3. Drug Distribution

Front 1

What has to happen to drugs after they get absorbed from the route of administration into the circulation?

Back 1

Distribution to target tissues and organs.

Front 2

What are 4 factors that drug distribution depends on?

Back 2

1. Regional bloodflow
2. Capillary permeability of the drug
3. Drug binding to plasma proteins
4. Tissue accumulation of drugs

Front 3

What are the 2 phases of bloodflow during drug distribution?

Back 3

1. First phase to highly perfused organs
2. 2nd phase to more poorly perfused organs

Front 4

What are the highly perfused organs that receive the drug first?

Back 4

-Brain
-Liver
-Kidney

Front 5

What organs receive less drug during its first phase of bloodflow?

Back 5

-Muscle
-Skin
-Viscera
-Fat

Front 6

How does drug equilibration with tissues contrast in first phase vs second phase bloodflow?

Back 6

First phase = fast equilibration

Second phase = very slow

Front 7

Why is the equilibration of the drug with less perfused organs and tissues so slow during 2nd phase bloodflow?

Back 7

Because there is so much more body mass involved

Front 8

What are the 2 important determinants in 2nd phase distribution of a drug?

Back 8

-Tissue volume
-Lipophilicity

Front 9

What are most capillary endothelial cell junctions?

Back 9

Loose

Front 10

What do loose endothelial junctions allow for drugs?

Back 10

Paracellular movement from the circulation to the tissues.

Front 11

Where are capillary endothelial cell junctions TIGHT?

Back 11

In the brain

Front 12

So the 2 factors that influence capillary permeability of drugs for distribution are:

Back 12

-Cell junctions (loose vs tight)
-Drug lipophilicity

Front 13

What influences distribution of drugs that are weak acids/bases? Is it very important?

Back 13

pH - not particularly significant because the blood pH is pretty similar to tissue pH

Front 14

How do drugs circulate in the bloodstream?

Back 14

Bound to plasma proteins

Front 15

What are the 2 predominant plasma proteins that carry drugs?

Back 15

-Albumin
-a1-Acid glycoprotien

Front 16

What is the nature of how drugs associate with the plasma proteins?

Back 16

-Easily reversible
-Low affinity

Front 17

What determines how much drug binds to the plasma proteins?

Back 17

The law of mass action - the more drug there is, the more drug-protein complex is formed.

Front 18

How does the fact that the therapeutic concentration range for most drugs is limited effect the amounts of bound/unbound drug?

Back 18

They are relatively constant.

Front 19

What determines drug response, toxicity, and elimination?

Back 19

UNBound drug

Front 20

What is the equation for the concentration of protein-bound drug?

Back 20

[PROTEIN][DRUG]
[DP]= ----------------
Kd + [DRUG]

Front 21

How does protein binding affect the amount of unbound drug at steady state?

Back 21

It doesn't; the amount of unbound drug will be fairly constant.

Front 22

What are 2 conditions that can transiently pertub the equilibrium between protein-bound and unbound drug?

Back 22

-Sudden changes in plasma protein concentrations
-Changes in exogenous or endogenous competitors for the protein binding sites.

Front 23

What is a clinical scenario that can perturb the equilibrium?

Back 23

Drug interactions; a patient is stabilized on drug A, but drug B competes for binding and now more A is free to exert its effect

Front 24

What are 2 disease states that can affect the extent of protein binding of a drug?

Back 24

1. Liver disease
2. Immune activation

Front 25

How does liver disease affect the extent of protein binding?

Back 25

-Albumin is decreased so free drug is increased; you might need to decrease the drug dose.

Front 26

How does immune activation affect the extent of protein binding?

Back 26

-a1-acid glycoprotiein might be increased; you might need to increase the drug dose.

Front 27

What 2 tissues are capable of accumulating drug?

Back 27

-Fat
-Bone

Front 28

What drugs can be stored for long periods in the fat?

Back 28

Lipophilic drugs (marijuana)

Front 29

What 2 drugs can accumulate in bone?

Back 29

-Tetracycline (binds divalent cations)
-divalent heavy metals

Front 30

How do drugs accumulate in bone?

Back 30

By absorbing onto the surface of the bone crystal, eventually being incorporated into the crystal lattice.

Front 31

What happens when drugs that chelate lead or radium get incorporated into bone?

Back 31

The bone can become a reservoir for the slow release of the same substances.

Front 32

What is drug REdistribution?

Back 32

A mechanism for the termination of action of a drug due to its redistribution from the site of action to one where its inactive

Front 33

For what 3 drugs is redistribution really an issue?

Back 33

-Highly lipid soluble drugs
-Drugs that act on a highly perfused organ (brain/heart)
-Drugs administered by IV injection or inhalation

Front 34

What is a specific example of a drug that gets inactivated by redistribution?

Back 34

Thiopental

Front 35

What is Thiopental?

Back 35

A very lipophilic anesthetic that is given intravenously

Front 36

Where is the site of action of Thiopental?

Back 36

The brain

Front 37

What happens after thiopental administration is stopped?

Back 37

The blood concentration goes down, so the drug goes out of the brain and back into the blood.

Front 38

What happens to the thiopental that returns to the blood?

Back 38

It gets redistributed to Adipose, where it is inactive

Front 39

What is the general result of thiopental redistribution?

Back 39

-Fast onset
-Fast offset

Front 40

What forms the blood:brain barrier?

Back 40

Tight junctions between capillary endothelial cells

Front 41

What forms the blood:CSF barrier?

Back 41

Tight junctions between epithelial cells of the choroid plexus

Front 42

What are the 3 requirement for drugs to be able to cross the BBB?

Back 42

-Nonionized
-Lipophilic
-Not bound to plasma proteins

Front 43

What can allow for drugs to cross the BBB if they are ionized, are not lipophilic, or are protein-bound?

Back 43

If a specific Uptake transporter that normally transports nutrients and endogenous compounds can bind the drug and transport it instead.

Front 44

What opposes drug entry into the brain?

Back 44

Efflux mechanisms

Front 45

What are 2 drug efflux mechanisms in the brain?

Back 45

-P-glycoprotein
-Organic anion transporting polypeptide (OATP)

Front 46

What type of drugs are effluxed by the P-glycoprotein mechanism?

Back 46

Lipophilic

Front 47

What does the OATP mechanism efflux?

Back 47

Negatively charged drugs

Front 48

What drug is the OATP mechanism specifically responsible for effluxing?

Back 48

Loperamide

Front 49

What is Loperamide?

Back 49

An opiate that as a result has no effect on the CNS and can be used for peripheral pain

Front 50

What can increase the local permeability of the BBB?

Back 50

-Meningeal inflammation
-Encephalic inflammation

Front 51

What is intentional disruption of the BBB used for?

Back 51

Enhanced delivery of chemotherapy to the brain for treating brain tumors

Front 52

What are the 3 important determinants of placental transfer of drugs?

Back 52

-Drug lipophilicity
-Ionization state (nonionized)
-Protein binding

Front 53

How do drugs cross the placenta?

Back 53

-Via passive diffusion
-Via carriers sometimes

Front 54

What type of carriers are present in the placental barrier?

Back 54

-Influx
and
-Efflux

Front 55

How does fetal plasma compare to maternal?

Back 55

Fetal is more acidic

Front 56

So what drugs can become trapped after crossing the placenta?

Back 56

Basic