Lecture 2 - Translocation of drugs Flashcards
What are the two fundamental processes that determine drug concentrations in different body compartments?
-Translocation of drug molecules
- chemical transformation
what is translocation of drugs? 2 types transfer
drug movement around the body
- bulk flow
- diffusional transfer
What is bulk flow transfer? (blood stream)
chemical nature of drug has no effect
what is diffusional transfer? (molecule by molecule over short distances)
- hydrophobic diffusion barrier
- aqueous diffusion
differes markebly between drug with different chemical properties
theory of a compartmentalised body?
‘Body made of inter-connected compartments separated by cell
membranes’
what does the ability of drugs and other chemicals to move between these
compartments depend on?
selectivity of the membranes and the
chemical properties of the drug
What type of membrane does the epithelial barrier have in the GI and kidneys ?
single layer
what is a vascular endothelium ?
non selective mostly
- acts as a filter
what are the gaps between cells filled with in VE ?
protein matrix - tightly packed
- acts as MW filters
Large _____ allow drugs to exchange
____ between _____ and _______ in the
liver
fenestrations
freely
blood
interstitium
In liver and spleen, e__othelium is
______
end
discontinuous
_____ junctions in CNS and placenta
Tight junctions in CNS and placenta
- only way chemicals go through is lipid soluble
Give ways drug can transverse across cell membrane
- diffuse direct through the lipid
- diff through aqueous pores
- combination with transmembrane carrier protein
- pinocytosis (for macromolecuels e.g. insulin)
which ways are important for drug pharmacokinetics across membranes?
- diffusing direct through the lipid
- combination with a transmembrane carrier protein
- maybe pinocytosis
Describe diffusion through lipid
- non-polar substances dissolve readily in non-polar solvents - cell membranes are lipid - rich environments
- nonpolar substances can penetrate cell membranes very freely (permable)
what is the permability coefficient (P) determined by?
- number of molecules crossing the membrame per unit area in unit time (J)
- concentration difference across the membrane (change C)
- J= P difference C
____ correlation between lipid solubility and permeability of cell membrane to different substances
Close
what can be predicted from measuring / predicting lipability?
-rate of absorbion from gut
- penetration into brain and other tissues
- extent of renal elimination
many drugs are either _____ acids or ____ bases
weak
Many drugs are either ____ acids or ____ bases
They exist in both ____ and ____ forms.
The ____ form is much less able to penetrate cell membranes
weak
inionsed
unionised
ionised
Ratio of Charged Drug/Uncharged Drug concns is determined by the __ of the compartment
pH
For many drugs the _____ species is sufficiently lipid
soluble (except e.g. aminoglycosides)
uncharged
which has a greater surface area for absorption … sml intes vs stomach?
Small intestine
what is aspirin absorption increased by?
metoclopramide
what is aspirin absorption decreased by?
propantheline
Urinary acidification
^ extretion of weak bases
v excretion of weak acids
Urinary alkalinisation
v excretion of weak bases
^ excretion of weak acids
What does increased plasma pH cause?
extraction of weakly acidic drugs from CNS into plasma
what does decreased plasma pH cause ?
weakly acidic drugs to
accumulate in the CNS
if we increase plasma pH - weak _____ are ___
acids
charged
What increased excretion of aspirin?
urinary alkalinsation
Passive transport::
move molecules in the
direction of electrochemical gradient (facilitated
diffusion)
Active transport:
Movement against an electrochemical
gradient, coupled to an energy source by:
Direct use of ATP or electrochemical gradient of another
species (e.g. Na+) (active transport)
Carrier-mediated transport is:
- Saturable
- Can be inhibited (competitive inhibition)
Carrier-mediated transport
higher exposure of Cisplatin results in distructrion of what incracellular thing?
Mitochondria
> > proximal tubular cell death
Levodopa ‘hitches a ride’ on which system?
carrier responsible for phenylalanine (L-amino acid transporter)
- blood to brain
Where is iron absorbed ?
jejunum (sml intest)
- using a specific carrier system
what does calcium absorption depend on and where does it activate a specific transporter ?
calcium absorption depends on vitamin D
vitamin D helps activate transporter in intestine to absorb calcium
what are other factors affecting drug pharmacokinetics?
- binding to plasma protein
- partition into body fat and other tissues
what percentage of H2O and solutes are reabsorbed in the proximal tubule?
70%
Function of distal tubule collecting duct ?
control of Na and h2o balance
Function of loop of henle?
urinary concentration
Function of glomerulus ?
renal blood flow
filtration
how many L is filtered a day in nephron ?
180
What happens at normal pH with salicylate?
a proportion of salicylate is unionised – can be absorbed back into the SYSTEMIC circulation in the NEPHRON
what happens when urine is alkaline with salicylate?
salicylate is charged — reabsorption is much more reduced
why is cisplatin nephrotoxic to certain individuals?
because
- efficiently taken up into proximal tubule
but
- rate of secretion into urine is lower
what is Fanconi syndrome
organic solutes lost to urine increased Na loss increased H2O
Cisplatin enters cells using a specific transporter. If you block this transporter with a non-toxic blocker, cisplatin can’t get into the kidney’s proximal tubule cells, preventing it from building up and causing kidney damage.
