[PHARM] Pharmacology of Epilepsy [Segars]

Question 1

At the most basic level, what is the neuronal imbalance involved in epilepsy?

Answer 1

TOO MUCH glutamate, aspartate [excitation]

TOO LITTLE gaba [inhibition]

Question 2

What are the (4) general MOAs of antiepileptic drugs?

Answer 2

1. Suppress excitatory (glutamate) transmission
2. Enhance inhibitory (GABA) transmission
3. Block T-type Ca2+ channels
4. Novel mechanisms

Question 3

When are Na channel blockers most effective in exerting their effects?

Why does this make sense?

Answer 3

Most effective : Open state and Fast-inactivated state

If the activation gate is open, then the drugs can access the pore of the Na+ channel!

Question 4

If the Na+ channel activation gate is OPEN… anti epileptic drugs __________

If the Na+ channel activation gate is CLOSED… anti epileptic drugs _________

Answer 4

If the Na+ channel activation gate is OPEN… anti epileptic drugs CAN access the pore

If the Na+ channel activation gate is CLOSED… anti epileptic drugs CANNOT access the pore

Question 5

The probability of Na blockade is proportional to ___________________

Answer 5

The probability of Na blockade​ is proportional to the frequency of Nav channel opening and dose

Question 6

What are the (6) drugs contained in the Na blockers that specifically prolong fast inactivation state?

Answer 6

Carbamazepine (oxcarbazepine/eslicarbasepine)

Lamotrigine

Phenytoin

Topiramate

Valproic acid

Lacosamide** (Zonisamide_, Rufin_amide**)

Question 7

What is the one drug within the Na Blockers that prolong fast inactivation has an additional effect?

What is that effect?

Answer 7

Lacosamide

Enhance slow inactivation of Nav channels

Question 8

What are the (2) AMPA receptor blockers?

Answer 8

Topiramate

Perampanel

Question 9

What is the (1) NMDA receptor blocker?

Answer 9

Felbamate

Question 10

What enzymes break down GABA endogenously?

Answer 10

GABA Transaminase : GABA-T

Succinic Semialdehyde Dehydrogenase : SSD

Question 11

What is responsible for reuptake of GABA in the synaptic cleft?

Answer 11

GABA Transporter 1 (GAT-1)

Question 12

What drugs (2) inhibits GABA-T?

Answer 12

Vigabatrin

Valproic acid

Question 13

What drug inhibits GAT-1?

Answer 13

Tiagabine

Question 14

What drug has dual action by inhibiting GABA-T AND SSD?

Answer 14

Valproic acid

Question 15

GABA promoting agents

What are the (2) categories of pre-synaptic drugs?

Answer 15

GAT-1 inhibitor

GABA-T inhibitors

Question 16

GABA Promoting agents

What is the (1) GAT-1 pre synaptic inhibitor?

Answer 16

Tiagabine

Question 17

GABA promoting agents

What are the (2) GABA-T inhibitors?

Answer 17

Vigabatrin

Valproic acid

Question 18

What are three classes of drugs that will enhance the post synaptic GABAergic neuronal transmisson?

Answer 18

1. Barbiturates
2. Benzodiazapines
3. Topiramate

Question 19

What is the major difference b/w the MOA of benzodiazepines and barbiturates?

Answer 19

Benzos are GABA DEPENDENT

Barbiturates are GABA INDEPENDENT

Question 20

What are the (3) MOA of topiramate?

Answer 20

GABA(A) agonist = Increases frequency of GABA(A) receptor activation

Increases fast inactivation of Na channels

Acts as an AMPA receptor ANTAGONIST

Question 21

What are the (7) post synaptic GABA promoting agents?

Answer 21

(2) Barbiturates : Phenobarbital, Primidone

(4) Benzos : Clonazepam, Clobazam, Lorazepam, Diazepam

1 Rando: Topiramate

Question 22

What are the key MOA to absence seizures?

Answer 22

T-type Ca2+ that mediate a 3Hz spike and wave activity in the thalamus

Question 23

What drug class is used to treat ansence seizures?

Answer 23

Antagonists of T-type Ca2+ channels

Question 24

What is the ONE drug that is ONLY used for absence seizures?

Answer 24

Ethosuximide

Question 25

There are two other drugs that have multiple MOAs that also block the **Ca2+ T-type channels**. What are they?

Answer 25

Valproic acid Zonisamide

Question 26

What are the (2) **synaptic vesicle 2A** protein blockers?

Answer 26

Levetir**acetam** Brivar**acetam**

Question 27

What (2) drugs inhibit the **alpha2delta Ca2+** channel?

Answer 27

Gabapentin Pregabalin

Question 28

What is the BRAND NEW drug that **opens K+ channels?**

Answer 28

Ezogabine

Question 29

What are the (2) drugs with **3 MOAs?**

Answer 29

Topiramate Valproic acid

Question 30

What are the (3) MOAs of **topiramate?**

Answer 30

Na+ channel blocker AMPA receptor blocker Post synaptic GABA promoting

Question 31

What are the (3) MOA of **valproic acid?**

Answer 31

Na+ channel blockers GABA-T inhibition [GABA promoting agents] Ca2+ T-type channel blockers

Question 32

What is a drug OUTSIDE the drug tree that is used for **dravet** and **lennox-gastaut** syndrome?

Answer 32

Cannabidiol (Epidiolex)

Question 33

What are the **2 broad warning/risks** of ALL antiepileptic medications?

Answer 33

1. Abrupt **withdrawal** of antiepileptic medication may cause **status epilepticus** 2. **Suicidal behavior** and ideation

Question 34

What is the **pharmacokinetic** profile of **phenytoin?**

Answer 34

Zero-order (dose titration upward may **exceed Vmax** of patient)

Question 35

What is a profound interaction **phenytoin** has?

Answer 35

Inducer of CYP-450

Question 36

What are the two major toxicities of **phenytoin?**

Answer 36

Gingival hyperplasia Hypocalcemia/vit D deficit/osteoporosis

Question 37

What are the interactions of **carbamazepine?**

Answer 37

Inducer of CYP-450 enzymes

Question 38

What are the toxicities associated with **carbamazepine?**

Answer 38

Leukopenia Neutropenia Thrombocytopenia

Question 39

What is the major benefit to using **Oxcarbazepine** over carbamazepine?

Answer 39

It's an alternative active metabolite that is **a less potent CYP450 inducer**

Question 40

What is the **major toxicity** associated with **vigabatrin?**

Answer 40

Permanent vision loss

Question 41

What is the only way a physician can prescribe **vigabatrin?**

Answer 41

REMS program Risk evaluation and mitigation strategy \*It is vastly important that physicians understand this devestating side effect of permanent vision loss before prescribing

Question 42

What are the major AED interactions with other medications?

Answer 42

**_Contraceptives_** [decrease efficacy] **_Anticoagulants_** [increase clearance] **_Antivirals_** [increase clearance]

Question 43

What are the **newer AEDs** attempting to utilize as a clearance method?

Answer 43

RENAL clearance

Question 44

What is your first line agent for **status epilepticus** during INITIAL THERAPY? First IV? No IV access? Second IV?

Answer 44

In first IV: Lorazepam, Diazepam No IV access: Midazolam In second IV: Fosphenytoin, phenytoin, valproic acid, levetiracetam

Question 45

What are your **SECONDARY therapies** for status epilepticus?

Answer 45

Fosphenytoin Midazolam