Segars: Antiepileptic Agents

Question 1

List the 9 antiepileptic drugs which work as pre-synaptic voltage-gated Na+ channels blockers via enhanced fast inactivation.

Answer 1

1) Carbamazepine
2) Oxcarbazepine
3) Lamotrigine
4) Phenytoin
5) Rufinamide
6) Topiramate
7) Valproic acid
8) Zonisamide
9) Lacosamide

Question 2

Which AED is unique in its ability to prolong fast inactivation of Na_v ion channels and also enhance slow inactivation of Na_v channels?

Answer 2

Lacosamide

Question 3

Which 2 antiepileptic drugs are AMPA-receptor antagonists?

MOA?

Answer 3

1. Topiramate
2. Perampanel

MOA = bind AMPA receptor and block glutamate binding; channel doesn’t open –> AP does not propogate downstream

Question 4

Which antiepileptic drug is an NMDA-receptor antagonist?

Answer 4

Felbamate

Question 5

The pharmacological activity of AED Na_v channel blockers is _______ and ________-dependent

Answer 5

State and Use-dependent

Question 6

Which gate must be open for AED’s to access the pore of Na_v channels?

Which states can this occur?

Answer 6

• Activation gate
• Open state and Fast-inactivated state

Question 7

The probability of Na_v blockade is proportional to what?

Answer 7

FREQUENCY of Na_v channel opening and dose

Question 8

Why do the AED’s that are Na_v blockers act preferentially on the neurons involved in epileptic seizures?

Answer 8

The neurons involved will be firing at higher freqeuncy than normal, allowing more chances for these drugs to slip right in and bind

Question 9

What is the water-soluble pro-drug of phenytoin which is given via IV and is an Na_v channel blocker used as an antiepileptic?

Answer 9

Fosphenytoin

Question 10

Which AED acts as a Na_v channel blocker (fast inactivation), AMPA-receptor antagonist, and GABA_A agonist?

Answer 10

Topiramate

Question 11

What occurs when the post-synaptic GABA_A receptor becomes occupied by GABA?

Answer 11

• Cl^- channel opens
• Hyperpolarization occurs blunting AP propogation

Question 12

What is the MOA of the AED, Tiagabine?

Answer 12

• Blocks pre-synaptic reuptake of GABA by blocking the GABA transporter, GAT-1
• Causes GABA to go post-synaptically, bind GABA_A receptor leading to hyperpolarization and decreased AP propogation

Question 13

What are the 3 MOA’s of Valproic acid used as a AED at the pre-synaptic GABA terminal?

Answer 13

1) Increase activity of glutamic acid decarboxylase, leading to increased GABA presynaptically
2) Inhibit GABA-T, which typically metabolizes GABA
3) Inhibit Succinic Semialdehyde Decarboxylase (SSD), which typically metabolized GABA

Question 14

Which 2 AED’s inhibit the metabolism of GABA through the inhibition of GABA-T?

Answer 14

1. Vigabatrin
2. Valproic acid

Question 15

Which drug in the barbiturate family gets metabolized to phenobarbital in the body?

Answer 15

Primidone

Question 16

Where do Benzodiazepines bind the GABA_A receptor and what effects does this have?

Answer 16

• Bind to a distinct site –> Allosteric change potentiate GABA binding
• Cl^- channel opens with greater frequency

Question 17

Where do Barbiturates bind the GABA_A receptor and what is their effect?

Answer 17

• Bind a distinct site
• Increases the duration of Cl^- channel opening

Question 18

Of the GABA_A receptor agonists used as AED’s which is more lethal at higher doses and why?

Answer 18

• Barbituates are more lethal due to being GABA INdependent
• Benzodiazepines are GABA-dependent

Question 19

What are the 7 AED’s which act post-synaptically to potentiate GABA_A-receptor Cl^- currents?

Answer 19

1) Phenobarbital
2) Primidone
3) Clonazepam
4) Lorazepam
5) Diazepam
6) Clobazam
7) Topiramate

Question 20

Which type of ion channel mediates the 3-Hz spike and wave activity in the thalamus which is the hallmark of absence (petit mal) seizures?

Answer 20

T-type Ca²⁺ channels

Question 21

Which narrow spectrum drug is only used for absence seizures and only limits excitation (Ca²⁺ channels)?

Answer 21

Ethosuximide

Question 22

Which 3 AED’s are antagonists of T-type Ca²⁺ channels?

Answer 22

1. Ethosuximide (narrow spectrum)
2. Valproic acid (also GABA-T inhibitor and prolongs fast inactivation of Na_v channels)
3. Zonisamide (also prolongs fast inactivation of Na_v channels)

Question 23

Which 2 AED’s act as both antagonists of T-type Ca²⁺ channels and prolong fast inactivation of Na_v channels?

Answer 23

1. Valproic acid (also GABA-T inhibition)
2. Zonisamide

Question 24

Which AED blocks synaptic vesicle 2A protein on the presynaptic terminal of glutamate neuron?

Answer 24

Levetiracetam

Question 25

Which 2 AED's block the α2δ1 Ca²⁺ channel on the presynaptic terminal of the glutamate neuron?

Answer 25

1) **Gaba**pentin 2) Pre**gaba**lin

Question 26

The abrupt withdrawl of **any** antiepileptic medication may precipitate? May lead to what type of behavior?

Answer 26

- Precipitate **status epilepticus** - **Suicidal** behavior and ideation

Question 27

Which AED follows zero-order (saturable) pharmacokinetics?

Answer 27

Phenytoin \*\*\*if you give more than the body can handle, it just builds up. thus, it is easy to give too much

Question 28

Phenytoin is a well-known inducer of?

Answer 28

CYP-450 enzymes \*Frequent drug-drug interactions

Question 29

What are 2 toxicities associated with the AED, Phenytoin?

Answer 29

1. Gingival hyperplasia 2. Hypocalcemia/Vit. D deficit/Osteoporosis

Question 30

Osteopenia/Osteoporosis is a side effect associated with chronic administration of which 4 AED's? What do these drugs induce?

Answer 30

1. Carbamazepine 2. Phenytoin 3. Phenobarbital 4. Valproic acid \*These drugs **induce** CYP450-dependent vitamin D **catabolism**

Question 31

What are some of the issues associated with the AED, Carbamazepine (i.e., serum drug level, inducer of, toxicities)?

Answer 31

- Serum drug level monitoring (**4-12 mcg/mL**) = **narrow window** - **Inducer** of CYP-450 enzymes - **Induces** **auto-induction** (self-metabolism) - Hematological toxicities: **leukopenia/neutropenia/thrombocytopenia**

Question 32

Which AED induces its own metabolism? Also occurs to a lesser extent with what other AED drug? What may occur because of this?

Answer 32

- **Carbamazepine** induces own metabolism - Also, to lesser extent (25%), with **lamotrigine** **\*This may lead to a potential loss of efficacy and recurrence of seizures**

Question 33

Before administering which AED is a CBC required as this drug has potential side effects including leukopenia, neutropenia, and thrombocytopenia?

Answer 33

Carbamazepine

Question 34

What analogue of carbamazepine was formulated which has fewer CNS/hematological SE's and is a less-potent CYP450 inducer?

Answer 34

Ox**carb**azepine

Question 35

What are some of the issues associated with the AED, Phenobarbital?

Answer 35

- Need serum drug level monitoring (**10-40 mcg/mL**) - Well known **inducer** of CYP-450 enzymes (frequent drug-drug interactions) - Toxicities: **hypocalcemia/Vit. D deficit/Osteoporosis**

Question 36

Which AED is only prescribe-able via *REMS* program; why?

Answer 36

- Vigabatrin - May cause progressive, permanent, bilateral, concentric **vision loss**

Question 37

Which 4 AED's are associated with hepatic CYP450 **induction**?

Answer 37

1. Carbamazepine 2. Phenytoin 3. Phenobarbital 4. Valproate

Question 38

What are 3 major AED-drug interactions associated with the CYP450 inducers?

Answer 38

1. Increased clearance of **oral contraceptives** --\> 2-4 fold rise in OHC failure rate; risk for **unplanned pregnancy** 2. Increase clearance of **warfarin** --\> **less anticoagulation**; elevated risk for arterial/venous thrombosis 3. Increase clearance of **HIV meds** --\> **elevated risk for HIV replication**

Question 39

Which 2 AED's inhibit conjugation of drugs by UGT causing accumulation of parent drug (esp. each other when used together)?

Answer 39

**Valproic acid** and **Lamotrigine**

Question 40

Which 3 AED's **induce** conjugation of drugs by UGT causing a **reduction** of parent drug (i.e., when given with valproic acid will decrease levels of valproic acid)?

Answer 40

1) Phenytoin 2) Carbamazepine 3) Phenobarbital

Question 41

What are some of the example causes of Status Epilepticus?

Answer 41

- Abrupt withdrawl of AED's, BZD's, Opioid's, Alcohol - Brain mass/trauma - Infection - Fever

Question 42

What is the initial therapy for convulsive status epilepticus (i.e., the first IV, alternative drug, and if no IV access)?

Answer 42

**- In first IV:** - Lorazepam **- Alternative** - Diazepam \*Wait 1 minute for response then additional lorazepam PRN

Question 43

Which AED opens pre/post-synaptic **K channels** to prevent seizures?

Answer 43

Ezogabine

Question 44

What are the 3 MOAs of Valproic acid? Topiramate?

Answer 44

**Valproic acid** = Na channel blocker, GABA-T inh, _Ca t-type blocker_ **Topiramate** = Na channel blocker, AMPA blocker, _post-syn GABA promotor_

Question 45

What drug may be beneficial for the treatment of **Dravet** and **Lennox-Gastaut** syndrome?

Answer 45

Cannabidiol

Question 46

What are 3 options for 2nd therapy for status epilepticus?

Answer 46

- **Fosphenytoin** - Intubation - Continuous BP and CV monitor - Continuous **midazolam** OR **propofol** infusion