Science of Medicines Week 19/20 Flashcards
define drug distribution
the reversible transfer of drug from one site to another within the body
What does the rate and extent of tissue distribution depend on?
the drug and the tissue
What factors determine the kinetics (how fast) drug distribution occurs?
whether distribution is rate-limited by permeability or perfusion rate
What factors determine the extent to which drug distribution occurs?
- tissue perfusion
- drug-tissue affinity
- binding to plasma proteins or tissue factors
- passive permeability
- transporters
What path do drug molecules take from the blood into tissues?
capillaries -> interstitial fluid -> cells
What are the 2 main potential steps for drug distribution?
- passage over the capillary membrane
- passage over the cell membrane
How does movement of drugs across membranes occur?
by transcellular and paracellular pathways
What is paracellular movement across a membrane influenced by?
the tightness of the intracellular junctions
Which 2 categories is transcellular movement across membranes divided into?
- those involving passage by simple diffusion
- those involving facilitated mechanisms like transporters
What are the 3 processes of drug distribution?
- passive diffusion
- transporters
- hydrostatic pressure (very minor effect)
What is passive diffusion defined by?
Fick’s 1st law
What is passive diffusion across membranes influenced by?
diffusivity, partitioning, ionisation, pH, thickness of membrane, EFFECT OF PLASMA BINDING
What are transporters important for?
some drugs with poor passive permeability
How does hydrostatic pressure influence distribution process?
arterial end pressure > tissue pressure
tissue pressure > venous pressure
By which process do drug molecules usually pass from blood to interstitial fluid?
paracellular movement through membranes of blood capillaries
What factors is drug transport through membranes of blood capillaries INdependent of?
lipophilicity, charge and molecular size
For larger molecules, which factor becomes important in determining its distribution over capillary membranes?
charge - for example, negatively charged molecules have lower permeability across the renal glomerulus
What does passage of a drug molecule across the cell membrane from the interstitial space depend on?
drug physicochemical properties AND/OR the drug being a substrate for influx/efflux transporters
What do drug physicochemical properties include?
size, charge, lipophilicity
For which membranes is drug transport highly dependent on lipophilicity, charge and MW?
- blood-brain barrier
- hepatocytes
- renal tubules
How does pH affect drug distribution?
- pH determines the degree of ionisation of drugs
- membrane transport is slower for charged drugs
Which equation links pH and degree of ionisation?
Henderson-Hasselbalch equation
What is the 1st assumption of the pH-partition hypothesis?
only unionised drugs penetrate membranes
What is the 2nd assumption of the pH-partition hypothesis?
at equilibrium:
1. the concentrations of the unionised species are equal on both sides
2. the concentrations of ionised species is larger on the side with the lower pH (for a weak base)
3. the total concentration (ionised + unionised) is larger at the side with the lower pH
What does the pH-partition coefficient state?
when a drug is a weak acid or weak base, its total concentration on one side of a lipophilic membrane may be very different from that on the other at equilibrium, if the pH values of the 2 aqueous phases are different
What are the 2 types of transporters?
- equilibrating transporters
- active transporters or concentrating transporters
What do equilibrating transporters do?
help passive diffusion by facilitated diffusion
What do active (or concentrating) transporters do?
concentrate a drug on one side against a concentration gradient
What are the 2 types of transporter directions?
- efflux
- influx or uptake
define efflux
transport out of a cell
define influx (uptake)
transport into a cell
What are the two types of side for transporters?
- apical side
- basolateral side
define apical side
side of the membrane next to lumen
define basolateral side
side of the membrane next to the blood
What do transporters have an important role in?
- distribution of some drugs
- absorption
- elimination
- therapy success
What is the trend with drugs diffusing across the blood-brain barrier?
permeability increased with increasing lipophilicity
What is an exception to this trend over the blood-brain barrier?
vinblastine and vincristine have a permeability lower than expected, largely explained because they are substrates for the efflux transporter, P-glycoprotein
What 3 things can drugs bind to?
- tissue components
- plasma proteins
- red blood cells
What is the binding equilibrium like in plasma?
very fast and usually reversible
What is important about bound drugs?
they cannot diffuse across biological membranes as the cannot cross capillary membranes
What is a key determinant of drug distribution?
plasma binding
What is the degree of binding for a drug to plasma proteins expressed as?
its bound fraction (f bound)
Which values does f bound vary between?
0-1
When is a drug considered ‘highly bound’?
when f bound is equal to or more than 0.9
What is the equation for f bound?
f bound = [drug] bound / [drug] total
What is the equation for the free drug (f free)?
f free = [drug] free / [drug] total
What is the other equation for the unbound (or free) fraction?
fu = 1 - f bound
What is the equation for the free (or unbound) concentration of a drug in plasma?
C free = C total x fu
What is fu commonly expressed as?
alpha
What is f bound commonly expressed as?
beta
Why can’t drug-protein complexes diffuse across membranes?
too large to diffuse efficiently
Which is able to distribute out of the plasma?
ONLY the free (unbound) drug
What is drug distribution VERY dependent on?
the drug’s binding affinity to BOTH plasma and tissue components
How does the tissue reach the equilibrium of distribution with the plasma?
the tissue will ‘take’ drug from the blood until the unbound drug in the tissue is equal to the unbound drug in the plasma
Why might the concentration of drug in plasma and tissue vary?
the drug may bind to plasma proteins or tissue components - for example, if a drug binds to plasma proteins, equilibrium between the unbound drug will be reached, but there will be a much higher concentration of drug in the plasma as some if bound to plasma proteins
For some drugs, what can be used to describe the affinity for a tissue instead of a binding process?
by a partitioning idea
How can the partition coefficient describe this?
P tissue / blood = C drug in tissue / C drug in plasma
What does a P tissue/plasma of 10 indicate?
the concentration of drug in the tissue will be 10x higher than concentration of drug in the plasma for the equilibrium of distribution to be achieved- the tissue will ‘take’ drug from the blood until this occurs
What is the concentration of a drug in plasma (Cp) a function of?
- dose (or concentration) given
- the extent of drug distribution into tissues
- elimination kinetics
What is the extent of distribution for a drug given by?
its ‘apparent’ volume of distribution (V or Vd)
Why is knowing the volume of distribution of a drug important?
allows us to work out dosages, particularly estimation of the loading dose
What is the equation for volume of distribution (V)?
V = amount of drug in the body / concentration of drug in the plasma
define volume of distribution
the apparent volume into which a drug distributes in the body once the equilibrium of distribution has been achieved
Which 2 parameters are most important in determining the fate of a drug in the body and its plasma concentration?
the volume of distribution and clearance (elimination)
What are the 4 examples of different cases for volume of distribution?
- all the drug stays in the plasma
- the drug also distributes into tissues
- the drug distributes more into tissues
- the drug distributes excessively into tissues
The more drug the distributes into tissues…
the higher the apparent volume of distribution
What is volume of distribution (V) used to?
- relate the amount of drug in the body with the drug plasma concentration
- estimate the DOSE required to achieve a given concentration
What is C required?
the dose needed to achieve a given concentration
What is the equation for loading dose?
dose = volume of distribution x concentration required = V x C required
When equilibrium of distribution is achieved, what is true?
concentration of unbound drug in plasma = concentration of unbound drug in tissue
What is the equation for volume of distribution at equilibrium of distribution?
V = Vp + VT x (fu / fu, tissue)
The larger the affinity of a drug for a tissue…
the larger the volume of distribution in that tissue
What is the equation linking volume of distribution and partition coefficient?
V = Vp + (VT x P)
comes from V tissue x P tissue/plasma
What is the equation for the percentage of drug present in plasma?
% plasma = (Vp x Cp) / (V x Cp) x 100
= Vp / V x 100
What is the equation for the percentage of a drug present in tissues?
% tissues = (V x Cp - Vp x Cp) / V x Cp x 100
= (V-Vp) / V x 100
When is the equilibrium of distribution reached?
when Cu = Cu tissue, so
C drug, tissue = P x C drug, plasma
Which 2 ways is drug distribution rate-limited?
perfusion rate-limited or permeability rate-limited
What is the overall rate of drug distribution determined by?
the slowest of either perfusion or permeability of the drug
When may drug distribution be permeability rate-limited?
when drugs diffuse slowly across some membranes
What are the 2 key facts about diffusion rate-limited distribution?
- changes in membrane permeability will modify distribution e.g. diseases
- kinetics of distribution are very dependent on the drug properties
When does perfusion rate-limited distribution occur?
when tissue membranes are NO barrier to distribution, but access to tissues is limited by blood flow
Which is most frequent out of these two?
perfusion rate-limited distribution
What is the equation for rate of drug into tissue?
Q x Ca = blood flow x concentration of drug into tissue
What is the equation for rate of drug out of tissue?
Q x Cv = blood flow x concentration of drug out
What is the equation for perfusion rate?
Q / Vt = blood flow x volume of distribution in tissue
What does the difference between the concentration of drug entering and leaving equal?
the concentration of drug uptaken into the tissue
What is the equation for the rate of uptake of a drug by a tissue?
Q x CA - Q x Cv = Q(CA - Cv)
blood flow x (concentration of drug in - concentration of drug out)
What is the equation for the amount of drug in a tissue?
VT x P x Cv
volume of tissue x partitioning x concentration of drug out
What is KT?
a first order, tissue distribution rate constant OR
rate of ‘drug exit from the tissue’ relative to the ‘amount of drug in the tissue’
What is the equation for KT?
KT = rate of exit / amount of drug in tissue
= Q x Cv / VT x P x Cv
= Q / VT x P
= (Q / Vt) / P
What is the equation for the half life of tissue distribution?
t 1/2 = 0.693 / KT
= 0.693 x P / (Q/Vt)
What does KT tell us?
how quickly the distribution process occurs for a drug and tissue
What does a larger KT indicate?
the faster the distribution process
What does a larger tissue distribution half life indicate?
a slower distribution process
For which type of tissue will the distribution of a drug be higher in (high KT, short half-life)?
tissues with high perfusion (Q/VT) and low affinity for the drug (low P)
