Drug Distribution Flashcards
What does drug distribution refer to?
the reversible transfer of a drug between the blood and the extra vascular fluids and tissues of the bidy.
What is tissue distribution dependent on?
- plasma protein binding
- tissue perfusion
- membrane characteristics
- transport mechanisms
- diseases and other drugs
- elimination
What proteins do drugs bind to in the plasma?
- albumin
- a1-glycoprotein
What must a drug be to be biologically active?
Unbound
How can the amount of bound drug be changed?
- renal failure
- hypoalbuminaemia
- pregnancy
- other drugs
- 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
What parameters are important to characterise in therapeutic range?
- volume of distribution
- clearance
- half-life
What is the apparent volume of distribution?
The volume in which the amount of drug would be uniformly distributed to produce the observed blood concentration
What does a greater Vd tell us?
the greater the ability of the drug to diffuse into and through membranes
In theory what should the value of Vd be?
42L
If the drug stays in the extracellular fluid but cannot penetrate cells what is the theoretical value of Vd?
12L
What is the theoretical value of Vd if the drug is highly protein bound?
3L
What is the theoretical value of Vd if the drug is sequestered in extravascular lipid compartment?
> 40L
What is clearance?
the theoretical volume of fluid from which a drug is completely removed over a period of time
What is clearance a measure of?
elimination
What is clearance dependent on?
- concentration and urine flow rate for renal clearance
- metabolism and biliary excretion for hepatic clearance
What is half-life?
the time taken for the drug concentration in the blood to decline to half of the current value
What is half life dependent on?
the volume of distribution and rate of clearance
Why will prolongation of the half life increase the toxicity of the drug?
- due to reduction in clearance
- due to large volume of distribution
How must most drugs be given to have a therapeutic benefit?
chronically
When is steady state concentration achieved?
approximately after 4 half times
What is the relationship between time to steady state concentration and dosage
they are independent
What is drug elimination?
the removal of active drug and metabolites from the body
What is drug elimination made up of?
-drug metabolism (usually in the liver) drug excretion (usually in the kidney but also biliary system/gut, lung, milk)
What are the primary organs involved in drug excretion?
kidneys
What are the 3 principal mechanisms used in excretion?
- glomerular filtration
- passive tubular reabsorption
- active tubular secretin
How much is filtered by the glomerulus each day?
190 litres
What will be filtered by the glomerulus?
all unbound drugs as long as their molecular size, charge or shape are not excessively large.
What will reduce the clearance of a drug?
factors that affect the glomerular filtration
Describe active tubular secretion.
- some drugs are actively secreted into the proximal tubule (acidic and basic compounds)
- this is the most important system for eliminating protein bound cationic and anionic drugs.
How does passive tubular reabsorption occur?
- as the filtrate moves down the renal tubule any drug present is concentrated.
- passive diffusion along the concentration gradient allows the drug to move back through the tubule into the circulation.
Where does passive diffusion occur?
In the distal tubule and collecting duct
What drugs can be reabsorbed?
un-ionised drugs such as weak acids
How much bile does the liver secrete a day?
1 litre
How can drugs be secreted in bile?
actively or passively
What is entero-hepatic circulation?
many drugs are then reabsorbed from the bile into the circulation
What does metabolism in the liver often leads to?
- conjugation of the drug
- the conjugated drug is not reabsorbed from the intestine
What may reduce the rates of conjugation and biliary secretion?
damage to the liver which then allows the build up or reabsorption of the drug with resultant toxicity
