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

Exam 3: Drug distribution and TDM Flashcards

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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
For efficient filtration of drugs into the urine,
a high arterial hydrostatic pressure must exist
26
Decreased blood flow due to congestive heart failure
may reduce renal clearance through reduced blood flow
27
A higher arterial hydrostatic pressure causes
fluid to leave the capillaries and enter the tissues
28
A lower hydrostatic pressure causes
fluid to leave the tissues and return to the capillaries
29
Permeability-Limited Distribution
``` 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) ```
30
Ex of Permeability-Limited Distribution
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
31
Distribution Processes and Blood Flow
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
Inflammation and burns yield
increased permeability which may increase a drug’s ability to permeate tissues
33
Rate of distribution
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
Rate of distribution formula
• kd=Q/(VR)
35
The greater the blood flow
the faster the distribution | - Exercise increases blood flow and increases distribution
36
The larger the organ
the slower the distribution | - It will take longer to fill a larger organ with drug than a smaller organ
37
Distribution to Kidney is
fast
38
Distribution to skin, muscle and fat
are slow
39
R pertaining to distribution
ratio of drug concentration in the tissues to drug concentration in the blood
40
A high log P generally correlates with
- 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
If a drug extensively partitions into the tissues, we would expect the volume of distribution to be
large plasma drug conc. will be low because drug is in tissues
42
If a drug partitions extensively, we would expect it to have a (long/short) elimination half life
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
If it takes a long time for a drug to partition into the tissue
it will take a long time for it to leave the tissue once the blood concentration decreases
44
Increased drug-lipid solubility and drug-protein binding yield
longer distribution half-lives
45
Drug uptake into a tissue depends on
partitioning and binding to specific components/receptors | • This is a reversible process
46
A drug that has weak affinity for the tissues will
re-equilibrate rapidly with the plasma | - Its plasma drug concentration will decline rapidly as it then is eliminated from the body
47
A drug that has high affinity for the tissues will
re-equilibrate slowly with the plasma | - Its prefers the tissue, hence plasma drug concentration will be low and elimination will be slow
48
Blood flow to the adipose tissue is
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
OATP
Organic Anion Transporting Polypeptide | - influx
50
OCT
Organic Cation Transporters - Influx and Efflux movement of ions in cell vs out of cell
51
p-glycoprotein involved in
efflux
52
Efflux transporters
shunt drugs out of cells Limits toxicity, but can impede therapy! Not limited to GI tract!
53
Complexation and Protein binding
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
In certain tissues
there may be binding to certain proteins
55
In the blood, there may by binding to many constituents, including
RBCs WBCs Plasma proteins
56
Plasma Protein binding
Protein binding has marked effects on drug distribution, metabolism, and excretion - Only the free drug passes biological membranes
57
Free drugs can
be metabolized or excreted by the kidneys! | - typically exerts a biological effect
58
Plasma and Extracellular Protein Binding
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
Most drugs are
extensively protein bound | - The dose is adjusted to provide therapeutic effect
60
The extent of protein binding affects
the VD, Cl, t1/2
61
Fu
fraction of drug that is protein bound
62
If fu is high
, the drug is readily available for metabolism/distribution/excretion
63
If fu is low
not much of the drug is readily available for these processes
64
The total drug concentration of drug in the body (Cb) is a function
of its concentrations (C) and volumes (V) in the plasma (p) as well as the tissues (t) CB=Vp*Cp+VtCt
65
Drug protein bound. At steady state
``` there is an equilibrium between bound and unbound (u) drug in the plasma (p) and tissue (t) ``` Cup = Cut
66
If your drug has reversible binding
then the proteins act as a pool | - As it releases, it serves as a continual pool that can be metabolized and eliminated
67
If your drug binds tightly to proteins
then the proteins act as a sink | - Proteins accumulate the drug reducing its activity/clearance
68
The levels of plasma proteins can vary by condition/disease state
* 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
A molecule that becomes more active after metabolism is a _____________. • A. Drug • B. Prodrug
• B. Prodrug
70
If enzymes are induced, metabolic activity for a drug will_____________. • A. Increase • B. Decrease
• A. Increase
71
If enzymes are induced, clearance for a drug will_____________. • A. Increase • B. Decrease
• A. Increase
72
If enzymes are induced, the hepatic extraction ratio will_____________. • A. Increase • B. Decrease
• A. Increase
73
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
• B. Decrease
74
An herbal supplement which competes for the same CYP450 as Drug A will cause the plasma concentration to _____________. • A. Increase • B. Decrease
A. Increase
75
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. Increase will stop metabolism of phenytoin which will cause more drug to accumulate in the plasma conc
76
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. 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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