The importance of lipid solubility in membrane permeation

Routes by which solutes can traverse cell membranes

Theoretical partition of a weak acid (aspirin) and a weak base (pethidine) between aqueous compartments (urine, plasma and gastric juice) according to the pH difference between them.

The effect of urinary pH on drug excretion

The main routes of drug administration and elimination

The two phases of drug metabolism

Stimulation of hepatic metabolism of benzpyrene

The glucuronide conjugation reaction

Predicted behaviour of single-compartment model with continuous or intermittent drug administration

To achieve a steady state plasma concentration (Css)

Drug entry = Drug exitDosing rate = Excretion rateDosing rate = Css x Clearance Dosing rate = Css x (ke x Vd)/FDosing rate = Css x (0.693 x Vd)/F

t1/2 = 0.693 x Vd/Clearance = 0.693/ke

t1/2

Clearance = Vd x keke = 0.693/ t1/2

Drug T needs to be given intravenously:Clearance = 70 ml/minDesired plasma concentration = 3 mg/L

Maintaenance dose = ?????

Dosing rate = Clearance x Desired plasma concentration/F

Dosing rate = 70 ml/min/1000 x 3 mg/L = 0.21 mg/min

Multiple Doses

Drug T needs to be given intravenously every 5 hours:Clearance = 70 ml/minDesired plasma concentration = 3 mg/L

Dosing rate = Cl x Css x Dosing interval /F

Dosing rate = 70 ml/min/1000 x 3 mg/L x (5hr) = 70 ml/min/1000 x 3 mg/L x (300 min) = 63 mg every 5 hours

Loading dose = ??????

Vd = 50 LDesired plasma concentration = 3 mg/L

Loading dose = Vd x Desired plasma concentration = 3mg/L x 50L = 150 mg

Note: LD = 1.44 x Css x Vd (more accurate calculation) F

First Order KineticsRate of elimination is directly proportional to the drug cocentrationdC/dt α C dC/dt = -ke x C

Time

Cp

Time

Log Cp

)C1, t1(

)C2, t2(

C1 = C2 x e ke x tC2 = C1 x e -ke x t

t = t2 - t1

A patient’s acetaminophen level at 2:00 PM is 86.2 μg/mlat 6:00 PM the same day is 27.8 μg/mlke = 0.283 h-1

What was the level at 10:00 AM?

C1 = C2 x e ke x t

C1 = 86.2 x e 0.283 x 4

C1 = 267.3 μg/ml

A patient’s acetaminophen level at 2:00 PM is 86.2 μg/mlat 6:00 PM the same day is 27.8 μg/ml

What is Ke?

C1 = C2 x e ke x t C1 = e ke x t

C2

ln C1 = ke x t C2

ln 86.2 = ke x 4 27.8ke = 0.283 h-1

A patient’s acetaminophen level at 9:00 AM is 250 μg/ml. What is the level at 5:00 PM the same day? (C2 = C1 x e -ke x t )

ke = 0.283 h-1

A. 27 μg/mlB. 26 μg/mlC. 252 μg/mlD. 28 μg/ml

If the t1/2 of drug T is 6 hrs. What would u expect the t1/2 of drug T to be in a patient with kidney failure?

A. < 6 hrsB. > 6 hrsC. = 6 hrsD. non of the above

Which of the following statements is CORRECT?

A. Weak bases are absorbed efficiently across the epithelial cells of the stomachB. Potency of a drug may be reduced if the drug is ionized at physiologic pHC. Alkalinization of the urine enhances the exretion of weak bases D. All of the above

The addition of glucuronic acid to a drug A. decreases the polar nature of the drugB. increases the rate of excretion of the drug C. is an example of a Phase 1 reaction D. involves cytochrome P-450

A drug, given as a 100 mg single dose, resultsin a peak plasma concentration of 20 µg/ml. The Vd is: A. 0.5 LB. 1 LC. 2 L D. 5 L

Drugs showing zero-order kinetics of elimination A. decrease in concentration exponentially with timeB. show a plot of drug concentration versus time that is linearC. show a constant fraction of the drug eliminated per unit timeD. Non of the above

Which of the following statements is CORRECT for a drug whose elimination from plasma shows first-order kinetics? A. The t1/2 of the drug is proportional to the drug conc.B. The amount eliminated per unit time is constant.C. The rate of elimination is proportional to the CpD. A plot of drug concentration versus time is a straight line

If the Vd for the drug is small. This means that:

A. most of the drug is in the extraplasmic spaceB. higher dose can be tolerated C. most of the drug is in the plasmaD. B & C

Induction of hepatic metabolizing enzymes

A. results in an increase in a drug t1/2B. results in a decrease in the rate of cyt P450 synthesisC. leads to drug tolerance and the dosage may need to be increasedD. All of the above

Assume that a drug has a t1/2 of 6 hrs. How long will ittake for 87.5% of the drug to be cleared from the body?

A. 6 hrsB. 12 hrsC. 18 hrsD. 24 hrsc

All of the following statements are correct EXCEPT?

A. Drugs with low partition coefficient are likely to to distribute in the plasmaB. The more lipophilic a drug is, the lower is its partition coefficientC. Drugs with high partition coefficient will distribute in the adipose tissueD. A & C