Clinically Significant Drug Interactions

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

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

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

Pharmacokinetic Drug Interactions Inhibition of Absorption Mechanism Examples Drug binding in GIT Iron may chelate ciprofloxacin, resulting in decreased absorption GI motility Increased GI motility caused by metoclopramide may decrease cefprozil absorption GI pH GI alkalinization by omeprazole may decrease absorption of ketoconazole GI flora Decreased GI bacterial flora caused by antibiotic administration could decrease bacterial production of vitamin K, augmenting the anticoagulant effect of warfarin

Pharmacokinetic Drug Interactions Distribution Mechanism Examples Displacement from plasma proteins Displacement of methotrexate from plasma proteins by NSAIDs may increase risk of methotrexate toxicity

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

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

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

Pharmacokinetic Drug Interactions Metabolism Mechanism Examples Enzyme Inhibition Resulting in Increasing Risk of Toxicity Inhibitors of CYP2C9 (e.g. amiodarone) can increase risk of toxicity from phenytoin, warfarin Enzyme Inhibition Resulting in Reduced Drug Effect Analgesic and toxic effects of codeine result from its conversion to morphine by CYP2D6. Thus, CYP2D6 inhibitors can impair therapeutic effect of codeine.

Pharmacokinetic Drug Interactions Metabolism Mechanism Examples Enzyme Induction Resulting in Reduced Drug Effect Examples of enzyme inducers include barbiturates, carbamazepine, phenytoin, rifampin Some drugs, e.g. ritonavir, may act as either an enzyme inhibitor or an enzyme inducer, depending on the situation Enzyme Induction Resulting in Toxic Metabolites A small amount of acetaminophen is converted to a cytototoxic metabolite Enzyme inducers can increase formation of toxic metabolite & increase risk of hepatotoxicity N-acetyl-p-benzoquinone imine (NAPQI)

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.

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

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

Examples of P-glycoprotein Substrates/Inhibitors/Inducers Amitriptyline Atorvastatin Azithromycin Carvedilol Colchicine Cyclosporine Dexamethasone Digoxin Erythromycin Ethinyl estradiol Glyburide Amiodarone Clarithromycin Cyclosporine Diltiazem Felodipine Indinavir Itraconazole Ketoconazole Nicardipine Quinidine Ritonavir Sirolimus Tacrolimus Verapamil Rifampin Carbamazepine St. John’s wort

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

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

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

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

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

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

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)

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

Managing Drug Interactions Tips 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

Managing Drug Interactions Tips 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

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 po BID 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?

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?