Lect 5 - Drug distribution in special compartments Flashcards
what are the 4 factors that distribution depends on
- permeability across tissue barrier
- binding within compartments
- pH partitioning
- fat-water partitioning
can drugs cross the cappilaries, what factors determine this
yes, small to intermediate drugs can.
- lipid solubility
- molecular weight
- degree of protein binding
distribution of molecules is mostly via capillaries, what are the 3 types of capillaries in the body, what is unique about each, and where are they normally found?
- continuous - these capillaries are the most abundant. they only allow diffusion of water and small ions, this is because their gaps - intercellular clefts are very small. these are found in skeletal and smooth muscles, connective tissue, and lungs.
- fenestrated - these have fenestrations (pores) in addition to intercellular clefts. as such, they allow rapid exchange and objects as large as peptides to pass. they are found in the kidney, and small intestines.
- sinusoids - these are wider and more winding capillaries, they have incomplete basement membrane, larger fenestrations, and very large clefts. these allow protein to pass and are found in the liver and spleen.
drugs can move across the cell membrane via diffusion or transport, which drug properties are more likely to use diffusion versus transport.
smaller molecules will diffuse, as will molecules that are more oil than water, i.e. a higher oil/water coefficient, and charged particles.
transport usually involves molecules that are analogous to the transporter’s natural substrate.
how does higher lipid solubility help a molecule get through the cell membrane?
molecules with greater lipid solubility are more likely to exist in the lipid membrane, increasing the transmembrane concentration gradient. this gradient results in faster diffusion rate of more lipid molecules.
what effects does pH have on drug distribution, how can pH be used to trap drugs in a particular compartment?
because many drugs are acidic or basic, pH can determine the rate of distribution and the steady state distribution of the drug.
if a weak base in put in 7.4pH blood, it will not dissociate much, and the uncharged form can easily diffuse into another solution such as urine, which is slightly acidic. the acidity will result in drug dissociating becoming charged particles, which can’t move across as easily thereby the concentration of weak base drug in urine is much higher than that in blood.
in practice, partitioning is not realistic, as charged particles still diffuse and equilibrium is never reached.
what are the 4 compartments of drug distribution, which have the greatest drug storage capacity, why isn’t this reflected on the normal curves.
blood, VRG, muscle, fat. this is based on the perfusion rate of each compartment.
fat has the highest storage capacity but this is not reflected because it takes so long for drugs to reach fat, by which time some of the drug would have been eliminated already.
although blood flow to the brain is very high, drug distribution does not reflect this. what is unique about the blood-brain barrier that causes this? how can we over come this?
the blood-brain/blood-CSF barriers have:
- tight endothelial junctions
- no fenestrations
- diminished trans-endothelial vesicles
this forms barrier for polar molecules.
we can overcome this by osmotically shrinking the cells which opens up the tight endothelial junctions.
how does the drug get across the blood-brain barrier?
more lipid soluble
smaller in size
not a substrate of active transport process such as P-glycoprotein which will just pump the drug molecule back out
what are the characteristics needed for drug to go into breast milk?
breast milk is more lipid, less protein and more acidic than plasma. therefore, drug need to be weak bases, low protein binding, and highly lipid soluble.
drugs into the fetus?
drugs can get into the placenta by diffusion, transport, pinocytosis, filtration.
