Kinetics: Lecture 9: Physiologic Drug Distribution And Protein Binding

Front 1

Drug is borne by ? to the site of ?.

Back 1

Drug is borne by blood (via blood vessels) to the site of action.

Front 2

? pumped by heart per minute (?) is important.

Back 2

The volume of blood pumped by heart per minute (cardiac output) is important.

Front 3

What is cardiac output equivalent to?

Back 3

Cardiac output = stroke volume X heart rate

Front 4

At rest, average cardiac output is what? What is this due to?

Back 4

At rest, avg cardiac output (due to 69 left ventricle contractions per minute) is 5.5L per minute.

Front 5

What is blood pressure equivalent to?

Back 5

Blood pressure = cardiac output X peripheral resistance

Front 6

Left ventricle contraction produces a systolic blood pressure of ?, and moves blood at ? through the aorta.

Back 6

Left ventricle contraction produces a systolic blood pressure of 120mmHg, and moves blood at 300mm/sec thru the aorta.

Front 7

In a 70 kg adult what is the intracellular water volume?

Back 7

27

Front 8

What is the interstitial water volume in a 70kg adult?

Back 8

12

Front 9

What is the plasma water volume in a 70kg adult?

Back 9

3

Front 10

What is the blood cell water volume in a 70kg adult?

Back 10

2

Front 11

What is the total blood volume in a 70kg adult?

Back 11

5L

Front 12

Name 2 factors affecting drug entry into tissues.

Back 12

1. physicochemical nature of cell membranes

2. physicochemical properties of drug

Front 13

List some aspects of the physicochemical nature of cell membranes that are factors affecting the entry of drug into tissues.

Back 13

1. Protein + bi-layer of phospholipid

2. Under certain pathophysiological conditions (ex, burns and meningitis) permeability could change.

3. Unique features of tissue such as blood-brain barrier.

Front 14

List some aspects of the physicochemical properties of drugs that are factors affecting the entry of drug into tissues.

Back 14

1. Lipophilic drugs traverse cell membranes more easily than polar ones.

2. Small molecules traverse membranes more easily than larger ones or those forming drug-protein complexes.

Front 15

How do most drugs enter cells?

Back 15

Most drugs enter cells by way of spontaneous passive diffusion.

Front 16

Passive diffusion is ? dependent and governed by ?. What is the rate of drug diffusion?

Back 16

Passive diffusion is temperature dependent and governed by Fick's Law of Diffusion.

The Rate of drug diffusion:
dQ/dt = -DKA(Cp - Ct)/h

Front 17

Give the rate of drug diffusion and define the variables?

Back 17

dQ/dt = -DKA(Cp - Ct)/h

h = thickness
A = surface area of membrane
D = diffusion constant
K = lipid-water partition coefficient
Cp = drug concentration in plasma
Ct = drug concentration in tissue

Their is a negative sign because there is a net transfer of drug from the capillary lumen to the extracellular fluid and tissue.

Front 18

What is hydrostatic pressure?

Back 18

It is the pressure difference between capillaries entering and those leaving tissue.

Front 19

Hydrostatic (filtration) pressure is caused by what?

Back 19

Hydrostatic (filtration) pressure is caused by capillary blood pressure being higher than that of tissue at the arterial end.

Front 20

What is hydrostatic pressure responsible for?

Back 20

It is responsible for the transfer of water-soluble drugs penetrating spaces between endothelial cells.

Front 21

When blood pressure of tissues is higher than venous capillaries what does it create?

Back 21

It creates 'absorptive' pressure, so filtrate gets transferred to venous capillary.

Front 22

What may distribution be limited by?

Back 22

1. Flow limited (such as in congestive failure)

2. Diffusion limited (such as during inflammation when there is increased capillary permeability)

Front 23

What is the first-order distribution constant for a drug into an organ?

Back 23

Kd = Q/VR

Kd = distibution constant
Q = blood flow to the organ
V = volume of the organ
R = ratio of drug concentration in the organ to that in the venous blood

Front 24

The ratio of drug concentration in the organ to that in venous blood (R) may be estimated from what?

Back 24

R may be estimated from the oil/water partition coefficient (Po/w).

Front 25

A drug with a high oil/water partition coefficient (Po/w) will have a ? ratio of drug conc. in the organ to that in venous blood (R).

Back 25

A drug with a high Po/w will have a high R.

Front 26

A large blood flow (Q) ? distribution time. A large volume (V) ? distribution time.

Back 26

A large blood flow (Q) decreases distribution time; a large volume (V) increases distribution time.

Front 27

What is the formula for the first-order distribution half-life?

Back 27

td1/2 = 0.693/kd

Front 28

What does R indicate?

Back 28

R = ratio of drug concentration in the organ to that in the venous blood.

It indicates the extent to which an organ accumulates a drug.

Front 29

What does a high R indicate?

Back 29

A high R (due to either protein binding or high solubility of the drug in the tissue) means it takes longer for distribution to complete. (ex. flutamide, digoxin)

Front 30

A high level of accumulation in tissues results in what?

Back 30

A high level of accumulation in tissues results in a long elimination half-life (ex. etretinate, DDT); plasma levels may not correlate well with pharmacodynamic action if tissue is target tissue.

Front 31

Name 4 mechanisms of accumulation.

Back 31

1. Dissolution in lipids

2. reversible binding to biomolecules (ex. protein, melanin, calcium)

3. Irreversible binding to biomolecules (ex. in chemotherapy purine/pyrimidine drugs that bind to nucleic acids)

4. Enzymatic or active transport systems.

Front 32

Any undetected source that reduces the plasma drug concentration increases what?

Back 32

Any undetected source that reduces the plasma drug concentration increases the apparent volume of distribution.

Front 33

Give two examples of sources that may reduce the plasma drug conc; thus increasing the apparent volume of distribution.

Back 33

Sources may include:

1. Binding to proteins within tissues

2. Binding of metabolites to tissues following metabolism of drug

Front 34

What may be an indication of a reduction in plasma drug concentration that increases the apparent volume of distribution?

Back 34

A Vd greater than combined plasma volume and body water indicates that this could be the situation.

Front 35

When might an irreversible binding of a drug to a protein sometimes occur?

Back 35

Irreversible binding to protein sometimes occurs when an activated form of a drug attaches to a protein via a covalent bond (ex. acetaminophen hepatoxicity, chemical carcinogenesis)

Front 36

Which is more typical, reversible or irreversible binding?

Back 36

Reversible binding is more common.

Front 37

What is reversible binding usually due to?

Back 37

Reversible binding is usually due to weak bonds such as hydrogen bonds and van der waals bonds.

Front 38

Are protein-bound drugs active?

Back 38

Protein-bound drugs are usually not active pharmacologically?

Front 39

What are protein bound drugs unable to cross?

Back 39

Protein-bound drugs are unable to cross cells or cell membranes.

Front 40

Drug-protein binding may be ?: There can be ? in protein binding. (ie, ?)

Back 40

Drug-protein binding may be allosteric: There can be cooperativity in protein binding (ie, binding of first drug molecule can affect the binding of successive molecules to the same protein molecule)(ex, O2 binding to Hb)

Front 41

List 5 factors affecting protein binding.

Back 41

1. Drug properties

2. protein properties

3. Drug-protein affinity: Ka

4. Drug-Drug interactions

5. Disease condition of the patient

Front 42

Generally speaking, what are the drug properties that affect protein binding?

Back 42

The physicochemical properties and quantity of drug in the body.

Front 43

Generally speaking, what are the protein properties that affect protein binding?

Back 43

The physicochemical properties and quantity of protein available for binding.

Front 44

The variable associated with the drug-protein affinity that may affect protein binding?

Back 44

Ka

Front 45

What drug-drug interaction may affect protein binding?

Back 45

1. Competition for binding sites.

2. The binding of one drug alters the affinity of protein for another drug.

Front 46

How may a disease condition for a patient affect protein binding?

Back 46

It may reduce blood-protein binding (ex. hepatic disease)

Front 47

List some of the blood proteins involved in drug protein binding?

Back 47

1. Albumin

2. Alpha1-acid glycoprotein

3. Lipoproteins

Front 48

What is the mw of albumin?

Back 48

65kDa

Front 49

What is albumin largely responsible for?

Back 49

It is largely responsible for maintaining the osmotic pressure of blood.

Front 50

What might bind to albumin?

Back 50

1. Weak acidic drugs (like salicylates and penicillin)

2. Free Fatty Acids

3. Bilirubin

4. Some hormones (like cortisone and thyroxine)

Front 51

Albumin has ? binding sites for which different drugs ?.

Back 51

Albumin has several binding sites for which different drugs compete.

Front 52

Name some drugs that compete for binding site I of albumin?

Back 52

Sulfonamides, phenytin, valproic acid and phenylbutazone compete for binding site i.

Front 53

Name some things that compete for binding site II of albumin?

Back 53

Medium chain fatty acids, probecinid, benzodiazepines, and some penicillins compete for binding site II.

Front 54

The blood protein alpha1-acid glycoprotein is aka what?

Back 54

AAP or orosomucoid

Front 55

What is alpha1-acid glycoprotein?

Back 55

It is a globulin.

Front 56

What is the mw of alpha1-acid glyoprotein?

Back 56

44kDa

Front 57

What drugs might bind to AAP?

Back 57

Many basic drugs bind to AAP. Such as propranolol or lidocaine.

Front 58

Globulins (like AAP) (alpha, beta, and gamma) have a ? ? and ? ? for endogenous substances such as ?.

Back 58

Globulins have a high affinity and low capacity for endogenous substances such as corticosteroids.

Front 59

What is the mw of lipoproteins?

Back 59

Range, 200-3400kDa.

Front 60

Give 3 examples of lipoproteins?

Back 60

1. VLDL (very low density ")

2. LDL (low-density)

3. HDL (high-density)

Front 61

What do the lipoproteins do?

Back 61

They bind to and transport plasma lipids to the liver.

Front 62

Give an examples of an immunoglobulin blood protein that is involved in drug protein binding?

Back 62

IgG

Front 63

Some drugs bind ? to RBCs. What does this mean?

Back 63

Some drugs bind strongly to RBCs. For such, the hematocrit influences the total amount of drug in the blood. Binding to albumin reduces binding to RBCs.

Front 64

What does the variable fu represent?

Back 64

Unbound drug fraction

Front 65

Generally speaking drugs with little ? ? ? have large fu (unbound drug fraction). What does this mean?

Back 65

Generally drugs with little plasma protein binding have large fu (unbound drug fraction). So they diffuse more into tissues and so have a large Vds.

Front 66

High protein binding in blood ? ? to targets of action in tissues?

Back 66

High protein binding in blood reduces penetration to targets of action in tissues.

Front 67

What does the variable fut represent?

Back 67

Unbound drug fraction in the tissue.

Front 68

The volume of distribution, fu and fut should only be measured when?

Back 68

They should only be measured under equilibrium conditions. (when drug concentrations between the plasma and tissue equilibrate)

Front 69

For drugs excreted mainly by filtration in the kidney, as plasma protein binding increases, so does what else?

Back 69

The elimination half-life.

Front 70

For drugs eliminated by active renal secretion, the elimination half-life can be ? even with high protein binding.

Back 70

The elimination half-life can be short even with high protein binding. (Recall secretion preferentially strips blood protein of drug)

Front 71

For drugs eliminated by both renal and biliary secretion what is there poor correlation between?

Back 71

There is poor correlation between plasma protein binding and clearance.

Front 72

What does clearance equal?

Back 72

Cl = kVd

Front 73

In relation to Vd and Cl what does t1/2 equal?

Back 73

t1/2 = 0.693(Vd/Cl)

Front 74

What does a high Vd ensure?

Back 74

A large Vd may assures a long t1/2 but a low Vd may also assure a long t1/2 (?)

Front 75

What does non-restrictively eliminated mean?

Back 75

A non-restrictively eliminated drug (like propranolol) are eliminated even when they are protein bound.

Front 76

For non-restrictively eliminated drugs elimination is not exclusively what?

Back 76

It is not exclusively hepatic.

Front 77

What does restrictively eliminated mean?

Back 77

Restrictively eliminated drugs (like phenylbutazone and piroxicam) generally have small hepatic extraction ratios (ER<fu) and do not have first pass effects.

Front 78

What is the law of mass action?

Back 78

The rate of a chemical reaction is proportional to the product of the concentrations of the reactants.

Front 79

What does the variable r represent?

Back 79

The moles of bound drug/total moles of protein.

r = [PD]/([PD] + P)

PD = drug-protein complex

Front 80

Can a protein have more than one kind of binding site for a molecule.

Back 80

yes (ex. binding of salicyclic acid to albumin)

Front 81

What does the dissociation constant (kd) equal?

Back 81

kd = 1/ka

Front 82

What is a double reciprocal plot?

Back 82

1/r against 1/[D].

It gives a slope of 1/nKa and a y-int. or 1/n.

Since both r and [D] can be determined, ka may be calculated.

Slope = 1/nKa

Front 83

What is a scatchard plot?

Back 83

r/[D] vs r

Front 84

What is the slope of a scatchard plot?

Back 84

-ka

Front 85

What would a non-linear scatchard plot indicate?

Back 85

Suggest complexities exist, like there could be more than one type of binding site.

Front 86

At constant protein levels, what happens to all available binding sites?

Back 86

They get bound even at low drug concentrations. At low drug concentrations the fraction of bound drug is high. After saturation free drug levels rapidly increase.