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Tutorial

- Two Case Studies to underscore concepts in PK and ADME


- Go over three exam style questions:
Formulas for Cases:

C = Dose
Vd

t1/2 = 0.693
ke

Cl = Vd x ke

For constant infusion rate of drug:

Cp = R = R
Vd x ke Cl
C = plasma concentration of drug

Vd = apparent volume of distribution of drug

t1/2 = elimination half-life of drug

ke = elimination rate constant of drug

Cl = body clearance of drug

Cp = plasma concentration of drug at steady-state (plateau)

R = infusion rate of drug

Cp* = average plasma concentration of drug at steady-state (plateau)

D = individual dose of drug

T = dosage interval

B = oral bioavailability
Case 1

A 55-year-old, 70-kg male patient, with normal renal and hepatic


function, develops ventricular arrhythmia (VA) associated with his acute
myocardial infarction. You have decided to treat the patient’s VA with
procainamide (P), a class 1 sodium-channel-blocking antiarrhythmic
agent:
- Vd, 2.0 L/kg body weight;
- elimination t1/2, 4 hr;
- therapeutic plasma drug concentration range, 4 - 8 mg/L.
- recommended maintenance intravenous (i.v.) infusion rate of P is
30 µg/min/kg body weight.
1.(b) How long would it take to reach the steady-state plasma P
concentration?
2. Is this time lag to steady-state plasma Procainamide
concentration too long?

What alternate drug regimen would you consider?


3) Calculate the loading dose of procainamide
A loading dose is not enough – we also need a maintenance dose
Cp = R = R
t1/2 = 0.693
Vd x ke Cl
ke

Vd = 2 L/kg bw t1/2 = 4 hr Patient weighs 70 kg


Case 2

You are monitoring a 77-year-old woman with chronic kidney


disease (CKD) secondary to poorly controlled diabetes. Her
baseline serum creatinine is 250. She also has atrial fibrillation
and has been on a stable warfarin dose with usual INR values
of 2.2 to 2.5. You prescribe fluconazole, in the recommended dose,
for her persistent toenail infection. Later the patient develops severe
flank pain and presents to the emergency room. She is found to be
anaemic with an INR of 7, and has bruising over her left flank. A CT
abdominal scan subsequently demonstrates a retroperitoneal
haematoma.
What is INR?

If you are taking an anticoagulant drug, your doctor will check your
PT/INR regularly to make sure that your prescription is working
properly and that your PT/INR is appropriately prolonged.

Most laboratories report PT results that have been adjusted to the


International Normalized Ratio (INR) for patients on anticoagulant
drugs. These patients should have an INR of 2.0 to 3.0 for basic
"blood-thinning" needs. For some patients who have a high risk of
clot formation, the INR needs to be higher - about 2.5 to 3.5.
Questions
(1) What does the patient’s blood creatinine value tell you?
(Normal clinical range is about 45-90 μmol/L)

(2) What would you estimate her creatinine clearance values to be


(relative to normal)?

(3) What effect might this have on drug excretion?


Case 2, Questions cont’d

(4) What caused the elevation in the patient’s INR and why?

(5) Why was this patient at increased risk of this adverse event?
Case 2, Question cont’d

(5) What would have been more appropriate management of this


patient if medications for both conditions were needed
simultaneously?
Case 2, Questions cont’d

(6) How would you adjust the dosages of the drugs and would any
additional laboratory investigations be needed?