Rate-dependent (block increases with increased frequency of neuronal discharge)
- Prolonged inactivated state of the Na+channel and the refractory period of the neuron
Benzodiazepenes
- Interact with specific receptors on the GABAAreceptor–chloride ion channel
- Facilitate the inhibitory effects of GABA
Phenobarbitaland other barbiturates
- Enhance the inhibitory actions of GABA but interact with a different receptor site on chloride ion channels
- Results in an increaseddurationof chloride ion channel opening
GABA aminotransaminase (GABA-T)
- Important enzyme in the termination of action of GABA
- Irreversibly inactivated by vigabatrin
- Inhibits a GABA transporter (GAT-1) in neurons and glia, prolonging the action of the neurotransmitter
Ethosuximide
- Inhibits low-threshold (T type) Ca2+currents, especially in thalamic neurons
- Similar action is reported forvalproic acid,as well as for bothgabapentinandpregabalin with unknown mechanism
Levetiracetam
- Binds the SV2A protein on glutamate-containing transmitter vesicles
- Reduces glutamate release
Retigabine
- Enhances K+channel activity
- Inhibits depolarization of glutamate terminals
Perampanel
- Noncompetitive antagonist at glutamate AMPA receptors
- Prevents spread of abnormal excitation in susceptible neurons
Felbamate
- Blocks glutamate NMDA receptors
Althoughphenobarbitalacts on both sodium channels and GABA-chloride channels,
- It also acts as an antagonist at some glutamate receptors
Topiramate
- Blocks sodium channels
- Potentiates the actions of GABA
- May also block glutamate receptors
The oral bioavailability of phenytoin
- Variable because of individual differences in first-pass metabolism
Phenytoin metabolism
- Nonlinear elimination kinetics
Phenytoin binding
- Binds extensively to plasma proteins (97–98%)
- Free (unbound) phenytoin levels in plasma are increased transiently by drugs that compete for the same binding (eg, carbamazepine, sulfonamides, valproic acid).
The metabolism of phenytoin is enhanced in
- Presence of inducers of liver metabolism (eg, phenobarbital, rifampin) and inhibited by other drugs (eg, cimetidine, isoniazid)
Phenytoin itself induces
- Hepatic drug metabolism
- Decreases the effects of other antiepileptic drugs including carbamazepine, clonazepam, and lamotrigine.
Fosphenytoin
- Water-soluble prodrug form of phenytoin
- Used parenterally
Carbamazepine
- Induces metabolism of many other anticonvulsant drugs (including clonazepam, lamotrigine, and valproic acid)
- Metabolism can be inhibited by other drugs (eg, propoxyphene, valproic acid)
Valproic acid inhibits
- Metabolism of carbamazepine, ethosuximide, phenytoin, phenobarbital, and lamotrigine
Valporic acid competes for
- Phenytoin plasma protein binding sites
Hepatic biotransformation of valproic acid leads to formation of
- A toxic metabolite that has been implicated in the hepatotoxicity of the drug
Drugs eliminated by the kidney, largely in unchanged form
- Gabapentin
- Pregabalin
- Levetiracetam
- Vigabatrin
Neural tube defects (eg, spina bifida) are associated with the use of
- Valproic acid
- Carbamazepine
- Phenytoin
Most of the commonly used anticonvulsants are
- CNS depressants
- Respiratory depression may occur with overdosage
- Life-threatening toxicity
Fatal hepatotoxicity has occurred with
- Valproic acid
Lamotrigine has caused
- Skin rashes
- Life-threatening Stevens-Johnson syndrome
- Toxic epidermal necrolysis
Zonisamide may also cause
- Severe skin reactions
- Reports of aplastic anemia and acute hepatic failure have limited the use of felbamate to severe, refractory seizure states
Withdrawal from antiseizure drugs should be accomplished gradually to avoid
- Increased seizure frequency and severity
Cytochrome P450 enzyme system inducers
- Phenobarbital
- Primidone
- Phenytoin
- Carbamazepine
- Felbamate (CYP3A)
- Topiramate (CYP3A)
- Oxcarbazepine (CYP3A)
Cytochrome P450 enzyme system inhibitors
- Valproate
- Topiramate (CYP2C19)
- Oxcarbazepine (CYP2C19)
- Felbamate (CYP2C19)
Anti-seizure drugs with active metabolites
- Carbamazepine
- Primidone
- Fosphenytoin
Anti-seizure drugs with zero order kinetics
- Phenytoin
Anti-seizure drug that can cause gingival hyperplasia
- Phenytoin induced gingival hyperplasia
Fosphenytoin is a prodrug that will become
- Phenytoin
General adverse effects of anti-seizure medications
- Nausea/vomiting
- Drowsiness/sedation
- Ataxia
- Rash
- Hyponatremia
- Weight gain/loss
- Teratogenicity
- Osteoporosis
