Pharm 2060B Module 3

Front 1

Name 4 Body compartments drugs can distribute to

Back 1

1. Total Body Water: (includes blood plasma, interstitial space, and intracellular fluid)

2. Adipose tissue: Fat

3. Muscle

4. Bone: Some drugs absorb to the surface of bones and become absorbed in the crystal lattice. Bones can also be a reservoir for the slow release of drugs

Front 2

If a drug is given parenterally, where does it go first and where could it distribute to next?

Back 2

A parenterally administered drug will be absorbed in the plasma first. If the drug is absorbed as a free drug, it can distribute to bone, muscle, interstitium, fat, kidney (for excretion) or liver (for metabolism). If the drug is absorbed as a protein bound drug, it will stay in the plasma.

Front 3

If a drug is given orally, where does it go first and where could it distribute to next?

Back 3

First the drug will go to the liver for metabolism, then either the drug or the metabolite will go into the plasma. If the drug is a free drug, it can go to the muscle, bone, fat, interstitium, or kidney/liver for excretion. If the drug is protein bound it will remain in the plasma

Front 4

What are the three factors that affect drug distribution

Back 4

1. Blood flow to tissues

2. Ability of drug to move out of capillaries

3. Ability of drug to move into cells

Front 5

Name 3 tissues that are highly perfused/have high blood flow

Back 5

Brain, Kidney, Liver

Front 6

Name 3 tissues that are not highly perfused/have lower blood flow

Back 6

Skin, Fat, Bone

Front 7

T/F poor blood flow rarely limits drug distribution in humans

Back 7

False. Poor blood flow rarely limits drug distribution in adults, however is a limiter of drug distribution in neonates.

Front 8

What are 3 examples where poor blood flow can limit drug distribution?

Back 8

1. Patients experiencing heart failure or shock

2. Solid tumours. They have low regional blood flow, even though they have high external blood flow. It is difficult to attain high drug concentrations in tumours.

3. Abcesses (infections filled with pus) have no blood supply.

Front 9

A drug has successfully exited the vasculature and is attempting to enter a cell. Name 2 barriers to entry.

Back 9

1. Chemical nature. It must be either lipophilic or able to be taken by an uptake transporter.

2. Efflux transporters

Front 10

What is P-glycoprotein?

Back 10

The most widely studied efflux transporter. Promotes drug excretion from cells and protects the body from exposure to drugs.

Front 11

What does PGP need to function and why does it need this?

Back 11

PGP actively pumps out drugs, so it needs ATP. It needs ATP because it effluxes these drugs against a concentration gradient.

Front 12

Name 4 areas PGP is expressed/localized, and to where it pumps drugs to.

Back 12

1. Liver: PGP is expressed in hepatocytes and actively pumps drugs into the bile canalicular membrane, where they become eliminated

2. Intestine. PGP is expressed on enterocytes on the apical membrane (facing the lumen). It actively pumps drugs into the lumen, preventing absorption.

3. Kidney: PGP is expressed in the proximal tubule on the apical membrane, preventing reabsorption

4. Brain: PGP is expressed in the brain, facing capillary endothelial cells, pumping drugs from the brain back into the blood, limiting the brains exposure to drugs.

Front 13

T/F Only the free drug can elicit a pharmacological response

Back 13

True

Front 14

Explain the equilibrium of free and protein-bound drugs

Back 14

Free drugs and protein bound drugs are in equilibrium. Since binding is reversible, if some of the free drug is removed, protein bound drugs will dissassociate from their proteins and become free drugs

Front 15

You have a condition where the kidney overactively eliminates all drugs in the body. What will happen to levels of protein bound drugs?

Back 15

They will decrease, because p-bound drugs and free drugs are in equilibrium, if the levels of free drugs decreases, p-bound drugs will dissassociate from their constituent proteins and become free drugs

Front 16

Name and describe the two major plasma proteins

Back 16

1. Albumin. The most common one. Binds lipophilic, and anionic/weakly acidic drugs. Think: Albumin --> Fat Albert --> probably has acid reflux

2. Alpha 1 acid glycoprotein: Binds hydrophilic and cationic/weakly basic drugs

Front 17

What factors affect albumin concentrations in the blood, and what are the effects of these changes?

Back 17

Malnutrition, trauma, aging, liver disease and kidney disease decrease albumin concentrations in the blood. This Causes an increase in free drug concentration, which could lead to increased therapeutic and toxic effects.

Front 18

What factors affect alpha 1 acidic glycoprotein concentrations in the blood, and what are the effects of these changes?

Back 18

Aging, trauma, and hepatitis increase alpha 1 acidic glycoprotein concentrations in the blood. This leads to decreased free drug concentration and so ineffective therapy.

Front 19

Define Volume of Distribution

Back 19

Apparent volume that a drug distributes into. Ratio of the total amount of drug in the body to the plasma concentration of the drug

Front 20

Why can the VD sometimes be larger than the actual volume of water in the body

Back 20

The drugs can extensively bind to tissues, giving a large numerator and small denominator

Front 21

For a 70kg person, how much total body water is there?

Back 21

42 L

Front 22

for a 70kg person, how much intracellular fluid is there?

Back 22

28L

Front 23

For a 70kg person, how much interstitial fluid is there?

Back 23

10L

Front 24

For a 70kg person, how much plasma is there?

Back 24

4L

Front 25

What are 2 characteristics of a drug with a small VD. Where do these drugs distribute primarily?

Back 25

1. It is bound to plasma proteins

2. It is large and cannot pass through capillary fenestrations

For these reasons the drug stays in the plasma

Front 26

What is volume of plasma per kg in a 70 kg patient?

Back 26

4/70 = 0.057 L/kg

Front 27

Name 3 characteristics of drugs with an intermediate VD. Where do these drugs distribute to primarily?

Back 27

1. Low molecular weight. Can pass through capillary fenestrations.

2. Hydrophilic, can't directly penetrate cell membranes

3. Intermediate protein binding: some are free some are bound in plasma

Since these drugs can leave the vasculature, but can't enter cells, these drugs will distribute in the extracellular space, comprised of the interstitium and the plasma

Front 28

What is volume of extracellular fluid per kg in a 70 kg patient?

Back 28

14/70 = 0.2 L/kg

Front 29

What are 3 characteristics of drugs with a high VD? Where do they distribute to?

Back 29

1. Low molecular weight (can pass through capillary fenestrations)

2. Lipophilic (can directly penetrate cell membranes)

3. Minimal plasma protein binding

These drugs can leave the vasculature AND enter cells (due to their lipophilicity). They can distribute into the total body water. This includes extracellular AND intracellular fluids, cells of which include fat, muscle and bone

Front 30

A plasma protein bound drug with a small VD is displaced by another drug. What happens to the free drug concentration, and the apparent VD of the drug?

Back 30

Free drug concentration increases, because the drug cant leave the vasculature so it stays in the plasma. Apparent VD, however, stays the same, due to the amount and plasma concentration of the drug remaining the same

Front 31

A plasma protein bound drug with a large VD is displaced by another drug. What happens to the free drug concentration, and the apparent VD of the drug?

Back 31

The free drug concentration will decrease as the displaced drug will leave the vasculature and enter cells. The apparent VD of the drug will also increase because, although the amount of the drug in the body stays the same, the plasma concentration decreases.

Front 32

Decreasingly order water as % of body weight between infants, healthy adults, obese, and elderly

Back 32

baby --> healthy adult --> obese --> elderly

Front 33

Decreasingly order fat as % of body weight between infants, healthy adults, obese, and elderly

Back 33

obese --> elderly --> healthy adults --> baby

Front 34

Decreasingly order muscle as % of body weight between infants, healthy adults, obese, and elderly

Back 34

healthy adult --> obese, --> elderly --> infant

Front 35

T/F as we get older drugs that distribute in fat will have a lower VD

Back 35

False. higher VD.

Front 36

T/F as we get older drugs that distribute in muscle will have a lower VD

Back 36

True.