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Pharmacology > PK: Drug Distribution > Flashcards

PK: Drug Distribution Flashcards

1
Q

Total body water = _______ % of body weight

A

50-70%

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2
Q

Fat = ______ % of body weight

A

20%

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3
Q

EC fluid consists of:

A

Blood plasma - 4.5%

IS fluid - 16%

Lymph - 1.2%

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4
Q

How much of total body water does IC fluid constitute

A

30-40%

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5
Q

What is IC fluid

A

Sum of all fluid contents of all cells in the body

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6
Q

How much of total body water does transcellular fluid constitute

A

2.5%

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7
Q

What is transcellular fluid made up of

A

CSF

Intraocular fluids

Peritoneal fluids

Pleural fluids

Synovial fluids

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8
Q

Body fluid compartments overview

A
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9
Q

Define drug distribution

A

Process by which a drug reversibly leaves bloodstream and enters the EC fluid and/or cells of the tissue (IC fluid)

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10
Q

What are the 3 factors drug distribution depends on

A

BLOOD FLOW:

  • capillary permeability
  • capillary structure - BBB due to endothelial cell tight junctions, reduced pores and layers of astrocytes

DRUG STRUCTURE:

  • hydrophobic drugs (no net charge) readily move across most membranes
  • hydrophilic drugs (charged) do not penetrate cell membranes

BINDING OF DRUGS TO PROTEINS

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11
Q

Drug distribution after IV injection

A

Rapid equilibriation with WELL PERFUSED TISSUES

  • Lung
  • Kidneys
  • Liver
  • Heart
  • Brain (BBB)
  • Intestines

Slower entry to poorly perfused tissues

  • Skin
  • Skeletal muscle
  • Connective Tissue
  • Fat
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12
Q
A
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13
Q

Define volume of distribution

A

The extent of distribution of a drug from plasma to the tissue determines:

  • The relationship between plasma conc and total amount of drug in the body
  • The amt of drug that has to be administered in order to produce a particular plasma conc
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14
Q

Clinical example of Vd

A
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15
Q

Where are drugs with low Vd primarily retained

A

Within the vascular compartment

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16
Q

Where are drugs with high Vd retained

What is the Vd often higher than

A

Highly distributed into muscle, adipose tissue and other non-vascular compartments

Much higher than the total body water (= 42L)

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17
Q

What does the capacity to take up and retain drug depend on

A

The volume (mass) of the tissue and the density of specific and non-specific binding sites for the drug within that tissue

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18
Q

Use of Vd

A

Vd is the determinant of the loading dose

allows us to get to steady state quicker

If we start with a maintenance dose, it takes some time to accumulate a steady state

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19
Q

Formula for loading dose

Effect of High vs low Vd on loading dose

A

Vd x desired plasma conc

Large Vd - need larger dose to load

Low Vd - need smaller dose to load

20
Q

When might Vd exceed total body volume

A

For drugs that accumulate outside the plasma compartment (eg in fat or by being bound to tissues)

21
Q

Name 2 drugs localised mainly in plasma (with little in tissues)

A

Aspirin

Amoxycillin

22
Q

Name 2 drugs that have a similar concentration in both plasma and tissues

A

Theophylline

Diazepam

23
Q

Name 2 drugs mainly located in tissue, with very little in plasma

A

Digoxin

Haloperidol

24
Q

Vd of aspirin

A

9.8

25
Q

Vd of amoxycillin

A

14

26
Q

Vd of theophylline

A

35

27
Q

Vd of diazepam

A

105

28
Q

Vd of digoxin

A

490

29
Q

Vd of haloperidol

A

1750

30
Q

Permeability of the BBB

A

Inflammation can allow normally impermeant substances to enter the brain e.g. penicillin and meningitis

In some places, the barrier is leaky e.g. the chemoreceptor trigger zone - domperidone will act here

31
Q

What sort of association is the binding of drugs to plasma proteina

A

REVERSIBLE association

32
Q

Vd and location of highly protein bound drugs

A

Highly protein bound drugs tend to remain within the vasculature and thus have low Vd

33
Q

What drugs can cross the capillary membrane

A

Only free drug

34
Q

State of protein bound drugs

A

Protein bound drugs are PHARMACOLOGICALLY INACTIVE

=> protein binding slows the rate at which the drug reaches its site of action

hence protein bound drug can act as a drug reservoir - as conc of free drug decreases to elimination, the bound drug dissociates from the protein

Extensive protein binding will increase the amount of drug that must be absorbed before effective therapeutic levels of unbound drug occur

35
Q

What are the main plasma proteins drugs bind to

A

Albumin - mainly acidic drugs

Beta-globulin & alpha 1 acid glycoprotein - basic drugs

36
Q

What does the amount of drug bound depend on

A

Conc of free drug

Affinity for binding sites

Conc of protein

37
Q

Conc of albumin in plasma

A

0.6 mmol/L

4 g/100ml = 4 g/dL

38
Q

How many binding sites does each albumin molecule have

A

2 binding sites

39
Q

Drug binding capacity of albumin

A

1.2 mmol/L

Usual therapeutic dose is much less than this

  • not saturated
  • fraction bound is independent of drug conc
40
Q

What drugs work at conc near saturation

A

eg tolbutamide

Sulfonamides

adding more drug results in a disproportionate increase in free conc

41
Q

In clinical practice, what is the effect of co-administering 2 highly protein bound drugs

A

Theoretically, it should lead to increased free drug conc - but this does not seem to be a problem in clinical practice

42
Q

4 instances of altered protein binding

A

REDUCED PROTEIN

  • hypoalbuminaemia eg low albumin in nephrotic syndrome or hepatic failure

URAEMIA

  • Excess urea in the blood from kidney damage, affects the binding sites such that drugs are less extensively bound than in non-uraemic patients

AGE

  • Lower binding capacity in the foetus and neonates

DISPLACEMENT FROM BINDING SITES - COMPETITION

  • Drug removed from its binding site as a result of competition with another compound eg warfarin
43
Q

Competition example

A
44
Q

MCQ

A
45
Q

MCQ

A

Pharmacology (23 decks)

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