Qualitative Pharmacokinetics: ADME

Question 1

What is the primary way in which drugs diffuse throughout the body and what is the driving force?

Answer 1

Passive diffusion - driving force is the concentration gradient.

They must have enough hydrophobic character to pass freely

Question 2

How do hydrophilic drugs distribute in the body?

Answer 2

Primarily rely on larger aqueous compartments (interstitial space, cytosol), and movement across tight junctions and endothelial lining of blood vessels

Question 3

What is the significance of special carriers for drug transport?

Answer 3

Many drugs which mimic naturally occurring peptides, amino acids, and sugars can utilize these special carriers for facilitated transport of too large / insoluble particles

Question 4

What is one additional mechanism which is important in movement of drugs in and out of the cells?

Answer 4

endocytosis / exocytosis

Question 5

What is the Henderson-Hasselbalch equation?

Answer 5

pH = pKa + log [A-]/[HA]
or
pH = pKa + log [B]/[HB+]

Question 6

Where does an acid tend to get trapped and why?

Answer 6

Only uncharged substances can move across a membrane. So, acids are easily absorbed in the stomach (low pH), where they are uncharged. They get stuck in the plasma where they are deprotonated and thus negatively charged

Question 7

Where does a base tend to get trapped and why?

Answer 7

Bases are neutrally charged in basic conditions, so they diffuse well from the plasma or duodenum, and tend to get stuck in low pH environments like the stomach, where they are protonated and thus positively charged

Question 8

What is the general pH of breast milk, stomach, prostate, and vaginal secretions?

Answer 8

breast milk ~7.0
Stomach ~2.0
Prostate ~7.0
Vaginal ~4.0

Question 9

What is the definition of bioavailability?

Answer 9

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

-> drugs with very high first pass metabolism will be less bioavailable

Question 10

What are the bioavailability trends of drugs given IV vs IM, oral, or subcutaneously?

Answer 10

IV: immediately 100% bioavailable

Oral / subcut / IM: delay to peak plasma concentration, generally less than 100% bioavailable

Question 11

What are the only routes of drug delivery which we worry about first pass metabolism?

Answer 11

Oral and rectal

Question 12

What is the formula for Vd?

Answer 12

amount of drug administered / (concentration at time 0)

Question 13

How is the concentration at time 0 of a drug determined? Why do we do this?

Answer 13

Administer the drug, and take blood samples. Extrapolate backwards to 0 from the log-linear portion of the graph (at true time 0, you are in the distribution phase and the drug has not fully distributed to the tissues(includes cells and plasma) to the full “volume of distribution”)

We do this because we know that the only thing controlling drug concentration in the linear portion of the graph is elimination, versus both elimination and distribution

Question 14

What is the significance of Vd?

Answer 14

Vd is the apparent volume of plasma that would have yielded the extrapolated concentration at t=0 upon administration of the dose

Question 15

What is the significance of Vd = 5-10, 20-40, 40, and >40 liters?

Answer 15

5-10 = drugs are highly charged or bound to plasma protein i.e. plasma (do not distribute well)
20-40 - moderately lipid soluble
40 - lipid soluble enough to distribute to total body water (for a 70kg person)
>40 liters - highly lipid soluble, sequestered in fat, nervous tissue, and muscle

Question 16

What drugs will have a high Vd?

Answer 16

Highly lipid soluble ones, whose plasma concentration at t=0 will measure very low (drug has diffused out of plasma)

Question 17

What are the features of CNS-active drugs? How are they metabolized?

Answer 17

Highly lipid-soluble in order to cross the lipoidal glial cell BBB, and will thus have very large Vd values.

They will be eliminated via hepatic drug metabolsim rather than renal excretion because they are highly lipophilic and cannot be urinated

Question 18

Why do lipophilic drugs concentrate in the liver?

Answer 18

they gain easy access to liver cells and tend to concentrate in the membranes of the rough ER, where CYP drug metabolism takes place

Question 19

How are most drugs excreted, and what are some other avenues?

Answer 19

Most are excreted via kidneys, and can be excreted directly if hydrophilic enough

Also excreted via bile, sweat, saliva, exhaled air, or milk

Question 20

What state must drugs be to be filtered by the renal glomerulus? What drugs cannot be reabsorbed? Give an example drug.

Answer 20

They must be unbound to proteins, and hydrophilic. i.e. digoxin, kanamycin

Drugs which become charged in the urine cannot re-enter the tubules

Question 21

How can some drugs be transported in the kidney against their concentration gradient, and what drug inhibits this?

Answer 21

Via renal tubular secretion / active transport, even if the drugs are protein-bound (since the complex rapidly dissociates).

This process is competitively inhibited via probenecid, which inhibits the tubular secretion of penicillins

Question 22

What drugs are most likely to be reabsorbed in the renal tubules? What plays a very important role?

Answer 22

Non-ionized, lipid-soluble drugs.

Thus, pH of the urine plays a very important role -> determines the ionization state of the drug

Question 23

How does protein binding of drug affect the free drug concentration and metabolism?

Answer 23

Drug action correlates with only free drug concentration. Extensive binding will slow metabolism of the drug (only unbound drug is metabolized), and can act as a depot / reservoir for the drug

Question 24

What drugs are known to displace drugs with high plasma protein binding?

Answer 24

Warfarin and other anticoagulants

Question 25

What is given in salicylic acid overdose?

Answer 25

sodium bicarbonate -> causes alkalinization of urine, inhibiting the reabsorption of salicylate in the kidney tubules as it is a weak acid

Question 26

What is enterohepatic cycling? What drug can inhibit this?

Answer 26

Excretion of drugs in the bile, and reabsorption from the intestine into the body

Drug: cholestyramine, a nonspecific adsorbent

Question 27

What helps excrete drugs from the CSF into the blood?

Answer 27

choroid plexus

Question 28

What is the function of Ezetimibe?

Answer 28

Reduces the intestinal absorption of cholesterol via reduction of enterohepatic cycling.

Reduces LDL cholesterol.