Clinically Significant Drug Interactions

1. Clinically Significant Drug Interactions

2. Drug Interaction Definition • A clinically meaningful alteration in the effect of one drug as a result of coadministration of another • Drug affected by interaction is called the “object drug” • Drug causing interaction is called the “precipitant drug” • Interactions may be desirable or undesirable

3. Types of Drug Interactions • Drug-drug • Drug-disease • Drug-herbal • Drug-alcohol • Drug-food • Drug-nutritional status • Drug-lab

4. Mechanisms of Drug Interactions • Pharmacokinetic interactions • Percipitant drug affects the absorption, distribution, metabolism, or excretion of object drug • Pharmacodynamic interactions • Effect of object drug is modified by the precipitant without changes in pharmacokinetics of object drug

5. Pharmacokinetic Drug Interactions • Inhibition of Absorption

6. Pharmacokinetic Drug Interactions • Distribution

7. Pharmacokinetic Drug Interactions • Metabolism • Enzymes associated with drug metabolism are called cytochrome P450 enzymes • ‘’cytochrome’’ is derived from color of liver cells (dark red) attributed to iron content of the enzymes • P450 refers to ultraviolet light wavelength absorbed by enzymes

8. Pharmacokinetic Drug Interactions • Metabolism • Cytochrome P450 nomenclature CYP3A4 CYP Human cytochrome P450 3 Family A Subfamily 4 Gene • Enzymes belonging to the 3A and 2D subfamilies account for most of the well-identified drug interactions

9. Pharmacokinetic Drug Interactions • Metabolism • Drugs that undergo hepatic biotransformation are frequently substrates for the same enzymes • While requiring these enzymes for their own metabolism, they also may induce or inhibit enzyme activity on other drugs taken concurrently

10. Pharmacokinetic Drug Interactions • Metabolism

11. Pharmacokinetic Drug Interactions • Metabolism

12. Pharmacokinetic Drug Interactions • Elimination • Altered Renal Elimination • For some drugs, active secretion into the renal tubules is an important route of elimination • Example • Digoxin is eliminated primarily through renal excretion, and drugs such as amiodarone, clarithromycin, itraconazole can inhibit this process. Digoxin toxicity may result.

13. P-Glycoprotein • P-glycoprotein is a transporter found in the liver, intestine, kidney, and brain • P-glycoprotein acts as an efflux pump to pump toxic materials out of the cell • Example • Digoxin, a PGP substrate • Quinidine is a PGP inhibitor. It inhibits expulsion of digoxin back into intestine, so increases digoxin concentrations • Rifampicin stimulates PGP and so decreases serum digoxin

14. P-Glycoprotein • In the kidney there is a similar effect with PGP enhancing clearance of substances • Quinidine and cyclosporine inhibit PGP, so clearance of digoxin is inhibited • In the CNS, PGP inhibits the passage of some medicines across the blood–brain barrier, e.g. loperamide • A PGP inhibitor allows greater passage across the blood–brain barrier

16. Pharmacodynamic Drug Interactions • Additive Pharmacodynamic Effects • When two or more drugs with similar pharmacodynamic effects are given, additive effects may result in excessive response and toxicity • Examples • Combining ACEI with potassium-sparing diuretics results in augmented hyperkalemia • Combining a diuretic with a beta blocker provides a greater reduction in blood pressure than either can impart alone

17. Pharmacodynamic Drug Interactions • Antagonistic Pharmacodynamic Effects • Drugs with opposing pharmacodynamic effects may reduce the response to one or both drugs • Example • NSAIDs may inhibit the antihypertensive effect of ACEI • Reduction in the synthesis of the vasodilating renal prostaglandins

18. Drug Interaction Risk Factors • Patient Factors • Number of medications (polypharmacy) • Severity of the diseases being treated • Age (the very young and elderly) • Renal and hepatic dysfunction • Acute medical condition (eg, dehydration, infection) • Pharmacogenetics

19. Drug Interaction Risk Factors • Drug Factors • Higher dose • Narrow therapeutic range (e.g.digoxin) • NSAIDs • Anticoagulants • Hypoglycemics • Antiarrythmics • Anticonvulsants • Antibiotics • Antiretrovirals

20. Drug Interaction Risk Factors • Other Considerations • Increasing use of prescription drugs • Increasing complexity of medication regimens • Fragmented health care system • Incomplete problem or med lists • Multiple prescribers managing • Multiple pharmacies dispensing • Self-medication with OTC, herbals

21. Relevance of Drug Interactions • Impossible to memorize all drug interactions (2500 drug pairs) • Most potential drug interactions never lead to actual clinical effect • Necessary to determine which drug interactions are most clinically important • Ones most likely to cause harm if not detected

22. Drug Interaction Resources • Print & Electronic Resources • Micromedex • Lexicomp • Facts and Comparisons • Hansten and Horn’s The Top 100 Drug Interactions • Stockley's Drug Interactions • Websites • Drug Interaction Checker (Medscape) • Drug Interaction Checker (Drugs.com)

23. Managing Drug Interactions • Comprehensive medication review • Identify potential drug interactions • Assess clinical significance • Continue/discontinue/substitute • Monitor and follow-up • Document • Communicate with patient & healthcare professionals

24. Managing Drug InteractionsTips for Pharmacists • Learn to recognize factors that alter a patient’s risk for an adverse event when exposed to interacting drug pairs • Consider the risk of the potential interaction against the benefit of administering the drugs • If the risk to patient appears to be greater than expected benefit, identify a suitable alternative

25. Managing Drug InteractionsTips for Pharmacists • Drug interaction classification systems should be used for general guidance • No book, PDA, or computer based classification system can replace pharmacist’s informed evaluation • Regard each interaction– patient pair as unique

26. Case Study-1 • A 23 y/o woman with a seizure disorder & diabetes is being admitted with ataxia and tremors. She was initiated on Bactrim 10 days ago for UTI. Her Phenytoin level is 28. Her current medication list includes: • Sulfamethoxazole/trimethoprim DS 1 tab poBID • Phenytoin 400 mg po QD • Lantus 15 units SQ q HS • Novolog 5 units SQ with each meal • What actual drug-drug interaction(s) do you identify? • Could it have been prevented? What will you recommend?

27. Case Study-2 • A 75 y/o woman with hypertension and atrial fibrillation is prescribed levofloxacin for community acquired pneumonia. Her other medications include: • Sotalol 80 mg PO BID • Aspirin 81 mg PO QD • Enalapril 20 mg PO BID • HCTZ 50 mg PO QD • Felodipine 5mg PO QD • What potential drug-drug interaction(s) do you identify? • What will you recommend?