Pharmacologics for Seizure, PK, TDM Flashcards
Background on excitatory synapses:
- What are the excitatory receptors
- How do they respond to excitatory neurotransmitter, glutamte
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
Background on inhibitory synapses:
- What are the inhibitory receptors
- How do they respond to inhibitory neurotransmitter, GABA
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)
Name the 1st generation ASMs
- Carbamazepine
- Phenobarbital
- Phenytoin
- Sodium Valproate
Name the 2nd generation ASMs
- Lamotrigine
- Levetiracetam
- ## Topiramate
- Gabapentin
- Pregablin
- Oxcarbazepine
Treatment options for new onset focal onset epilepsy
- Carbamazepine
- Lamotrigine - caution in elderly
- Levetiracetam
Less evidence:
- Sodium valproate, Oxcarbazepine, Phenytoin, Topiramate, Gabapentin - caution in elderly, Zonisamide
Adjunctive treatment options for focal onset epilepsy
- Carbamazepine
- Clobazam
- Gabapentin
- Lamotrigine
- Levetiracetam
- Oxcarbazepine
- Sodium valproate
- Topiramate
Treatment options for refractory focal onset epilepsy
- Clobazam (Benzodiazepine)
- Lacosamide
- Pregabalin
- Perampanel
Treatment options for new onset GTC epilepsy
- Carbamazepine
- Lamotrigine
- Valproate
Less evidence:
- Topiramate
- Oxcarbazepine
Adjunctive reatment options for GTC epilepsy
- Clobazam
- Lamotrigine
- Levetiracetam
- Sodium valproate
- Topiramate
Treatment options for refractory GTC epilepsy
- Clobazam (Benzodiazepine)
- Levetiracetam
Treatment options for absence seizures
- Lamotrigine
- Sodium Valproate
- Ethosuximide
[Pharmacokinetics]
What aspects of ADME may be of concern with ASMs?
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
[Pharmacokinetics]
Describe the protein binding of the 1st gen ASMs
Phenytoin: 90%
Valproate acid: 75-95%
Carbamazepine: 75-85%
Phenobarbital: 50%
[Pharmacokinetics]
Describe the elimination of the 1st gen ASMs (H/R)
Phenytoin: 100% Hepatic, non-linear
Valproate acid: 100% H
Carbamazepine: 100% H, autoinduction
Phenobarbital: 75% H
[Pharmacokinetics]
Half life of the1st gen ASMs
Phenytoin: 12-60h
Valproate acid: 6-18h
Carbamazepine: 6-15h
Phenobarbital: 72-124h
[Pharmacokinetics]
Of the four 1st gen ASMs, which are enzyme inducers and which are enzyme inhibitors
Name which CYPs
Enzyme inducers
- Carbamazepine: CYP1A2, 2C, 3A4, UGTs
- Phenytoin: CYP2C, 3A, UGTs
- Phenobarbital: CYP1A, 2A6, 2B, 3A, UGTs
Enzyme inhibitor
- Valproate acid: CYP2C9, UGT, PGP
[Pharmacokinetics]
2nd generation ASMs tend to have fewer DDIs because ______
Specifically, mention Lamotrigine, Levetiracetam, Topiramate
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
[Pharmacokinetics]
CYP interactions of 2nd gen ASMs:
- Gabapentin
- Levetiracetam
- Pregabalin
- Topiramate
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
[Pharmacokinetics]
Enzyme inducing ASMs have DDI with the following drug classes:
- 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
[Pharmacokinetics]
Enzyme inducing ASMs have interactions with the following states
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)
[PK of Phenytoin]
What are the available dosage forms of Phenytoin?
- Oral suspension (125mg/5ml): Phenytoin acid (100%)
- Capsules (30mg, 100mg) (92%)
- IV Phenytoin sodium (92%)
Phenytoin salt requires correction
[PK of Phenytoin]
Bioavailability of Phenytoin
- 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
[PK of Phenytoin]
Interaction with enteral feeds?
Phenytoin is reduced interaction with enteral feeds
- Recommended to space apart by 2h
[PK of Phenytoin]
Volume of distribution, protein binding
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
[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.?
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
[PK of Phenytoin]
Phenytoin follows ______ PK and ______ order kinetics
Phenytoin
- Non-linear PK
- Zero-order kinetics (saturation kinetics)
Additionally, it has narrow therapeutic range (40-100um)
[PK of Phenytoin]
Describe the clearance of phenytoin
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
[PK of Phenytoin]
Due to the non-linear PK of phenytoin, what dose considerations should be made?
- 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
[PK of Valproate]
Available dosage forms
- Injection (400mg/vial)
- Enteric-coated tablets (200mg)
- Sustained-release tablets (Chrono 200mg, 300mg, 500mg)
- Syrup (200mg/5ml)
[PK of Valproate]
Bioavailability
100%, F ~1
[PK of Valproate]
Volume of distribution, protein binding
Problems a/w protein binding
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
[PK of Valproate]
Describe valproate protein binding characteristics
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.
[PK of Carbamazepine]
Available dosage forms
- Immediate-release tablets (200mg)
- Controlled-release CR tablets (200mg, 400mg)
[PK of Carbamazepine]
Bioavailability
80%, F = 0.8
[PK of Carbamazepine]
Protein-binding
Volume of distribution
Highly protein bound: 75-85%
- Bound to albumin and alpha 1-acid glycoprotein
Vd = 1.4L/kg
[PK of Carbamazepine]
Metabolism of Cabramazepine
- What’s special about it, and what’s the implication of this
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
[PK of Benzodiazepine] (IC4)
List examples of short-acting, intermediate-acting, and long-acting BZDs. How long are their durations of action?
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
[PK of Benzodiazepine] (IC4)
BZDs are the initial therapy of choice for _________
Status epilepticus
[PK of Barbiturates]
List examples of ultra-short-acting, short-acting, and long-acting barbiturates. How long are their durations of action?
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)
[PK of Lamotrigine]
Half-life of lamotrigine
- Generally shorter in children - require more frequent dosing
- Significantly reduced by coadministration with carbamazepine and phenytoin (inducers)
- Significantly increased by coadministration with valproate (inhibitor)
[PK of Topiramate]
- Long plasma half life
- Predominantly renally cleared
- NOT a potent inducer of drug metabolizing enzymes
[TDM for ASM]
Why might TDM be needed for ASMs?
- Plasma ASM concentration (rather than dose) correlate better with clinical effects
- 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
- Not easy to recognize signs of toxicity
- ASMs subjected to substantial PK variability; patients require large differences in dosage
- No lab markers for clinical efficacy or toxicity of ASMs
[TDM for ASM]
ASM is used to:
- 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
- Assess lack of efficacy
- E.g., fast metabolizer of the drug, adherence issue
- Assess potential toxicity
- E.g., slow metabolizer of the drug, disease (hypoalbuminemia, liver impairment, uremia), DDIs, concentration-dependent adverse effects
- Assess loss of efficacy (breakthrough seizures)
- E.g., changes in physiology (age, pregnancy), changes in pathology, changed formation (brand, dosage form), DDIs
[TDM for ASM]
What information is required for TDM of ASMs?
- 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)
[TDM for ASM]
Reference range for:
- Phenytoin
- Valproate
- Carbamazepine
- Phenobarbital
- Phenytoin: 10-20mg/L
- Valproate: 50-100mg/L
- Carbamazepine: 4-12mg/L
- Phenobarbital: 15-40mg/L
[TDM for ASM]
Is TDM routinely required?
No
But for phenytoin titration (due to non-linear PK and narrow therapeutic index, may be required)
