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Drug Disposition > Drug Distribution > Flashcards

Drug Distribution Flashcards

1
Q

Definition of distribution?

A

reversible transfer of drug between the blood and other tissues in the body

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2
Q

What affects the rate of distribution?

A
  • delivery of drug to tissue by perfusion
  • the permeability of tissue membranes
  • physicochemical properties of the drug (lipophilic/polar?)
  • binding of drug to plasma proteins (only unbound drug crosses membranes)
  • binding to acidic phospholipids in the tissue membranes
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3
Q

What is perfusion rate limited distribution?

A

movement from blood to tissue across the membrane is fast, so the rate of distribution is dependent on the rate at which the blood delivers the drug to the tissues

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4
Q

What types of drugs are prone to perfusion rate limited distribution?

A
  • likely to occur when molecules are small and lipophilic
  • perfusion is not the same across tissues, rapid equilibrium is achieved faster in highly perfused organs e.g. kidneys, brain
  • slower equilibrium in poorly perfused tissues e.g. skin, adipose, resting muscle
  • lipophilic molecules have a high affinity for adipose tissue
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5
Q

What is permeability rate limited distribution?

A

Distribution into tissues is detemined by the drug being able to cross the membrane between the blood and the tissue

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6
Q

What types of drugs are prone to permeability rate limited distribution?

A 
polar molecules (as well as impermeable membranes e.g. BBB)
there may also be active transport involved in the transport
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7
Q

Effects of properties of drugs on the ability to cross the blood brain barrier?

A

lipophilicity, fraction unbound to proteins, ionisation,

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8
Q

Why is the BBB so hard to cross?

A

very tight junctions, barrier is at capillary level

  • compared to muscle capillary wall, porous to small moleucles. barrier at cellular level
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9
Q

What is the apparent volume of distribution?

A

(apparent because it can’t be measured directly)
- based on equilibrium concept
- relates the measured plasma drug conc (C) to the amount of drug in the body (A)
V = A/C

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10
Q

Definition of volume of distribution?

A

Volume that the drug occupies at a concentration equal to that in plasma (litres)

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11
Q

What is the lowest possible volume of distribution?

A

3L - the volume of plasma

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12
Q

Important note about volume of distribution?

A

does not refer to a physical volume

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13
Q

What is Cb?

A

Concentration in the blood (incl cells etc)

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14
Q

What is C?

A

Concentration in plasma

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15
Q

What is Cu?

A

Concentration unbound - plasma water (no plasma proteins)

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16
Q

Clincal relevance of volume of distribution?

A

important PK parameter to determine the loading dose of a drug

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17
Q

Typical volume of plasma?

A

3L

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18
Q

Typical volume of Extracellular water?

A

13-16L

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19
Q

Typical volume of interstitial fluids?

A

10-13L

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20
Q

Typical volume of intracellular water?

A

25-28L

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21
Q

Typical volume of transcellular water?

A

0.7-2L

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22
Q

Typical total body water?

A

40-46L

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23
Q

Examples of drugs with a high volume of distribution?

A

Quinacrine, chloroquine (10,000-50,,000L)

24
Q

Examples of drugs with a low volume of distribution?

A

MAbs, warfarin, tolbutamide

25
Q

General principles of how types of drugs distribute?

A

basic drugs tend to have higher Vd, as they bind to acidic phospholipids
acidic molecules tend to reside in the plasma - ionise and bind to plasma proteins

26
Q

How is digitoxin special in how it distributes?

A

Vd is 40L, but we know it accumulates highly in cardiac tissue (range within physiological volumes, need to be careful how these are interpreted)

27
Q

How to determine the fraction of drug in body in plasma?

A

Plasma volume (i.e. 3L) /Volume of distribution

28
Q

How to determine the fraction of the drug in the body outside plasma?

A

1- fraction in plasma

29
Q

What is subcellular distribution?

A

Distribution in organelles

30
Q

What types of molecules tend to distribute in lysosomes?

A

Cationic amphiphilic drugs

LogP >2, pKa 6.5-11 (e.g. antibody drug conjugates)

31
Q

Consequences of distribution in the lysosomes?

A

Reduced ability of the protonated drug to diffuse back into the cytosol - trapped in the lysosome (lungs and liver have a lot of lysosomes)

occasionally the drug target is the lysosomes e.g. antimalarials

  • reduced acitivity and off target effects: less efficacy and potential for side effect
  • safety issue - phospholipidosis
32
Q

What is phospholipidosis?

A

lysosomal storage disorder characterized by the excess accumulation of phospholipids in tissues.

33
Q

General points on plasma protein binding?

A

a very rapid and usually reversible process

bound drugs cant cross membranes

34
Q

Which plasma proteins do drugs tend to bind to?

A

Albumin, a1-acid glycoprotein, globulins

35
Q

What types of drugs bind to albumin?

A

acidic (e.g. warfarin) and neutral (e.g. ciclosporin)

36
Q

What types of drugs bind to a1-acid glycoprotein?

A

basic drugs

37
Q

What types of drugs bind to globulins?

A

Steroids

38
Q

How to calculate the fraction of unbound drug in plasma?

A

Concentration unbound / total plasma concentration

39
Q

How to calculate the fraction of bound drug in plasma?

A

1 - fraction unbound

40
Q

What factors can alter fraction unbound?

A

pregnancy, or some diseases (liver cirrhosis, renal impairment) - expression of plasma proteins may be altered

41
Q

What does fraction unbound depend on?

A
  • affinity of the drug for the protein

- protein and drug concentration

42
Q

What is the importance of knowing the fraction of unbound drug?

A

total plasma conc is usually measured - changes in plasma conc reflect changes in unbound drug conc when fu is constant

only unbound drug can cross membranes and have a pharmacological effect

43
Q

Examples of drug with v high unbound fraction?

A

Atenolol, metformin, lithium

44
Q

Examples of drugs with v low unbound fraction?

A

Warfarin, Flurbiprofen

45
Q

How is tissue distribution normally measured?

A

Inferred from plasma data, rarely measured directly

46
Q

How does tissue distribution occur?

A

Unbound molecule corsses membranes and enters the tissue, then can bind to proteins eithin the tissue (equilibrium between Cu in tissue and C bound in tissue

47
Q

What things does the distribution of a drug within the body depend on?

A

binding of the drug to both plasma proteins and tissue components

involvement of transporters (influx and efflux)

48
Q

What coefficient characterises tissue binding?

A

tissue-to-plasma partition coefficient, Kp

can have a different Kp for each organ (relative to plasma)

49
Q

What is the volume of aqueous volume outside plasma?

A

approx 39L

50
Q

Equation linking the total amount of drug in the body?

A

A = V•C = Vp•C + Vtw•Ct

Vp = volume of plasma, Vtw = volume outside plasma

51
Q

What causes high Volume of distribution in terms of tissue distribution?

A

High fraction unbound in the blood, or low fraction unbound in the tissue (ie extensive tissue binding)

52
Q

What do hepatic uptaketransporters do in terms of drug disposition?

A

mediate active uptake of drugs into the hepatocyte

can result in a higher concentration in the liver than the plasma

53
Q

What do hepatic efflux transporters do in terms of drug disposition?

A

Excretion of drugs into bile by efflux transporters

54
Q

Effect on tissue concentrations if active transport/rapid metabolism in cell occurs?

A

C unbound in plasma ≠ C unbound in tissue

metabolism: Higher conc in plasma than in tissue
efflux: higher conc in plasma than in tissue
Uptake: higher conc in tissue than in plasma

55
Q

How can Kp be determined?

A

In vitro - using tissue homogenate or isolated perfused organs

in silico - predictive equations based on physicochemical properties and tissue composition

56
Q

What is PBPK moedelling?

A

physiologically based pharmacokinetic modelling

the body is represented as a multi-compartment of individual organ compartments. organ compartments are connected by blood flows in a physiologically meaningful way. physiological parameters can be adjusted for the population you are studying

Drug Disposition (11 decks)

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