drug distribution Flashcards
To be active a drug must
leave the blood stream and enter the inter or intracellular spaces.
Once a drug has been absorbed it must be available for
biological action and distribution to the tissues.
Drug Distribution =
Reversible Transfer of a Drug between the Blood and the Extra Vascular Fluids and Tissues of the body (for example, fat, muscle, and brain tissue).
Tissue Distribution takes into account
- Plasma protein binding
- Tissue perfusion
- Membrane characteristics
- Blood-brain barrier
- Blood-testes/ovary barrier
- Lipid soluble drugs
- Actively transported - Transport mechanisms
- Diseases and other drugs (esp renal failure, liver disease, obesity)
- Elimination
Plasma protein binding:
Only unbound drug is
biologically active.
Many drugs bind to proteins in the plasma such as
albumin or a1-glycoprotein (eg phenytoin).
Binding is reversible.
Plasma protein binding:
Amount of bound drug can be changed by:
Renal failure Hypoalbuminaemia (level of albumin in the blood is low.) Pregnancy Other drugs (major factor) Saturability of binding
Why does protein binding matter?
For this to be an important factor, the drug must be more than 90% bound and the tissue distribution small.
eg-
If a drug is 96% protein bound then only 4% of the drug is free and available for action.
If the unbound level changes to 6% then plasma levels of free drug will increase by 50%.
As many drugs have an ideal therapeutic range over which they are active, it is important to characterise certain parameters such as
- volume of distribution
- clearance
- half-life.
The greater the Vd (Apparent Volume Of Distribution) the greater the ability of the drug to
diffuse into and through membranes.
In theory the Vd should be
42L.
If Vd stays in the extracellular fluid but can not penetrate cells =
12L.
If Vd is highly protein bound =
3L (warfarin).
Clearance of drug =
theoretical volume from which a drug is completely removed over a period of time.
Measure of elimination.
Clearance of drug is dependent on
- Concentration and urine flow rate for renal clearance.
- Metabolism and biliary excretion for hepatic clearance.
half life =
Time taken for the drug concentration in the blood to decline to half of the current value.
Half life depends on the volume of distribution and rate of clearance.
Prolongation of the half life will increase
increase the toxicity of a drug.
- due to reduction in clearance - due to a large volume of distribution (amiodarone)
Knowledge of the half life will help us to work out how often a drug needs to be administered.
To have a therapeutic benefit most drugs needed to be given
chronically.
Plasma levels of a drug take many doses before they stabilise, usually 4-5 half-lives.
This may necessitate a loading dose.
Drug Elimination =
removal of active drug and matabolites from the body.
This determines the length of action of the drug.
Drug Elimination is made up of 2 parts:
Drug Metabolism (usually in the liver) Drug Excretion (usually in the kidney but also biliary system/gut, lung, milk)
primary organ for drug excretion
kidneys
Excretion
Three principal mechanisms are used:
- Glomerular filtration
- Passive tubular reabsorption
- Active tubular secretion
Renal damage is therefore important in causing drug toxicity.
The glomerulus filters
All unbound drugs as long as their molecular size, charge or shape are not excessively large.
(190 litres of fluid a day)
Factors that affect the glomerular filtration rate will
reduce the clearance of a drug.
