Drug metabolism by liver Flashcards
how can drugs cross the epithelium/ endothelium?
paracellular (inbetween cells)
Transcellular (through the cells - diffusion,active transport, pinocytosis)
solute carriers
organic anion transporters (drugs that are weak acids)
organic cation transporters (drugs that are weak bases)
which epithelium/endothelium is easiest for drugs to cross?
kidney (glomerulus)
what affect permeability?
cell type, number of cell layers, junction between cells
SLC carrier that moves in same direction
symporter
SLC carrier that moves in the opposite direction?
antiporter
Example of ATP-binding cassesttes
P-glycoprotein (P- gp) transporters
symport vs antiport
certain barriers are more permeable
- to allow substances to be metabolised (liver endothelium)
- and eliminated (renal endothelium in glomerulus)
examples of barrier that are less permeable
blood-brain barrier
why are other barriers less permeable?
to protect sensitive organs from circulating chemicals or pathogens
simple epithelium has how many layers?
one
stratified has how many layers?
multiple
Warfarin (acidic drug) has a pKa of 5.
If blood pH of blood increases from 7 to 7.5, what effect would this have on diffusion of warfarin across cell membranes and why?
becomes more ionised
ionised is lipid?
insoluble
unionised is lipid?
soluble
what crosses the barrier more easily : ionised or unionised?
unionised
if a drug is a weak acid and you add it in area that is more acidic what happens?
it will bind and become more unionised
( A- + H+ gives AH)
at pKa = pH, what is the % of drug ionised and unionised?
50%
medication such as proton pump inhibitors are used for?
treat conditions like reflux disease or gastric ulcers to increase gastric pH
-in theory might change absorption of drugs but insufficient to impact clinically
weak acid, increase alkaline conditions what happens?
less H+ ions so more of it ionised
most common plasma protein
albumin 55%
Percentage of plasma proteins
globulin- 38%
fibrinogen- 7%
others <1%
in blood drugs can bind to plasma proteins therefore can exists in what forms?
bound and unbound
reversible reaction between bound and unbound drugs means?
it is in equilibrium
etc can have more binding if increase in protein
importance of protein binding (2)
protein are too large to pass through
only free drugs can bind to site of action
implications of protein binding
-typically remain in the blood
-cant be metabolised or excreted
-becomes stored in reservoir and can impact volume of distribution
-cant exert their pharmacological effect
what effect does protein binding have on a drugs half-life?
longer half life b/c of reservoir effect
factors affecting protein binding
affinity of drug to protein binding sites
drug concentration
drug charge (ionised form more likely to bind)
plasma protein concentration
albumin is negatively charged what does this mean to its affinity of drug to protein binding sites?
high affinity for acidic drugs but has low capacity
low affinity for basic drugs but has high capacity
what is warfarin
a blood thinner
what is trimethroprim and amoxicillin
antibiotic
in most cases drug & protein concentrations dont affect ratio of bound to free drugs but can at higher doses why?
plasma proteins become more saturated (increase of unbound fraction as drug increases (
plasma proteins all taken up)
information of tissue binding is limited why?
because it requires solid tissue samples to test
some drugs bind readily to substances outside of the bloodstream like?
fat, bone, muscle
which drug can travel more easily across a cell membrane? highly lipophilic or highly hydrophilic?
highly lipophilic
lipophilic
like lipids
hydrophilic
likes water
highly lipophilic will bind extensively to?
fat stores
if someone is overweight what happens to plasma concentration and why?
plasma concentration is less because the drug goes to store within the fatty tissues and not within the plasma
osteoporosis leads to increased risk of fractures why?
increase resorption causing thinning of the bones
bisphosphonates work by?
binding to calcium in bones and inhibits resportion
resorption
process in which a substance, such as tissues, is lost by being destroyed and then absorbed by the body
what do osteoclasts do?
break down the tissue and release the minerals, resulting in a transfer of calcium from bone tissue to the blood
what is volume of distribution?
apparent volume into which a drug disperses in order to produce the observed plasma concentation
equation of vd
total amount of drug in body/ plasma concentration of drug
if a drug remains in the plasma will vd be low or high?
low
Vd is a theoretic number to…
help describe how well drugs distribute, rather than actual real-life volume
how does protein binding affect Vd?
-Bound drugs cant leave circulatory system
-higher proportion remains in the plasma
-so, total plasma concentration will be higher
hence vd will be lower
drug factors affecting Vd
plasma protein binding
tissue binding
physiochemical properties of drug
patient factors affecting vd
age
sex
body muscle
level of hydration
water distribution
examples of physiochemical properties of drug
size, charge, pKa, lipid/water solubility
