4) Pharmacology - Drug Distribution

Front 1

what factors affect drug distribution?

Back 1

(1) reversible movement between blood and tissues (2) water volumes (3) volume of distribution drug factors (4) volume of distribution physiological factors (5) rate of distribution

Front 2

how does the reversible movement between blood and tissues affect drug distribution?

Back 2

drug remaining in compartments have prolonged drug action, toxicity, depots, residues

Front 3

where do water volumes affect drug distribution?

Back 3

(1) intracelular (2) interstitial (3) plasma (4) blood cells

Front 4

what drug factors affect the volume of distribution?

Back 4

(1) lipid solubility (2) pH-pKa relationship (3) plasma protein binding (4) intracellular protein binding

Front 5

how does lipid solubility of a drug affect the volume of distribution?

Back 5

lipid solubility is more important for intracellular vs extracellular and some special tissue sites have additional tissue layers (blood-brain barrier, prostate/testes, joint, placenta/mammary gland, ocular compartments) that drugs must penetrate

Front 6

how does the pH-pKa relationship affect the volume of distribution?

Back 6

only unionized drug fraction will diffuse freely and thus distribute and only unbound or free drug fraction will diffuse freely and thus distribute

Front 7

how does plasma protein binding affect volume of distribution?

Back 7

drugs bound to plasma proteins will not be distributes as extensively

Front 8

how does intracellular protein binding affect volume of distribution?

Back 8

drug will want to be distributed in those organs and there are specific receptors or transport systems

Front 9

name some examples of specific receptor tissues and and drugs that rely on intracellular protein binding to affect volume of distribution?

Back 9

tetracyclince to bone, chlorinated pesticides to adipose tissue, aminoglycosides to kidney proximal tubules

Front 10

the intracellular protein binding of tetracyclince to bone, chlorinated pesticides to adipose tissue, aminoglycosides to kidney proximal tubules affects what?

Back 10

volume of distribution

Front 11

tetracyclince to bone, chlorinated pesticides to adipose tissue, aminoglycosides to kidney proximal tubules affect the volume of distribution via what mechanism?

Back 11

intracellular protein binding

Front 12

what physiological factors affect the volume of distribution?

Back 12

(1) tissue perfusion and mass of tissue (2) ratio of blood flow to tissue mass or perfusion rate (3) transcellular tissue compartments (4) tissue-specific transport processes (5) plasma and tissue protein binding (6) factors that alter plasma protein concentrations (7) plasma protein binding

Front 13

how does tissue perfusion and mass of tissue affect volume of distribution?

Back 13

well-perfused tissue takes up drug more rapidly and larger tissue mass has more drug binding sites

Front 14

what is another term for the ratio of blood flow to tissue mass?

Back 14

perfusion rate

Front 15

what is another term for perfusion rate?

Back 15

the ratio of blood flow to tissue mass

Front 16

what are the units of perfusion rate?

Back 16

ml/min/ml tissue

Front 17

what organs have a high perfusion rate?

Back 17

brain, kidney, heart, endocrine, liver

Front 18

what happens in organs with high perfusion rates?

Back 18

have a very rapid rise or rate in drug concentration and must be monitored for toxicosis

Front 19

what organs have a low perfusion rate?

Back 19

muscle, skin, fat, bone

Front 20

what happens in organs with low perfusion rates?

Back 20

have a greater capacity to increase extent of drug distribution

Front 21

how do transcellular tissue compartments affect volume of distribution?

Back 21

have additional membranes and potential pH differences

Front 22

how do tissue-specific transport processes affect volume of distribution?

Back 22

by selectivly transporting drugs against a gradient

Front 23

what are examples of tissue-specific transport processes that affect volume of distribution?

Back 23

blood-brain barrier and active drug efflux

Front 24

what are examples of tissue-specific transport processes at the blood brain barrier?

Back 24

glucose, transferrin, L-amino acids

Front 25

what are examples of tissue-specific transport processes with active drug efflux?

Back 25

P-glycoprotein associated transport system

Front 26

how do plasma and tissue protein binding affect volume of distribution?

Back 26

when the drug is free in blood or bound in tissue it has physiological effects

Front 27

name common plasma and tissue proteins that affect volume of distribution?

Back 27

albumin, alph1-acidic glycoproteins, hormone transport proteins, lipoproteins

Front 28

what does albumin bind that affects volume of distribution?

Back 28

binds neutral and weakly acidic drugs

Front 29

what does alpha1-acidic glycoproteins bind that affects volume of distribution?

Back 29

binds basic drugs

Front 30

what does hormone transport proteins bind that affects volume of distribution?

Back 30

bind steroids

Front 31

what does lipoproteins bind that affects volume of distribution?

Back 31

bind very lipophilic pesticides

Front 32

what type of interactions are plasma and tissue protein binding?

Back 32

reversible noncovalent interactions resulting in a dynamic equilibrium

Front 33

what are plasma and tissue protein binding dependent on?

Back 33

drug-protein affinity and drug concentration and protein concentration

Front 34

what law does plasma and tissue protein binding follow?

Back 34

law of mass action where the concentration of protein and the concentration of drug sum to the concentration of protein bound drug

Front 35

illustrate the law of mass action?

Back 35

[P] + [D] > [PD]

Front 36

in plasma and tissue protein binding what is k1?

Back 36

forward association constant

Front 37

in plasma and tissue proteing binding what is k2?

Back 37

reverse association constant

Front 38

in plasma and tissue protein binding what does Ka stand for?

Back 38

association constant

Front 39

in plasma and tissue protein binding illustrate Ka?

Back 39

Ka = [PD]/[P]{D]

Front 40

in plasma and tissue proteint binding what happens if the Ka is large?

Back 40

most of the drug is bound and large dose may be needed for effect

Front 41

in plamsa and tissue protein binding what happens with multiple drugs?

Back 41

competition may occur (ex warfarin and phenylbutazone) and the drug with the highest Ka will displace the other drug and increase the free drug concentration of the drug with lower Ka

Front 42

in plasma and tissue protein binding what happens if tissue Ka is larger?

Back 42

little drug will stay in plasma

Front 43

in plasma and tissue protein binding what happens if plasma Ka is larger?

Back 43

more drug will stay in plasma

Front 44

in plamsa and tissue protein binding when does physiological effect occurs?

Back 44

when drug is free in blood or bound in tissue

Front 45

in plasma and tissue protein binding what factors alter plasma protein concentrations?

Back 45

(1) reduced serum albumin (2) increased alpha1-acid glycoprotein (3) changes in body temp or acid-base balance

Front 46

in plasma and tissue protein binding what causes reduced serum albumin?

Back 46

malnutrition, pregnancy, age, cancer, liver abscess, renal disease

Front 47

in plasma and tissue protein binding what causes increased alpha1-acid glycoprotein?

Back 47

age, inflammation, infection, obesity, renal failure

Front 48

in plasma and tissue protein binding what affect do changes in body temp or acid-base balance have?

Back 48

alter binding

Front 49

in plasma and tissue protein binding, when is it clinically important?

Back 49

when [bound drug] > 90% because a physiologic change (drug intoxication or disease) in [free drug] will be pharmacologically significant

Front 50

what does the rate of distribution depend on?

Back 50

tissue perfusion and membrane permeability

Front 51

what does the apparent volume of distribution reflect?

Back 51

dilution of drug in body

Front 52

what factors determine the apparent volume of distribution?

Back 52

dose, plasma water, body water

Front 53

how can we illustrate the apparent volume of distribution of a drug?

Back 53

dose (mg/kg) = [plasma] (mg/L) x Vd (L/kg)

Front 54

what is the average amount of plasma water?

Back 54

50mL/kg (0.05 L/kg)

Front 55

what is the average amount of body water?

Back 55

600 mL/kg (0.6 L/kg)

Front 56

what happens when apparent volume distribution is 0.05 to >250L/kg has protein binding?

Back 56

the drug can occupy space greater than physiologically available water volume

Front 57

what determines the extent of distribution?

Back 57

lipophilicity and plasma/tissue protein binding

Front 58

what does Vd stand for?

Back 58

volume of distribution

Front 59

what is the Vd for drugs confined to plasma?

Back 59

0.05 L/kg

Front 60

what do drugs confined to a plasma with a Vd of 0.05 L/kg include?

Back 60

drugs that are strongly bound to proteins or whose molecular size is too large to cross capillary wall (heparin, insulin)

Front 61

what are examples of drugs that are strongly bound to proteins or have molecular size that is too large to cross capillary walls?

Back 61

heparin and insulin

Front 62

what is the Vd for drugs distributed in extracellular compartment?

Back 62

0.2-0.4 L/kg

Front 63

what do drugs distributed in extracellular compartment with a Vd or 0.2-0.4 L/kg include?

Back 63

polar compounds (tubocurarine, gentamicin) with low lipid solubility

Front 64

for drugs distributed in extracellular compartment, where else will drug be?

Back 64

some drug will still be in blood with some minor protein binding in plasma and tissues

Front 65

what is the Vd for drugs distributed throughout body water?

Back 65

0.55 L/kg

Front 66

what do drugs distributed throughout body water with a Vd of 0.55 L/kg include?

Back 66

(1) relatively lipid soluble drugs that cross cell membrane, (2) drugs that can bind outside of plamsa and body fat so Vd >>>Vd for body water (3) such drugs can reach fetus, brain, other transcellulr comparments (4) extensive drug tissue binding results in very large Vd

Front 67

what does extensive drug tissue binding result in?

Back 67

very large Vd

Front 68

what is Vd useful for?

Back 68

predicting where drug is distributed and calculating dose needed for desired plasma concentration

Front 69

how do we predict the effect of plasma and tissue binding on Vd?

Back 69

Vd = Vp + Vtw(fup/fut)

Front 70

what does Vp stand for?

Back 70

plasma water (constant)

Front 71

what does Vtw stand for?

Back 71

total water (constant)

Front 72

what does fup stand for?

Back 72

fraction unbound in plasma

Front 73

what does fut stand for?

Back 73

fraction unbound in tissue

Front 74

what does incrased plasma binding result in?

Back 74

decreased Vd

Front 75

what does increased tissue binding result in?

Back 75

increased Vd