4 - Volume of distribution Flashcards
Volume of Distribution definition and equation
V - is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma.
-links drug conc to amount of drug in body
Amount (mg) (loading dose) = V (L) . C (mg/L)
Factors influencing Volume of Distribution
Tissue binding - to tissue or plasma proteins, or partitioning into fat
Tissue binding
e. g digoxin - binds to Na/K atpase - however this is also the site of action
- decreases measured conc, which increase apparent volume of distribution (larger than physical volume)
Fat partitioning
- obese people - can have larger volume of distribution because of this
- e.g lipophilic druge - thopentone
- bone absorption - tetracycline
Plasma protein binidng
-extracted from plasma which increases plasma conc, decrease V
e.g albumin - warfarin binds
(red herring model)
-apparent volume can be worked out by both bound and unbound measurements as long as plasma protein binding fraction is the same
-can get competition of binding by another drug, and because plasma proteins are only a small part of the tissues that bound drug this has a negligible effect on unbound drug conc
Small - e.g gentamicin - does not bing plasma proteins - apparent V is close to physical volume of ECF (indicates that it does not bind extensively to tissues)
Pharmacokinetic compartments + Distribution Rate
Apparent central compartment V - approx ECT
Apparenttissue compartment volume - depends on tissue binding and partition
Initially drug goes into plasma volume, then diffuses into ECF, then into cells, mixing in plasma fluid and diffusion to tissues takes time - apparent voluem of distribution changes with time then wil reach a steady stae V.
Distribution Rate
- minutes - thiopentone - Distribute rapidly to brain, then to rest of tissues in body
- Hours - dixogin - bidns to tissue recpetors, this is quite slow, takes hours to reach binding equlibirim, aparent V takes longer time to reach steady state
Days - lithium due to to exchanging for sodium in cells
What will be found in vascular volume, ECF, Total body water
Vascular volume - large proteins or blood cells
ECF - molecules that can leave the vascular space but cannot easily cross the membrane E.g highly ionised molecules
Total body water - molecules that can cross cell membrane easily (theophylline - total body water - nonpolar and can cross cell membrane)
What happens when there is a competing drug for plasma protein binding?
-Plasma proteins are only a small part of where the drug is bound in the body
-Plasma is approx. 25% of warfarin volume, however if have ibuprofen, this can bind to the plasma proteins in competition and can displace 10%
-however the overall effect on unbound amount is that it increases by 2.5% which is not much
-so there is a negligible acute effect on total unbound amount in body
=no steady state change in conc or effect if unbound drug clearance is unaffected and drug dose rate is unchanged.
Drugs with tiny, medium and large V
tiny - warfarin (apparent volume less than ECF, but larger than plasma volume - impossible)
medium - theophylline (non-polar, crosses cell membrane easily - apparent V close to total body water)
Large - digoxin - due to large bining to Na K _ atpase -
Apparent central compartment volume
Apparent tissue compartment volume
Central compartment - represents rapid initial distribution space, while the tissue comapartment reflects the space after sufficient time has passed to reach a steady state of distribution
one compartment model - for whne tap is on and off - initial conc the same
Distribution half life - drugs that take minutes, hours or days
minutes - thpetntone - non-polar, easily crosses cell membrane, distributes rapidly to brian and body
Digoxin - binds to itusue receptors - takes a while to reach an equilibirium
Lithium - exhcanges slowly for sodium inside cells - long proces
