Lecture 21 Drugs Flashcards
Main action of Carbamazepine and Phenytoin
Blocks voltage gated sodium channels
Side effect of Carbamazepine
Powerful inducer of hepatic microsomal enzymes (CYP450s)
Increases rate of metabolism of drugs, inactivating them
Dosage of Phenytoin
Subject to zero-order kinetics: small dose increase causes large increase in plasma concentration
Side effects of Phenytoin
1) Drug-drug interaction (competition from plasma protein binding)
2) Induces haptic P450 enzymes (metabolizes drugs)
Main actions of Valproate
1) Blocks Na+ channels and stabilizes them in the inactivated state
2) Inhibits GABA transaminase (inhibiting GABA breakdown)
3) Inhibits T-Type Ca+ channels (inhibiting 3Hz pattern in generalized absence seizures)
Does NOT induce hepatic microsomal enzymes
What does Valproate treat
Focal seizures, generalized tonic clonic seizures, and generalized absence seizures
Main action of Ethosuximide
Blocks T-type Ca+ channels
What does Ethosuximide treat
Generalized absence seizures
Characteristic of generalized Absence seizures
Abnormal thalamocortical rhythmicity responsible for the 3Hz pattern, driven by thalamic T-type Ca+ channel (sensitive to voltage, only need weak depolarization to activate)
How are T-Type Ca_ channels activated
Low threshold depolarization transiently activated T-type Ca+ channels
Open with weak depolarization but then rapidly close
Main action of Phenobarbital
Increases GABA inhibition, AND decreases glutamate transmission
What does Phenobarbital treat
Focal seizures and generalized tonic-clonic seizures
Side effects of Phenobarbital
1) Inducer of hepatic microsomal enzymes (decrease efficacy of other drugs)
2) Risk of overdose (especially when combined with alcohol)
3) Sedation
4) Teratogen
Main action of Benzodiazepines
Increase GABA inhibition through positive allosteric modulation of GABAa receptors (facilitating the opening to ion channels)
What does Benzodiazepines treat
Focal seizures, generalized tonic-clonic seizures, and generalized absence seizures
Side effects of Benzodiazepines
Risk of drug abuse, only used in emergency like status epilepticus
Rapid onset but quickly redistribute from brain to tissues so quick decrease in brain can cause seizure to start again
Anti-seizure drugs during pregnancy
Epilepsy can cause malformations of fetus
Many drugs are teratogens
IDEALLY: discontinue drugs, but then increased risk of seizure
LAST RESORT: try monotherapy at minimal effective dose
What is Status Epilepticus
Seizures that can last 1 hour or more if left untreated (normal seizures are self-limited to 1-2 minutes)
EMERGENCY
Results from long seizures
Hypoxia, acidemia, high body temperature, cardiovascular collapse, renal shutdown, brain damage, and death
Treatment for Status Epilepticus
IV benzodiazepines (valium) (to counteract seizure) followed by longer-acting anticonvulsant (to prevent seizure from returning)
Main action of Vigabatrin
Inhibitor of GABA transaminase with higher selectivity than valproate
Need to be used with other drugs, not alone
Glutamate levels during seizures
Glutamate surge
Extracellular glutamate increases during seizures
Way to counteract glutamate surge during seizures (AMPA)
Glutamate activates AMPA glutamatergic receptors that open Na+ channels (allowing for cell depolarization), hence want to block these channels
Non-competitive antagonists of AMPA receptor (perampanel) which cannot be outcompeted by glutamate (unlike competitive antagonist)
Way to counteract glutamate surge during seizures (NMDA)
Glutamate also activated NMDA glutamatergic receptors (blocked by magnesium when at rest, magnesium is pulled out when depolarized)
Use-dependent blockers (MK-801) bind to open/most active NMDA channels
HOWEVER, motor side effects cannot be distinguished from therapeutic effect
Non-pharmalogic epilepsy treatment
1) Surgery (remove seizure focus) (most effective)
2) Neuro-stimulation (implanted device to stimulate vagus nerve or thalamus)
3) dietary therapies (ketogenic diet, but poorly tolerated)
