Drug Distribution Flashcards
Define drug distribution
Reversible transfer of a drug between the blood and the tissues of the body (fat, muscle, brain etc)
What factors determine distribution?
- Plasma protein biding
- Tissue perfusion
- Transport mechanisms
- Diseases and other drugs
- Elimination
What proteins do drugs bind to?
Albumin or alpha1-glycoprotein (phenytoin)
Is a drug active when it is unbound or bound to a plasma protein?
Unbound
Factors that can increase concentration of unbound drug
- Renal failure
- Hypoalbuminaemia
- Pregnancy
- !!Other drugs!!
- Saturability of binding
Affects of other drugs on unbound drug concentration?
Some drugs can displace drugs from bound state, therefore increasing that drug’s concentration and becoming toxic
Why is protein binding important?
Drug must be more than 90% bound and tissue distribution small
i.e. 96% bound, so 4% free for action. If unbound levels change to 6% - then levels of free drug increase by 50%
What is important to know bout a drug to determine therapeutic range?
- Volume of distribution
- Clearance
- Half-life
What is the volume of distribution (Vd)?
Volume of fluid required for the total amount of drug at a concentration equal to that in plasma - should be 42L
What does a high Vd indicate?
More drug in tissues therefore greater ability to diffuse through membrane
What does a 12L Vd indicate?
Stays in extracellular fluid but cannot penetrate cells
What does a low Vd indicate?
Drug is highly protein bound
What is clearance?
Theoretical volume from which a drug is completely removed over a period of time (elimination)
Rate at which the drug is being removed from the body
What does renal clearance depend on?
Concentration and urine flow rate
What does hepatic clearance depend on?
Metabolism and biliary excretion
What does high and low clearance indicate?
- High: removed from bloodstream rapidly
- Low: removed slowly
What is the half life (t1/2) of a drug?
The time taken for the drug conc. in blood to decline by half
What does half life depend on?
Volume of distribution and rate of clearance
T1/2 = 0.693Vd/Cl
Affect of clearance on half life and toxicity
If Cl is low, then half life is increased which increases toxicity of drug
Why is it important to know the half life of a drug?
Work out how often a drug needs to be administered to keep levels in therapeutic range
Define drug elimination
The removal of active drug and metabolite from the body
What does drug elimination determine
The length of action of the drug
What two parts are involved in drug elimination?
- Drug metabolism - liver
- Drug excretion - usually kidneys but also biliary system/gut, lung, milk (pregnancy)
What are the primary organs for drug excretion?
Kidneys
Mechanisms used in kidneys for excretion
- Glomerular filtration
- Passive tubular reabsorption
- Active tubular secretion
What does renal damage cause?
Drug toxicity
Importance of glomerular filtration
Unbound drugs are filtered as long as size, charge or shape are not large and re-enetered into circulation
Factors affecting the GF rate reduce the clearance of a drug
GF and clearance
Factors that affect GF rate will reduce the clearance of a drug
Describe active tubular secretion
Drugs are secreted into the proximal tubule (acid and basic compounds ) - important for cationic and anionic drugs
Describe passive tubular reabsorption
Drug present in renal tubule is concentrated and passive diffusion allows drug to move back through tubule into circulation - only unionised drugs such as weak acids
Also affected by renal failure
Where does passive diffusion occur in tubular reabsorption?
Distal tubule and collecting duct
What type of drugs are reabsorbed from kidney tubules?
Un-ionised drugs such as weak acids
Describe biliary secretion
Liver secretes bile and drugs may be passively secreted into the bile
What is entero-hepatic circulation?
Process of reabsorbing drugs from the bile into the circulation
What does metabolism of drug in the liver lead to?
Conjugation of drug which is not reabsorbed from the intestine - activity terminated and ready for excretion
Affect of liver damage
Reduces rate of conjugation (excretion) and biliary secretion - this allows build up or reabsorption causing toxicity
