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PHRM 501 > Exam 3: Drug distribution and TDM > Flashcards

Exam 3: Drug distribution and TDM Flashcards

1
Q

Therapeutic Drug Monitoring (TDM)

A

Using assays to measure drug concentration to develop safe and effective dosing regimens

  • The aim is to maintain the plasma drug concentration within a therapeutic range
  • safe and effective drugs
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2
Q

When to use Therapeutic Drug Monitoring

A
  • Drugs with a narrow therapeutic range
  • When the consequences to giving too much are
    serious or irreversible
  • When the consequences to giving too little are
    serious or irreversible
  • Strong correlation of plasma [drug] w/response
    -Wide interpatient variability
    -• Cannot assess response clinically such as BP, Respiratory rate
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3
Q

Drugs with narrow therapeutic range examples

A 
Ex: 
• Phenytoin: 10-20 mcg/mL
• Theophylline : 5-15 mcg/mL
• Digoxin: 0.5-2 ng/mL
• Tacrolimus: 5-20 mcg/L
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4
Q

Tacrolimus example of being given too little and too much

A

immunosuppressant in organ
transplant
- Too much: Acute renal failure
- Too little: Graft rejection

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5
Q

When not to use Therapeutic Drug Monitoring

A
  • Wide therapeutic index
  • No significant consequences to too low or too high levels
  • Minimal patient to patient variability
  • ## Weak correlation of [drug] w/response
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6
Q

Distribution

A

Ideally, we want the drug to reach the target sites rapidly with limited accumulation in non-target organs and at a concentration that is effective and non-toxic
- function of blood flow

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7
Q

What can impact drug distribution

A

Individual patient characteristics and disease states

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8
Q

Vascular space

A

Within blood vessels
• Intracellular (blood cells)
• Plasma

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9
Q

Extravascular space

A

Intracellular space

• Interstitial fluid

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10
Q

Most drugs are

A

selective’, not ‘specific’

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11
Q

Drugs bind to

A

to target receptors, but also can bind to non-target entities

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12
Q

Drugs may be distributed to organs that eliminate them

A

Liver- Metabolism

Kidneys-Excretion/ Elimination

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13
Q

Drugs can be distributed to other places as well such as

A

• into fat or saliva
• into breast milk and the placenta
- may have impact on developing fetus

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14
Q

How many liters of blood in body

A

Approximately 5 L of blood is in the adult human
body
The heart pumps the entire volume in ~1 minute
- Flow rate: ~5 L/min.

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15
Q

Certain organs recieve more of this blood flow than others such as

A

Liver, heart and kidney

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16
Q

What is the function of arteries

A

carry blood leaving the heart to the tissues

- carries blood away from heart

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17
Q

Process of blood from arteries to capillaries to tissues

A
  • Arteries branch into small arterioles
  • Small arterioles branch into capillaries
  • Capillaries feed the interstitial fluid between cells
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18
Q

Q represents

A

blood flow

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19
Q

Perfusion-Limited Distribution

A

Uptake is limited by delivery, rather than passage
- Permeability (PA) across cellular or membrane barriers is much greater than blood flow (Q) to
that tissue

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20
Q

Distribution Processes and Blood Flow

A

In some disease states, blood flow is the limiting step for drug distribution

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21
Q

Hydrostatic pressure

A

Pressure gradient from the arterial end of the capillaries entering the tissue to the venous capillaries leaving the tissue

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22
Q

Filtration pressure

A

, fluid leaves the capillaries and enters the tissues

- This is bc there is an ~8 mm Hg greater pressure in the capillaries at the arterial end than the tissue

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23
Q

Absorptive pressure

A

fluid leaves the tissues and returns to the capillaries

-This is bc at the venous end, the pressure is ~8 mm lower than the tissue

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24
Q

Absorptive pressure

A

fluid leaves the tissues and returns to the capillaries

-This is bc at the venous end, the pressure is ~8 mm lower than the tissue

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25
Q

For efficient filtration of drugs into the urine,

A

a high arterial hydrostatic pressure must exist

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26
Q

Decreased blood flow due to congestive heart failure

A

may reduce renal clearance through reduced blood flow

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27
Q

A higher arterial hydrostatic pressure causes

A

fluid to leave the capillaries and enter the tissues

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28
Q

A lower hydrostatic pressure causes

A

fluid to leave the tissues and return to the capillaries

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29
Q

Permeability-Limited Distribution

A 
Uptake is limited by permeation, rather than delivery
Blood flow (Q) to that tissue is much greater than permeability across cellular or membrane
barriers (PA)
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30
Q

Ex of Permeability-Limited Distribution

A

The brain gets plenty of blood flow, but restricted permeation
Blood-brain barrier (BBB) -tight junctions between glial cells as well as acting as a thicker lipid barrier

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31
Q

Distribution Processes and Blood Flow

A

Unless there is pressure, entry into an organ is based primarily on concentration-dependent diffusion
- Ficks law
In some disease states, permeability is altered which affects drug distribution

32
Q

Inflammation and burns yield

A

increased permeability which may increase a drug’s ability to permeate tissues

33
Q

Rate of distribution

A

Kd
- takes into account blood flow (Q), the volume of an organ (V), and the partitioning of the drug into the organ (R=ratio of drug concentration in the tissues to drug concentration in the blood)

34
Q

Rate of distribution formula

A

• kd=Q/(VR)

35
Q

The greater the blood flow

A

the faster the distribution

- Exercise increases blood flow and increases distribution

36
Q

The larger the organ

A

the slower the distribution

- It will take longer to fill a larger organ with drug than a smaller organ

37
Q

Distribution to Kidney is

A

fast

38
Q

Distribution to skin, muscle and fat

A

are slow

39
Q

R pertaining to distribution

A

ratio of drug concentration in the tissues to drug concentration in the blood

40
Q

A high log P generally correlates with

A
  • large R values in vivo
  • There may be plenty of drug that reaches the kidney, liver, and lung, but little accumulation in
    the brain
41
Q

If a drug extensively partitions into the tissues, we would expect the volume of distribution to be

A

large

plasma drug conc. will be low because drug is in tissues

42
Q

If a drug partitions extensively, we would expect it to have a (long/short) elimination half life

A

long
- it will take drug a long to get out of the body bc the plasma drug conc. is low

  • Only drug in plasma can be cleared
43
Q

If it takes a long time for a drug to partition into the tissue

A

it will take a long time for it to leave the tissue once the blood concentration decreases

44
Q

Increased drug-lipid solubility and drug-protein binding yield

A

longer distribution half-lives

45
Q

Drug uptake into a tissue depends on

A

partitioning and binding to specific components/receptors

• This is a reversible process

46
Q

A drug that has weak affinity for the tissues will

A

re-equilibrate rapidly with the plasma

- Its plasma drug concentration will decline rapidly as it then is eliminated from the body

47
Q

A drug that has high affinity for the tissues will

A

re-equilibrate slowly with the plasma

- Its prefers the tissue, hence plasma drug concentration will be low and elimination will be slow

48
Q

Blood flow to the adipose tissue is

A

low
- It will take a long time for a drug to accumulate there, but once it does, it will take a long time for it to
be removed

49
Q

OATP

A

Organic Anion Transporting Polypeptide

- influx

50
Q

OCT

A

Organic Cation Transporters
- Influx and Efflux
movement of ions in cell vs out of cell

51
Q

p-glycoprotein involved in

A

efflux

52
Q

Efflux transporters

A

shunt drugs out of cells
Limits toxicity, but can impede therapy!
Not limited to GI tract!

53
Q

Complexation and Protein binding

A

Drug molecules can complex with components which hinder absorption, distribution, metabolism,
or excretion
-In the gut, there may be complexation with: Multivalent ions
- Usually a reversible process

54
Q

In certain tissues

A

there may be binding to certain proteins

55
Q

In the blood, there may by binding to many constituents, including

A

RBCs
WBCs
Plasma proteins

56
Q

Plasma Protein binding

A

Protein binding has marked effects on drug distribution, metabolism, and excretion
- Only the free drug passes biological membranes

57
Q

Free drugs can

A

be metabolized or excreted by the kidneys!

- typically exerts a biological effect

58
Q

Plasma and Extracellular Protein Binding

A

Drugs bound to plasma proteins are in an equilibrium with free drug
- The free drug can pass the capillaries to reach extracellular water and remain free, be in
complex with other proteins, or pass cellular membranes

59
Q

Most drugs are

A

extensively protein bound

- The dose is adjusted to provide therapeutic effect

60
Q

The extent of protein binding affects

A

the VD, Cl, t1/2

61
Q

Fu

A

fraction of drug that is protein bound

62
Q

If fu is high

A

, the drug is readily available for metabolism/distribution/excretion

63
Q

If fu is low

A

not much of the drug is readily available for these processes

64
Q

The total drug concentration of drug in the body (Cb) is a function

A

of its concentrations (C) and
volumes (V) in the plasma (p) as well as the tissues (t)
CB=Vp*Cp+VtCt

65
Q

Drug protein bound. At steady state

A 
there is an equilibrium between bound and unbound (u) drug in the plasma (p)
and tissue (t)

Cup = Cut

66
Q

If your drug has reversible binding

A

then the proteins act as a pool

- As it releases, it serves as a continual pool that can be metabolized and eliminated

67
Q

If your drug binds tightly to proteins

A

then the proteins act as a sink

- Proteins accumulate the drug reducing its activity/clearance

68
Q

The levels of plasma proteins can vary by condition/disease state

A
  • May be suppressed or elevated
  • Dehydration, bone marrow disorders, infections, inflammation
  • Malabsorption of nutrients, kidney/liver disease, bowel disorders
  • Certain proteins are elevated with certain disease states
69
Q

A molecule that becomes more active after metabolism is a _____________.
• A. Drug
• B. Prodrug

A

• B. Prodrug

70
Q

If enzymes are induced, metabolic activity for a drug will_____________.
• A. Increase
• B. Decrease

A

• A. Increase

71
Q

If enzymes are induced, clearance for a drug will_____________.
• A. Increase
• B. Decrease

A

• A. Increase

72
Q

If enzymes are induced, the hepatic extraction ratio will_____________.
• A. Increase
• B. Decrease

A

• A. Increase

73
Q

The blood flow to the liver has decreased due to congestive heart failure, but the
liver’s metabolic capacity is unchanged. Your hepatic clearance
will_____________.
• A. Increase
• B. Decrease

A

• B. Decrease

74
Q

An herbal supplement which competes for the same CYP450 as Drug A will cause
the plasma concentration to _____________.
• A. Increase
• B. Decrease

A

A. Increase

75
Q

A patient drinks a glass of grapefruit juice while taking their daily dose of
phenytoin. The plasma concentration of phenytoin will likely _____________.
• A. Increase
• B. Decrease

A

• A. Increase

will stop metabolism of phenytoin which will cause more drug to accumulate in the plasma conc

76
Q

A patient is taking an herbal supplement which competes for plasma proteins with
your drug. The hepatic clearance of your drug will_____________.
• A. Increase
• B. Decrease

A

• A. Increase
If drug is happily bound to plasma protein, it is protected so that it is not metabolized or excreted. But now the drug is displaced and is now feee

PHRM 501 (21 decks)

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