Podgorski - ADME

Question 1

Predominant mech of membrane crossing:

Driving force:

Answer 1

passive diffusion

conc. gradient

Question 2

Other means by which drugs cross membranes (4)

Answer 2

aq channels in the intercellular junctions

lipid cell membranes

active pumps or co-transpoters

cellular endocytosis/exocytosis

Question 3

Larger lipid solubility =

Answer 3

Larger lipid solubility = Greater ability to cross membranes.

Access to cells, cellular organelles, nervous system

Question 4

Henderson-Hasselbalch Equation

Answer 4

pH = pKa + log (unprotonated/protonated)

Question 5

Where does acid accumulate?

Answer 5

basic compartments. Aspirin goes from stomach to plasma

Question 6

Acids vs. Bases protonation

Answer 6

A- = HA
B = HB+

Question 7

Body fluids with potential for drug “trapping”

Answer 7

Urine (pH 5-8)
Breast Milk (6.4-7.2)
Jejenum, ileum (7.5-8)
Stomach (1.9-2.6)
Prostate secretions (6.45-7.42)
Vaginal secretion (3.4-4.2)

Question 8

Ampicilin is a weak organic acid with a pKa of 2.5. What percentage of a given dose will be in a lipid soluble form in the duodenum at pH of 4.5?

Answer 8

about 1%

Question 9

How does first pass metabolism affect the bioavailability of propranolol?

Answer 9

propranolol – 73% of oral dose

destroyed by first pass metabolism

Question 10

Bioavailability def:

Answer 10

Percent or fraction of the orally administered dose that actually enters systemic circulation

Question 11

Vd=

Answer 11

Vd=(amount administered)/(concentration at t=0)

or otherwise written
Vd = Dose/Plasma Drug Conc.at t=0

-t=0 is found via extrapolation

Question 12

How do you determine the volume of distribution? (4 steps)

Answer 12

1. Administer known amount of drug i.v.
2. Take blood samples at various times and
   measure drug concentrations.
3. “Plot log concentration as a function of time.
4. Extrapolate straight line through linear data
   points back to time = 0 to estimate blood
   concentration when amount in body is known
   and before any loss due to elimination
   occurs.

Question 13

significance of Vd

Answer 13

Vd is the apparent volume of plasma that would have yielded the extrapolated conc. at t=0 upon administration of the dose. It relates the amount of drug in the body to the conc. in blood or plasma

Question 14

Early vs. late time points

Answer 14

Early time points- plasma concentration depends on distribution out of the plasma and elimination process from the body

Later time points – controlled by elimination only (straight line)

Question 15

What property of the drug determines Vd?

Answer 15

lipid solubility: high lipid solubility = low plasma concentration = large Vd

binding to plasma protein: high binding = trapping of drug in the blood = small Vd

Question 16

Range of Vd values in a 70kg person:

Answer 16

5 -10 liters – drugs highly charged or bound to plasma protein

20-40 - moderately lipid soluble

40 - lipid soluble enough to distribute to the total body of water

> 40 - high lipid soluble; sequestered in fat, nervous tissue, and muscle

Question 17

Can some highly lipid soluble drugs have Vd <40?

Answer 17

Note: some highly lipid soluble drugs are bound to plasma proteins and, as a result, have Vd values of less than 40 liters

Question 18

Consequences of high lipid solubility

Answer 18

Access to liver cells and
accumulation in the ER where
cytochrome P450 enzymes responsible
for hepatic metabolism are located.

Access to CNS. Tight junctions in the
capillary endothelium and lipoidal glial
cells provide a barrier against entry of
compounds into the brain.

Question 19

How are CNS drugs eliminated?

Answer 19

hepatic metabolism

Question 20

Effect of plasma protein binding on elimination of drugs

How is there a possibility of drug-drug interaction?

Answer 20

Drug action correlates with free drug
concentration rather than total plasma drug

Slower elimination because bound drug is not
filtered in the kidney and not metabolized in
the liver

Possibility of drug-drug interaction if a second
drug is administered that competes for plasma
protein binding (Example – WARFARIN and
other oral anticoagulants can displace some
drugs causing temporary rise in their free
drug concentration).

Question 21

Elimination types:

rule of thumb:

Answer 21

Urinary, liver, combo

RULE OF THUMB: drugs can be directly eliminated if they’re hydrophilic (polar)

Question 22

Urinary excretion (3)

Answer 22

Renal glomerular filtration
Tubular secretion (active)
Passive reabsorption

Question 23

Renal glomerular filtration

Answer 23

Unbound drugs only -

­‐ Changes in glomerular filtration rate affect the rate of elimination of drugs, (e.g., digoxin, kanamycin).

Question 24

Tubular secretion (active)

Probenecid

Answer 24

• transport against concentration gradient -­
  ‐ drug/metabolite selectivity -­
  ‐ probenecid and secretion of penicillins

Probenecid: competitively inhibits the tubular secretions of the penicillins, prolongs the duration of the effect of penicillins

Question 25

Passive reabsorption

Answer 25

enhanced lipid solubility favors reabsorption -­
‐ pH -
­‐ rate of renal flow

nonionized, lipid-solubule drugs are extensively reabsorbed into plasma, while ionized and polar molecules will remain in the renal filtrate and are excreted via urine.

Question 26

What does intravenous sodium bicarb do?

Answer 26

alkanlinizes urine to pH 8

Question 27

How do you acidify urine?

Answer 27

administer ammonium chloride. Changes pH to 5.

Question 28

Biliary excretion

Answer 28

works for high molecular weight or glucuronidated drugs

enterohepatic cycling (results in prolonged presence of drug or toxin

cholestyramine – as approach to interrupt enterohepatic cycling

Question 29

Ezetimibe

Answer 29

Reduced intestinal absorption of cholesterol -

­‐ t1/2 in the body > 20 hrs -­

‐ Benefit: lower LDL cholesterol

Question 30

Choroid plexus

Answer 30

Choroid plexus: active secretion of compounds from cerebral spinal fluid into the blood