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Flashcards in Drug Distribution Deck (34):
1

For tissues with tight junctions between cells, including____(4)______, distribution will require drugs to pass through _________________

GI mucosa
BBB
Placenta
Renal tubules

pass through lipid membranes to or from this compartment and into or out of the the blood

2

Drugs that can't pass through membranes (those that are (____4____) will be unable to move between these compartments and blood limiting their distribution

large size
protein bound
highly charged
high water solubility

3

Oral Drugs and the GI mucosa?

negligible absorption of drugs if administered orally

4

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

5

Non-brain capillary drug passage

solutes move through fenestrations by passive diffusion

6

brain capillary drug passage

solutes must diffuse through two membranes

7

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

8

Where can drugs selectively accumulate and have either harmful or beneficial effects?

kidney
eye
lung
bone
ear

9

Acids are charged when?

At high pH when they release their proton

10

Bases are charged when?

At low pH when they snatch up a proton

11

For consistency how do we write equilibrium AB reactions?

always as acid dissociations

12

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

13

When are acids unionized

acidic pH

14

When are bases unionized

basic pH

15

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

16

How can we determine extent of ionization?

HHB equation

pH-pKa = log (A-/HA)

17

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

18

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

19

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

20

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

21

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

22

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

23

Where will acidic drugs be trapped

More basic solution

24

Where will basic drugs be trapped

More acidic solution

25

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

26

Clinical significance of ion trapping
Alteration of urinary pH?
Break milk?
Acidic stomach?

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

27

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

28

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

29

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)

30

Acidic drugs bind primarily to?

albumin

31

Basic drugs bind primarily to?

alpha-1 acid glycoprotein

32

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

33

how does protein binding influence volume of distribution

decreases
by enhancing apparent solubility in blood

34

how does protein binding influence ability to enter CNS

decreases