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 body (for example, fat, muscle, and brain tissue).
What does tissue distribution depend on?
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
What can be said about an unbound drug (not bound to plasma protein)?
Only unbound drug is biologically active.
What can change the amount of bound drug?
Renal failure
Hypoalbuminaemia
Pregnancy
Other drugs
Saturability of binding
When does protein binding matter?
When there is a very large percentage of the drug that is bound to plasma proteins
- a small increase in unbound level has a massive percentage change of the free drug level (4% to 6% means a 50% increase in free drug levels)
What are the parameters of the therapeutic range?
volume of distribution, clearance and half-life
What is the 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 indicate?
the greater the ability of the drug to diffuse into and through membranes
What is the Vd in theory
42L (in equal distribution in the body)
What is the definition of clearance?
The theoretical volume of fluid from which a drug is completely removed over a period of time.
What is the measurement of clearance?
Measured in units of time (ml/min)
What does clearance depend on?
Dependent on concentration and urine flow rate for renal clearance.
Dependent on metabolism and biliary excretion for hepatic clearance.
What is the definition of half life?
The time taken for the drug concentration in the blood to decline to half of the current value.
What is half life dependant on?
Volume of distribution and rate of clearance.
What is the result of prolongation of the half life of a drug?
Will increase the toxicity of a drug.
Due to reduction in clearance
Due to a large volume of distribution (amiodarone)
How many doses are usually required before plasma levels of a drug stabilise?
4-5 half-lives
What is drug elimination?
Removal of active drugs and metabolites from the body
What are the two components of drug elimination?
Metabolism (usually in the liver)
Excretion (kidney, biliary system/gut, lung, milk)
What are the three main mechanisms for drug excretion by the kidney?
- Glomerular filtration
- Passive tubular reabsorption
- Active tubular secretion
What is renal damage often a cause of?
Drug toxicity
What system is important for the elimination of protein bound cationic and anionic drugs?
Active tubular secretion
What kind of drugs are passively reabsorbed from the renal tubule into the circulation?
Un-ionised drugs
At this point they are concentrated and the diffusion occurs at the distal tubule and the collecting duct
What accounts for 5%-95% of drug elimination?
Biliary secretion
What is the entero-hepatic circulation?
The reabsorption of drugs from the bile to the circulation
When does the reabsorption of drugs from the bile to the circulation stop?
When the drug has been completely excreted by the kidney or metabolised by the liver
What is conjugation of a drug? Often caused by the metabolism of the liver
The combination of toxic substances formed by drugs with glucaronic or suphuric acid in the liver
- It is a means by which the biological activity of a certain chemical is terminated and the substance is made ready for excretion
Is the conjugated drug reabsorbed by the small intestine?
NO
What may happen after damage to the liver?
Reduce rates of conjugation and biliary secretion and so allow the build up or reabsorption of the drug with resultant toxicity
