drug interactions

Question 1

Types of DDIs

Answer 1

DDI

Drug-food: can also be due to poor absorption in full stomach, or for lipophilic drugs: good absorption in high fat diet.

drug-supplement

PD-interactions

Question 2

Anti-HIV drugs exploitation of DDIs

Answer 2

Co-administration of lopinavir with a sub-therapeutic dose of ritonavir found higher plasma [lopinavir], thus increasing efficacy. Now marketed as a fixed dose combination.

Zidovudine and lamivudine are co-administered, having a synergistic effect. Marketed as combivir.

Question 3

examples of different types of CYP inhibition (e.g., reversble competitive, irreversible, etc…)

Answer 3

Reversible competitive: e.g., theophylline and duloxetine CYP1A2.
Grapefruit inhibits CYP3A4/5/7

Reversible non-competitive: e.g., fluvoxamine (CYP2C19) and terbinafine (CYP2D6)

Reversible mixed: e.g., ketoconazole (CYP3A4)

Reversible uncompetitive: very rare

Also irreversible inhibition of enzymes can lead to altered metabolism of drugs. Irreversible inhibitor binds to the intermediate enzyme complex.

Question 4

examples of CYP induction DDIs

Answer 4

Activation of aryl hydrocarbon receptors increase the expression of CYP1A1/2 and UGTs.

Activation of CAR increases CYP2B6, 2C8/9, 3A4, 1A2, and some UGTs.

Activation of PXR increases GI expression of 3A4

Broccoli induces CYP1A2

Phenytoin induces CYP2B6

rifampicin and phenytoin induce CYP3A4

Enzyme induction usually takes longer due to upergulation of the enzyme taking time.

Question 5

Physiochemical drug interactions examples

Answer 5

pH can alter the absorption of drugs from the GIT. Increase in pH from proton pump inhibitors (omeprazole) can decrease the absorption of cefpodoxime (antibiotic) and ketoconazole.

Chemical interactions of the drug can occur in the GIT, e.g., doxycycline being chelated by ions (e.g., Fe, Ca, Mg, Al)

Gastric motility can alter rate of absorption. An increase in gastric motility from metoclopramide decreases the absorption of digoxin.

Question 6

PPB competition example

Answer 6

Diazepam displaces phenytoin from plasma proteins, increasing [unbound phenytoin]: toxic.

Question 7

Terfenadine and ketoconazole interaction

Answer 7

Terfenadine is a prodrug completely metabolised by CYP3A4 in first pass to produce the antihistamine fexofenadine. Unmetabolised terfenadine is cardiotoxic due to its blocking of Kv 11.1.

Ketoconazole potently inhibits CYP3A4, leading to toxic amount of terfenadine accumulating, which can cause abnormal heart rhythm, and may develop tornado de pointes.

Consequently terfenadine was withdrawn and fexofenadine was approved.

Question 8

examples of Renal DDIs

Answer 8

ACEIs and NSAIDs decrease the renal excretion rate of digoxin.

Methotrexate excretion is inhibited by NSAIDs competition for tubular OATs.

Probenecid prolongs the half-life of penicillin by reducing renal excretion rate. Used therapeutically.

Renal diseases increase risk of these DDI