Drug Distribution -Dr Issar

Question 1

What is distribution

Answer 1

back and forth movement of drug in various tissues of the body and relative proportion of drugs in tissues

Question 2

Where are the regions the drugs can go

Answer 2

1. ECF (1/3 TBW)
2. ICF (2/3 TBW)
3. Interstitial fluid (3/4 ECF)
4. plasma (1/4 ECF)

Question 3

Maximum volume that your body has is

Answer 3

42 liters
(Total body water x 70kg)
.60 x 70 kg

Question 4

VD = 3 L
Plasma distribution = 3.5
so..confined to _____

Answer 4

vasculature

Question 5

what are the drug distribution patterns

Answer 5

1. drugs confined to blood have high plasma protein binding. high mw (dextran)
2. Low mw water soluble compounds uniformly distributed in body water (ethanol)
3. concentrate in specific tissues
4. non uniform distribution: ability to penetrate membranes and lipid/water solubility

Question 6

What is volume of distribution

Answer 6

a proportionality factor (Vd) that relates the amount of drug in the body (Db) to the corresponding plasma concentration (Cp)
*not a true volume! apparent volume

Question 7

what does concentration of drug in body after distribution depends upon

Answer 7

1. dose

2. extent of distribution

Question 8

The larger the Vd, the ____is the fraction of drug in the plasma

Answer 8

smaller

Question 9

Why is the volume of distribution terms of some drugs much greater than the total body water?

Answer 9

Bc for some tissues the value of Kp is large.

Kp = tissue to plasma equilibrium distribution ratio

Question 10

which factors can determine the fraction of drug in body within and outside of plasma

Answer 10

1. volume of plasma (Vp)

2. volume of distribution (Vd)

Question 11

which factors affect rate of drug distribution

Answer 11

1. perfusion rate limited distribution:
2. permeability limited distribution
3. blood flow/tissue perfusion

Question 12

describe perfusion rate limited distribution

Answer 12

in special hepatic capillaries, they lack a complete lining which results in more extensive distribution of drugs out of the capillary beds in which they dont act as anatomical barriers

Question 13

describe permeability limited distribution

Answer 13

the distribution of polar compounds across the biological barrier is slow and is governed by the rate of diffusion that occurs across this barrier

• drugs hydrophilic in nature
• brain capillary

Question 14

in which organs is total blood flow the greatest

Answer 14

1. brain
2. kidneys
3. liver
4. muscle

Question 15

which organs have the highest perfusion rate

Answer 15

1. brain
2. kidney
3. heart
4. liver
   * total drug conc’s would rise most rapidly in these organs

Question 16

which factors alter the extent of distribution

Answer 16

1. lipid solubility;
2. pH- pKa
3. plasma protein binding
4. intracellular binding
5. extent of elimination that continuosly competes with the distribution phenomenon by removing the drug from the system

Question 17

the faster the rate of perfusion the buildup of concentrations is gont to be ____in those tissues

Answer 17

faster

Question 18

higher lipophilicity, buildup of concentrations is going to be much ______

Answer 18

higher

Question 19

High perfussion in brain allows drugs to get in and out easily. Characteristics include:

Answer 19

1. small
2. lipophilic
3. remain in unionized form in plasma bc of pka

Question 20

Describe a drug in free form

Answer 20

Drug in free form which has abilty to move around in different compartments bind to proteins and keep them loosely bound to them.

Question 21

Drug protein binding may be a ___ or an irreversible process

Answer 21

reversible

Question 22

What is a protein bound drug

Answer 22

1. pharmacologically inactive
2. has restricted distribution
3. can’t be metabolized
4. cant be excreted.

Question 23

what is irreversible drug protein binding a result of?

Answer 23

chemical activation of the drug which attaches strongly to the protein/macromolecule by covalent chemical bonding. The affinity of the drug to the protein is very strong and stable and very difficult to break.

Question 24

describe reversible drug protein binding

Answer 24

implies that the drug binds the protein with weaker chemical bonds, such as H bonds or Van der Waals forces.

Question 25

what is the most common binding protein to which drugs bind

Answer 25

albumin

Question 26

albumin binds ___ drugs. alpha 1-acid glycoprotein binds ____ drugs and lipoproteins bind ___ drugs like steroids

Answer 26

acidic; basic; neutral

Question 27

High drug protein binding has a low ___ fraction which means you will have a ___Vd because most of drug is bound to protein and not enough drug to distribute to tissues

Answer 27

free; lower

Question 28

Low drug protein binding, means high ___ form interaction which leads to ___volume of distribution

Answer 28

free; high

Question 29

what is an ex of drug-drug interaction

Answer 29

warfarin and phenylbutazone (PBZ)

Question 30

when a highly protein bound drug is displaced from binding by a second drug/agent, a sharp increase in the ____ concentration in the plasma may occur, leading to toxicity.

Answer 30

free

Question 31

Albumin has ___ known binding sites that share the binding of many drugs. When does displacement occur?

Answer 31

two; when a second drug is taken that competes for the same binding site in the protein as the initial drug.

Question 32

what is the clinical concern with warfarin-PBZ interaction due to?

Answer 32

inhibition of CYP2C9 which metabolizes warfarin

Question 33

____ can displace bilirubin from their protein binding sites. As a consequence, less bilirubin is bound and is available in the free form which causes adverse effects in the newborn

Answer 33

Sulfonamides

Question 34

The accumulation of drug into tissues is dependent on both the ___ ____ and the _____ of the drug for the tissue.

Answer 34

blood flow; affinity

Question 35

what are characteristics of drugs going in and out of blood brain barrier

Answer 35

1. diffusion dependent on lipid solubility & molecular mass 2. pH and pKa 3. P-glycoprotein efflux transporters (PGP) 4. Channels and ion transporters - nutrients

Question 36

what role does Thiopental play in fat

Answer 36

blood concentraitons in brain decline. As drug gets eliminated it distributes to brain and adipose tissue. Go in and out of brain easily. It gets redistributed into various organs. In adipose it takes more until it satures. Have to saturate reservoir fat first in order to have sustained amounts

Question 37

what role does DDT play

Answer 37

even though pesticide was removed...has high affinity to adipose tissue

Question 38

what are physiological barriers to drug distribution

Answer 38

1. blood brain barrier | 2. placental barrier

Question 39

what are other routes of entry into the brain

Answer 39

1. choroid plexus and other circumventricular organs | 2. choroid plexus P-gp: pumps out penicillin out of brain

Question 40

what is permeable through the BBB

Answer 40

1. carbon dioxide 2. oxygen 3. most lipid soluble substances such as alcohol and anesthetics 4. water

Question 41

what is impermeable through BBB

Answer 41

1. electrolytes 2. plasma proteins 3. non lipid soluble large organic molecules

Question 42

In placenta, Lipid soluble materials readily diffuse from maternal to fetal circulation according to their _______partition coefficients and degree of _____. ____ soluble drugs move much more slowly and _____ to their molecular size

Answer 42

lipid/water; ionization Water; inversely

Question 43

The placental barrier is not perfect. It has ___ and efflux transporters that are relevant to drug distribution across the maternal- fetal interface that can allow ___ to pass through the placental barrier

Answer 43

influx; xenobiotics