Kinetics Lecture 9-30 Part 12

Front 1

fat free tissues

Back 1

-high water content, decreases with age mainly due to reduction in extracellular water
-lipophilic drug molecules bind to proteins and accumulate in membranes

Front 2

body fat

Back 2

- practically no water
- constant density ~ 900g/L
- lipophilic drug molecules: accumulate in membranes and in triglyceride oil that almost completely fills the adipocytes, bind to proteins

Front 3

volume of blood

Back 3

adults: ~70 mL/kg (about 5 L in the standard person)

children: ~80mL/kg

Front 4

hematocrit

Back 4

the volume fraction of formed elements ~ 0.45

Front 5

volume of plasma

Back 5

(5*0.55) ~2.8L (3L)

Front 6

Blood: circulation data

cardiac output=

Back 6

the volume of blood pumped by heart per minute

heartbeats per min * the stroke volume of the heart

69/min * 0.08 L = ~5.5L/min

Front 7

Blood: composition

Back 7

plasma
erythrocytes
leukocytes
platelets
chylomicra (fat droplets)

Front 8

capillaries consist of:

Back 8

- endothelial layer: large, polygonal, flat cells of irregular shape, joined by interstitial cement substance

diameter: ~ 8 micrometers, minimum ~4 micrometers (comparable to the diameter of the erythrocytes- pass slightly deformed)

Front 9

capillaries: porosity

Back 9

continuous( continuous lining of epithelial cells, uninterupted layer of basement membrane)

fenestrated (interrupted by fenestrae - 30 to 60 nm in diameter, complete basement membrane)

discontinuous (endothelial layer has openings - 100 to 300 nm in diameter, basement membrane missing)

Front 10

capillaries: permeability

fenestrated and discontinuous capillary walls

Back 10

-very permeable, even to small peptides

-no selectivity besides size limitations

Front 11

capillaries: permeability

continuous capillary walls

Back 11

-barrier function
-selective perm based on drug properties
-active protein-mediated transport for
(intake of nutrients- glucose, AA, ions and efflux of some substances- P-clycoprotein, MDR proteins)

Front 12

capillaries: density

high density in lungs:

Back 12

the interspaces are smaller than the capillaries themselves

Front 13

capillaries: density

intermediate density:

Back 13

in kidney: the interspace are about 3 x the volume of capillaries

in brain, liver, myocardium: the interspaces are about 10 x the volume of capillaries

Front 14

capillaries: density

low density

Back 14

in muscles, fat, connective tissue: the interspaces are about 30 x the volume of capillaries

Front 15

most living cells lie within:

Back 15

20 cell layers from a capillary

Front 16

nearly all cells are within:

Back 16

100 to 200 micrometer from a capillary

Front 17

capillaries: permeability

continuous capillary walls

Back 17

-barrier function
-selective perm based on drug properties
-active protein-mediated transport for
(intake of nutrients- glucose, AA, ions and efflux of some substances- P-clycoprotein, MDR proteins)

Front 18

capillaries: density

high density in lungs:

Back 18

the interspaces are smaller than the capillaries themselves

Front 19

blood flow through organs:

Back 19

see chart on page 2

** lungs- 100% cardiac output, blood flow 10 ml/min/g
** kidney- 22% cardiac output, blood flow 4 ml/min/g

Front 20

capillaries: density

intermediate density:

Back 20

in kidney: the interspace are about 3 x the volume of capillaries

in brain, liver, myocardium: the interspaces are about 10 x the volume of capillaries

Front 21

tissue uptake (extravasation)

Back 21

-drug molecules easily reach the interstitial space through fenestrated and discontinuous capillary walls
-transport through continuous capillary walls and tissue cell membranes determined by the rate of trans-bilayer transport
-procedes towards equilibrium of the drug between tissue and the blood perfusing it

Front 22

capillaries: density

low density

Back 22

in muscles, fat, connective tissue: the interspaces are about 30 x the volume of capillaries

Front 23

the rate of tissue uptake can be:

Back 23

- perfusion limited (drug amount brought in the bloodstream is completely distributed in the 1st run
- permeability limited ( drug molecules stay in the bloodstream for longer time)

Front 24

most living cells lie within:

Back 24

20 cell layers from a capillary

Front 25

lipophilicity

Back 25

-tendency to accumulate in the hydrophobic core of the membranes

-parameter: the reference partition coefficient P o/w

Front 26

nearly all cells are within:

Back 26

100 to 200 micrometer from a capillary

Front 27

blood flow through organs:

Back 27

see chart on page 2

** lungs- 100% cardiac output, blood flow 10 ml/min/g
** kidney- 22% cardiac output, blood flow 4 ml/min/g

Front 28

tissue uptake (extravasation)

Back 28

-drug molecules easily reach the interstitial space through fenestrated and discontinuous capillary walls
-transport through continuous capillary walls and tissue cell membranes determined by the rate of trans-bilayer transport
-procedes towards equilibrium of the drug between tissue and the blood perfusing it

Front 29

the rate of tissue uptake can be:

Back 29

- perfusion limited (drug amount brought in the bloodstream is completely distributed in the 1st run
- permeability limited ( drug molecules stay in the bloodstream for longer time)

Front 30

lipophilicity

Back 30

-tendency to accumulate in the hydrophobic core of the membranes

-parameter: the reference partition coefficient P o/w

Front 31

amphilicity

Back 31

-tendency to absorb to membrane/water interfaces
-dramatically reduces the transport rates

Front 32

the reference partition coefficient

the system:

Back 32

1- octanol/water

Front 33

the reference P can be predicted from drug structure:

Back 33

logP= sum of fragment contributions (as if each fragment of drug molecule had its own logP value

Front 34

fragment contribution to logP

similar solvents tend to dissolve similar solutes:

Back 34

- 1-octanol has the structure of inverted micelles, more volume is nonpolar
- carbon containing fragments are better dissolved in 1 octanol and have positive fragment contributions
- heteroatom containing fragments are better dissolved in water and have negative fragment contributions

Front 35

transbilayer transport and accumulation

Back 35

see slide page 3 and page 4

Front 36

lymphatic system I

functions:

Back 36

-removal of excess interstitial fluid
-transport of fatty acids from the GI tract to the bloodstream
-production of immune cells (lymphocytes, monocytes...)

Front 37

lymphatic system

Back 37

-starts as lymph capillaries collecting excess interstitial fluid
-progressively larger vessels connect to right lymphatic duct (for lymph from the right upper body) and the thoracic duct (for the rest of the body)
-these ducts drain into the circulatory system at the right and left subclavian veins

Front 38

lymph

Back 38

- originates as plasma leaking from blood capillaries that becomes interstitial fluid
- local compostion depends on the vasculature- leaky capillaries (liver...) allow more proteins out
- the transparent fluid containing immune cells, chylomicra, proteins, and ions

Front 39

the lymph components serve as drug carriers

Back 39

- albumin
-chylomicra (especially lipophilics drugs)
-cells

Front 40

drug distribution in fetus

Back 40

- capillary walls separating fetal blood from maternal blood are continuous

- many drugs can be found in fetus shortly after the administration to mother (fetus can be pharmaceutically treated through mother's body and risk of the undesireable effects is high- testing of drugs for teratogenicity, minimal drug use during pregnancy