Drug Distribution

Question 1

What is drug distribution

Answer 1

Movement of a drug to/from blood and tissues of the body
Where does it get to/where doesn’t it?
Helps understand the relative proportions of drug in the tissues, and to predict dose/response/risk

Question 2

What factors that affect distribution

Answer 2

Cardiac output and blood flow Plasma protein binding
Lipid solubility
Degree of drug ionisation
pH of compartments Capillary permeability

Question 3

Discuss relative organ perfusion

Answer 3

Kidneys - 20%
Liver - 10%
Heart - 4%
Brain - 13%
Skeletal muscle - 20%
Fat - 2%

Initial rate of distribution of drugs depends heavily on blood flow

Question 4

Discuss albumin binding

Answer 4

Predominate plasma binding protein (40g/L)
• Lipid-soluble drugs bind non-specifically
• Weak acids bind to a specific, saturable site

What would competition at saturable sites do to free drug levels in the plasma?

Hyperalbuminemia - caused by dehydration and reduces free drug levels

Hypoalbuminemia - caused by burns, renal disease, hepatic disease or malnutrition and increases free drug levels

Question 5

Discuss lipid solubility

Answer 5

Hydrophilic drugs are highly soluble in aqueous, polar media.
Lipophilic drugs are soluble in fats and non-polar solutions.
Rate of distribution dependent on diffusion characteristics of the drug
Rate of distribution dependent on the rate of delivery to tissues
(e.g. blood flow)

Question 6

Discuss drug ionisation

Answer 6

Many drugs are weak acids or bases
• Ionised:un ionised ratio depends on pH
• Ionised drugs have low lipid solubility

Therefore Ionised drugs will not diffuse across cell membranes

Question 7

What factors should be considered when considering capillary diffusion

Answer 7

Diffusion
Surface area
Time

Continuous
Fenestrated
Discontinuous

Question 8

Discuss the blood brain barrier in drug distribution

Answer 8

Physical barrier Functional barrier
Characteristics of drugs that may pass the BBB?
Can disease state change the ability of drugs to pass through the BBB?

Question 9

Discuss other specialised barriers/compartments in drug distribution

Answer 9

Placenta
Tight endothelial cell junctions in maternal and fetal capillaries
Partially protective, except with:
– lipid soluble drugs
– unionised forms of weak acids and bases

Chronic abscesses
Avascular tissue compartments

Lung infection
Local low PO2 and high PCO2 cause vasoconstriction

Question 10

Discuss body fluid volumes

Answer 10

Extracellular fluid - 15 litres
(3 in plasma, 12 in interstitial fluid)

Intracellular fluids - 27 litres

42 litres in total for 70kg adult

Question 11

How do you calculate the volume of distribution

Answer 11

The apparent volume of distribution (Vd) of a drug is:
total amount of drug in the body
OVER
blood plasma concentration of drug

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

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

Vd is a theoretical volume and may suggest physiological compartments, but may also exceed them!

Question 12

Discuss the single compartment model of distribution

Answer 12

Dose Q (IV) will pass into volume Vd of a single well stirred compartment. It will then be excreted or metabolised

Assumes rapid mixing of drug in plasma
Assumes drug in plasma is in rapid equilibrium with drug in extravascular tissues

Question 13

Discuss the two compartment model of distribution

Answer 13

An IV dose will pass into a central compartment, eg blood and well perfused tissues
It will then either pass into a peripheral compartment, eg poorly perfused tissues. It will pass back and forth between these two compartments

The dose while in the central compartment will be excreted or metabolism

Question 14

What may cause Vd to vary?

Answer 14

Vd varies with:
– Height

–Weight

–Age

–Fluid accumulation
• ascites
• oedema
• pleural effusion

–Accumulation of fat

Question 15

What is the clinical relevance of the volume of distribution equation?

Answer 15

The apparent volume of distribution (Vd) of a drug is:
total amount of drug in the body (A)
OVER
blood plasma concentration of drug (C)

i.eVd=A/C
Can be rearranged to A = C x Vd
So IF you know the Vd, you can calculate what amount of drug (i.e. the dose) will give a certain plasma concentration…

Question 16

Main points

Answer 16

The chemical properties of a drug will dictate how it can distribute
The volume of distribution is a key factor for determining a drug’s half life
Vd is not always physiologically possible!
Drugs may distribute into more than one compartment

Question 17

Learning outcomes

Answer 17

To describe the factors which affect drug distribution once they are absorbed into the blood stream.
To define what is meant by the volume of distribution (Vd) of a drug and perform basic interpretation of what a Vd indicates.
To relate Vd to clinical parameters (e.g. how changes in Vd influence the elimination half-life of a drug, or how patient-specific factors may influence Vd).