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Practice problems Multiple Dosing

1.

A drug has a clearance of 5.0 L/hr. and a volume of distribution of 15L. The

half-life is 2 hours. A constant-rate infusion of 50 mg/hr. is started and infused for

12 hours. It is then discontinued. On the graph below, sketch the

concentration-time curve you would expect to see from t=0 to t=24 hours. (You

should not need your calculator to draw this graph).

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2.

Butler et al. showed that after the oral administration of phenobarbital (Pb) to man,

plasma levels of Pb were still rising after 12 days on a fixed dosage regimen. The

following steady state plasma levels were observed after prolongedadministration

of 65 mg t.i.d. to various subjects:

Body weight

Plateau level (mg/L)

Patient

(kg)

tl/2* (days)

observed

1

67

6.3

33

2

74

4.1

21

3

64

4.3

18

4

64

5.3

32

5

94

6.3

25

calculated

Assuming Pb is completely absorbed into the systemic circulation and given that the

volume of distribution of Pb is equivalent to 75% of body weight, calculate the expected

plateau levels for any two of the five subjects. Comment on the predicted versus observed

results.

*Determined upon cessation of therapy.

3.

Gentamicin is an antibiotic used for the treatment of a number of microorganisms

particularly E. coli and Pseudomonas. The compound is given either IV. or IM.,

with absorption from the I.M. site both complete and very rapid. The volume of

distribution is about 0.3 liter/kg body weight. The half-life of the compound is

about 2 hours in a person with normal kidney function. What would be the

maximum and minimum steady-state levels of gentamicin in a person given a

dose of 1.5 mg/kg every eight hours either by intermittent IV or IM. therapy?

Assume the person is a standard 70 kg adult.

4.

Chlorpropamide, an oral hypoglycemic agent, is administered once daily to a

patient in whom it has a half-life of 36 hours. The dose is 250 mg, and it is

completely absorbed into the systemic circulation.

a. What will be the average amount in the body at plateau?

b. What is the accumulation ratio?

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5.

The following data were obtained after the intravenous administration of sodium

warfarin, 1.5 mg/Kg, to an adult subject :

Plasma warfarin

Time (days)

concentration (µg/ml)

1

11.0

2

8.2

3

6.4

4

4.3

5

3.5

6

2.3

7

1.8

a. Graphically estimate the half-life of the drug.

b. Estimate the volume of distribution in this individual in L/kg.

c. An initial oral dose of 50 mg was then given to this patient and oral maintenance therapy

was continued with a daily dose of 7.5 mg. The subject weighs 70 kg. What would be

the average concentration of warfarin in the plasma at plateau if the drug is completely

bioavailable?

6.

Administration of 1.5 mg/kg of gentamicin, IM., results in an area under the plasma

concentration time curve of 25.2 mg-hr./liter in normal subjects. What would be

the maximum and minimum plasma concentrations of this drug atsteady-state in

a patient of average body weight and normal renal function receiving 1.5 mg/kg

q8h? The half-life for gentamicin averages 2.8 hours.

7.

Calculate a suitable dosage regimen (LD, MD and ) for an 80 kg patient who is to

be put on chronic procainamide therapy. The desired range of plasma

concentrations is from 4 to 8 µg/ml. The drug is rapidly and completely absorbed.

Half-life = 3.0 hours

V = 2.0 liters/kg

8.

Administration of 0.4 mg/kg t.i.d. of nortriptyline gave rise to an average steadystate level of 111 ng/ml in plasma. Upon cessation of therapy, the half-life

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was found to be 32 hours. A separate study has shown that approximately 65% of

each oral dose is bioavailable. Assuming this applies to this patient as well:

a. Calculate the volume of distribution of this drug in this patient, in L/kg, and

b. Estimate the accumulation ratio.

9.

A study involving 12 normal adults gave rise to the following parameters for

clindamycin after single oral doses of 150 mg:

V/F

53.9 L

K

0.231 hr-1

Estimate the maximum and minimum plasma concentration that would be observed at

steady state if one of these subjects were to take 300 mg of this drug q 6 h.

10.

Study Questions Chapter 11 Rowland and Tozer

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