Module 1 Section 3 (Clinical Pharmacokinetics)

Question 1

What is the goal of clinical pharmacokinetics?

Answer 1

The goal of clinical pharmacokinetics is to determine a dosage regimen that provides optimal drug therapy for an individual. That is, the drug concentration is in the therapeutic range and it produces minimal adverse effects.

Question 2

What is the apparent volume of distribution?

Answer 2

The volume in which a drug appears to be distributed is called the apparent volume of distribution (Vd).

Question 3

What is the volume of Vd?

Answer 3

Vd = the total amount of drug in the body divided by the concentration of drug in the plasma.

Vd = dose of drug/ [drug in plasma]

Question 4

What is the total body water for a healthy 70kg person?
- Total body water = ___
- Intracellular fluid = ___
- Extracellular fluid = ___
• Intravascular fluid (plasma water; blood) = ___
• Interstitial fluid (small spaces in tissue) = ___

Answer 4

What is the total body water for a healthy 70kg person?
- Total body water = 42L (0.6L/kg body weight)
- Intracellular fluid = 28L
- Extracellular fluid = 14L
• Intravascular fluid (plasma water; blood) = 3L
• Interstitial fluid (small spaces in tissue) = 11L

Question 5

What is a possible explanation for a calculated Vd of less than 14L in a 70kg person?

a) The drug is only in the intracellular fluid
b) The drug may be bound to plasma protein
c) The drug is only in the total body water
d) The drug has accumulated in extravascular storage depots, such as fat

Answer 5

b) The drug may be bound to plasma protein

If the Vd is less than 14L, then the concentration of drug in the plasma is greater than expected. This would occur when a drug is bound to plasma protein. Drug bound to plasma protein cannot move freely in and out of the blood to exert a pharmacological effect, so more drug would be in the blood to maintain equilibrium between the blood and sites of action.

Question 6

What is a possible explanation for a calculated Vd of greater than 42L in a 70kg person?

a) The drug has distributed to an accumulated in extravascular storage depots such as fat.
b) The drug has accumulated only in the intracellular fluid
c) The drug is being excreted
d) The drug is only distributing to the extracellular fluid

Answer 6

a) The drug has distributed to an accumulated in extravascular storage depots such as fat.

If the Vd is greater than 42L, the drug is being distributed to extravascular storage depots, such as fat, which aren’t included in the calculation for total body water. The plasma concentration of the drug will be lower than expected, since the drug is distributing to and remaining in extravascular depots, resulting in an increased Vd.

Question 7

What is clearance?

Answer 7

Clearance is the term used to describe the process of removing a drug from the body.

Question 8

What are the 2 routes of elimination?

Answer 8

1) Drugs can be eliminated unchanged via the kidneys

2) Drugs can be biotransformed in the liver and then excreted by the kidneys and GI tract.

Question 9

True or false: Drug clearance predicts the rate of elimination of the drug in relation to drug concentration.

Answer 9

True

Question 10

What is the formula for clearance?

Answer 10

Clearance = drug concentration in the blood / rate of elimination

Question 11

True or false: elimination is not saturable, and the rate of elimination of a drug is directly proportional to the concentration of the drug.

Answer 11

True

Question 12

What is first order kinetics?

Answer 12

Elimination is not saturable, and the rate of elimination of a drug is directly proportional to the concentration of the drug.
- Thus, if the concentration of drug is high, more drug is excreted, as the liver and kidney have higher amounts of drug available to eliminate, and vice versa.

A constant fraction of the drug is eliminated over a set period of time.

Ex: drug is eliminated at a constant of 50%. Less drug is eliminated over time. This is known as first order elimination.

Question 13

Consider a drug that is being administered to give a blood concentration of 20 mcg/ml. If the body eliminates 50% of the drug over the next four hours, what will the plasma concentration of the drug be at 4 hours?

Answer 13

Clearance = drug concentration in the blood / rate of elimination

C = 20 / 2 = 10
or
C = 20 x 0.5 = 10

= 10 mcg/mL

Question 14

If the body continues to eliminate 50% of the drug over the next 4 hours, what will the plasma concentration of the drug be 8 hours after administration

Answer 14

C = 10 x 0.5 = 5

= 5 mcg/mL

Question 15

What is zero order kinetics? Give an example.

Answer 15

Only a few drugs are eliminated by zero order kinetics (also called saturable kinetics).

Under these conditions, a constant amount of the drug is eliminated in a set period of time (instead of a constant proportion), as the enzymes responsible for elimination are saturated and there is more drug than can be transformed.

Ex: alcohol is eliminated following zero order elimination kinetics. Regardless of how much alcohol is consumed, only 10 to 13 mL of absolute ethanol (equivalent to about one drink) can be metabolized by the liver each hour.

Question 16

What is half-life? What can it be used to calculate?

Answer 16

The half-life of a drug is the time needed for the liver and kidney to remove 50% of the drug from the blood.

Question 17

What can half life used to calculate? Provide an example.

Answer 17

The half-life of the drug can be used to calculate the drug concentration in the blood after each half-life.

Ex: if we give a person 100 mg of acetaminophen, after one half-life, 50 mg would remain in the body, and after 2 half-lives, 25 mg would remain.

Question 18

What is the formula of half life?

Answer 18

t1/2 = 0.7 x Vd/CL

t1/2 = half-life
0.7 is a constant as elimination is exponential
Vd = apparent volume of distribution
CL = clearance

Question 19

What is the plateau principle?

Answer 19

The plateau principle tells you that when a drug is administered repeatedly, the plasma concentration of the drug will increase until the rate of administration is equal to the rate of elimination.

In other words, drug input = drug output

Question 20

How many half-lives does it take for drug input to equal drug output?

Answer 20

It takes 5 half lives to reach steady state (if the dosing frequency is kept the same).

Doubling the drug dose doubles the concentration of drug in the blood, however, the time to reach the new plateau is still five half-lives

Question 21

Drug A has a half-life of 4 hrs, a Vd of 14 L, and a dose of 140 mg given every 4hours.

1) What will be the plasma drug concentration after distribution of the first dose (clearance)?

During the first half-life, 50% of the drug concentration in the blood will be eliminated.

2) What will the drug concentration after the first half life?

A second dose of 140 mg is given.

3) What is the drug concentration now?

During the next four hours, another 50% of the drug is eliminated.

4) What is the drug concentration now?

A third dose is administered (140 mg)

5) What is the drug concentration now?

During the next four hours, another 50% of the drug is eliminated.

6) What is the drug concentration now?

Answer 21

1) C = 140 mg / 14L = 10 mcg/mL
2) 10 x 0.5 = 5 mcg/mL

3) 140mg is added so:
C = 140 mg / 14L = 10 mcg/mL
Add that to the current concentration after the halflife (question 2).
10 mcg/mL + 5 mcg/mL = 15 mcg/mL

4) C = 15 mcg/mL x 0.5 = 7.5 mcg/mL

5) answer from Q1 (drug added) + answer from Q4 (concentration after half life)
10 mcg/mL + 7.5 mcg/mL = 17.5 mcg/mL

6) C = 17.5 mcg/mL x 0.5 = 8.75 mcg/mL

Question 22

How are drug dosage intervals determined?

Answer 22

In determining a dosing schedule, we dose to replace the drug that is lost from the body since the last dose. Generally, we replace the amount of drug lost every half-life.

Dosage regimens are established to produce plasma drug concentrations in the therapeutic range. Inter-individual differences in absorption, distribution, biotransformation, and excretion require dosage adjustment to maintain therapeutic drug concentrations.

Question 23

Convert:

• 1000mcg to mg
• 1000mg to g
• 1000g to kg

Answer 23

• 1000 mcg = 1 mg
• 1000 mg = 1 g
• 1000 g = 1 kg

Question 24

What are the units of measurement by weight and volume?

Answer 24

Volume

• liters (L)
• milliliters (mL)

Weight

• kilograms (kg)
• grams (g)
• milligrams (mg)
• micrograms (mcg)

Household
- Teaspoons

Vitamins, pepties or protein
- units

Weight

• mcg/lb
• mcg/kg

Question 25

How are dosages for adults determined?

Answer 25

Dosages for adults are determined from clinical trials and the required dose is often available as a tablet or capsule.

For parenteral drugs, which are prepared as a concentration, the total dose required is determined and the volume containing that amount of drug is calculated using the concentration of the drug solution.

Question 26

If a dose of 150 mg is ordered and the concentration of the drug solution is 300 mg in 2 ml, what is the volume of the drug that will contain 150 mg?

Answer 26

Desired (D) x Vehicle (V) / On hand (H)
(150 mg x 2 mL) / 300 mg = 1 mL

or

150/(300/2) = 1mL

Question 27

What are the 3 methods for calculating drug doses for children?

Answer 27

1) Age
2) Weight
3) Body surface area

Question 28

What is the most accurate method for calculating doses for children?

Answer 28

Body surface area (BSA)

Question 29

How is the BSA determined? What is the formula

Answer 29

The body surface area (in square meters) is determined from a nomogram (i.e. a graph in which a child’s BSA can be estimated based on their height and weight) using the formula:

Child’s dose = (body surface area (m^2) / 1.73) X adult dose

Most common nomogram = west nomogram

Question 30

A 3-year-old boy has a BSA of 0.71m^2. The dosage for a given drug for a 40-year-old man is 300 mg. What is the dosage for the child? Answer to the nearest whole number

Answer 30

Child dose = (BSA of the child m^2 / 1.73) x 300mg

(0.71 m^2 / 1.73 m^2) X 300 mg = 123 mg

Question 31

True or false: when medication is self-administered, compliance can range anywhere from 20% to 90%

Answer 31

True

Question 32

What are several reasons for noncompliance? (6)

Answer 32

1) Dissatisfaction with the diagnosis
2) The cost of the drugs
3) Inconvenience with having to take the drug several times a day
4) Having to take several different drugs daily
5) The onset of minor adverse events
6) The individual may just forget

Question 33

Non-compliance is a huge barrier to providing patients with the care they need. What strategies do you think health care providers could implement to try to increase the compliance rate of their patients and overcome this obstacle?

Answer 33

Education of the patient is key to improving compliance with drug therapy. At each visit to a health care provider (e.g. physician, nurse, or pharmacist), the patient should be instructed on why the drugs are prescribed and how to take them.

For drugs that are taken several times a day, consideration should be given to whether a long acting preparation, perhaps taken once a day, is available.

Question 34

What is the correct definition of half-life

a) The amount of time it takes for a drug to be completely removed from the blood
b) The amount of time it takes for 50% of a drug to be removed from the blood
c) The amount of time it takes for drug input to equal drug output
d) The amount of time it takes for the drug to be completely absorbed into the blood

Answer 34

b) The amount of time it takes for 50% of a drug to be removed from the blood