1. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Drug Interactions Chapter 6

2. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Drug-Drug Interactions  Basic mechanisms of drug-drug interactions  Clinical significance of drug-drug interactions  Minimizing adverse drug-drug interactions 2

3. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Consequences of Drug-Drug Interactions  Intensification of effects  Increased therapeutic effects Sulbactam and ampicillin  Increased adverse effects Aspirin and warfarin  Reduction of effects  Reduced therapeutic effects  Reduced adverse effects  Creation of a unique response 3

4. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Drug-Drug Interactions  Reduction of effects  Inhibitory: Interactions that result in reduced drug effects  Reduced therapeutic effects Propranolol and albuterol  Reduced adverse effects Naloxone to treat morphine overdose  Creation of a unique response  Alcohol with disulfiram 4

5. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Basic Mechanisms of Drug-Drug Interactions  Drugs can interact through four basic mechanisms: 1.Direct chemical or physical interaction 2.Pharmacokinetic interaction 3.Pharmacodynamic interaction 4.Combined toxicity 5

6. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Direct Chemical or Physical Interaction  Never combine drugs in the same container without establishing compatibility  Most common in intravenous solution  Precipitate: Do not administer 6

7. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Basic Mechanisms of Drug-Drug Interactions  Pharmacokinetic interactions  Altered absorption  Altered distribution  Altered renal excretion  Altered metabolism  Cytochrome P450 (CYP) group of enzymes 7

8. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Pharmacokinetic Interactions  Altered absorption  Elevated gastric pH  Laxatives  Drugs that depress peristalsis  Drugs that induce vomiting  Adsorbent drugs  Drugs that reduce regional blood flow 8

9. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Pharmacokinetic Interactions  Altered distribution  Competition for protein binding  Alteration of extracellular pH  Altered renal excretion  Drugs can alter: Filtration Reabsorption Active secretion 9

10. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Pharmacokinetic Interactions  Altered metabolism  Most important and most complex mechanism in which drugs interact  Cytochrome P450 (CYP) group of enzymes Inducing agents: Phenobarbital  Increase rate of metabolism two- to three-fold over 7 to 10 days  Resolve over 7 to 10 days after withdrawal Inhibition of CYP isoenzymes  Usually undesired 10

11. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Pharmacokinetic Interactions  Interactions that involve P-glycoproteins (PGPs)  Transmembrane protein that transports a wide variety of drugs out of cells  Reduced or increased PGP Intestinal epithelium: Affects absorption Placenta: Affects drug export from placental cells to maternal blood Blood-brain barrier: Affects drug export from the cells of brain capillaries into the blood Liver: Affects drug export from liver into bile Kidney tubules: Affects drug export from renal tubular cells into the urine 11

12. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Basic Mechanisms of Drug-Drug Interactions  Pharmacodynamic interactions  At the same receptor Almost always inhibitory (antagonist/agonist)  At separate sites May be potentiative (morphine and diazepam) OR Inhibitory (hydrochlorothiazide and spironolactone)  Combined toxicity  Drugs with overlapping toxicities should not be used together 12

13. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Clinical Significance of Drug-Drug Interactions  Drug interactions have the potential to significantly affect the outcome of therapy  Responses may be increased or reduced  The risk for serious drug interaction is directly proportionate to the number of drugs a patient is taking  Interactions are especially important for drugs with low therapeutic indices  Many interactions are yet to be identified 13

14. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Minimizing Adverse Drug-Drug Interactions  Minimize the number of drugs a patient receives  Take a thorough drug history  Be aware of the possibility of illicit drug use  Adjust the dosage when metabolizing inducers are added or deleted  Adjust the timing of administration to minimize interference with absorption  Monitor the patient for early signs of toxicity  Be especially vigilant when a patient is taking a drug with a low therapeutic index 14

15. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Drug-Food Interactions  Impact of food on:  Drug absorption Decreased absorption  Rate  Extent of absorption (occasionally) – Milk and tetracycline – Fiber and digoxin Increased absorption  High-calorie meal and saquinavir  Without food, not enough is absorbed 15

16. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Drug-Food Interactions  Drug metabolism  The grapefruit juice effect (not occurring with other citrus fruits or juices) Inhibits the metabolism of certain drugs Raises the drugs’ blood levels  Increase in felodipine  Others: Lovastatin, cyclosporine, midazolam, and so on 16

17. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Drug-Food Interactions  Impact of food on:  Drug toxicity Monoamine oxidase inhibitors (MAOIs) and tyramine-containing foods Theophylline and caffeine Potassium-sparing diuretics and salt substitutes Aluminum-containing antacids and citrus beverages 17

18. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Drug-Food Interactions  Impact of food on:  Drug action Warfarin and foods rich in vitamin K  Timing of drug administration Some drugs are better tolerated on an empty stomach Others should be taken with food, especially for nausea 18

19. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Drug-Herb Interactions  Conventional drugs can interact with herbal preparations  Interactions with herbal medicines are just as likely as they are with prescription medications  Reliable information about drug-herb interactions is lacking  Example of known interaction:  St. John’s wort induces drug-metabolizing enzymes and reduces the blood levels of many drugs 19

20. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Chapter 7 Adverse Drug Reactions and Medication Errors

21. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adverse Drug Reactions  Defined by the World Heath Organization:  Any noxious, unintended, and undesired effect that occurs at normal drug doses  Excludes excessive dosages  Can range from annoying to life-threatening 21

22. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Two Issues Related to Drug Safety  Adverse drug reactions (ADRs)  Also known as adverse drug events (ADEs)  Medication errors 22

23. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adverse Drug Reactions  Scope of the problem  Mild reactions Drowsiness, nausea, itching, and rash  Severe reactions (potentially fatal)  Respiratory depression, neutropenia, hepatocellular injury, anaphylaxis, and hemorrhage  Most common in the elderly and the very young  Risk increased by severe illness 23

24. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adverse Drug Reactions  AHRQ (2011): Dramatic rise in adverse drug reactions  Adverse drug reactions: More than 800,000 outpatients sought emergency treatment for adverse drug reactions  Hospitalized patients: 1,735,500 experienced adverse outcomes as a result of drug reactions and medical errors  Of these 1,735,500, more than 53,800 died 24

25. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Helen Haskell Story 25

26. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Terms Related to Adverse Drug Reactions  Side effect  Toxicity  Allergic reaction  Idiosyncratic effect  Paradoxical effect  Iatrogenic disease  Physical dependence  Carcinogenic effect  Teratogenic effect 26

27. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Organ-Specific Toxicity  Many drugs are toxic to specific organs  Common examples include:  Kidneys: Amphotericin B (antifungal)  Heart: Doxorubicin (anticancer)  Lungs: Amiodarone (antidysrhythmic)  Inner ear: Aminoglycoside (antibiotic) 27

28. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Organ-Specific Toxicity  Hepatotoxic drugs  QT interval drugs 28

29. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Hepatotoxic Drugs  Leading cause of liver failure in the United States  More than 50 drugs are known to be hepatotoxic  As some drugs undergo metabolism, they are converted to toxic products that can injure liver cells  Combining hepatotoxic drugs may increase the risk for liver damage (e.g., acetaminophen and alcohol)  Monitor aspartate aminotransferase (AST) and alanine aminotransferase (ALT) for liver injury  Watch for signs of liver injury; educate patients about jaundice, dark urine, light-colored stools, nausea, vomiting, malaise, abdominal discomfort, and loss of appetite 29

30. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. QT Interval Drugs: More Than 100 Are Known  QT interval: Measure of the time required for the ventricles to repolarize after each contraction  QT drugs: Drugs that prolong the QT interval on electrocardiography (ECG)  Creates serious risk of life-threatening dysrhythmias  Examples: Torsades de pointes, ventricular fibrillation  Minimizing the risk:  Most patients are at higher risk, including women, older adults, and patients with bradycardia, congestive heart failure (CHF), congenital QT prolongation, low potassium, and low magnesium  Do not use two QT drugs concurrently 30

31. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved.  Is it relatively easy to determine whether a specific drug is responsible for an observed adverse event? 31

32. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Identifying Adverse Drug Reactions  Did symptoms appear shortly after the drug was first used?  Did symptoms abate when the drug was discontinued?  Did symptoms reappear when the drug was reinstituted?  Is the illness itself sufficient to explain the event?  Are other drugs in the regimen sufficient to explain the event? 32

33. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adverse Reactions to New Drugs  Half of all new drugs have serious ADRs that are not revealed during Phase II and Phase III trials  Be alert for unusual responses when giving new drugs, because newly release drugs may have as-yet-unreported adverse effects  Drugs that are suspected of causing a previously unknown adverse effect should be reported to MedWatch, the FDA Medical Products Reporting Program 33

34. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Ways to Minimize Adverse Drug Reactions  Responsibility for reducing ADRs lies with everyone associated with drug production and usage:  Pharmaceutical industry: Strive to produce the safest medications possible  Prescriber: Select the least harmful drug; balance potential risks with probable benefits  Nurse: Evaluate patient for ADRs; educate patients and families about how to minimize harm  Patients and families: Watch for signs that an ADR may be developing; see medical attention if one appears 34

35. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Ways to Minimize Adverse Drug Reactions  The anticipation of ADRs can help to minimize them  Target the evaluation of the function of any at-risk organs  Important sites of toxicity: Liver: Signs of jaundice; monitor liver function tests Kidney: Routine urinalysis and serum creatinine level (periodic creatinine clearance testing) Bone marrow: Periodic blood cell counts  Patients with chronic disorders are especially vulnerable to ADRs 35

36. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Medication Guides  MedGuides  FDA-approved documents created to educate patients about how to minimize harm from potentially dangerous drugs  Required when the FDA has determined that (1) patient adherence to directions for drug use is essential for efficacy and (2) patients need to know about potentially serious effects when deciding whether to use a drug 36

37. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Boxed Warnings  Also known as black box warnings  Strongest safety warning a drug can carry and still remain on the market  Purpose of this warning is to alert prescribers to:  Potentially severe side effects (for example, life- threatening dysrhythmias, suicidality, major fetal harm)  Ways to prevent or reduce harm (for example, avoiding a teratogenic drug during pregnancy) 37

38. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Risk Evaluation and Mitigation Strategies (REMS)  REMS: A plan to minimize drug-induced harm  For example, the REMS for isotretinoin is called iPLEDGE  Isotretinoin can cause serious birth defects  iPLEDGE was designed to ensure that those who are pregnant or who may become pregnant will not have access to the drug 38

39. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Risk Evaluation and Mitigation Strategies (REMS)  REMS: A plan to minimize drug-induced harm  For example, the REMS for isotretinoin is called iPLEDGE  Isotretinoin can cause serious birth defects  iPLEDGE was designed to ensure that those who are pregnant or who may become pregnant will not have access to the drug 39

40. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Medication Errors  Major cause of morbidity and mortality  Documented in two landmark reports from the Institute of Medicine:  To Err Is Human, 1999  Preventing Medication Errors, 2006  It is estimated that medication errors:  Injure 1.5 million people per year  Kill 7000 people per year 40

41. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Helen Haskell Story 41

42. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. What’s a Medication Error and Who Makes Them?  The risk for error in hospitals is high because each medication order is processed by several people  The nurse is the last person in this sequence  Thus, the nurse is the last line of defense against mistakes  This places a heavy responsibility on the nurse to ensure patient safety 42

43. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Types of Medication Errors  Direct  Indirect  Fatal medication errors  Overdose: 36.4%  Wrong drug: 16.2%  Wrong route: 9.5% 43

44. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Causes of Medication Errors  Of the human factors that can cause errors, performance deficits are the most common, followed by knowledge deficits and the miscalculation of dosage  90% of all errors are due to:  Human factors  Communication mistakes  Drug name confusion 44

45. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Ways to Reduce Medication Errors  Help and encourage patients and their families to be active and informed members of the healthcare team  Create an institutional culture that is dedicated to safety  Give healthcare providers the tools and information they need to prescribe, dispense, and administer drugs as safely as possible  Institute safety checklists for high-alert drugs  About 20 drugs cause 80% of medication error– related deaths 45

46. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Ways to Reduce Medication Errors  Replace handwritten medication orders with a computerized order entry system  Have a senior clinical pharmacist accompany physicians on rounds  Use a barcode system  Do not use error-prone abbreviations  Perform medication reconciliation 46

47. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. How to Report a Medication Error  Medication Errors Reporting (MER) program:  Reporting is confidential  Reporting can be done by phone, fax, or Internet  Program encourages all healthcare providers – including pharmacists, nurses, physicians, and students – to report errors  https://www.ismp.org/orderforms/reporterrortoismp.asp https://www.ismp.org/orderforms/reporterrortoismp.asp  All information is forwarded to the U.S. Food and Drug Administration (FDA), the Institute for Safe Medication Practices (ISMP), and the product manufacturer 47

48. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Chapter 8 Individual Variation in Drug Responses

49. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Individual Variation in Drug Responses  Key factors that cause one patient to respond to drugs differently than another patient  Important for nurses to know these factors to be better prepared to reduce individual variation in drug responses 49

50. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Individual Variation in Drug Responses  Body weight and composition  Age  Pathophysiology  Tolerance  Pharmacodynamic tolerance  Metabolic tolerance  Tachyphylaxis  Decreased responsiveness to a drug as a result of repeated drug administration  Higher doses required 50

51. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Placebo Effect  Any response that a patient has to a placebo is based solely on his or her psychologic reaction to the idea of taking a medication and not to any direct physiologic or biochemical action of the placebo itself  Nurses need to present a positive but realistic assessment of the effects of therapy  Placebos are primarily used for the control groups in clinical trials 51

52. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Variability in Absorption  Bioavailability  Ability of the drug to reach the systemic circulation from its site of administration  Occurs primarily with oral preparations rather than with parenteral administration  Tablet disintegration time, enteric coatings, and sustained-release formulations affect this  Other causes of variable absorption  Changes in gastric pH, diarrhea, constipation, and food in the stomach 52

53. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Genetics and Pharmacogenomics  Pharmacogenomics: Study of how genes affect individual drug responses  Altered drug metabolism  May accelerate or delay the metabolism  Warfarin, succinylcholine, isoniazid, cytochrome P450 53

54. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Variations  Altered drug targets  Other ways genetics can influence drug responses  Gender  Race  Comorbidities  Diet  Genetic variations  Psychosocial factors  Failure to take medicine as prescribed  Drug interactions 54