Chapter 10 Kinetics

Front 1

After the drug is absorbed, the drug molecules are distributed throughout the body by

Back 1

systemic circulation

Front 2

This type of drug is deposited in fat where the drug can slowly be released

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lipophilic drugs

Front 3

distribution is generally...

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rapid

Front 4

cell membrane is made up of what two things

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protein and a lipid bilayer

Front 5

what two types of drug diffuse easily across the cell membrane

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lipid soluble drugs and small molecule drugs

Front 6

drugs bound to what form a larger complex making diffusion more difficult

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plasma proteins

Front 7

what are the two processes of drug transfer from capillary into tissue

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diffusion and hydrostatic pressure

Front 8

what is the main process of drug transfer from capillary into tissue

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passive diffusion

Front 9

passive diffusion is

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drug molecules moving from HIGH concentration to LOW concentration

Front 10

Three important factors in determining rate of drug diffusion

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1. membrane thickness
2. diffusion coefficient of drug
3. concentration gradient across capillary membrane

Front 11

If a drug diffuses RAPIDLY in such a way that BLOOD FLOW is the rate limiting step then this process is called

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perfusion or flow limited

Front 12

an example of perfusion of flow limited drug diffusion

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congestive heart failure: decreased cardiac output leads to impaired blood flow-->reduced renal clearance through reduced filtration pressure

Front 13

If a drug diffuses SLOWLY across membrane in the tissue, this process is called

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diffusion or permeability limited

Front 14

Drugs that are this may have an increased distribution volume in diseases that cause inflammation and an increased capillary membrane permeability

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permeability limited

Front 15

These three things are ALSO important in determining time for drug to be fully distributed

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blood flow, tissue size and tissue storage

Front 16

The partitioning and accumulation of drug in the tissue

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drug affinity

Front 17

These factors help determine what?
blood flow to the organ, the volume of the organ, and the partitioning of the drug into the organ tissue

Back 17

determine the distribution constant of a drug into an organ

Front 18

a physical property that measures the ratio of the solubility of the drug in the oil phase and in aqueous phase

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partition coefficient

Front 19

This is defined as a ratio of the drug concentration in the oil phase (octanol) divided by the drug concentration in the aqueous phase measured at equilibrium under specified temp

Back 19

partition coefficient

Front 20

this is one of the most important factors that determine the tissue distribution of a drug

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partition coefficient

Front 21

If each tissue has the same ability to store the drug, then the distribution half life is governed by what two things

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blood flow (Q) and organ volume (V)

Front 22

A large blood flow to the organ ________ the distribution time, whereas a large organ size/volume ________ the distribution time (because a longer time is needed to fill a large organ with drug)

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decreases, increases

Front 23

This is an important consideration in determining how rapid and how much drug reaches the receptor site

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blood flow

Front 24

Some tissues have great ability to store and accumulate drug as shown by large what values

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large R values

Front 25

Digoxin has a high what ratio, leading to a long distributional phase despite abundant blood flow to the heart

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high R ratio

Front 26

If a tissue has a long distribution half life, then does it need a longer or shorter period of time for the drug to leave the tissue when blood levels decrease

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a longer period of time is needed

Front 27

What two things lead to longer distribution times in the tissue site

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protein binding and favorable solubility in the tissue site

Front 28

Chemical knowledge in _______ ________ often helps to estimate the lipid solubility of a drug

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molecular structure

Front 29

A drug with a large _________ tend to have high R values in vivo

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oil/water partition coefficient

Front 30

A reduction of this often reduces the rate of drug uptake into the brain

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partition coefficient

Front 31

The uptake of the drug into tissue is generally controlled by

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diffusional barrier of the capillary membrane

Front 32

Drugs with good ______ _______ have high kidney, liver and lung concentrations

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aqueous solubility

Front 33

The brain capillaries are surrounded by a layer of tightly joined ______ ________ that act as a lipid barrier to stop diffusion of polar or highly ionized drugs

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glial cells

Front 34

The accumulation of drugs into tissues is dependent on what two things

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blood flow and the affinity of the drug for the tissue

Front 35

Is drug uptake reversible?

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YES, generally

Front 36

Drugs with high this tend to accumulate or concentrate in the tissue

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high tissue affinity

Front 37

Is the process of lipid soluble drugs partitioning from the aqueous environment of the plasma into the fat reversible?

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YES

Front 38

Drug accumulation and drug removal from adipose tissue is slow because

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adipose tissue is poorly perfused with blood

Front 39

This highly lipid soluble drug remains in fat tissues for years

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chlorinated hydrocarbon DDT

Front 40

How else may drugs be accumulated in tissues

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by binding to proteins

Front 41

capillary membranes in the liver and kidneys are ______ permeable to transmembrane drug movement than capillaries in the brain

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MORE

Front 42

The added layer of glial cells on cell membranes in the brain and spinal cord do what
*blood brain barrier

Back 42

slow the rate of drug diffusion into the brain

Front 43

Can the permeability of cell membranes be altered?

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YES, under certain pathophysiological conditions
*BURNS of the skin, MENINGITIS

Front 44

The concentration of drug in the plasma or tissues depends on what two things

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the amount of drug systemically ABSORBED and the VOLUME in which it is distributed

Front 45

This is used to estimate the extent of drug distribution in the body

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Vd, volume of distribution

Front 46

Does Vd represent a true, anatomical or physical volume?

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NO

Front 47

This represents the result of dynamic drug distribution between the plasma and the tissues and accounts for the mass balance of the drug in the body

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volume of distribution, Vd

Front 48

If the amount of drug added to the system and the drug concentration after equilibrium in the system are known, can the volume of the system be estimated?

Back 48

YES

Front 49

This is used in pharmacokinetics because the tissues compartments are not easily sampled and the true volume is not known

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Vd

Front 50

As the amount of drug in the cell compartment increases, the apparent Vd of the fluid compartment ________

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increases also

Front 51

Extensive cellular drug binding pulls drug molecule out of the fluid compartment, _______ the drug concentration in the fluid compartment and ________ Vd

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decreases, increases

Front 52

In biological systems, the quantity of cells, cell compartment volume and extent of drug binding within cells can all affect what

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Vd

Front 53

A large cell volume or extensive drug binding in the cells _______ the drug concentration in the fluid compartment and _______ the apparent Vd

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reduces, increases

Front 54

Can the Vd for a drug exceed the physical volume of the body?

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YES, if the drug is distributed widely or concentrates unevenly

Front 55

Cellular binding and partitioning of drug into lipid cellular components can affect Vd how?

Back 55

inflating it

Front 56

Drugs with very large Vd values have very ______ drug concentrations in plasma

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low

Front 57

This type of drug binding increases the apparent Vd

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extravascular drug binding

Front 58

Greater tissue drug binding and drug accumulation ______ Vd while greater plasma protein drug binding _______ Vd distribution

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increases, decreases

Front 59

THis can relate the plasma drug concentration to the amount of drug in the body

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Vd

Front 60

Only this type of drug diffuses between the plasma and tissue fluids

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free unbound drug

Front 61

For many protein bound drugs, is the ratio of drug in the body to plasma drug concentration constant?

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NO
**ratio best determined at steady state

Front 62

Protein binding to tissue has an apparent effect of ________ the apparent Vd

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increasing

Front 63

Penicillin, cephalosporin, valproic acid and furosemide are polar compounds that stay mostly within the plasma and extracellular fluids and therefore have a relatively ____ Vd

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LOW

Front 64

Drugs with lower distribution to the extracellular water are more extensively distributed inside the tissues and tend to have a ______ Vd

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large

Front 65

For many protein bound drugs, is the ratio of drug in the body to plasma drug concentration constant?

Back 65

NO
**ratio best determined at steady state

Front 66

Protein binding to tissue has an effect of ________ the apparent Vd

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increasing

Front 67

Penicillin, cephalosporin, valproic acid and furosemide are polar compounds that stay mostly within the plasma and extracellular fluids and therefore have a relatively ____ Vd

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LOW

Front 68

Drugs with lower distribution to the extracellular water are more extensively distributed inside the tissues and tend to have a ______ Vd

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large

Front 69

This drug has a large Vd, is highly protein bound and concentrated in the plasma

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imipramine

Front 70

The formation of a drug protein complex is often called

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drug-protein binding

Front 71

Is drug-protein binding reversible or irreversible?

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both

Front 72

This type of drug binding is usually a result of chemical activation of the drug, which then attaches strongly to the protein or macromolecule by covalent chemical bonding

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irreversible drug-protein binding

Front 73

Why do protein-bound drugs have restricted distribution

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because they are a large complex and cannot easily transverse cells or membranes

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are protein-bound drugs pharmacologically active?

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NO, they are usually inactive

Front 75

Are free or unbound drug therapeutically active compared to protein bound drug?

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YES

Front 76

This is a protein that is a major component of plasma proteins (60% in plasma) responsible for reversible drug binding

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albumin

Front 77

This protein binds highly with weakly acidic drugs (salicylates, phenylbutazone, penicillins)

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albumin

Front 78

These (RBCs) may bind both endogenous and exogenous compounds

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erythrocytes

Front 79

Penetration into RBCs is dependent on what

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free concentration of the drug

Front 80

Drugs highly bound to plasma proteins have a low fraction of this in the plasma water

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free drug (fu=unbound / free drug)

Front 81

Plasma bound drugs do not diffuse easily so how are they distributed?

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less extensively distributed in the tissues

Front 82

Drugs with low plasma protein binding have a larger fu (free/unbound drug) and diffuse more easily into tissues so how are they distributed?

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greater volume of distribution

Front 83

Basic drugs (like imipramine, nortriptyline and propranolol) are extensively bound to both plasma proteins and tissues, so what is their Vd?

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very large Vd

Front 84

Displacement of drugs from plasma proteins directly increases this

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the free/unbound drug concentration

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Displacement of drugs from plasma proteins directly _______ the free drug concentration as a result of reduced binding in the blood

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increases

Front 86

Displacement of drugs from plasma proteins ________ the free drug concentration that reaches the receptor sites directly causing a more intense (toxic) response

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increases

Front 87

Displacement of drugs from plasma proteins _______ the free drug concentration causing a _______ in Vd and decreasing the increase of free plasma drug concentration

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increases

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Displacement of drugs from plasma proteins _______ the free drug concentration resulting in more drug diffusion into tissues, increasing drug elimination

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increases

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When are unbound drug in plasma and tissue in equilibrium?

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Steady state

Front 90

When is Vd constant?

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When drug concentrations are in equilibrium between the plasma and tissue

Front 91

Compartment models are based on

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mass balance and the amount of drug in each compartment
*NOT on tissue volume or tissue drug concentration

Front 92

As the fraction of unbound drug (fu) in the plasma increases, the apparent volume _________

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increases

Front 93

Reduced drug binding in the plasma results in _______ free drug concentration which diffuses into the extracellular water

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increased

Front 94

Drug showing exceptionally large volumes of distribution may have unusual what

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tissue binding

Front 95

Drugs that do not obey the general binding rule may have what two features

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very large volumes of distribution and undiscovered tissue binding

Front 96

Drugs that are highly bound to plasma protein have reduced overall what

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drug clearance

Front 97

The elimination half-lives of some drugs are ________ when the percent of drug bound to plasma proteins increases

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increases

Front 98

Some drugs (tetracycline analogs) have serum protein binding... the more bound to serum they are, the ______ their elimination half life is

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larger

Front 99

Drug that is extensively bound and actively secreted by the kidneys (penicillin) has a ______ elimination half life because active secretion takes preference in removing the drug from the proteins

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short

Front 100

This is governed by renal and other metabolic processes in the body

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drug elimination

Front 101

Extensive drug distribution has the effect of diluting the drug in a large volume... this would affect elimination how?

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making it harder for the kidney to filter the drug

Front 102

____ plasma drug concentration may be due to extensive distribution into tissues due to favorable lipophilicity/protein binding in peripheral tissues or lack of drug plasma protein binding

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Low plasma drug concentration

Front 103

When Vd is large, clearance is

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also large because it will take a long time for the drug to be removed when it is distributed extensively over a large volume

Front 104

When a drug is tightly bound to a protein, only the _______ drug is assumed to be metabolized. This is called restrictive elimination

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unbound drug is metabolized

Front 105

Drugs with this type of elimination are recognized by very small plasma clearances and extensive plasma protein binding

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restrictive elimination

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Drugs that may be eliminated even when they are protein bound are called this

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non-restrictively eliminated

Front 107

Drug protein binding is influenced by what five factors:

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1. the drug (physicochemical props, total concentration)
2. the protein (quantity,quality)
3. the affinity between drug and protein
4. drug interactions (competition, alteration of protein)
5. pathophysiologic condition of patient (uremic/hepatic disease)

Front 108

Do plasma drug concentrations (total drug concentrations) include both protein-bound drug and unbound drug concentrations?

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YES

Front 109

Because of the high plasma protein binding of phenytoin and the narrow therapeutic index of the drug, more hospital labs are measuring both free and total phenytoin plasma levels using what

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ultra filtration

Front 110

The ______ of drug bound is often used to describe the extent of drug-protein binding in the plasma

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percent

Front 111

At low drug concentrations how much of the drug may be bound to the protein

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most of the drug

Front 112

At high drug concentrations the protein binding sites become saturated with a rapid ________ in the free drug concentration

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increase

Front 113

Is protein binding linear?

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NO, its nonlinear usually

Front 114

As the protein concentration increases, the percent of drug bound ______ to a maximum

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increases