Lecture 30

Question 1

4 Mechanisms of drug permeation

Answer 1

1. paracellular pathway (aqueous diffusion)
2. transcellular pathway (lipid diffusion)
3. special carriers
4. transcytosis (endocytosis & exocytosis)

Question 2

What exactly is absorption of drug?

Answer 2

transfer of a drug from its site of administration to bloodstream.
EX) IV = 100% Absorption
other route = partial absorption

Question 3

3 types of enteral routes and extent of first-pass effect on each

Answer 3

1. oral
2. sublingual (bypass first-pass effect)
3. rectal (partial avoidance of the first-pass effect)

Question 4

first-pass effect

Answer 4

a fraction of the drug is metabolized in the gut wall and liver before reaching systemic circulation

Question 5

4 types of parenteral routes

Answer 5

1. IV
2. IM (intramuscular)
3. Subcutaneous
4. Intradermal

Question 6

5 factors that influence drug absorption

Answer 6

1. effect of pH on drug absorption
2. surface area available for absorption
3. blood flow to absorption site
4. contact time at absorption surface
5. P-Glycoprotein

Question 7

For weak acid, which will permeate through membrane: protonated or unprotonated?

Answer 7

protonated form = uncharged = HA

• Due to Chatlier principle, as conc of HA decrease outside the cell, equilibrium shift to left, thus A- gets protonated into HA, thus all drug eventually enters membrane but slow.

Question 8

For weak base, which will permeate through membrane?

Answer 8

upprotonated form = uncharged = B

Question 9

Henderson-hasselbalch equation

Answer 9

pH-pK = log ([unprotonated form]/[protonated form])

Question 10

When pH=pK what happens to concentration of unprotonated and protonated?

Answer 10

[unprotonated] = [protonated]

Question 11

When pH-pK is 1,-1,2,-2 what is % of unprotonated and protonated

Answer 11

When 1, ratio is 10 so % unprotonated = 90 , %protonated = 10

When -1, ratio is 0.1 so %unprotonated = 10, %protonated = 90

When 2, ratio is 100 so %unprotonated = 99 , %protonated = 1

When -2, ratio is 0.01 so %unprotonated = 1, %protonated = 99

Question 12

What is ion trapping and its relationship to H-H equation?

Answer 12

In kidney, if a drug is in a liposoluble form during its passaage down the renal tubule, a significant fraction will be reabsorbed by passive diffusion. So by manipulating pH of urine, drug excretion can be manipulated. To accelerate excretion of drug, pH should be adjusted to ionize the drug so that drug can be trapped in urine.

• Weak acid excreted fast in alkaline urine
• Weak base excreted fast in acidic urine.

Question 13

What does it mean by contact time at absorption surface affect drug absorption

Answer 13

if a drug moves through GI tract very quickly i.e, diarrhea, it is not well absorbed.

Question 14

What is P-glycoprotein?

Answer 14

P-glycoprotein (MDR1) is a transporter protein responsible for transporting several drugs across cell membrane into lumen for excretion. Thus it reduces drug absorption.

Question 15

What is bioavailability?

Answer 15

fraction of administered dose of a drug that reach systemic circulation.

Question 16

How is bioaviliability of a drug is determined?

Answer 16

by comparing area under the curve (AUC) after a particular route of administration with AUC after IV injection
*AUC reflects extent of absorption of drug

Question 17

Bioavailability equation

Answer 17

F= (AUC oral) / (AUC IV) *100

Question 18

What is drug distribution?

Answer 18

the process by which a drug leaves the bloodstream and enters extracellular fluid and/or the cells of the tissue.

Question 19

4 factors that determine drug distribution

Answer 19

1. blood flow (well-perfused organ receive more drug eg liver, brain etc)
2. drug binding to plasma and tissue proteins (drug biniding to plasma protein such as albumin slows distribution)
   * Many liposoluble drugs accumulate in fat prolonging drug action.
3. capillary permeability
4. drug hydrophobicity

Question 20

Features of blood-brain barrier

Answer 20

1. continuous tight junction of endothelial cells of brain capillaries
2. astrocytic “end feet” surround outside of capillary endothelial cells which reduce blood flow to brain
3. P-glycoprotein actively transport drug back into systemic circulation.

Question 21

Why is metabolism of drug into hydrophilic metabolites essential?

Answer 21

for termination of their biological activity

and their elimination from the body

Question 22

Which organ is actively involved in drug metabolism?

Answer 22

Liver the most

- GI tract, kidney, skin and lungs

Question 23

Which system in hepatocyte is responsible for 80% of drug metabolism?

Answer 23

cytochrome p450

Question 24

How can activity of cytochrome p450 induced?

Answer 24

drugs can enter hepatocytes and bind to xenobiotic receptor, activated receptor would translocate to nucleus and bind to promoter of enzymes (p450), thus increasing transcription.

Question 25

What are the drugs that induce p450 activity?

Answer 25

rifampin, phenobarbital, carbamazepine

Question 26

3 clinical consequences of enzyme induction

Answer 26

1. a drug can increase its own metabolism
2. a drug can increase the metabolism of a coadministered drug
3. This may reduce drug plasma concentrations below therapeutic levels.

Question 27

4 drugs that inhibit cytochrome p450

Answer 27

Cimetidine
Erythromycine
Chloramphenicol
Grapefruit juice

Question 28

What could be the result of inhibiting enzyme involved in metabolism?

Answer 28

drug level may reach toxic concentration.

Question 29

2 ways of drug excretion

Answer 29

1. renal excretion (major)

2. bile excretion (small number of drugs)