IC7 Seizure & epilepsy II

Question 1

What is the MOA of carbamazepine?

Answer 1

It is a sodium channel blocker.

Question 2

What is carbamazepine used for?

Answer 2

It is used for:
1. Epilepsy
2. Neuropathic pain
3. Bipolar disorder

Question 3

What are the 4 ADRs of carbamazepine?

Answer 3

1. Drowsiness, dizziness, N&V
2. Blood dyscrasia
3. Hyponatremia
4. Hypersensitivity*

Question 4

What are the most severe hypersensitivity reactions of carbamazepine?

Answer 4

1. SJS
2. TEN

Question 5

Which race has higher risk of carbamazepine induced hypersensitivity?

Answer 5

Asians have 10x higher risk than Caucasians.

This is due to the presence of HLA-B*1502

Question 6

Apart from HLA-B*1502, what other allele have a wider range of hypersensitivity reactions with carbamazepine?

Answer 6

HLA-B*3101

Question 7

In SG, which allele is mandatory for testing before starting pt on carbamazepine?

Answer 7

HLA-B*1502 testing is mandatory before starting pt on carbamazepine.

HLA-B3101 is optional. if pt has HLA-B1502, we still try to avoid using carbamazepine & use an alternative medcation.

Question 8

If a patient has HLA-B*1502 and is on carbamazepine for >3 months with no severe ADR, what should we do?

Answer 8

Allow pt to continue on therapy as it is less likely that it will cause any severe ADRs.

Question 9

What are some alternatives to carbamazepine in epilepsy treatment?

Answer 9

Levetiracetam, valproate, topiramate

Question 10

What are the 1st generation antiseizure medications (ASM) that we need to know?

Answer 10

1. Carbamazepine
2. Phenytoin
3. Phenobarbital
4. Sodium valproate

Question 11

For the 1st generation ASM, what are the common similarities that exist?

1. High / low protein binding?
2. Hepatically or renally cleared
3. Do all of them have drug drug interactions?

Answer 11

For all 4 first generation drugs (CBZ, PB, PHT, VPA) that we need to know:

1. They all have high protein binding, except phenobarbital with 50% protein binding
2. They are all largely hepatically cleared
3. They all have DDIs

Question 12

What are the 2nd generation antiseizure medications that we need to know?

Answer 12

1. Levetiracetam
2. Topiramate
3. Lamotrigine
4. Clobazam

Question 13

For 2nd gen ASM, what are the common similarities that exist?

(Levetiracetam, topiramate, lamotrigine, clobazam)

1. High / low protein binding?
2. Hepatically or renally cleared
3. Do all of them have drug drug interactions?

Answer 13

Protein binding:
- Levetiracetam & topiramate have low protein binding
- Lamotrigine has moderate protein binding (50%)
- Clobazam have high protein binding

Renally or hepatically cleared:
- Levetiracetam (66%), topiramate (55%), clobazam (90%) are renally cleared
- Lamotrigine is 100% hepatically cleared

DDI:
- Levetiracetam has no DDI
- Lamotrigine has a few DDI
- Topiramate DDI is dose dependent
- Clobazam has DDI

Question 14

What are the MOAs for all the 1st and 2nd generation medications that we need to know?

1st Gen:
1. Carbamazepine
2. Phenytoin
3. Phenobarbital
4. Sodium valproate

2nd Gen:
1. Levetiracetam
2. Topiramate
3. Lamotrigine

Answer 14

1st Gen:
1. Carbamazepine - Na+ channel blocker
2. Phenytoin - Na+ channel blocker
3. Phenobarbital - Ca2+ channel blocker
4. Sodium valproate - inhibits GABA, Na+ & Ca2+ channels

2nd Gen:
1. Levetiracetam - presynaptic SV2A release modulator
2. Topiramate - Na+ channel blocker
3. Lamotrigine - Na+ channel blocker

Question 15

Which drug is the GOLD standard for focal onset epilepsy?

Focal onset seizures aka simple partial seizures - a seizure that happens while a person is awake, alert and aware of what is going on.

Answer 15

Carbamazepine

Question 16

What are first line drugs used in GTC seizures?

Answer 16

1. Carbamazepine
2. Lamotrigine
3. Sodium valproate

Question 17

What is the first line drug used in tonic or atonic?

Answer 17

Sodium valproate

Question 18

What are the 1st line drugs to use in absence seizures?

Answer 18

1. Lamotrigine
2. Sodium Valproate

Question 19

What are the 1st line drugs to use in myoclonic seizures?

Answer 19

1. Levetiracetam
2. Sodium valproate
3. Topiramate

Question 20

What are the 1st line drugs for focal seizures?

Answer 20

1. Carbamazepine
2. Lamotrigine
3. Levetiracetam
4. Sodium valproate

Question 21

Can you name which ASM are inducers or inhibitors of CYP enzymes / transporters?

1st gen:
Carbamazepine -
Phenobarbital -
Phenytoin -
Sodium valproate -

2nd gen:
Lamotrigine -
Levetiracetam -
Topiramate -
Clobazam -

Answer 21

1st gen:
Carbamazepine - inducer
Phenobarbital - inducer
Phenytoin - inducer
Sodium valproate - inhibitor

2nd gen:
Lamotrigine - inducer
Levetiracetam - no effect , hence no DDI
Topiramate - CYP3A4 inducer & CYP2C19 inhibitor
Clobazam - inhibitor

Note that sodium valproate & clobazam the only inhibitors.

The rest are all inducers.

Topiramate is the only drug that is both an inducer and inhibitor.

Question 22

What are the 4 classes of drugs that have DDIs w ASMs?

Answer 22

1. Antidepressants & antipsychotics
2. Immunosuppressive therapy
3. Antiretroviral therapy
4. Chemotherapeutic agents

Question 23

What are the different dosage forms for phenytoin?

Answer 23

1. Oral suspension
2. Capsules

Question 24

Must we space apart enteral feeds & phenytoin? If yes, how long must we space them apart for?

Answer 24

Yes, we must space apart enteral feeds and phenytoin.

They are to be spaced apart every 2 hours.

Question 25

What is the PK of phenytoin? (ADME)

Answer 25

A: phenytoin is completely absorbed w 100% bioavailability D: 0.7 L/kg. 90% Albumin bound M: Metabolized by CYP2C9 & CYP2C19 E: Zero order kinetics. Clearance is dependent on concentration. Clearance decreases when concentration increases

Question 26

What are the different dosage forms of sodium valproate?

Answer 26

1. Injection 2. Enteric coated tablet 3. Sustained-release tablets 4. Syrup

Question 27

What are the PK characteristics of sodium valproate? No need to know excretion.

Answer 27

A: Oral bioavailability 100% D: 0.15L/kg, 95% albumin bound. *Has saturable protein-binding within therapeutic range. At high concentrations, there is decreased protein binding. M: Metabolized by many CYP enzymes

Question 28

What are the dosage forms for carbamazepine?

Answer 28

1. Immediate-release tablet 2. Controlled-release CR tablets

Question 29

What are the PK characteristics of carbamazepine?

Answer 29

A: bioavailability = 0.8 D: Highly protein bound (80%) M: Metabolised >99% by CYP3A4. Carbamazepine undergoes autoinduction - it induces its own metabolism.

Question 30

What are the ways we can mitigate ADRs in anti seizure medications?

Answer 30

1. Initiate at low dose & slowly titrate 2. Avoid large dosage changes 3. Restricting therapy to 1 drug only 4. Adjusting the administration schedule

Question 31

What are common ADRs of antiseizure medications?

Answer 31

1. Gingival hyperplasia 2. Hirsutism 3. Alopecia - hair loss 4. Peripheral neuropathy 5. Weight gain 6. Anorexia, weight loss 7. Metabolic bone disorder Gingival hyperplasia, hirsutism, peripheral neuropathy are often associated w phenytoin use. Metabolic bone disorder is associated w phenytoin, phenobarbital, carbamazepine Alopecia , weight gain are often associated w sodium valproate use. Anorexia & weight loss are associated with topiramate.

Question 32

What are the special considerations of titrating the dose for lamotrigine?

Answer 32

Dose for lamotrigine should be titrated slowly. Risk of serious cutaneous reaction is higher w high starting doses, rapid dose escalation, and concomitant use with valproate. When patient is taking valproate, we uptitrate the dose of lamotrigine even slower.

Question 33

Aromatic ASMs have cross-sensitivity reactions. Which of the common drugs that we have learnt are aromatic?

Answer 33

Carbamazepine Phenytoin Phenobarbital Lamotrigine

Question 34

Summary slide for ASM ADRs. Just click open the link

Answer 34

https://nusu-my.sharepoint.com/:i:/r/personal/e0725451_u_nus_edu/Documents/Pharmacy/Year%203/Y3S2/PR3153/ICs/IC7%20Seizure%20%26%20Epilepsy%20II/ADR%20summary.png?csf=1&web=1&e=hd43pm

Question 35

How can we optimise ASM treatment?

Answer 35

Using therapeutic drug monitoring (TDM). TDM allows us to establish a patient's therapeutic range, and identify for any toxicity.

Question 36

When can we discontinue ASM?

Answer 36

ASM discontinuation may be considered after: 1. Minimum of 2 years without seizure 2. Discussion with pt and their family. However, pt w increased risk of seizure recurrence should wait longer than 2 years.

Question 37

List out the special populations involved in ASM.

Answer 37

1. Women of childbearing potential 2. Women on oral contraceptives 3. Pregnancy 4. Lactation 5. Male of reproductive potential Caution w use of ASM in women of childbearing potential as they can be teratogenic. For women on oral contraceptives (OC), OC can lower lamotrigine's concentration, causing breakthrough seizures For pregnancy, levetiracetam and lamotrigine are safer options. Do NOT use valproate as it is teratogenic. For breastfeeding, no CI have been found. In fact, all breastfeeding women are encouraged to do so. For male w reproductive capabilities, valproate increases the risk of neurodevelopmental disorders (NDDs) in their children

Question 38

What is status epilepticus?

Answer 38

Status epilepticus - a seizure that lasts longer than 5 minutes, or having more than 1 seizure within a 5 minutes period, without returning to a normal level of consciousness between episodes. Has long term consequences.

Question 39

What is the treatment procedurefor status epilepticus? 0-5min: 5-20min: 20-40min: 40-60min:

Answer 39

0-5min: - stabilize the patient and prevent mortality 5-20min: - If seizure continues, initiate benzodiazepine - If seizure stops, provide symptomatic care 20-40min: - If seizure continues, use IV ASM - If seizure stops, provide symptomatic care 40-60min: - If seizure continues, repeat IV ASM - If seizure stops, provide symptomatic care