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PR3153 > IC7- Seizures and Epilepsy II > Flashcards

IC7- Seizures and Epilepsy II Flashcards

1
Q

Name the 1st generation ASMs? (4)

A
  • Carbamazepine
  • Phenobarbitone/ phenobarbital
  • Phenytoin
  • Sodium valproate
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2
Q

Name the 2nd generation ASMs? (3)

A
  • Lamotrigine
  • Levetiracetam
  • Topiramate
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3
Q

Carbamazepine- protein binding %, elimination, DDIs (Yes/ No)?

A
  • Protein binding: 75-85%
  • Elimination: 100% H (autoinduction)
  • ✅ DDIs
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4
Q

Phenobarbital- protein binding %, elimination, DDIs (Yes/ No)?

A
  • Protein binding: 50%
  • Elimination: 75% H
  • ✅ DDIs
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5
Q

Phenytoin- protein binding %, elimination, DDIs (Yes/ No)?

A
  • Protein binding: 90%
  • Elimination: 100% H (non-linear)
  • ✅ DDIs
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6
Q

Sodium valproate- protein binding %, elimination, DDIs (Yes/ No)?

A
  • Protein binding: 75-95% (non-linear)
  • Elimination: 100% H
  • ✅ DDIs
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7
Q

What are the problems with 1st gen ASMs? (4)

A

Poor water solubility
Extensive protein binding
Extensive oxidative metabolism
Multiple DDIs

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8
Q

What are the advantages of newer ASMs compared to 1st generation ASMs?

A
  • Improved water solubility → predictive bioavailability
  • Negligible protein binding → no need to worry about hypoalbuminemia + less reliant on CYP metabolism
  • More are eliminated with a mix of renal and hepatic
  • Fewer DDIs
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9
Q

Which are the key enzymes involved in DDIs of antiepileptics? (3)

A
  • CYP-P450
  • UGT
  • Transporters
  • SDRs (Short-chain dehydrogenases/reductases)
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10
Q

Which ASMs are inducers/ inhibitors of hepatic metabolic enzymes?

A
  • CBZ
  • Lamotrigine
  • Phenobarbital
  • Phenytoin
  • Topiramate
  • Sodium valproate
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11
Q

Is Carbamazepine an inducer/ inhibitor of metabolic enzymes?

What are the metabolic enzymes/ transporters involved?

A

Inducer

CYP1A2, CYP2C9, CYP2C19, CYP3A, UGT, PGP

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12
Q

Is Lamotrigine an inducer/ inhibitor of metabolic enzymes?

What are the metabolic enzymes/ transporters involved?

A

Inducer

UGT

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13
Q

Is Phenobarbital an inducer/ inhibitor of metabolic enzymes?

What are the metabolic enzymes/ transporters involved?

A

Inducer

CYP1A, CYP2A6, CYP2B, CYP2C9, CYP3A, UGT

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14
Q

Is Phenytoin an inducer/ inhibitor of metabolic enzymes?

What are the metabolic enzymes/ transporters involved?

A

Inducer

CYP2C9, CYP2C19, CYP3A, UGT, PGP

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15
Q

Is Topiramate an inducer/ inhibitor of metabolic enzymes?

What are the metabolic enzymes/ transporters involved?

A

Inducer- CYP3A4

Inhibitor- CPY2C19

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16
Q

Is Valproate an inducer/ inhibitor of metabolic enzymes?

What are the metabolic enzymes/ transporters involved?

A

Inhibitor

CYP2C9, UGT, epoxide hydrolase

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17
Q

What classes of medications have DDIs with enzyme-INDUCING ASMs?

A
  • Antidepressants & antipsychotics
  • Immunosuppressive therapy
  • Antiretroviral therapy
  • Chemotherapeutic agents
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18
Q

How might enzyme-INDUCING ASMs affect health?

A
  • Reproductive hormones, sexual function, OC in women (become less effective)
  • Sexual function & fertility in men
  • Bone health
  • Vascular risk

(avoid giving them ASMs)

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19
Q

What are the different forms that phenytoin is available in? (3)

A
  • PO (oral suspension [125mg/5ml]
  • PO Capsule (30mg, 100mg)
  • IV (phenytoin sodium)
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20
Q

In which situations is bioavailability of phenytoin reduced? (2)

A
  1. At higher doses > 400mg/dose
  2. By interaction with enteral feeds (hence space apart by 2h)
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21
Q

Vd of phenytoin?

A

Vd = 0.7 L/kg (0.5 - 0.8 L/kg)

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22
Q

What can you say about phenytoin’s binding to albumin?

A

Phenytoin is highly albumin bound (~90%)

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23
Q

In what situations will there be an ↑ in free phenytoin?

A
  • Low albumin (hypoalbuminemia)
  • Displacement of phenytoin by another highly-protein bound drug
  • Displacement by endogenous compound uremia
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24
Q

What is the equation we use to calculate the corrected (free) phenytoin level?

Can you write it out?

A

Winter-Tozer eqn

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25
Q

What kind of kinetics does phenytoin follow?

Why?

A
  • Non-linear kinetics (changes to zero order kinetics when conc is high)
  • Capacity-limited clearance: clearance dependent on concentration → clearance ↓ when conc ↑ (until any increase in phenytoin substrate will not result in a corresponding inc in rate of metabolism)
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26
Q

For phenytoin, what is the relationship between the dose and the amount of time it takes to reach steady state?

A

The higher the dose, the longer it takes for steady state to be reached

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27
Q

For phenytoin, small increments in dose make it very easy for conc to move out of therapeutic ranges- is this true?

A

Yes

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28
Q

What are the available forms of valproate? (4)

A
  1. Injection (400mg/ vial)
  2. Enteric-coated tablet (200mg)
  3. Sustained-release tablets (Chrono 200mg, 300mg, 500mg)
  4. Syrup (200mg/ 5ml)
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29
Q

Vd of valproate?

A

Vd = 0.15 L/kg

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30
Q

Carbamazepine is highly bound to which enzymes? (2)

A
  1. Albumin
  2. α1-acid glycoprotein
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31
Q

In what situations will free valproic acid levels ↑?

A
  • Displacement by endogenous compounds → uraemia, hyperbilirubinemia
  • Compete for binding with PHT, warfarin, NSAIDs
  • Low albumin → higher free fraction of drug
  • Saturable protein-binding within therapeutic range: ↑ conc, ↓ protein binding
    ⚠️ Hence need to interpret VPA levels for pts with hypoalbuminemia
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32
Q

What are the available forms of carbamazepine? (2)

A
  1. PO immediate release tab (200mg)
  2. PO CR tablets (200mg, 400mg)
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33
Q

Vd of carbamazepine?

A

Vd = 1.4 L/kg (1 - 2 L/kg)

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34
Q

Which enzyme metabolises carbamazepine?

What is the active metabolite called?

A

Metabolism > 99% by CYP3A4

Active metabolite: Carbamazepine-10,11-epoxide

35
Q

What is one important thing to note about carbamazepine regarding its metabolism?

A

Undergoes autoinduction → clearance ↑ and t1/2 shorten

36
Q

When does maximal induction by carbamazepine occur? Hence, how should we dose the patient?

A

Maximal induction usually 2-3w AFTER dose initiation
∴ Do not start with desired maintenance dose first, gradually increase over initial few weeks

37
Q

What is usually the main limiting factor in the treatment of epilepsy?

A

Dose/ plasma concentration-related adverse effects

38
Q

When are the rare but serious idiopathic/ hypersensitivity-related ADEs that all current ASMs have (except some 2nd gen ASMs) most likely to occur?

A

Most likely to occur in first few months of therapy

39
Q

What are some dose/ plasma concentration-related ADEs of ASMs?

A
  • CNS: somnolence, fatigue, dizziness, visual disturbances (double/ blurred vision), nystagmus, ataxia
  • GI: N/V (CBZ, VPA)
  • Psychiatric: behavioural disturbances (Levetiracetam)
  • Cognition: usually speech fluency (Topiramate)
40
Q

Due to dose/ plasma concentration-related adverse effects of ASMs, what are some ways we can dose the patients? (7)

A
  • Avoid large doses: start low and slowly titrate up
  • Avoid large dosage changes
  • Giving monoTx only if possible
  • Giving larger doses at bedtime
  • Dividing the doses into smaller doses throughout the day
  • Giving sustained release formulation instead of immediate release formulations
  • Reducing total daily dose (if clinically safe)
41
Q

What happens with long-term ASM therapy?

Is it related to plasma conc of ASMs?

A

Chronic (systemic) adverse effects

No, it tends to be drug-specific and not directly related to plasma
concentration of ASM

42
Q

What are some non-dose related, rare but serious idiopathic/ hypersensitivity-related ADEs that all current ASMs (except some 2nd gen ASMs) are associated with? (6)

If applicable, name the type of ASM associated with the ADE

A
  • Blood dyscrasia (Aplastic anaemia, agranulocytosis)
  • Hepatotoxicity (1st-generation ASMs phenytoin, valproate, carbamazepine)
  • Pancreatitis (only sodium valproate)
  • Lupus-like reaction
  • Exfoliative dermatitis
  • Toxic epidermal necrolysis/ Stevens-Johnson syndrome
43
Q

What are the ADEs of chronic use of ASMs for Phenytoin? (4)

Elaborate on each ADE

A
  1. Gingival hyperplasia → in almost ½ of all pts on chronic Tx
  2. Hirsutism (common in children and young adults on chronic Tx)
    - Facial hirsutism may affect up to 30% of young females
  3. Peripheral neuropathy (8.5-18% of pts on long-term Tx + high doses → sensory loss)
    - May/ may not improve with ↓ dose
    - May respond with folate supplementation
  4. Endocrine
    - Osteomalacia (hepatic enzyme inducer → increase clearance of vit D → secondary hyperparathyroidism → increased bone turnover → reduced bone density
44
Q

What are the ADEs of chronic use of ASMs for Sodium valproate? (2)

Elaborate on the ADE

A
  1. Alopecia (2-12% of pts on chronic Tx)
  2. Metabolic
    - Weight gain (reverses spontaneously if Tx stopped)
45
Q

What are the ADEs of chronic use of ASMs for Carbamazepine and Phenobarbitone (they have the same ADEs)? (2)

Elaborate on the ADE

A
  1. Peripheral neuropathy
  2. Endocrine
    - Osteomalacia (hepatic enzyme inducer → increase clearance of vit D → secondary hyperparathyroidism → increased bone turnover → reduced bone density
46
Q

What are the ADEs of chronic use of ASMs for Topiramate and Felbamate (same ADE)? (1)

A

Metabolic
- Anorexia and weight loss (reversible if Tx stopped)

47
Q

What are the ADEs of chronic use of all ASMs (esp Levetiracetam)?

A
  1. Sucidal ideation
  2. Rash due to hypersensitivity
48
Q

How do we deal with the ADE of suicidal ideation associated with all ASMs (esp Levetiracetam)?

A

Risk is very low, so don’t refuse to start ASMs due to the possibility of this ADE. Monitor SSx closely

49
Q

How do we deal with the ADE of rash due to hypersensitivity associated with all ASMs? (3)

A
  1. Pharmacogenetic testing for Carbamazepine
  2. Follow dosing guidance for Lamotrigine
  3. Identify potential cross-sensitivity reaction (ASMs with aromatic rings)
50
Q

Elaborate on the demographics of carbamazepine-induced hypersensitivity (ie. which ethnicity it affects more)?

How long is the onset?

A
  • Risk ~10x higher in Asian countries
  • Strong association between risk of SJS/ TEN and HLA-B*15:02 in Chinese (esp Han Chinese)
  • Onset: 4-28 days (within first month)
51
Q

Elaborate on carbamazepine-induced hypersensitivity and HLA-A*31:01? (include demographics)

A
  • Associated with wider range of hypersensitivity (including maculopapular exanthema, DRESS) esp with European and Japanese. Also risk factor for Han Chinese
52
Q

What allele do we test for when conducting pharmacogenetic testing for Carbamazepine?

What do we avoid if the pt is positive for that allele?

A
  • Testing for HLA-B*1502 before initiation (relevant for Han Chinese and other Asians)
  • If positive → ❌ AVOID Carbamazepine and Phenytoin
53
Q

What is the recommendation for carbamazepine-induced hypersensitivity testing in SG?

A

HLA-B*15:02 genotyping is the standard of care for new patients of Asian ancestry initiating carbamazepine

54
Q

What are the recommendations for prescribing for carbamazepine-induced hypersensitivity?

A
  • AVOID initiating carbamazepine for HLA-B15:02 and HLA-A31:01 carriers, choose alternative
  • But if carrier pt has already been taking CBZ for > 3 months, can continue
55
Q

What alternative treatments for carbamazepine should we give for HLA-B15:02/ HLAA 31:01 carriers?

What drugs have cross reactivity to CBZ that we should avoid in HLA-B*15:02 carriers?

A
  1. Neuropathic pain
    - Gabapentin
  2. Mood stabilizer
    - Lithium, valproate, quetiapine, aripiprazole, olanzapine
  3. Epilepsy
    - Levetiracetam, valproate, topiramate, perampanel

Potential cross-reactivity in HLA-B*15:02: AVOID phenytoin, phenobarbital, lamotrigine

56
Q

What is the dosing guidance for Lamotrigine to prevent the ADE of hypersensitivity?

A
  • Slow titration (risk of serious cutaneous reaction higher w high starting doses, rapid dose escalation, concomitant valproate)
57
Q

Elaborate more on identifying potential cross-sensitivity reaction (ASMs with aromatic rings).

Which drugs have aromatic rings and which do not?

A
  • Aromatic rings: CBZ, Lamotrigine, Phenytoin, Oxcarbazepine, Phenobarbital
  • No aromatic rings (✅ safe to change to these): Valproate, Levetiracetam, Topiramate, Gabapentin
58
Q

What are some factors to consider when deciding on which medication to choose? (5)

A
  1. Efficacy and effectiveness
  2. Tolerability
  3. Pharmacokinetics
  4. Personal preferences
  5. Nation-specific factors
59
Q

Why is it difficult to do TDM for ASMs? (5)

A
  1. Plasma ASM concentrations correlate much better than dose with the clinical effects.
  2. Assessment of therapeutic response on clinical grounds alone is difficult in most cases
    – because ASM treatment is prophylactic, and seizures occur at irregular intervals.
    – difficult to ascertain whether the prescribed dose will be sufficient to produce long term
    seizure control
  3. It is not always easy to recognize signs of toxicity purely on clinical grounds
  4. ASMs are subject to substantial pharmacokinetic variability and thus large differences in dosage are
    required in different patients
  5. There are no laboratory markers for clinical efficacy or toxicity of ASM
60
Q

Why is ASM TDM needed? (4)

A
  1. To establish an individual’s “therapeutic” range (i.e. document effective level which controls
    seizures while minimising side effects)
  2. To assess lack of efficacy (eg. “fast metabolizers”/ adherence issues etc?)
  3. To assess potential toxicity (eg. “slow metabolisers”/ changes in renal (uremia, hypoalbuminemia), liver (CYP enzymes), new DDIs/ danger levels- conc. dependent ADEs!)
  4. To assess loss of efficacy (changes in physiology (age, pregnancy), pathology, formulation, DDIs)
61
Q

What is the information required from the pt for TDM? (6)

A

– Indication for ASM (diagnosis)
– Dose (when, how long, how much)
– Sample (when taken, type?)
– Clinical condition (seizure control [at baseline vs currently], comorbidities)
– Other lab values?
– Other drugs (when, how long, how much)

62
Q

What is the reference range for TDM of phenytoin?

A

10 – 20 mg/L

63
Q

What is the reference range for TDM of valproate?

A

50 – 100 mg/L

64
Q

What is the reference range for TDM of Carbamazepine?

A

4 – 12 mg/L

65
Q

What is the reference range for TDM of Phenobarbitone?

A

15 – 40 mg/L

66
Q

After how long then we can consider ASM discontinuation?

A

After a minimum of two years
without a seizure. (for pts with increased risk of seizure recurrence AND pts a low frequency of
seizures (less than once a year) before remission, both should still wait > 2y before discontinuing)

67
Q

What should we consider when discontinuing ASM?

A

The decision to stop medication involves a balance of the risks of continuation (chronic toxicity, teratogenicity) with the implications of relapse (injury, SUDEP, employment).

68
Q

Under which circumstance can we declare a patient to have resolved epilepsy?

A

Epilepsy is considered to be resolved for individuals who had an age-dependent epilepsy syndrome but are now past the applicable age
OR
Those who have remained seizure-free for the last 10 years, with no seizure medicines for the last
5 years.

69
Q

How should we deal with pregnant pts/ women of childbearing potential with epilepsy?

A
  • Refer to specialist care to discuss fertility, contraception and family planning + potential risk to foetus (due to uncontrolled seizures/ teratogenic potential of ASMs)
70
Q

What should be documented when discussing discontinuation of ASM with pts? (4)

A

– Reasons for the discontinuation
– Taper schedule
– Plans for monitoring patients during and after the ASM taper
– Patient’s motivation for, attitude towards and understanding of the potential risks and benefits of ASM discontinuation compared with continuing ASM therapy

71
Q

What is the DDIs between ASMs and oral contraceptives?

What is something important to note about Lamotrigine?

A

ASMs which are potent enzyme inducers may render OCs ineffective → alternate methods required

For patients on lamotrigine, OC may lower lamotrigine concentrations, resulting in breakthrough seizures

72
Q

Since ASMs which are potent enzyme inducers may render oral contraceptives ineffective, what are some alternative contraceptive methods we can suggest?

A
  1. Levonorgestrel/copper intrauterine device IUD)
  2. Medroxyprogesterone depot injection every 10-12 weeks + barrier method
73
Q

Which ASMs are safe for use during pregnancy, and which is C/I?

A
  • Levetiracetam and lamotrigine are safer options for use during pregnancy
  • Valproate should NOT be used in female children/ women of
    childbearing potential unless other treatments are ineffective or not
    tolerated (foetus will be at high risk of serious developmental disorders and congenital malformations)
74
Q

In what special populations is valproate C/I in for epilepsy and bipolar disorder?

If this special population is currently using valproate, what steps do we need to take?

A

Epilepsy:
- C/I in pregnancy
- C/I in women of childbearing potential (unless fulfils pregnancy prevention programme)

Bipolar disorder:
- C/I in pregnancy
- C/I in women of childbearing potential (unless fulfils pregnancy prevention programme)

For women of childbearing potential currently using valproate:
- Review alternative Tx if possible
- Ensure communication of risks and need for contraception

75
Q

Which ASMs are associated with neurodevelopmental risk in pregnancy? (4)

A
  • Valproate, Phenobarbital, phenytoin
  • Topiramate (emerging data)
76
Q

Which ASMs are associated with major congenital malformations in pregnancy? (4)

Among these, which are dose-dependent?* (3)

A

*Carbamazepine, *phenobarbital,
phenytoin and *topiramate

77
Q

What are the implications of ASMs on male patients of reproductive potential?

A

↑ risk of neurodevelopmental disorders in children born to men treated with valproate in the 3
months prior to conception

78
Q

What patient education do we give to male patients of reproductive potential on ASMs? (2)

A
  • Potential risk
  • Need for effective contraception (including for female partner) WHILE USING valproate Tx and 3 months after stopping Tx
79
Q

What advice should we give to male patients of reproductive potential on ASMs (3)

A
  • Not to donate sperm during Tx and for 3 months after stopping the Tx
  • Consult his doctor to discuss alternative treatment options, as soon as he is planning to father a child, and before discontinuing contraception
  • He and his partner to contact the doctor in case of pregnancy if he used valproate within 3 months prior to conception
80
Q

Are ASMs C/I with lactation/ breastfeeding?

A
  • No
  • Studies have not indicated poorer
    outcome; breastfeeding mothers on ASM encouraged to continue breastfeeding
81
Q

Tx of status epilepticus in Stabilisation phase (0-5 min)?

A
  1. Stabilise patient (airway, breathing, circulation etc)
  2. Time seizure, monitor vital signs
  3. Assess oxygenation → give oxygen via nasal cannula/ mask/ consider intubation if respiratory assistance needed
  4. Initiate ECG monitoring
  5. Collect finger stick blood glucose → if glucose < 60 mg/dl then
    - Adults: 100mg thiamine IV then 50ml D50W IV
    - Children ≥ 2y: 2 ml/kg D25W IV
    - Children < 2y: 4 ml/kg D12.5W
  6. Attempt IV access, collect electrolytes, haematology, toxicology screen, anticonvulsant drug levels (if appropriate)
82
Q

Tx of status epilepticus in Initial Tx phase (5-20 min)?

A

Benzodiazepines as FIRST-LINE
Either one:
- IM midazolam (> 40kg: 10mg, 13-40kg: 5mg), single dose
- IV lorazepam (0.1mg/kg/dose, max 4 mg/dose), may repeat dose once
- IV diazepam (0.15-0.2mg/kg/dose, max 10mg/dose), may repeat dose once

If ALL 3 unavailable:
- IV phenobarbital (15mg/kg/dose), single dose
- Rectal diazepam (0.2-0.5mg/kg, max: 20mg/ dose, single dose
- Intranasal/ buccal midazolam

83
Q

Tx of status epilepticus in secondary therapy phase (20-40 min)?

A

No preferred Tx, choose any and give as single dose:
- IV phenytoin (20 mg PE/kg, max: 1500 mg PE/ dose, single dose)
- IV valproic acid (40 mg/kg, max: 3000 mg/dose, single dose)
- IV levetiracetam (60 mg/kg, max: 4500 mg/dose, single dose)

If none are available:
- IV phenobarbital (15mg/kg), max dose

84
Q

Tx of status epilepticus in third therapy phase (40-60 min)?

A

No clear evidence to guide Tx in this stage
Either:
- Repeat 2nd line Tx OR
- Give anaesthetic doses of thiopental/ midazolam/ pentobarbital/ propofol
ALL with continuous EEG monitoring

PR3153 (11 decks)

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