Distribution Principles Flashcards
What are the factors determining the rate and extent of distribution?
Q=tissue/organ blood flow rate
Ca=arterial concentration
Cv=venous concentration
Kp=partition ratio (Ct/Cv)
Ct=tissue concentration
Cu=free concentration
Cb=bound concentration
tissue perfusion, drug permeability characteristics, binding/partitioning
What is distribution equilibrium?
no net movement of drug between blood and tissue
-drug is being eliminated and distributed
How is distribution equilibrium determined?
distribution half-life
=0.693 x Kp/(Q/Vt)
When would approach to tissue equilibrium take longer?
poorer perfusion rates
higher tissue partitioning of the drug
Rate of distribution is either ___ rate-limited or ___ rate-limited.
perfusion rate-limited
permeability rate-limited
Describe perfusion-rate limited drugs.
tissue membrane presents no barrier to drug distribution (rapid equilibration)
only tissue blood perfusion rate limits movement between blood and tissue
small, lipophilic drugs
Describe permeability-rate limited drugs.
membrane (polarized epithelium) is a barrier to drug distribution (slow equilibration)
large or polar drugs
What are the factors that govern perfusion-rate limited distribution?
blood flow rate (Q)
drug affinity for tissue (Kp)
governs how drug is distributed and how much drug accumulates in tissue
Provide examples of well-perfused tissue and poorly-perfused tissue.
well-perfused:
-lungs, kidney, liver, heart, brain
poorly-perfused:
-muscle, fat, bone, skin
How quickly is distribution equilibrium approached when Kp is low and Q is high?
distribution equilibrium is approached quick
How quickly is distribution equilibrium approached when Kp is high and Q is low?
distribution equilibrium is approached slowly
What is the slow process for permeability rate-limited distribution?
permeation by passive diffusion or carrier-mediated processes
What is the significance of Kp?
influences time to equilibration
-higher Kp: longer to DE, slower release from tissue
What are the factors governing extent of distribution?
tissue blood flow
-determining rate and extent of drug access
tissue blood volume
-volume of blood available to hold drug in tissue
-greater vascularization, larger the blood volume and greater potential for rapid and extensive distribtution
partitioning
-ratio of drug concentrations in tissue and in blood (Kp)
-higher the ratio, greater the tissue concentration
binding
-drugs reversibly bind plasma and/or tissue proteins to influence availability of drug to site of action, extent of distribution, availability of drug for elimination
partitioning
-drug may partition into blood cells and into membranes/fats
apparent volume of distribution
What are the two main factors that can determine rate of distribution?
perfusion rate-limited
permeability rate-limited
drugs fall into one category or the other
What is the apparent volume of distribution?
a measure of the extent of drug distribution
-an indirect measure of tissue binding
a proportionality constant relating drug concentration in blood or plasma to amount in the body
-the volume of fluid that drug appears to distribute into
What is a large Vd and what does this mean?
> 0.6L/kg
=means more drug is in tissue
What is a simplified definition of volume of distribution?
extent to which drug stays in plasma
volume that would contain the total body content of a drug at a conc equal to that in plasma
What is the conceptual model of Vd?
Vd=Vb+Vt(fu(b)/fu(t)
What are the factors that influence Vd?
variation in binding parameters (Kd, nP)
competitive binding displacements
relative pH of tissue and fluid compartments
blood flow
barrier integrity
body weight and composition
What is the equation for loading dose?
LD=Css,ave x Vd/S x F
Why are variations in binding parameters (Kd, nP) an important influence on Vd?
interindividual differences in capacity (nP) and affinity (Kd) for binding to plasma protein (or tissue protein) results in differences in fu(b)
influences free concentration of drug at site of action (biophase)
What are the causes of variation in binding parameters (Kd, nP)?
genetic variations
stage of development
disease states
-uremia will alter affinity
-hypoalbuminemia will alter capacity
Why do drug-drug interactions impact Vd?
competition for the same binding sites between two highly protein bound drugs
-immediate effect may be potentiation of displaced drug
significant only if large fraction of drug originally present in plasma compartment
Which endogenous molecules can have an impact on Vd?
bilirubin
-conditions causing reduced bilirubing conjugation may lead to bilirubinemia
-highly bound to albumin, so acts as a displacer
free fatty acids
-highly bound to albumin and has high affinity, so acts as a displacer
For significant binding displacement to occur, what characteristics must the displacer show?
high affinity for the protein
bind at the same site or affect the binding site (conformation) of the drug to be displaced
be present in sufficiently high concentrations to saturate the binding capacity
-binding capacity is a limiting factor
How does pH of tissue and fluid compartments influence Vd?
affects ratio of total concentration
-unionized, unbound concentrations are in equilibrium
ion trapping phenomenon
What is the impact of CO on Vd?
cardiac output determines tissue perfusion
What might you expect to happen to Vd with a reduced CO?
decreased tissue perfusion
-decreased Vd for drugs extensively distributed
increased Vd for drugs distributed in total body water
How does exercise impact blood flow?
increase in blood flow to muscle alters fraction of drug reaching muscle tissues
How does blood loss impact distribution?
vasoconstriction of large veins redirects blood to needed areas and this will alter distribution
What is the impact of disease states on distribution?
loss of tissue barrier integrity allows for greater penetration of drug into tissues
-inflammation
-burns (skin permeability)
Why is transporter expression important in distribution?
facilitated diffusion and active transport may be determinants of tissue uptake/efflux
What is the relationship of Vd and body weight?
Vd often proportional to body weight
-if drug does not partition into fat, Vd proportional to LBW
-if drug partitions into fat, Vd related to TBW
