Lecture 21 Drugs

Question 1

Main action of Carbamazepine and Phenytoin

Answer 1

Blocks voltage gated sodium channels

Question 2

Side effect of Carbamazepine

Answer 2

Powerful inducer of hepatic microsomal enzymes (CYP450s)
Increases rate of metabolism of drugs, inactivating them

Question 3

Dosage of Phenytoin

Answer 3

Subject to zero-order kinetics: small dose increase causes large increase in plasma concentration

Question 4

Side effects of Phenytoin

Answer 4

1) Drug-drug interaction (competition from plasma protein binding)
2) Induces haptic P450 enzymes (metabolizes drugs)

Question 5

Main actions of Valproate

Answer 5

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

Question 6

What does Valproate treat

Answer 6

Focal seizures, generalized tonic clonic seizures, and generalized absence seizures

Question 7

Main action of Ethosuximide

Answer 7

Blocks T-type Ca+ channels

Question 8

What does Ethosuximide treat

Answer 8

Generalized absence seizures

Question 9

Characteristic of generalized Absence seizures

Answer 9

Abnormal thalamocortical rhythmicity responsible for the 3Hz pattern, driven by thalamic T-type Ca+ channel (sensitive to voltage, only need weak depolarization to activate)

Question 10

How are T-Type Ca_ channels activated

Answer 10

Low threshold depolarization transiently activated T-type Ca+ channels
Open with weak depolarization but then rapidly close

Question 11

Main action of Phenobarbital

Answer 11

Increases GABA inhibition, AND decreases glutamate transmission

Question 12

What does Phenobarbital treat

Answer 12

Focal seizures and generalized tonic-clonic seizures

Question 13

Side effects of Phenobarbital

Answer 13

1) Inducer of hepatic microsomal enzymes (decrease efficacy of other drugs)
2) Risk of overdose (especially when combined with alcohol)
3) Sedation
4) Teratogen

Question 14

Main action of Benzodiazepines

Answer 14

Increase GABA inhibition through positive allosteric modulation of GABAa receptors (facilitating the opening to ion channels)

Question 15

What does Benzodiazepines treat

Answer 15

Focal seizures, generalized tonic-clonic seizures, and generalized absence seizures

Question 16

Side effects of Benzodiazepines

Answer 16

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

Question 17

Anti-seizure drugs during pregnancy

Answer 17

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

Question 18

What is Status Epilepticus

Answer 18

Seizures that can last 1 hour or more if left untreated (normal seizures are self-limited to 1-2 minutes)
EMERGENCY

Question 19

Results from long seizures

Answer 19

Hypoxia, acidemia, high body temperature, cardiovascular collapse, renal shutdown, brain damage, and death

Question 20

Treatment for Status Epilepticus

Answer 20

IV benzodiazepines (valium) (to counteract seizure) followed by longer-acting anticonvulsant (to prevent seizure from returning)

Question 21

Main action of Vigabatrin

Answer 21

Inhibitor of GABA transaminase with higher selectivity than valproate
Need to be used with other drugs, not alone

Question 22

Glutamate levels during seizures

Answer 22

Glutamate surge
Extracellular glutamate increases during seizures

Question 23

Way to counteract glutamate surge during seizures (AMPA)

Answer 23

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)

Question 24

Way to counteract glutamate surge during seizures (NMDA)

Answer 24

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

Question 25

Non-pharmalogic epilepsy treatment

Answer 25

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)