Drug distribution Flashcards
What is drug distribution?
Reversible transfer of a drug between the blood and the extravascular fluids and tissues of the body (fat, muscle, brain tissue)
Factors that determine distribution
- Plasma protein binding
- Tissue perfusion
- Membrane characteristics
Plasma protein binding
- Many drugs bind to proteins in plasma
- Only unbound drugs are active
- Binding is reversible
Plasma protein binding can be changed by
- Renal failure
- Hypoalbuminaemia
- Pregnancy
- Other drugs
- Saturability of binding
Membrane characteristics
- Blood-brain barrier
- Blood-testes/ovary barrier: lipid soluble drugs, actively transported
Therapeutic range is characterised by…
- Volume of distribution
- Clearance
- Half life
Volume of distribution
- Volume in which amount of drug would be uniformly distributed to produce observed concentration
- ## Higher the Vd, the greater the ability of the drug to diffuse to and through membranes
Volume distribution, if whole body fluid, if just ECF, if highly protein bound or if sequestered extravascular lipid compartment
- Body fluid: 42L
- ECF, cannot penetrate cells: 12L
- Protein bound: 3L
- Extravascular lipid compartment: >40L
Clearance
- Measure of elimination: Theoretical volume of fluid from which a drug is completely removed over a period of time.
- Measure in units of time (ml/min)
Clearance depends on
- Concentration
- Urine flow rate for renal clearance
- Metabolism
- 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
- Volume of distribution
- Rate of clearance
- Kidneys and/or liver working
- Prolongation of the half-life will increase the toxicity of the drug for these reasons
- Links chemical properties of the drug and ability of the body to metabolise and excrete drugs
Chronic administration
- Best way to get therapeutic benefit
- Plasma levels need to be stabilised after 4-5 half lives
Drug elimination definition
- Removal of active drug and metabolites from the body
- Determines length of action of the drug
- 2 parts: drug metabolism -> liver. Drug excretion -> kidney but also biliary system, lung, milk
3 mechanisms of excretion
- Glomerular filtration
- Passive tubular reabsorption
- Active tubular secretion
Glomerular function
- GFR is how you measure renal function
- All unbound drugs will be filtered at the glorulus as long as not too large
- If you lower GFR, you lower excretion
Passive tubular resorption
- Concentration gradient created to allow drug to move back through tubule into circulation
- Occurs in distal tubule
- Unionised drugs are resorbed
Active tubular secretion
- Actively secreted into proximal tubule
- Important system for cationic and anionic drugs
Biliary secretion
- Drugs can be passively or actively secreted into bile
- Many drugs are reabsorbed from bile into the circulation -> entero-hepatic circulation
- Continues until drug is metabolised in the liver or excreted by the kidneys
- Damage to liver may reduce the rates of conjugation and biliary secretion -> build up or reabsorption of drug with resultant toxicity
