Flashcards in Drug Distribution Deck (34):
For tissues with tight junctions between cells, including____(4)______, distribution will require drugs to pass through _________________
pass through lipid membranes to or from this compartment and into or out of the the blood
Drugs that can't pass through membranes (those that are (____4____) will be unable to move between these compartments and blood limiting their distribution
high water solubility
Oral Drugs and the GI mucosa?
negligible absorption of drugs if administered orally
BBB/Placenta and Drugs?
Limited distribution of drug from blood into brain or into fetal circulation, respectively, due to structural differences between brain and non-brain capillaries
Non-brain capillary drug passage
solutes move through fenestrations by passive diffusion
brain capillary drug passage
solutes must diffuse through two membranes
renal tubules and drug passage
following filtration at glomerulus (not that large or protein bound drugs are not filtered), reduced reabsorption of drug back into blood, thus enhancing excretion via urine
Where can drugs selectively accumulate and have either harmful or beneficial effects?
Acids are charged when?
At high pH when they release their proton
Bases are charged when?
At low pH when they snatch up a proton
For consistency how do we write equilibrium AB reactions?
always as acid dissociations
What is the essential difference between an acid and a base (since we are writing both as equation with dissociable proton)
dissociation of a proton from an acid produces and ionized drug, whereas dissociation of a proton from a base produces an unionized drug
When are acids unionized
When are bases unionized
What is the extent of ionization dependent on? (2)
the strength of the acid or base (pKa)
the pH of the body fluid that contains it
How can we determine extent of ionization?
pH-pKa = log (A-/HA)
When the pH is lower than the pKa of the drug, which form predominates?
The protonated form will predominate
Unionized (lipophilic) form of the weak acid
ionized (hydrophilic) form of the weak base
For each log unit the pH is below the pKa,
there will be a 10 fold relative increase in the protonated form of the drug
When the pH is higher than the pKa of the drug, which forms predominate
there are relatively fewer protons and the unprotonated form predominates
which will be the ionized weak acid
or the unionized weak base
When is drug absorption favored vs
when is ion trapping favored?
drug absorption is favored when the unionized form predominates
ion trapping is possible when the ionized form predominates
Ion trapping: lipid barrier may separate two aqueous phases at different pHs (e.g. stomach pH 1.5 and plasma pH 7.4). Only non-ionized drug can diffuse through the membrane, what will happen to the concentration on each side?
The non-ionized form will equilibrate with its concentration the SAME on both sides of the membrane
There is a separate equilibrium between the ionized and unionized forms of the drug on each side of the membrane... the unionized concentration will be________ and the TOTAL concentration will be____
The unionized concentration of the drug is the SAME of both sides of the membrane
TOTAL concentration of drug is greater on side where ionization is greater - drug are trapped where they are predominantly ionized
Where will acidic drugs be trapped
More basic solution
Where will basic drugs be trapped
More acidic solution
What happens if the predominant form of the drug on both sides of the lipid barrier is the non-ionized form?
Ion trapping will be relatively insignificant - i.e. must have ions present to have ion trapping
Clinical significance of ion trapping
Alteration of urinary pH?
Alteration of urinary pH to ion trap weak acids or bases and hasten renal excretion. E.g,, alkalinization of urine can trap weak acid aspirin in overdose situations
There is a greater potential to concentrate basic drugs (e.g. opioids) in more acidic breast milk
In forensic pathology, weak base toxins are found concentrated in the acidic stomach contents
NOTE NOTE NOTE
Ionized drug molecules cannot pass through membranes and thus cannot move into or out of biologic compartments with tight junctions between cells (GI, brain, renal, placenta), HOWEVER, where can they cross?
However, they can cross capillary walls through pores. Thus, ionized drugs can enter the plasma circulation following parenteral administration and can enter the urine tubular fluid following filtration at the glomerulus
Lipid solubility and absorption... even if drugs have similar pKas
Lipid solubility of the non-ionized drug is also of great importance to the rate of passage of drugs across lipid membranes. It is possible that 2 drug may have similar pKa's (and similar % non-ionized), but will be absorbed differently based on the inherent lipid solubility of the non-ionized forms
How does protein binding influence drug distribution?
Only free drug is diffusible -
Thus, reduces concentration of active, free drug (can limit fetal exposure to drugs)
Acidic drugs bind primarily to?
Basic drugs bind primarily to?
alpha-1 acid glycoprotein
How does protein binding influence metabolism of drugs
Hinders metabolic drug degradation and reduces rate of excretion (will decrease elimination rate and increase half life) i.e. acts as circulating drug reservoir that can prolong drug action
how does protein binding influence volume of distribution
by enhancing apparent solubility in blood