Clinically Significant Drug Interactions

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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

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

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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

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Pharmacokinetic Drug InteractionsA. 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

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Pharmacokinetic Drug InteractionsB. Distribution

Mechanism Examples

Displacement from plasma proteins

Displacement of methotrexate from plasma proteins by NSAIDs may increase risk of methotrexate toxicity

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Pharmacokinetic Drug InteractionsC. 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

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Pharmacokinetic Drug InteractionsC. Metabolism•Cytochrome P450 nomenclatureCYP3A4

CYP Human cytochrome P4503 Family

A Subfamily4 Gene

•Enzymes belonging to the 3A and 2D subfamilies account for most of the well-identified drug interactions

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Pharmacokinetic Drug InteractionsC. 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

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Pharmacokinetic Drug InteractionsC. 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.

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Pharmacokinetic Drug InteractionsC. Metabolism

Mechanism Examples

Enzyme Induction Resulting in Reduced Drug Effect

Examples of enzyme inducers include barbiturates, carbamazepine, phenytoin, rifampinSome 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

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Pharmacokinetic Drug InteractionsD. 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.

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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

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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

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Examples of P-glycoprotein Substrates/Inhibitors/InducersSubstrates Inhibitors InducersAmitriptyline Atorvastatin Azithromycin Carvedilol Colchicine Cyclosporine Dexamethasone Digoxin Erythromycin Ethinyl estradiol Glyburide

AmiodaroneClarithromycinCyclosporineDiltiazemErythromycinFelodipineIndinavirItraconazoleKetoconazoleNicardipineQuinidineRitonavirSirolimusTacrolimusVerapamil

RifampinCarbamazepine St. John’s wort

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Pharmacodynamic Drug InteractionsA. 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

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Pharmacodynamic Drug InteractionsB. 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

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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

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

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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

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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

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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)

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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

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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

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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

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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?

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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?