L2 Drug Translocation

what are the 2 fundamental processes that determine drug concentrations in different body compartments

• translocation of drug molecules

• chemical transformation

where is bulk flow transfer

blood stream

how does bulk flow transfer effect drug translocation

chemical nature of drug has no effect

where is diffusional transfer

molecule by molecule over short distances

how does diffusional transfer effect drug translocation

differs markedly between drugs with different chemical properties

what are the 2 methods of diffusional transfer

• hydrophobic diffusion barrier

• aqueous diffusion

define the ‘compartmentalised body’

the body is made of inter-connected compartments separated by cell membranes

• the ability of drugs to move between them depends on the selectivity of the membranes and the chemical properties of the drug

what is on the outside of a single layer epithelial membrane in the GI and kidneys

GI tract lumen

what is on the inside of a single layer epithelial membrane in the GI and kidneys

portal circulation

what does the vascular endothelium act as

a filter

what is the cut off for the vascular endothelium filter

MW 80-100K

what are the gaps between cells of the vascular endothelium filter filled with

a protein matrix

• tightly packed

• act as MW filters

in liver and spleen, endothelium is…

discontinuous

what allow drugs to exchange freely between the blood and interstitium in the liver

large fenestrations

describe large fenestration structure

slit junctions between endothelial cells where drugs move out through the basement membrane

what are the 2 important ways solutes can traverse cell membranes that are important to drug pharmacokinetics

• diffusing directly through the lipid

• combination with a transmembrane carrier protein

what are other ways solutes can traverse cell membranes by

• diffusing through aqueous pores

• pinocytosis

what is pinocytosis for

macromolecules (e.g. insulin)

what do non-polar solvents dissolve readily in

non-polar solvents (e.g. Lipids)

• cell membranes are lipid-rich environments

non polar substances (lipids) can penetrate cell membranes…

very freely

• they are permeable

what is the permeability coefficient (P) determined by

• the number of molecules crossing the membrane per unit area in unit time (J)

• Concentration difference across the membrane (delta C)

what is the equation with permeability coefficient

J= P delta C

what is J in J= P delta C

the number of molecules crossing the membrane per unit area in unit time

what is delta C in J= P delta C

concentration difference across the membrane

what are the physicochemical factors contributing to permeability

• partition coefficient

• diffusion coefficient (1/square root MW)

what is the ionised form of drugs much less able to do

penetrate cell membranes

many drugs are either…

weak acids or weak bases

what does ionisation affect

• drug permeability across membranes

  • ionised drugs show much reduced permeability

• steady state distribution of drug molecules between aqueous compartments in the presence of a pH difference

what is Aspirin

weak acid (pKa 3.5)

what is pethidine

weak base (pKa 8.6)

what does aspirin have its ionisation greatest at

alkaline pH

what does pethidine have its ionisation greatest at

acid pH

what is aspirin absorption increased by

metoclopramide

what is aspirin absorption decreased by

propantheline

what is it important to remember (so we dont go assuming bc as scientists nothings perfect)

• ionised forms are not totally impermeable

• body compartments are rarely at equilibrium in ‘real life’

urinary acidification … excretion of weak bases and … that of weak acids

• increases

• decreases

urinary alkalinisation… excretion of weak bases and … that of weak acids

• decreases

• increases

what does increased plasma pH cause

extraction of weakly acidic drugs from CNS into plasma

give an example of something that increases plasma pH

sodium bicarbonate

what does decreased plasma pH cause

weaky acidic drugs to accumulate in the CNS

give an example of something that decreases plasma pH

acetazolamide

what can the pH partition mechanism be used to treat

drug overdose (eg aspirin overdose)

what percentage of H20 and solutes are reabsorbed in the proximal tubule

70%

what happens in the glomerulus

renal blood flow filtration

what happens in the loop of Henle

urinary concentration

what happens in the distal tubule collecting duct

control of Na and H2O balance

what example drugs does urinary alkalisation increase the excretion of

aspirin

at normal urinary pH a proportion of aspirin (salicylate) is … and can be put back into the systemic circulation in the nephron

unionised

when urine is alkaline, salicylate (aspirin) is … so reabsorption is much reduced

charged/ionised

define carrier-mediated transport

transport of physiologically important molecules in and out of cells (e.g. sugars, amino acids, neurotransmitters and metal ions)

define passive transport

movement of molecules in the direction of the electrochemical gradient (facilitated diffusion)

define 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+)

what can we say about carrier-mediated transport (uk just fun facts)

• saturable

• can be inhibited competitively

how is Cisplatin nephrotoxic (to certain individuals)

• it is efficiently taken into the proximal tubule through OCT2/3

• rate of secretion into urine is lower through MDR1/2

what does a higher exposure of cisplatin to cells result in

destruction of mitochondria

• proximal tubular cell death

• organic solutes lost to urine increases Na loss which increases H2O loss

define Fanconi syndrome

organic solutes lost to urine increases Na loss which increases H2O loss

what is cisplatin uptake inhibited by

an uptake blocker that is not nephrotoxic but prevents cisplatin binding OCT2/3

• so no accumulation in the proximal tubule cell

what is levodopa transported by

the carrier protein responsible for phenylalanine

what is fluorouracil transported by

the carrier for natural pyrimidines (thymine and uracil)

where is the Iron carrier system

the jejunum

what is the calcium carrier system

vitamin D-dependent

what do many CNS drugs inhibit

transport mechanisms

what is the Pgp transporter responsible for

MDR

• e.g. doxorubicin, vinblastine, actinomycin

where is Pgp responsible for MDR

neoplastic cells