Drug Interactions

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a. Pharmacodynamic interactions

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interactions at the receptor level and interactions due to independent effects of two drugs.

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b. Pharmakokinetic interactions:

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: involve a change in the availability of the drug at the site of action. The mechanisms involve drug induced alterations in the absorption, distribution, metabolism, or excretion of another compound.
i. Example: up or down regulation of an enzyme involved in the metabolism of a drug by another drug.

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c. Physiochemical incompatibility

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i. Example: a drug is administered IV, but is not compatible with the IV fluid used and precipitates out.

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4. Cite 1 examples of pharmacodynamic drug interactions and indicate the possible clinical implications.

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a. Sildenafil/Viagra and organic nitrates can cause severe hypotension due to the independent effects of the drugs. Organic nitrates release NO and increase production of cGMP; Sildenafil inhibits the breakdown of cGMP. (Only one mentioned in class).

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5. Describe 3 mechanisms of drug interactions involving altered gastrointestinal absorption. Cite an example of each and indicate the possible clinical implications

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a. One interaction that can lead to decreased GI absorption of a drug is binding in the gut lumen.
i. Cholestyramine + levothyroxine  decreased levothyroxine absorption
ii. Antacids (Ca, Al, Mg) + tetracycline  chelate formation and decreased tetracycline absorption
iii. Ferrous sulfate + tetracycline  decreased tetracycline absorption
iv. The decreased absorption of these drugs may lead to drug concentrations that are below the therapeutic window and ineffectiveness of the drug.
b. Another interaction involves altered gut motility.
c. Another interaction involves altered pH of gastrointestinal fluid.
i. Cimetidine (or ranitidine) + ketoconazole  decreased ketoconazole absorption. Cimetidine decreases acid secretion and therefore increases gastric pH.

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6. List examples of drugs capable of inducing hepatic cytochrome P450 enzymes. Cite an example of a drug interaction involving enzyme induction and indicate the possible clinical implications.

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a. Induces of CYPs: phenobarbital, carbamazepine, phenytoin, rifampin, and St. John’s wort.
b. An important interaction involving the induction of CYP450 enzymes involves phenobarbital and warfarin. When coadministered, phenobarbital induces CYP450s which increased metabolic inactivation of warfarin, leading to decreased anticoagulant effects and decreased PT (or INR).

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7. List examples of drugs capable of inhibiting cytochrome P450 enzymes.

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a. Inhibitors of CYPs: amiodarone, erythromycin, ketoconazole, grapefruit juice

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8. Cite examples of drug interactions involving inhibition of cytochrome P450 activity and indicate the possible clinical implications of each.

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a. Amiodarone inhibits P450s and when co-administered with warfarin decreases warfarin metabolism and elimination. This increases levels of warfarin and leads to an increased risk of bleeding. If these two drugs must be given together, the dose of warfarin must be reduced.
b. Ketoconazole inhibits P450s and when co-administered with terfenadine (an antihistamine) decreases terfenadine elimination. Terfenadine has the potential to prolong QT intervals by blocking K+ channels, so increased levels of terfenadine may lead to ventricular arrhythmia (torsades de pointes in the example).
i. Interestingly, the active metabolite of terfenadine, fexofenadine, does not increase the QT interval. Fexofenadine is now used instead (Allegra).

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9. Cite an example of a drug interaction involving inhibition of xanthine oxidase and indicate the possible clinical implications.

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a. Allopurinol is an inhibitor of xanthine oxidase. When administered with azathioprine (prodrug for 6-MP) or 6-MP, it leads to increased azathioprine/6-MP toxicity. Xanthine oxidase is responsible for the metabolism of 6-MP to a non-toxic/inactive metabolite. If it is inhibited, 6-MP metabolism proceeds in the direction that leads to a toxic metabolite instead. If these drugs must be administered together, you must decrease the dose of 6-MP/azathioprine.

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10. Cite an example of a drug interaction involving inhibition of monoamine oxidase and indicate the possible clinical implications.

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a. Tyramine is ingested in many of the foods that we eat. It has the potential to cause release of catecholamines from nerve endings and lead to hypertension, but this is usually not an issue because it is broken down by MAO. If an MAO inhibitor is administered, this may lead to decreased breakdown of tyramine and hypertension. Patients taking MAO inhibitors must be cautioned to avoid certain foods/drinks.
b. MAO inhibitor + selective serotonin reuptake inhibitor  serotonin syndrome

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11. Describe the possible mechanisms of drug interactions involving altered renal excretion of drugs. Cite an example illustrating each mechanism and indicate the possible clinical implications.

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a. Probenicd decreases penicillin excretion by inhibiting renal secretion of penicillin at the proximal tubule.
b. Thiazide diuretics decrease lithium excretion by causing increased reabsorption of lithium (in addition to Na+) at the proximal tubule.
c. This occurs because thiazide diuretics work at the distal tubule to block Na+ and water reabsorption, leading to diuresis. Decreased plasma volume causes the proximal tubule to start reabsorbing more electrolytes/Na+ and lithium gets reabsorbed as well. (I’m not sure if this is 100% proven, but it’s what they think happens.)

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12. Cite an example of a drug interaction with each of the items listed below. Include a description of the mechanism and possible clinical implications of each interaction.


a. Grapefruit juice + felodipine

b. St. John’s wort + indinavir, cyclosporine or digoxin

c. Tyramine-rich foods + MAO inhibitors

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a. Grapefruit juice + felodipine  increased plasma felodipine concentration due to inhibition of CYP enzymes by grapefruit juice.
b. St. John’s wort + indinavir, cyclosporine or digoxin  decreased plasma drug concentration due to induction of CYP enzymes by St. John’s wort.
i. St. John’s wort can also induce P-glycoprotein transporter, which contributes to increased digoxin concentrations because digoxin is a substrate of P-gp.
c. Tyramine-rich foods + MAO inhibitors  hypertension because MAO inhibitors decrease breakdown of tyramine, and tyramine causes release of catecholamines from nerve endings.