APPLIED PK: Exam 1

1st gen ASMs

Carbamazepine

Phenytoin (Special MOAs)

Valproic Acid

2nd Gen ASMs

Lamotrigine

Levetiracetam

IV ASMs

Phenytoin (Dilantin)

Fosphenytoin (Cerebryx)

Levetiracetam (Keppra)

Phenytoin dosage (loading + maintenance)

Loading → IV: 20mg/kg (max 1,500 mg)

Maintenance → PO: 300 mg QHS

Fosphenytoin dosage (loading + maintenance)

Loading: 20 PE/kg (max 1,500 mg)

Maintenance: N/A

Levetiracetam dosage (loading + maintenance)

Loading: IV 60 mg/kg (max 4,500 mg)

Maintenance: PO 1,000-1,500 mg BID

_ will precipitate out of solution in 1-2 hours. Must use within 1 hour.

Phenytoin IV

_ is dosed as phenytoin equivalents (PE) to make dosing interchangeable with phenytoin

Fosphenytoin

Which side effect of occurs with IV loading with phenytoin but is much less likely to occur with FOSphenytoin IV loading amd why?

Purple glove syndrome occurs with IV loading with phenytoin, but is much less likely to occur with fosphenytoin loading because propylene glycol does not need to be added to fosphenytoin solution for IV administration

What kind of monitoring is required if phenytoin is intravenously loaded?

Close BP monitoring (hypotension) and ECG monitoring (arrythmias)

Rate of Fosphenytoin IV administraion

150 mg/min

Rate of Phenytoin IV admin

50 mg/min

T/F: Phenytoin administered with tube feeds increases the absorption of phenytoin in the gut

F → reduces

Must stop tube feeds ~_ hours prior and ~_ hours after phenytoin administration

2

What is the total and free therapeutic window for Phenytoin/Fosphenytoin?

Total: 10-20 mg/L

Free: 1-2 mg/L

In normal individuals, phenytoin is _% protein bound

In patients with low protein status there is less <_% protein binding

90

90

T/F: Only bound phenytoin is pharmacologically active

F → Free phenytoin

FM was IV loaded with phenytoin and started on an appropriate NG phenytoin maintenance dose. His vitals and labs remain as above. His phenytoin trough level comes back at 9 mg/L. The doctors request your assessment and recommendation regarding his phenytoin therapy. Which Winter-Tozer equation is the most appropriate to use?

Corrected PHT (mg/mL) = Observed total PHT (mg/L)/ (0.1 x albumin [g/dL]) + 0.1

9/(0.1×2.5) + 0.1. = 25.7

ASMs: Broad Spectrum Inducers

Carbamazepine

Phenytoin

Phenobarbital

Selective CYP3A Inducers

Topiramate (TPM) at high doses (>200 mg/day)

Oxcarbazepine (OXC) at high doses (>900-1200 mg/day)

Broad Spectrum Inhibitor

Valproic Acid (VPA)

Inducers increases CYP or UGT enzyme activity

• Increases OR decreases: Clearance of other drugs metabolized by CYP or UGT

• Increases OR decreases: Levels of other drugs metabolized by CYP or UGT

Increases

Decreases

What is the DDI b/w CBZ + PHT?

CBZ increases clearance of PHT via CYP2C9/2C19 induction

PHT increases clearance of CBZ via CYP2C9/2C19 induction

Can cause subtherapeutic levels → Breakthrough seizures

What is the DDI b/w Lamotrigine + PHT?

PHT increases clearance of LTG via UGT induction

Can cause LTG subtherapeutic levels → Breakthrough seizures

What is the DDI b/w VPA + PHT?

VPA decreases clearance of PHT via CYP inhibition

Causes supra-therapeutic PHT levels → toxicity

What is the DDI b/w VPA + LTG?

VPA decreases clearance of PHT via UGT inhibition

Causes supra-therapeutic PHT levels → toxicity (e.g. rash/SJS)

What ASM requires dose adjustment in patients with renal disease?

Levetiracetam

T/F: Phenytoin has linear elimination.

F → Non-linear elimination

T/F: Elimination rate of phenytoin decreases at higher doses

T

T/F: A small change in PHT dose can lead to a large increase in phenytoin levels

T

Typical phenytoin dose is _mg daily.

Capsules are available in _mg and _mg.

300

30, 100

What your body does to a drug

PK

What the drug does to your body

PD

_ are antifungals used to treat a variety of fungal infections

Triazoles

Anticoagulation (apixaban, aspirin, clopidogrel) Case:

DDI

MOA

PLAN

DDI: Pharmacodynamic

MOA: Decreases risk for thrombosis but all increase bleeding risk when used together

PLAN: D/C Aspirin, Use Clopidogrel b/c data suggests you do not lose efficacy D/C aspirin

Anti-seizure medication (lamotrigine, oral contraceptive pills) Case:

DDI

MOA

PLAN

DDI → PK

MOA → Oral contraceptive pills decrease lamotrigine levels via UGT1A4 induction

PLAN →

This is likely a shared decision making situation that involves seeing what the patient would be comfortable with:

a. Continue as planned and accept the risk of having a breakthrough seizure

b. Increasing lamotrigine dose and still having a risk of breakthrough seizure (if dose increase insufficient) or increasing risk for lamotrigine adverse effects

c. Switching birth control to a medication that is either continuous with no placebo week while adjusting the lamotrigine dose or picking a non-oral contraceptive (e.g., IUD)

d. Measure lamotrigine levels prior to starting Yaz to establish a baseline, then check levels after initiation and titrate lamotrigine dose to achieve

Antimicrobials (posaconazole, rivaroxaban) Case:

DDI

MOA

PLAN

DDI → PK

MOA → Posaconazole is a relatively potent CYP3A4 inhibitor while rivaroxaban is a CYP3A4 substrate → Increased Rivaroxaban lvls → Bleeding

PLAN → Switch one of these agents to minimize the risk of bleeding → May switch Posaconazole w/ Isavuconazole

Anti-seizure medications (topiramate, oral contraceptive pills) Case:

DDI

MOA

PLAN

DDI → PK

MOA → Topiramate induces CYP3A4 metabolism, leading to faster metabolism of the hormones in birth control pills

PLAN → Let the patient know that there is a minor interaction with oral contraceptives and topiramate but at her dose of topiramate it should not be an issue to proceed.

Digoxin reversal agent

Digifab

Digifab indication

Life-threatening situations or large acute ingestions

T/F: Digifab reversibly binds to Digoxin

F → Irreversibly

Digoxin levels cannot be measured for _ after Digifab administration

Weeks

In Digifab, monitor for resolution of [] and [] A.E

Arrhythmias

G.I

Digoxin target levels w/ A.F

<1.2 mcg/L

Digoxin target levels w/ H.F

0.5-0.8 mcg/L

Optimal time to measure Digoxin lvls after administration

At least 6-12 hrs

12-24 hrs: Optimal

Optimal time to measure Digoxin lvls after administration w/o loading dose

3-5 days

T/F: Digifab dose is based on whether digoxin dose is known and timing of toxicity

T

Factors that would increase digoxin levels

Verapamil

Amiodarone

Quinidine

Hypothyroidism

Renal dysfunction (increase Scr.)

Heart failure

Factors that would decrease digoxin levels

Hyperthyrodism (decreased TSH)

Digifab acute unknown dose

10-20 vials and monitor closely

Digifab acute known dose

Digoxin load in mg / 0.5 mg digoxin bound per vial

Digifab chronic unkown dose

6 vials and monitor closely

Digifab chronic known dose

(Digoxin SS level x wt) / 100

Toxic effects of Digoxin are more likely at levels > _mcg/L in all pts

2

What are the toxic S.E of Digoxin?

• N/V, Diarrhea

• Brady/tachy cardia, EKG changes, hyperkalemia

• Visual s/x: Blurred vision, color changes, yellow

Increased mortality in HF pts with levels > _ mcg/L

1

What is Digoxin’s Vd?

2 compartment model

Initially distributes to plasma and other rapidly equilibrating tissues

Then distributes to more slowly equilibrating tissue

Digoxin usual dosing

0.125-0.25 mg

Lidocaine usual dosing

Bolus 1-1.5 mg/kg followed by continous infusion of 1-4 mg/min

Lidocaine PK can be altered by:

• Heart failure

• Liver dysfunction

• Critical illness

• Concur

• Severe trauma

• Concurrent methods

Lidocaine therapeutic concentrations

1-5 mg/L

Minor CNS effects of Lidocaine can be seen at _-_mg/L

3-5

Seizures of Lidocaine have been seen at >_mg/L

9

Calculate bolus dose (LD) using _

Calculate total dose using _

Vi

Vd

Vd of Lidocaine decreased with _

CHF

Severe trauma and critically ill

Higher lidocaine levels!

Vd of Lidocaine increased with _

Chronic liver disease

Lower lidocaine levels!

Lidocaine sampling time

4-8 after therapy

T/F: Lidocaine requires no renal adjustment

T

T/F: Lidocaine has a high first-pass effect

T