Lecture slides week 2

Question 1

What is pharmacotherapeutics?

Answer 1

The study of the therapeutic uses and effects of drugs

Question 2

Which two concepts are important for clinicians to understand to be safe and effective in their approach to therapeutics?

Answer 2

Kinetics and dynamics

Question 3

Define absorption

Answer 3

the movement of a drug from its site of administration into the systemic circulation

Question 4

What are factors that affect drug absorption?

Answer 4

rate of dissolution, surface area, blood flow, lipid solubility, pH

Question 5

Define bioavailability

Answer 5

The amount of drug that gets to the action site unchanged

Question 6

What impacts bioavailability?

Answer 6

route of administration, extent of absorption

Question 7

Define distribution

Answer 7

the movement of drugs from the systemic circulation to the site of drug action

Question 8

What impacts distribution?

Answer 8

manner in which the drug is introduced (intravascular vrs. extravascular)
blood flow
availability of binding molecules and other carriers or elements (ex. K+) that support distribution

Question 9

What is the equilibrium constant?

Answer 9

• determines the amount of bound versus unbound drug in each body compartment
• drugs placed in one compartment then move to other compartments, the body creates an equal distribution of drugs in each compartment
• once a drug binds to proteins it stays in that compartment

Question 10

What are some examples of body compartments?

Answer 10

Fat
Extracellular fluid
intracellular fluid
blood (plasma)
other

Question 11

What provides the driving force for distribution of the agent to tissues?

Answer 11

Unbound drug

Question 12

What are some possible outcomes once unbound drug leaves the blood and distributes to the tissues?

Answer 12

Can become tissue bound

Can remain unbound in tissue

can be rendered inactive (if the tissue has the ability to metabolize or eliminate the drug)

can bind to a receptor and cause its pharmacologic or toxic effects

can bind to a non specific binding site that causes no effect

Question 13

T/F tissue binding is usually reversible

Answer 13

True.
Tissue binding (as well as protein binding) is usually reversible so that unbound and bound can find equilibrium

Question 14

What is volume of distribution?

Answer 14

a proportionality constant that relates the amount of drug in the body to the plasma concentration at a given time

VD = total amount of drug in the body/conc. of drug in plasma

Question 15

How can the VD be applied in practice?

Answer 15

The VD is determined by the physiologic volume of blood and tissues and how the drug binds in blood and tissues (typically based on a male of a certain weight)

It can then be used to calculate how much drug needs to be in the body to reach a desired plasma concentration of drug

Can be used to calculate the needed loading dose of a drug

Question 16

What are some patient factors that would affect volume of distribution?

Answer 16

patient physiologic and disease processes like body size, maturation of organ function, etc.

Question 17

What is the main factor of a drug that impacts volume of distribution?

Answer 17

the propensity of the drug to remain in the plasma or redistribute to other tissues
Worded another way, the space in the body that is available to contain a drug

Question 18

What is clearance?

Answer 18

The ability of the body to eliminate the drug

Question 19

T/F: volume of distribution and clearance are unrelated

Answer 19

False
clearance impacts the volume of distribution

Question 20

What is the primary organ responsible for clearance ?

Answer 20

The kidneys will clear a given volume of fluid per unit of time

Question 21

Some drugs will be unable to move out of the compartment they were introduced to due to their molecular composition limiting their movement, what will be the result on their volume of distribution?

Answer 21

These drugs will not be homogeneously distributed and therefore will have a minimal possible volume of distribution equal to the blood component in which they are distributed

Therefore extravascular equilibrium will not be achieved for some drugs and VD outside of the compartment that the drug was introduced will be minimal

Question 22

What are some organs with enzymes for metabolism of drugs?

Answer 22

Liver, GI tract, lungs

Question 23

Where Phase I and phase II reactions occur?

Answer 23

In the liver

Question 24

Differentiate phase I and phase II reactions

Answer 24

Phase I: reactions that make the drug molecule more water soluble and therefore more able to be eliminated by the kidneys
Phase II: reactions that involve conjugation to form inactive metabolites so that they can be eliminated by the kidney.

Question 25

T/F: the metabolites resulting from metabolism are always rendered inactive for excretion

Answer 25

False
Metabolites can be inactive or can have their own pharmacologic effects

Question 26

Phase I involves: _______, _______, or ________.
Phase II involves: _________.

Answer 26

Phase I involves hydrolytic reactions, oxidation or reduction
Phase II involves conjugation

Question 27

Describe first-pass metabolism and its effect on bioavailability

Answer 27

When a drug is given orally, it must be absorbed across the gut wall and delivered to the liver prior to entering the systemic circulation - the drug can be metabolized in the gut wall and/or liver before entering systemic circulation, decreasing bioavailability

Question 28

What is the primary organ of drug elimination? Which other organs have the ability to excrete drugs or metabolites?

Answer 28

Kidneys
lungs, breast milk, sweat, tears, skin, hair, saliva, feces

Question 29

Enterohepatic recycling occurs between which organs?

Answer 29

drug travels in bile from liver to intestine and back again

Question 30

T/F: clearance depends on the body’s ability to eliminate

Answer 30

true
The body’s ability to eliminate drugs is called clearance, it is expressed mathematically as:

CL = rate of elimination/drug concentration

Question 31

T/F: clearance is a function of only the kidneys

Answer 31

False
The two major sites of drug elimination are the kidneys and liver
Clearance of unchanged drug in the urine represents renal clearance, while clearance via the liver occurs vis biotransformation of the drug into metabolites or excretion of the unchanged drug into bile, or both.

Question 32

How do you calculate total systemic clearance?

Answer 32

By combining the clearance of all organs involved.
ex. CL systemic = CL kidney + Cl liver + Cl other

Question 33

Define first order elimination

Answer 33

clearance is constant over the concentration range encountered in clinical settings - elimination is not saturable and the rate of drug elimination is directly proportional to the concentration
Rate of elimination = clearance X concentration

worded another way, a constant proportion of the drug is eliminated over time

Question 34

Describe capacity limited elimination

Answer 34

most drug elimination pathways can become saturated if the dose/concentration are high enough. Therefore elimination cannot keep up and the concentration continues rising. Clearance varies depending on concentration of drug achieved

Also termed mixed-order, zero order, dose/concentration dependent, nonlinear or Michaelis-Mentin.

So instead of the clearance being proportional to the concentration in first order elimination, the clearance maxes out and cannot keep up with doses at a certain point. Ex. alcohol

Question 35

Describe flow-dependent elimination

Answer 35

some drugs are cleared very rapidly by the organ of elimination so that at any clinically realistic concentration, most of the drug in the blood perfusing the organ is eliminated on the first pass of the drug through it

Elimination of these drugs depends on the rate of drug delivery to the organ of elimination

These drugs are known as “high extraction” drugs, since they are almost completely extracted from the blood by the organ

Question 36

What two dosing actions cause drug to accumulate in the body?

Answer 36

repeated drug dosing or continuous infusion

Question 37

How many half-lives does it take to eliminate one dose of a drug?

Answer 37

4

Question 38

How do you calculate accumulation ?

Answer 38

Accumulation is inversely proportional to the fraction of dose lost in each dosing interval

Accumulation = 1/fraction lost in one dosing interval
(fraction lost is 1-the fraction remaining just before the next dose)

Question 39

What is the accumulation factor useful for understanding?

Answer 39

useful to understand how often doses need to be administered to maintain “close to peak” concentration

Question 40

Regarding extraction ratios, what are some considerations regarding high extraction drugs?

Answer 40

Drugs with high extraction ratios will show marked variations in bioavailability between patients because of differences in hepatic function and blood flow

For drugs that are highly extracted by the liver, the use of routes of administration that bypass the first pass effect will substantially increase bioavailability

Drugs that are poorly extracted by the liver will not have their bioavailability affected as much by first pass.