Lecture 10: 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

AED’s binding site is at the _________ side Na_v channel ‘pore’

Answer 6

Interior

Question 7

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

Which states can this occur?

Answer 7

• Activation gate
• Open state and Fast-inactivated state

Question 8

The probability of Na_v blockade is proportional to what?

Answer 8

FREQUENCY of Na_v channel opening and dose

Question 9

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

Answer 9

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

Question 10

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 10

Fosphenytoin

Question 11

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

Answer 11

Topiramate

Question 12

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

Answer 12

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

Question 13

What is the MOA of the AED, Tiagabine?

Answer 13

• 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 14

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

Answer 14

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 15

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

Answer 15

1. Vigabatrin
2. Valproic acid

Question 16

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

Answer 16

Primidone

Question 17

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

Answer 17

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

Question 18

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

Answer 18

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

Question 19

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

Answer 19

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

Question 20

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

Answer 20

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

Question 21

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 21

T-type Ca²⁺ channels

Question 22

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

Answer 22

Ethosuximide

Question 23

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

Answer 23

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 24

What is a complication of using Zonisamide as an AED in some patients?

Answer 24

Is a sulfonamide and people may have allergies

Question 25

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

Answer 25

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

Question 26

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

Answer 26

Levetiracetam

Question 27

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

Answer 27

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

Question 28

Which 5 AED's are used as first-line treatment of both simple and complex **partial onset** seizures?

Answer 28

1. Lamotrigine 2. Oxcarbazepine 3. Perampanel 4. Primidone 5. Lacosamide

Question 29

Which 3 AED's are used for absence (petit mal) seizures?

Answer 29

1) **Ethosuximide** 2) Clonazepam 3) Valproic acid

Question 30

Which AED is used for myoclonic seizures?

Answer 30

Clonazepam

Question 31

Which 2 AED's are used for Tonic/Clonic seizures?

Answer 31

1. Primidone 2. Phenytoin

Question 32

Which 4 AED's are broad spectrum (i.e., partial onset and generalized onset, minus absence)?

Answer 32

1) Carbamazepine 2) Phenobarbital 3) Topiramate 4) Valproic acid

Question 33

Which 6 AED's are used for Lennox-Gastaut seizures?

Answer 33

1. Rufinamide 2. Topiramate 3. Clobazam 4. Clonazepam 5. Lamotrigine 6. Felbamate

Question 34

Which 6 AED's are used for Status Epilepticus seizures?

Answer 34

1. Lorazepam 2. Diazepam 3. Phenobarbital 4. Phenytoin 5. Valproic acid 6. Levetiracetam

Question 35

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

Answer 35

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

Question 36

Which AED follows zero-order (saturable) pharmacokinetics?

Answer 36

Phenytoin

Question 37

Due to the pharmacokinetics of Phenytoin, what serum drug level must be monitored and maintained?

Answer 37

10-20 mcg/mL

Question 38

Phenytoin is a well-known inducer of?

Answer 38

CYP-450 enzymes \*Frequent drug-drug interactions

Question 39

What are 2 toxicities associated with the AED, Phenytoin?

Answer 39

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

Question 40

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

Answer 40

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

Question 41

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

Answer 41

- 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 42

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

Answer 42

- **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 43

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

Answer 43

Carbamazepine

Question 44

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

Answer 44

Ox**carb**azepine

Question 45

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

Answer 45

- 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 46

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

Answer 46

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

Question 47

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

Answer 47

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

Question 48

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

Answer 48

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 49

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

Answer 49

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

Question 50

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 50

1) Phenytoin 2) Carbamazepine 3) Phenobarbital

Question 51

Which 6 AED's require us to look at the renal function (i.e., serum creatinine/creatinine clearance); why?

Answer 51

- Levetiracetam / Topiramate / Oxcarbazepine / Gabapentin / Pregabalin / Vigabatrin - 65-100% renal clearance; renal insufficiency requires **dose adjustment**

Question 52

What are some of the example causes of Status Epilepticus?

Answer 52

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

Question 53

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

Answer 53

**- In first IV:** - Lorazepam **- Alternative** - Diazepam \*Wait 1 minute for response then additional lorazepam PRN - **If no IV access**: - Midazolam via IM injection

Question 54

If treating convulsive status epilepticus adult and first IV treatment does not work, what are the AED's used in the second IV treatment?

Answer 54

- Fosphenytoin - Phenyotin - Valproic acid - Levetiracetam