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3153 Seizure & Epilepsy > Pharmacologics for Seizure, PK, TDM > Flashcards

Pharmacologics for Seizure, PK, TDM Flashcards

1
Q

Background on excitatory synapses:

  • What are the excitatory receptors
  • How do they respond to excitatory neurotransmitter, glutamte
A

Receptors of Glutamate: NMDA, AMPA on postsynaptic membrane

  • NMDA responds to Glutamate by opening ion channels that permit entry of Calcium ions
  • AMPA responds to Glutamate by opening ion channels that permit entry of Sodium ions
  • low-voltage-activated calcium channels (t-type calcium channels) open in response to small depolarizations at or below RMP, to permit Calcium ion entry
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2
Q

Background on inhibitory synapses:

  • What are the inhibitory receptors
  • How do they respond to inhibitory neurotransmitter, GABA
A

Receptor of GABA: GABA-A on postsynaptic membrane

  • GABA-A responds to GABA by opening Cloride ions, that allow negatively charged chloride ions to enter the cell, hence hyperpolarizing the cell and inhibiting the signal
  • GABA reuptake through GABA-transporter-1 (GAT-1), then degraded by enzyme gamma-aminobutyric acid aminotransferase (GABA-T)
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3
Q

Name the 1st generation ASMs

A
  • Carbamazepine
  • Phenobarbital
  • Phenytoin
  • Sodium Valproate
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4
Q

Name the 2nd generation ASMs

A
  • Lamotrigine
  • Levetiracetam
  • ## Topiramate
  • Gabapentin
  • Pregablin
  • Oxcarbazepine
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5
Q

Treatment options for new onset focal onset epilepsy

A
  • Carbamazepine
  • Lamotrigine - caution in elderly
  • Levetiracetam

Less evidence:
- Sodium valproate, Oxcarbazepine, Phenytoin, Topiramate, Gabapentin - caution in elderly, Zonisamide

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6
Q

Adjunctive treatment options for focal onset epilepsy

A
  • Carbamazepine
  • Clobazam
  • Gabapentin
  • Lamotrigine
  • Levetiracetam
  • Oxcarbazepine
  • Sodium valproate
  • Topiramate
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7
Q

Treatment options for refractory focal onset epilepsy

A
  • Clobazam (Benzodiazepine)
  • Lacosamide
  • Pregabalin
  • Perampanel
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8
Q

Treatment options for new onset GTC epilepsy

A
  • Carbamazepine
  • Lamotrigine
  • Valproate

Less evidence:
- Topiramate
- Oxcarbazepine

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9
Q

Adjunctive reatment options for GTC epilepsy

A
  • Clobazam
  • Lamotrigine
  • Levetiracetam
  • Sodium valproate
  • Topiramate
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10
Q

Treatment options for refractory GTC epilepsy

A
  • Clobazam (Benzodiazepine)
  • Levetiracetam
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11
Q

Treatment options for absence seizures

A
  • Lamotrigine
  • Sodium Valproate
  • Ethosuximide
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12
Q

[Pharmacokinetics]

What aspects of ADME may be of concern with ASMs?

A

Absorption: dosage form
Distribution: protein binding (think about albumin status, DDI)
Metabolism/Elimination: hepatic/renal (think about dose adj in organ impairment)

Also concern with DDIs

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13
Q

[Pharmacokinetics]

Describe the protein binding of the 1st gen ASMs

A

Phenytoin: 90%
Valproate acid: 75-95%
Carbamazepine: 75-85%
Phenobarbital: 50%

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14
Q

[Pharmacokinetics]

Describe the elimination of the 1st gen ASMs (H/R)

A

Phenytoin: 100% Hepatic, non-linear
Valproate acid: 100% H
Carbamazepine: 100% H, autoinduction
Phenobarbital: 75% H

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15
Q

[Pharmacokinetics]

Half life of the1st gen ASMs

A

Phenytoin: 12-60h
Valproate acid: 6-18h
Carbamazepine: 6-15h
Phenobarbital: 72-124h

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16
Q

[Pharmacokinetics]

Of the four 1st gen ASMs, which are enzyme inducers and which are enzyme inhibitors

Name which CYPs

A

Enzyme inducers

  • Carbamazepine: CYP1A2, 2C, 3A4, UGTs
  • Phenytoin: CYP2C, 3A, UGTs
  • Phenobarbital: CYP1A, 2A6, 2B, 3A, UGTs

Enzyme inhibitor

  • Valproate acid: CYP2C9, UGT, PGP
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17
Q

[Pharmacokinetics]

2nd generation ASMs tend to have fewer DDIs because ______

Specifically, mention Lamotrigine, Levetiracetam, Topiramate

A

Mostly cleared renally

Hence, less propensity for CYP interactions in the liver

Lamotrigine: 100% H, few DDIs
Levetiracetam: <10% protein bound, 66% R, no DDIs
Topiramate: 30-55% R, DDIs (dose dependent)

Gabapentin, Pregabalin: no protein binding, 100%, 90% R, no DDIs
Clobazam: Protein binding 80-90%, 82% R, DDIs

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18
Q

[Pharmacokinetics]

CYP interactions of 2nd gen ASMs:

  • Gabapentin
  • Levetiracetam
  • Pregabalin
  • Topiramate
A

No effects on CYP:

  • Gabapentin (no protein binding)
  • Levetiracetam (<10% protein binding)
  • Pregabalin (no protein binding)

Moderate inducer of CYP3A4, moderate inhibitor of CYP2C19:

  • Topiramate
  • inducer effect typically for pt receiving dose of >200mg of Topiramate a day
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19
Q

[Pharmacokinetics]

Enzyme inducing ASMs have DDI with the following drug classes:

A
  • Antidepressants and antipsychotics
  • Immunosuppressive therapy
  • Antiretroviral therapy
  • Chemotherapeutic agents

Important to consider deinduction interactions when inducer ASM is discontinued => adjust dose of affected drug from supratherapeutic back to normal levels

20
Q

[Pharmacokinetics]

Enzyme inducing ASMs have interactions with the following states

A

Reproductive hormones, sexual function, oral contraception

  • Endocrine side effects
  • Inducers may directly affect hormone levels

Sexual function and fertility in men

  • Endocrine side effects

Bone health

  • Incr risk of osteopenia or osteoporosis if Vit D or calcium not supplemented
  • (Inr metabolism of Vit D => secondary hyperparathyroidism => incr bone turnover => reduce bone density)

Vascular risk

  • Effects on cholesterol metabolism
  • Potential interaction with statins (CYP3A4 substrates)
21
Q

[PK of Phenytoin]

What are the available dosage forms of Phenytoin?

A
  • Oral suspension (125mg/5ml): Phenytoin acid (100%)
  • Capsules (30mg, 100mg) (92%)
  • IV Phenytoin sodium (92%)

Phenytoin salt requires correction

22
Q

[PK of Phenytoin]

Bioavailability of Phenytoin

A
  • 95%, F ~ 1
  • Complete absorption but slow
  • Bioavailability reduces at higher doses >400mg/dose

=> Avoid giving big oral doses due to delayed absorption; advised to split up the dose if dose >400mg

23
Q

[PK of Phenytoin]

Interaction with enteral feeds?

A

Phenytoin is reduced interaction with enteral feeds

  • Recommended to space apart by 2h
24
Q

[PK of Phenytoin]

Volume of distribution, protein binding

A

Vd = 0.7L/kg
Protein binding: 90%

Highly albumin bound

  • Low albumin (hypoalbuminemia): increases free phenytoin levels
  • Protein binding can be altered by displacement by other drugs (e.g., valproate can displace phenytoin, resulting in higher levels of free phenytoin)
  • Uremia (in renal impairment): decrease protein binding
25
Q

[PK of Phenytoin]

Most labs measure total (bound + unbound) phenytoin, however only the unbound phenytoin is biologically action and can exert pharmacologic effect.

How to determine unbound conc. of phenytoin from total conc.?

A

Winter-Tozer equation used for phenytoin correction for albumin <40g/L

C(corrected) = C(observed) / [x . (Alb/10) + 0.1]

Where X = 0.275 in CrCl >= 10ml/min,
X = 0.2 in CrCl <10ml/min on hemodialysis

C is in mg/L; Alb is in g/L

26
Q

[PK of Phenytoin]

Phenytoin follows ______ PK and ______ order kinetics

A

Phenytoin

  • Non-linear PK
  • Zero-order kinetics (saturation kinetics)

Additionally, it has narrow therapeutic range (40-100um)

27
Q

[PK of Phenytoin]

Describe the clearance of phenytoin

A

Capacity limited clearance

  • Clearance is dependent on concentration, because metabolic enzymes get saturated
  • Clearance will decrease with increasing concentration, clearance is not constant
  • Clearance is inversely related to concentration

=> Concentration increment is NOT proportional to dose increment
=> Rate of elimination is not concentration dependent, it is constant

28
Q

[PK of Phenytoin]

Due to the non-linear PK of phenytoin, what dose considerations should be made?

A
  • Dose adjustments made in small increments
  • Necessitates regular monitoring of plasma concentrations
  • Consider loading dose, since steady state may take quite long to be established
  • Requires dose adjustment in renal impairment
29
Q

[PK of Valproate]

Available dosage forms

A
  • Injection (400mg/vial)
  • Enteric-coated tablets (200mg)
  • Sustained-release tablets (Chrono 200mg, 300mg, 500mg)
  • Syrup (200mg/5ml)
30
Q

[PK of Valproate]

Bioavailability

A

100%, F ~1

31
Q

[PK of Valproate]

Volume of distribution, protein binding

Problems a/w protein binding

A

Vd: 0.15L/kd

Protein binding: 75-95% (highly albumin bound)

  • DDI (competition for binding): Phenytoin, Warfarin, NSAIDs
  • May get displaced by endogenous compounds (uremia, hyperbilirubinemia) which would increase free valproate concentrations
32
Q

[PK of Valproate]

Describe valproate protein binding characteristics

A

Saturable protein binding within therapeutic range

  • decreased protein binding at higher conc.
  • higher free fraction of drug with low albumin

=> Pt with hypoalbuminemia will have higher free fraction of valproate

In contrast to saturable metabolic enzymes with Phenytoin => decreased clearance at higher conc.

33
Q

[PK of Carbamazepine]

Available dosage forms

A
  • Immediate-release tablets (200mg)
  • Controlled-release CR tablets (200mg, 400mg)
34
Q

[PK of Carbamazepine]

Bioavailability

A

80%, F = 0.8

35
Q

[PK of Carbamazepine]

Protein-binding

Volume of distribution

A

Highly protein bound: 75-85%

  • Bound to albumin and alpha 1-acid glycoprotein

Vd = 1.4L/kg

36
Q

[PK of Carbamazepine]

Metabolism of Cabramazepine

  • What’s special about it, and what’s the implication of this
A

Metabolized by CYP3A4 >99%

  • 30+ metabolites
  • Active metabolite: Carbamazepine-10,11-epoxide

Autoinduction

  • Carbamazepine induces its own metabolism via CYP3A4
  • Clearance increases and half-life shortens (35h to 20h), CBZ concentration declines
  • Maximal autoinduction occurs in 2-3 weeks after dose initiation

=> IMPLICATION: do not start with desired maintenance dose, gradually increase over the initial few weeks

37
Q

[PK of Benzodiazepine] (IC4)

List examples of short-acting, intermediate-acting, and long-acting BZDs. How long are their durations of action?

A

Short-acting:

  • Midazolam, Triazolam
  • 3-8h
  • Not commonly used as Epilepsy is chronic, not acute; moreover, short-acting BZDs require repeated dosing

Intermediate-acting:

  • Clonazepam, Lorazepam
  • 10-20h

Long-acting:

  • Diazepam, Clobazam
  • 1-3 days
  • Faster onset, longer half-life
38
Q

[PK of Benzodiazepine] (IC4)

BZDs are the initial therapy of choice for _________

A

Status epilepticus

39
Q

[PK of Barbiturates]

List examples of ultra-short-acting, short-acting, and long-acting barbiturates. How long are their durations of action?

A

Ultra-short acting: 20min

  • IV induction of anesthesia (e.g., thiopental)

Short-acting: 3-8h

  • Sedative, hypnotic (e.g., pentobarbital, amobarbital)

Long-acting 1-2 days

  • Anticonvulsant (e.g., Phenobarbital)
40
Q

[PK of Lamotrigine]

Half-life of lamotrigine

A
  • Generally shorter in children - require more frequent dosing
  • Significantly reduced by coadministration with carbamazepine and phenytoin (inducers)
  • Significantly increased by coadministration with valproate (inhibitor)
41
Q

[PK of Topiramate]

A
  • Long plasma half life
  • Predominantly renally cleared
  • NOT a potent inducer of drug metabolizing enzymes
42
Q

[TDM for ASM]

Why might TDM be needed for ASMs?

A
  1. Plasma ASM concentration (rather than dose) correlate better with clinical effects
  2. Assessment of therapeutic response is difficult bc 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. Not easy to recognize signs of toxicity
  4. ASMs subjected to substantial PK variability; patients require large differences in dosage
  5. No lab markers for clinical efficacy or toxicity of ASMs
43
Q

[TDM for ASM]

ASM is used to:

A
  1. Establish individual’s therapeutic range
  • May not be within reference range, as long as at an effective level which controls seizures and minimizes side effects
  1. Assess lack of efficacy
  • E.g., fast metabolizer of the drug, adherence issue
  1. Assess potential toxicity
  • E.g., slow metabolizer of the drug, disease (hypoalbuminemia, liver impairment, uremia), DDIs, concentration-dependent adverse effects
  1. Assess loss of efficacy (breakthrough seizures)
  • E.g., changes in physiology (age, pregnancy), changes in pathology, changed formation (brand, dosage form), DDIs
44
Q

[TDM for ASM]

What information is required for TDM of ASMs?

A
  • Indication for ASM (diagnosis)
  • Dose (when, how long, how much)
  • Sample (when to draw - Ctrough better parameter to assess maintenance dose adequacy)
  • Clinical condition (current seizure control, comorbidities)
  • Other lab values
  • Other drugs (when, how long, how much)
45
Q

[TDM for ASM]

Reference range for:

  • Phenytoin
  • Valproate
  • Carbamazepine
  • Phenobarbital
A
  • Phenytoin: 10-20mg/L
  • Valproate: 50-100mg/L
  • Carbamazepine: 4-12mg/L
  • Phenobarbital: 15-40mg/L
46
Q

[TDM for ASM]

Is TDM routinely required?

A

No

But for phenytoin titration (due to non-linear PK and narrow therapeutic index, may be required)

3153 Seizure & Epilepsy (13 decks)

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