PK: Drug Distribution Flashcards
Total body water = _______ % of body weight
50-70%
Fat = ______ % of body weight
20%
EC fluid consists of:
Blood plasma - 4.5%
IS fluid - 16%
Lymph - 1.2%
How much of total body water does IC fluid constitute
30-40%
What is IC fluid
Sum of all fluid contents of all cells in the body
How much of total body water does transcellular fluid constitute
2.5%
What is transcellular fluid made up of
CSF
Intraocular fluids
Peritoneal fluids
Pleural fluids
Synovial fluids
Body fluid compartments overview
Define drug distribution
Process by which a drug reversibly leaves bloodstream and enters the EC fluid and/or cells of the tissue (IC fluid)
What are the 3 factors drug distribution depends on
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
Drug distribution after IV injection
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
Define volume of distribution
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
Clinical example of Vd
Where are drugs with low Vd primarily retained
Within the vascular compartment
Where are drugs with high Vd retained
What is the Vd often higher than
Highly distributed into muscle, adipose tissue and other non-vascular compartments
Much higher than the total body water (= 42L)
What does the capacity to take up and retain drug depend on
The volume (mass) of the tissue and the density of specific and non-specific binding sites for the drug within that tissue
Use of Vd
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
Formula for loading dose
Effect of High vs low Vd on loading dose
Vd x desired plasma conc
Large Vd - need larger dose to load
Low Vd - need smaller dose to load
When might Vd exceed total body volume
For drugs that accumulate outside the plasma compartment (eg in fat or by being bound to tissues)
Name 2 drugs localised mainly in plasma (with little in tissues)
Aspirin
Amoxycillin
Name 2 drugs that have a similar concentration in both plasma and tissues
Theophylline
Diazepam
Name 2 drugs mainly located in tissue, with very little in plasma
Digoxin
Haloperidol
Vd of aspirin
9.8
Vd of amoxycillin
14
Vd of theophylline
35
Vd of diazepam
105
Vd of digoxin
490
Vd of haloperidol
1750
Permeability of the BBB
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
What sort of association is the binding of drugs to plasma proteina
REVERSIBLE association
Vd and location of highly protein bound drugs
Highly protein bound drugs tend to remain within the vasculature and thus have low Vd
What drugs can cross the capillary membrane
Only free drug
State of protein bound drugs
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
What are the main plasma proteins drugs bind to
Albumin - mainly acidic drugs
Beta-globulin & alpha 1 acid glycoprotein - basic drugs
What does the amount of drug bound depend on
Conc of free drug
Affinity for binding sites
Conc of protein
Conc of albumin in plasma
0.6 mmol/L
4 g/100ml = 4 g/dL
How many binding sites does each albumin molecule have
2 binding sites
Drug binding capacity of albumin
1.2 mmol/L
Usual therapeutic dose is much less than this
- not saturated
- fraction bound is independent of drug conc
What drugs work at conc near saturation
eg tolbutamide
Sulfonamides
adding more drug results in a disproportionate increase in free conc
In clinical practice, what is the effect of co-administering 2 highly protein bound drugs
Theoretically, it should lead to increased free drug conc - but this does not seem to be a problem in clinical practice
4 instances of altered protein binding
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
Competition example
MCQ
MCQ
