L23 - Pharmacokinetics-Drug Distribution

Question 1

What are the factors that affect drug distribution?

Answer 1

• Blood Flow
• Capillary Permeability
• Plasma protein binding
• Solubility of the drug
• Volume of distribution (Vd)

Question 2

How does plasma protein binding affect drug distribution?

Answer 2

Plasma protein binding => the degree to which drugs bind to blood proteins, e.g. albumin, within blood plasma

• Dynamic equilibrium between protein-bound drug and free drug
• Only free drug can leave the circulation and exert therapeutic effect – needs to be factored in when determining dose
• More protein-bound drug – less free drug:
  => low distribution of drug into tissues
  => high drug concentration in plasma
• Protein-bound drugs can act like reservoir – free drug released over period of time as free drug leave the blood compartment, giving longer-lasting effect of drug
• Less protein-bound drug – more free drug:
  => high distribution of drug
  => low drug concentration in plasma

Question 3

Where is the higher blood flow and what effect does it have on drug distribution?

Answer 3

Blood is rapidly perfused in:

• Brain – blood flow of 0.75 L/min
• Liver – blood flow of 1.55 L/min
• Kidneys – blood flow of 1.2 L/min
• There would be higher distribution as flux is highest where cell barriers are thinnest and venous drainage maintains diffusion gradient.

Question 4

Where is the lower blood flow and what effect does it have on drug distribution?

Answer 4

Blood is less rapidly perfused in:

• Muscle – blood flow of 0.6 L/min
• Skin – blood flow of 0.4 L/min

Blood is poorly perfused in:

• Adipose tissues – blood flow of 0.25 L/min
• Skeleton – blood flow of 0.2 L/min
• There would be lower distribution of drugs due to there being less blood flow to these areas.

Question 5

What are the three main water compartments of the body and their Vd?

Answer 5

• Average adult = 70kg
• 70% of body is water,
  hence 70% x 70kg = 49 L of water compartment
• Hence, 49L/70kg = 0.7 L/kg

Blood compartment:
- approx. 4 L water
- 0.06 L/kg

Extravascular fluid compartment:
- 0.19 L/kg

Tissue compartment:
- approx. 45 L water
- 0.45 L/kg

0.06 + 0.19 + 0.45 = 0.7 L/kg total water

Question 6

What is Vd in the blood?

Answer 6

• All of drug dose stays in blood water:
  Vd = 0.06 L/kg
• Drug strongly bound to plasma protein
• E.g. Warfarin, diclofenac, tolbutamide

Question 7

What is Vd in the blood and extravascular fluid?

Answer 7

• Drug distributes between blood water and extravascular water:
  Vd = 0.06 + 0.19 = 0.25 L/kg
• Highly polar/lipid insoluble drugs tend not to enter the cellular compartments and stays in the extracellular fluid volume
• E.g Gentamicin, streptomycin

Question 8

What is Vd in all of the body compartments?

Answer 8

• Drug distributes between blood water, extravascular water and tissue water:
  Vd = 0.06 + 0.19 + 0.45 = 0.7 L/kg
• Some low molecular weight water soluble compounds become uniformly distributed throughout the body water
• E.g. Ethanol, paracetamol, a few sulphonamides

Question 9

What does it mean if Vd of a drug is larger than 0.7 L/kg?

Answer 9

• Indicates sequestration into specific compartments and bound up in the tissues – absence in the body water and deposited in the tissue matter
• Sequestration - artificially lowers the plasma concentration of the drug
• High Vd drugs are highly permeable into cells and highly bound to tissue components versus plasma proteins.
• These drugs tend to be highly lipophilic.
• Lipophilic basic drugs are examples. In this case, Vd exceeds body water volume (0.7 L/kg) and may reach high levels (e.g., 5-100 L/kg or greater).
• For a drug that is highly tissue-bound, very little drug remains in the circulation; thus, plasma concentration is low and volume of distribution is high.
• Most drugs exhibit a non-uniform distribution in the body with variation that are largely determined by the ability to pass through membranes – lipid/water solubility and if they are charged/ionised form
• Examples;
• Morphine = 3.5 L/kg
• Propanolol = 4 L/kg

Question 10

What are the factors affecting volume of distribution (Vd)?

Answer 10

• Relative lipid and water solubility
  => high lipid solubility = drugs cross membrane
• Plasma or tissue protein binding properties
  => high tissue binding = sequestration - very high Vd
  => high protein binding = low Vd

Question 11

What effect does ACIDIC drugs have on the volume of distribution?

Answer 11

• Plasma albumin - positively charged in order to transport fatty acids
• Acidic drugs - negatively charged at pH 7.4 in plasma
• Highly plasma protein bound
• Low uptake by tissues

==> Low Vd

• E.g. NSAIDs - aspirin, ibuprofen

Clinical considerations:
- High protein-binding - only small amount can leave to reach the target - implications for dose

-

Question 12

What effect does BASIC drugs have on the volume of distribution?

Answer 12

• High phospholipid content on membrane — high absorption into tissues
• Basic drugs - positively charged at pH 7.4 in plasma
• Move readily into tissues through mutual attraction to phospholipids
• In tissues - bound to tissue proteins

==> High Vd

Clinical considerations:
- Tissue binding - may be bound to tissues where there is no target – hence only small amount can get to the actual target - implications for dose

• Difficult to remove via haemodialysis in case of poisoning
• Anaemia - low plasma protein for the drug to bind to - more free drug means higher Vd to tissues