L2: Translocation of drugs

Question 1

What is pharmacokinetics?

Answer 1

The study of “drugs in motion” — how the body absorbs, distributes, metabolises, and excretes drugs (ADME)

Question 2

What two main processes determine drug concentrations in body compartments?

Answer 2

1) Translocation of drug molecules
2) Chemical transformation (metabolism)

Question 3

What are the two major types of translocation?

Answer 3

Bulk flow transfer and diffusional transfer

Question 4

How does bulk flow differ from diffusional transfer?

Answer 4

Bulk flow is via blood flow (not affected by drug properties); diffusion is molecule-by-molecule and influenced by lipophilicity, ionisation, etc

Question 5

What are the two main diffusion pathways?

Answer 5

Hydrophobic (lipid membrane) diffusion and aqueous diffusion

Question 6

Which property mostly governs passive membrane diffusion?

Answer 6

Partition coefficient (lipophilicity)

Question 7

Which substances are most likely to diffuse through lipid membranes?
A: Non-polar, lipophilic substances.

Answer 7

Non-polar, lipophilic substances

Question 8

What equation defines passive drug permeability?

Answer 8

J= P X A X C where P = permeability coefficient, ΔC = concentration gradient

Question 9

What does a higher LogKow indicate?

Answer 9

Higher lipophilicity → better membrane permeability (to a limit)

Question 10

Why do lipophilic drugs accumulate in fat or cells?

Answer 10

They cross membranes easily and partition into lipid-rich compartments

Question 11

What are the characteristics of vascular endothelium in general tissues?

Answer 11

Acts as a filter with protein matrix gaps that restrict large molecules

Question 12

What are fenestrations and where are they found?

Answer 12

Small pores found in liver/spleen vessels that allow free drug exchange

Question 13

Why can’t charged drugs cross brain capillaries?

Answer 13

The BBB has tight junctions and astrocyte foot processes, restricting entry to lipophilic or carrier-transported drugs

Question 14

What are the typical chemical forms of drugs?

Answer 14

Weak acids or weak bases

Question 15

Which drug form crosses membranes more easily?

Answer 15

Unionised (uncharged) drugs

Question 16

What determines the ionisation state of a drug?

Answer 16

The drug’s pKa and the pH of its environment

Question 17

State the Henderson-Hasselbalch equations.

Answer 17

Weak acid: pKa = pH + log([HA]/[A⁻])

Weak base: pKa = pH + log([BH⁺]/[B])

Question 18

What is the “pH partition mechanism”?

Answer 18

pH variation across compartments leads to differential ionisation and distribution of weak acids/bases (ion trapping)

Question 19

How does urinary pH affect excretion?

Answer 19

Alkaline urine: ↑ excretion of weak acids (e.g. aspirin)

Acidic urine: ↑ excretion of weak bases

Question 20

Why is carrier-mediated transport needed?

Answer 20

For polar or large molecules that cannot cross membranes passively

Question 21

What are the two types of carrier-mediated transport?

Answer 21

Passive (facilitated diffusion, no ATP)

Active (uses ATP, e.g. Na⁺/K⁺ ATPase)

Question 22

What are the two drawbacks of carrier-mediated transport?

Answer 22

It is saturable and can be competitively inhibited

Question 23

Give 4 examples of drugs using carrier systems.

Answer 23

Levodopa: phenylalanine transporter

Fluorouracil: pyrimidine transporter

Iron: jejunal carriers

Calcium: vitamin D-dependent carrier

Question 24

How does cisplatin enter renal tubule cells?

Answer 24

Via OCT2/3 transporters on the basolateral membrane

Question 25

Why does cisplatin cause nephrotoxicity?

Answer 25

It accumulates due to low efflux, causing mitochondrial damage, oxidative stress, and Fanconi syndrome

Question 26

How can Fanconi syndrome be prevented?

Answer 26

By co-administering uptake inhibitors to block OCT-mediated cisplatin transport

Question 27

Name two factors that affect drug distribution.

Answer 27

Binding to plasma proteins (↓ free drug) Partitioning into body fat (especially for lipophilic drugs)

Question 28

A drug is mostly unionised in the stomach, has high LogKow, and binds strongly to plasma proteins. Which factor would most reduce its filtration at the glomerulus? A) High LogKow B) Acidic stomach pH C) Plasma protein binding D) High permeability coefficient

Answer 28

C) Plasma protein binding

Question 29

Why might a weakly basic CNS drug with pKa 9 show low central activity despite being highly lipophilic? A) Its high LogKow impairs absorption B) It remains ionised in plasma and is excluded by the BBB C) It is actively removed by OCT transporters D) Its low molecular weight promotes renal clearance

Answer 29

B) It remains ionised in plasma and is excluded by the BBB

Question 30

A patient takes a drug with pKa 3.5. In which compartment is it likely to be ion-trapped and excreted faster? A) Stomach B) Blood C) Urine (alkaline) D) CNS

Answer 30

C) Urine (alkaline)

Question 31

Which scenario would most impair passive diffusion of a drug? A) High LogKow and unionised form B) Saturation of carrier proteins C) Drug existing mainly in ionised form at membrane interface D) Fenestrated capillary endothelium in the liver

Answer 31

C) Drug existing mainly in ionised form at membrane interface

Question 32

Which of the following statements about cisplatin toxicity is FALSE? A) It enters proximal tubule cells via OCT2/3 B) It accumulates due to high passive permeability C) It causes mitochondrial dysfunction and cell death D) It can lead to Fanconi syndrome

Answer 32

B) It accumulates due to high passive permeability