test 2

Question 1

Distribution

Answer 1

• After absorption, drugs must be distributed throughout the body
• Accomplished through circulation via the bloodstream

Question 2

Factors That Affect Distribution Dependent on

Answer 2

• Blood flow (CO)
• Capillary permeability
• Protein binding
• Lipophilicity
• Tissue volume

Question 3

Blood Flow affecting distribution

Answer 3

•Organs that receive higher flow receive higher drug concentrations
•High flow organs
-Heart, brain, kidneys, liver, skeletal muscles
•Low flow organs
- Adipose tissue
- Skin

Question 4

Capillary Permeability affecting distribution

Answer 4

•Determined by capillary structure

-Varies in how much of the basement membrane is exposed by slit junctions between endothelial cells

Question 5

Lipid solubility affecting distribution

Answer 5

•Move readily across most cell membranes
•Hydrophilic drugs do not penetrate the cell membrane
-Need slit junctions

Question 6

Plasma Protein Binding affecting distribution

Answer 6

•Reversible binding of drug to plasma proteins

• Sequesters drug
• Nondiffusible form
• Slows transfer out of the vascular compartment

Question 7

when does protein binding occur

Answer 7

•Occurs when a portion of drug is bound to protein and is therefore not able to be free to bind to active sites and produce an effect

Question 8

Albumin in the plasma

Answer 8

• Major drug binding protein
• Acts as a drug reservoir
• Concentration of free drug decreases due to elimination, bound drug will dissociate from protein

Question 9

less albumin leads to

Answer 9

-more free drug in the plasma that can cause an effect

Question 10

Competing drug in the plasma

Answer 10

• the competing drug takes up binding sites on the proteins allowing more free drug to cause more of an effect

Question 11

Tissue Protein Binding affecting distribution

Answer 11

•Higher concentration of drug in tissues than in the extracellular fluid and blood
-Due to drug binding to lipids, proteins, and nucleic acids
-Due to active transportation of drug
•Drugs sequestered in the tissues
- Prolong drug action
- Cause local toxicity

Question 12

what is Volume of Distribution (Vd)

Answer 12

•Fluid volume required to contain the entire drug in the body at the same concentration measured in the plasma

Question 13

Volume of Distribution equation

Answer 13

Volume of Distribution = [amount of drug in the body] / [serum concentration]
OR
volume (L) = dose (mg) / [plasma drug] (mg/L)

Question 14

what makes up the extracellular fluid

Answer 14

• intravascular fluid

- interstitial fluid

Question 15

what compartments do the drugs tend to be in

Answer 15

• intracellular fluid
• intravascular fluid
• interstitial fluid

Question 16

Plasma Compartment

Answer 16

•4% of body weight
•High MW drugs
•Extensive protein bound drugs
•Drugs with a low Vd
are confined in plasma (intravascular fluid)

Question 17

Extracellular Fluid Compartment

Answer 17

•20% of body weight
•Low MW drugs
•Hydrophilic drugs
-Confine in extracellular fluid (interstitial and plasma)
•Drugs confined to interstitial fluid have high Vd

Question 18

Volume of Distribution based on compartments

Answer 18

• Drugs that are mostly confined to the intravascular space have a smaller volume of distribution
• Drugs that have extensive distribution outside the plasma have a larger volume of distribution

Question 19

Calculating Vd:
500 mg of drug was added to a beaker with ? L of water. After mixing, measured drug concentration was 5mg/L.
What is the volume of distribution?

Answer 19

Vd = 500mg / 5 mg/L = 100 L

Question 20

Calculating Vd:
Patient weighing 70kg is given 1000mg of Drug A. Measured plasma concentration is 2mg/L.
What is the volume of distribution?

Answer 20

Vd (L)= 1000 mg / 2 mg/L = 500 L
500 L / 70 kg = 7.1 L/Kg
- a high Vd = low plasma concentration which means mainly extracellular
- you would need to put in 1000 mg of drug into a container that contains 500 L of water in order to get the measured concentration of 2 mg/L

Question 21

Calculating Vd:
Patient weighing 70kg is given 350mg of Drug B. Measured plasma concentration is 25mg/L.
What is the volume of distribution?

Answer 21

Vd = 350 mg / 25 mg/L = 14 L
14 L / 70 kg = 0.2 L/Kg OR 200 mL/Kg
- low Vd = high concentration in plasma which means mainly intravascular

Question 22

Affect of Vd on Drug Half-life

Answer 22

•High Vd increases drug half-life
•Drug bound to tissue (low plasma concentration) so not available to excretory organs
•Factors than increase Vd
increase half-life

Question 23

Half-life (t1/2)

Answer 23

• Time it takes for the drug concentration to decrease by ½ (once administered)
• Used to determine drug dosing frequency
• Depends on how quickly a drug is eliminated from plasma
• Determines length of drug effect

Question 24

•If a drug has a plasma concentration of 1000mg/L and the drug has a half-life of one hour. How much of the drug is present after:

• One hour?
• Two hours
• Three hours
• Four hours

Answer 24

1 hour: 500
2 hours: 250
3 hours: 125
4 hours: 62.5

Question 25

Three major routes of elimination

Answer 25

* Hepatic metabolism * Biliary elimination * Urinary elimination

Question 26

Most drugs are eliminated according to

Answer 26

* Firstorder kinetics * A constant fraction of drug is eliminated in a given unit of time * Drug half-life is used to measure drug clearance

Question 27

Clearance equation

Answer 27

CL = (0.639 x Vd) / t½

Question 28

Clearance Example: A 100kg patient is taking Lisinopril which exhibits first order elimination kinetics with a half-life of 12 hours and its distribution appears to be limited to the intravascular space. What is the clearance rate for Lisinopril in this patient?

Answer 28

CL = (0.639 x (4% of 100)) / 12 hr = 0.213 L/1 hr

Question 29

First-order kinetics

Answer 29

- increase the plasma concentration of the drug = increase in rate of elimination - rate of elimination is proportional to drug concentration - constant proportion being eliminated - dependent on initial drug concentration - half life is constant - 95% of the drug follow first order kinetics

Question 30

Zero-order kinetics

Answer 30

- increase plasma concentration of the drug = no increase in rate of metabolism - rate of elimination becomes independent of concentration - a constant rate being eliminated - 5% of the drug follow zero-order kinetics

Question 31

A patient was given 100mg of Drug A orally. Assume that the drug metabolism follows first-order kinetics at a rate of 10% per minute 1. dose given 2. proportion being metabolized 3. drug metabolized in the first min? 4. 2nd 5. 3rd 6. 4th

Answer 31

1. 100 mg 2. 10%/min 3. 10 mg 4. 9 mg 5. 8.1 mg 6. 7.29 mg

Question 32

A patient was given 100mg of Drug B orally. Assume that the drug metabolism follows zero-order kinetics at a rate of 10mg/min 1. How much drug is metabolized every minute? 2. drug is metabolized after 5 minutes? 3. 8 minutes 4. How long will it take for all of the drug to be metabolized? 5. How long will it take for 200mg of drug to be metabolized?

Answer 32

1. 10 mg 2. 50 mg 3. 80 mg 4. 10 minutes 5. 20 minutes

Question 33

Drug Metabolism

Answer 33

* Breaks drug down into metabolites * more water-soluble components * Aids in excretion of drug * Occurs by chemical reactions * Oxidation * Conjugation * Acetylation * Glucuronidation * Liver is the major organ for drug metabolism

Question 34

Liver Drug Metabolism

Answer 34

``` •Contains a microsomal drug oxidation system called the cytochrome P-450 system (CYP-450) - enzyme system •Induced •Increased activity •Inhibited •Decreased activity ```

Question 35

Phase I Biotransformations (breaks down the metabolites)

Answer 35

* Converts lipophilic drugs into more water soluble molecules * Introducing or unmasking polar groups * OH or NH2 * Chemical reactions involved: * Reduction * Oxidation * Hydrolysis * Metabolites often still too lipophilic

Question 36

Phase II Biotransformations (breaks down the metabolites)

Answer 36

* Consists of conjugation reactions * Linking an acid (glucuronic, acetic, amino, sulfuric) to phase I metabolite * Resulting in a more water-soluble compound * Often therapeutically inactive

Question 37

Inducers of cytochrome P-450

Answer 37

* Increase activity of CYP 450 enzymes * Increased biotransformation * Decreases plasma drug concentration and loss of therapeutic effect

Question 38

Inhibitors of cytochrome P-450

Answer 38

* Decrease CYP 450 enzymes * Can lead to adverse side effects * Prolongs therapeutic drug effect * Decreases elimination * Lead to toxicity

Question 39

Drug Clearance by the Kidneys

Answer 39

* Most important route of drug elimination * Renal elimination involves * Glomerular filtration * Tubular secretion * Tubular reabsorption

Question 40

Renal Elimination

Answer 40

Urine excretion = filtration + secretion - reabsorption