Basic Principles

Question 1

Give examples of drugs that inhibit PGP

Give examples of drugs that induce PGP

Give examples of drugs whose bioavailability is affected by PGP inhibition/induction

Answer 1

Inhibit

• Amiodarone
• Verapmail

Induce
- Rifampicin

Bioavailability

• Digoxin
• Dabigatran

Question 2

Do PGP inhibitors and inducers also commonly inhibit and induce CYP3A4

Answer 2

Yes

Question 3

What is Graham’s law

Answer 3

The rate of passive diffusion is inversely proportional to the square root of the molecular size

Question 4

What is Fick’s law

Answer 4

The rate of diffusion is proportional to the concentration gradient (which defines the Bowman’s principle –> increase dose NDMR leads to faster onset of effect)

Question 5

Fentanyl is 7 x more lipid soluble than alfentanil. Fentanyl has an onset 3 minutes. Alfentanil has an onset of 1 minute. How can the faster onset of action of alfentanil be explained

Answer 5

Alfentanil pKa 6.5

Fentanil pKa 8.4

Physiological pH = 7.4

Both are weak bases and bases ionize at pH BELOW their pKa.

So for alfentanil - the pH is above its pKa –> mostly unionized

And for fentanyl - the pH is BELOW its pKA –> mostly ionized

Hence, alfentanil has a faster onset of action despite its lower lipid solubility

Question 6

What is the danger of intrathecal morphine vs fentanyl

Answer 6

Fentanyl is highly lipid soluble with an octanol:water coefficient of 717 versus morphines of 1.42. Therefore, fentanyl dissolves into the local lipid tissues. Morphine on the other hand, remains in the CSF for longer and hence is liable to spread cranially with increased risk of respiratory depression.

Question 7

Why is the extent of protein binding only pharmacokinetically relevant in a small proportion of drugs. Give 2 examples.

Answer 7

Unbound drug / free drug crosses membrane

Protein binding only significant when > 90 %

In most cases, when protein levels change, the level of free drug changes which could influence its affect/toxicity. However, when the free drug concentration changes, for most drugs so does the rate of drug metabolism and therefore a new equilibrium is reached without altered effect or toxicity.

For a very small number of highly protein bound drugs the metabolic pathways are already close to saturation. This means that if there is a change in protein binding the affect might be altered or toxicity might ensue.

Question 8

Which type of plasma proteins bind acidic drugs

Which type of plasma protein bind basic drugs

Which type of plasma proteins bind iron

Which type of plasma proteins bind copper

Answer 8

Albumin –> acidic and neutral drugs (barbiturates)

Globulins (e.g. PGP) –> Bind basic drugs (morphine)

Iron –> B1 - globulin

Copper –> alpha 1 globulin