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MD3001 > Drug Distribution > Flashcards

Drug Distribution Flashcards

1
Q

What are the factors which affect drug distribution once they are absorbed into the blood stream?

A
  • Cardiac output and blood flow (e.g. fat does not get much blood flow, so drug will not distribute there very fast)
  • Plasma protein binding (drug that is bound to plasma proteins will remain within the plasma)
  • Lipid solubility (hydrophobic molecules will pass across membrane more easily)
  • Degree of drug ionisation (charged molecules will not readily pass across membrane)
  • pH of compartments (most drugs weak acids or bases so their charge will vary on the pH of the compartment)
  • Capillary permeability
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2
Q

Which factors affecting drug distribution also affected extent of drug absorption ?

A
  • Lipid solubility
  • Degree of drug ionisation
  • pH of compartments
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3
Q

What is the cardiac output to the kidney ? The blood flow to it ?

A

20% of CO

450 ml/min/100g tissue

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4
Q

What is the cardiac output to the liver ? The blood flow to it ?

A

10% of CO

25 ml/min/100g tissue

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5
Q

What is the cardiac output to the heart ? The blood flow to it ?

A

4% of CO

70 ml/min/100g tissue

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6
Q

What is the cardiac output to the brain ? The blood flow to it ?

A

13% of CO

55 ml/min/100g tissue

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7
Q

What is the cardiac output to the skeletal muscles ? The blood flow to it ?

A

20% of CO

3 ml/min/100g tissue

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8
Q

What is the cardiac output to the fat ? The blood flow to it ?

A

2% of CO

1 ml/min/100g tissue

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9
Q

What is the main factor affecting initial rate of distribution of drugs ? Give an example of a tissue which would initially receive low distribution of blood due to this factor.

A

Blood flow (for hydrophobic drugs) and diffusion characteristics of the drug (for hydrophilic drugs)

Blood flow to fat

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10
Q

What is the predominate plasma binding protein ? What is its concentration in blood ?

A

Albumin

40 g/L

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11
Q

How do drugs bind to albumin ?

A
  • Lipid-soluble drugs bind non-specifically (around surface of it)
  • Weak acids bind to a specific, saturable site (limited amount of capacity on albumin to bind a weak acid)
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12
Q

Give a clinical example as to why binding of drugs to albumin might be significant.

A

If 2 drugs competing as 2 weak acids, one with greater affinity for albumin will dislodge the other (so higher free concentration of the dislodged drug).
For instance, aspirin will dislodge warfarin from albumin, allowing free warfarin concentration to rise from 1% in the blood in normal conditions, to 2-3%.

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13
Q

What are possible reasons for albumin levels in the blood to rise or decrease ? What is the result of each of these on free drug levels.

A

Hyperalbuminemia: Due to dehydration (decreases free drug levels)

Hypoalbuminemia: Due to burns, renal disease (causing proteinuria), hepatic disease (because liver makes albumin), malnutrition (increases free drug levels)

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14
Q

What are some factors which affect the degree of binding of drugs with albumin ?

A
  • Temperature
  • pH
  • Drug interactions
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15
Q

Why is it a problem to lose albumin (separate from drug-binding issues) ?

A

Because albumin contributes to oncotic pressure

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16
Q

List the main types of capillaries and where each if found.

A
  1. Continuous Capillaries: very little gaps between cells, quite a few junctions so not a huge amount of cells or proteins traveling across membrane (Most tissues)
  2. Fenestrated Capillaries: Smaller molecules can make it across holes in membrane (Skeletal muscle)
  3. Sinusoid/Discontinuous Capillaries: larger molecules can make it across membrane (Liver)
17
Q

Which type of molecule will go through continuous capillaries ? through fenestrated capillaries ? through discontinuous capillaries ?

A

Continuous capillaries: lipophobic molecules (gases diffuse the fastest, followed by small molecules, followed by large molecules)
Fenestrated capillaries: small lipophobic molecules
Sinusoid capillaries: RBCs, large lipophobic molecules

18
Q

Give an example of a location in the brain with continuous capillaries.

A

BBB

19
Q

Describe how transport occurs across the BBB.

A

Very tight junctions between endothelial cells + basal membrane + astrocytic foot processes all serve to insulate the CNS (to prevent large molecules etc. getting through)

Hence, drugs need to be lipophilic to get across BBB (if so then they will have widespread effects because they’ll be able to get in all kinds of tissues) OR get transported actively

20
Q

What is the function of the BBB ?

A

Physical and functional barrier

21
Q

Identify a factor which can change the ability of drugs to pass through the BBB.

A

Disease state

For instance, meningitis disrupts BBB and allows more permeability

22
Q

Identify possible issues associated with specific specialised barriers / compartments (especially with regards to drug distribution to those compartments).

A

1) Placenta
Tight endothelial cell junctions in maternal and fetal capillaries
Partially protective, except with:
– lipid soluble drugs (must avoid some antihypertensive drugs)
– unionised forms of weak acids and bases
(If drug gets to fetal circulation, can get ion trapping in certain tissues if the pH in said tissues is different, resulting in gradual accumulation of drugs)

2) Chronic abscesses
- Avascular tissue compartments, so difficult to get antibiotics to abscess (no blood flow, so rate of drug distribution will be slow)
- Generally unfavorable pH to get distribution

3) Lung infection
-Local low PO2 and high PCO2 cause vasoconstriction (if a chest infection occurs, and an aspect of that lung is not being perfused optimally, a less than ideal amount
of blood flow will go to it so rate of drug distribution will be slow)

23
Q

Identify the fluid volume present in each of the main fluid substances of the body.

A

Extracellular fluid= 15 L

  • Plasma = 3 L
  • Interstitial fluids = 12 L

Intracellular fluid = 27 L

Total body water (for a 70kg adult) = 42 L

24
Q

Which kinds of molecules distribute specifically in each of the fluid substances of the body ?

A

Extracellular fluid-
Large, water-soluble molecules (e.g. mannitol)

Plasma-
Highly plasma-bound molecules
Highly charged molecules
Very large molecules (e.g. heparin)

All of the fluid substances (distribute around all body water without discriminating)-
Small, water-soluble molecules (e.g. ethanol)

25
Q

Name three reservoirs of the body (not fluid compartments). Name drugs which stick to these reservoirs.

A

Fat (Marijuana)
Bone (Alendronate)
Teeth

26
Q

Explain how volume of distribution works.

A

If we take a bucket, that is 10 L in capacity. We put a membrane within that (permable to drugs with the right properties).

A) If drug distributes readily with no barriers, case of working out how much drug is diluted by (e.g. ethanol, distributes readily, explained by 42 L)
B) Protein in central compartment which binds that drug and keeps it inside compartment, only little bit of drug will pass through membrane, but majority will stay
in central compartment (compartmentalisation occurring so drug explained by 3L instead of 42L)
C) Binding protein is outside of central compartment so still have bucket of the same size and the membrane is still permeable but
now something binding to it in external compartment (e.g. bone for biphosphonates)/
The drug can readily diffuse across membrane but then gets stuck outside (so when sample from middle, get low concentration because drug has been
distributed from central compartment. Can be explained by a) hundreds/thousands of liters or b) a reservoir effect) (usually/always b, which means Vd is not always physiologically possible!)

27
Q

Define apparent volume of distribution (Vd).

A

The theoretical volume required to account for the amount of drug in the body

28
Q

How do you calculate the apparent volume of distribution (Vd) of a drug ? What are the units of Vd ?

A

total amount of drug in the body /
blood plasma concentration of drug

Units are in litres (L) or sometimes L/kg of body weight.

29
Q

When given a Vd, how can you figure out which drug is most likely used ?

A

Multiply the Vd value by the weight of said person to obtain a volume in L.
This volume should be more or less the volume in a specific fluid compartment (or all fluid compartments together).
Specific types of molecules tend to stick to specific fluid compartments so this can help you figure out that drug used.

30
Q

What could the following drug be ?

Drug A = Vd of 0.2 L/kg

A

0.2L/kg x 70kg (assuming average physiological weight) = 14L

This means the drug is likely distributing in extracellular fluid.
Could be mannitol

31
Q

What could the following drug be ?

Drug B = Vd of 0.6 L/kg

A

0.6L/kg x 70kg = 42L

This means the drug will likely distribute throughout the body water without discriminating.
Could be ethanol

32
Q

What could the following drug be ?

Drug C = Vd of 6.0 L/kg

A

6.0L/kg x 70kg = 420 L

This means there is likely a reservoir effect going on.
Could be alendronate.

33
Q

Distinguish between the single compartment and the two compartment model of distribution.

A

1) Single compartment model of distribution

  • IV drugs start out circulating in a single, well-stirred compartment (PLASMA + potentially EXTRACELLULAR FLUID, depending on whether drug travels there or just stays in plasma, like warfarin). As soon as drug is in this compartment, it is susceptible to excretion and metabolism.
  • This first compartment can be explained as one volume (Vd)

This model assumes rapid mixing of drug in plasma, and assumes drug in plasma is in rapid equilibrium with drug in extravascular tissues.

2) Two compartment model of distribution

  • IV drugs start out circulating in a central compartment (e.g. blood and well-perfused tissues).
  • Some drugs will be excreted/metabolised, whilst others will move on to a second compartment (peripheral compartment, i.e. poorly perfused tissues) for instance biphosphonates in bone. Only way for them to get out again is for them to get back into the central compartment where they are susceptible to excretion and metabolism
34
Q

Explain the clinical relevance of Vd.

A

Vd can be used to determine a loading dose to achieve a desired plasma concentration of drug. Key to understand how you can give peak plasma concentration with a single bolus dose (if concerned only about getting to peak plasma concentration, not to steady state plasma concentration. In that case, clearance information is unnecessary)

35
Q

What are factors in a person which affect Vd?

A 
Vd varies with: 
– Height
– Weight
– Age
– Fluid accumulation 
• ascites
• oedema
• pleural effusion
– Accumulation of fat
– Permeability of capillaries (to things which would normally stay in plasma)
36
Q

Distinguish between Vd and CL, in terms of the information they provide.

A
  • Vd tells you information about peak plasma concentration (single doses)
  • Clearance gives you information about steady state plasma concentration
  • Both together, give you the half life of a drug

MD3001 (75 decks)

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