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Drug Interactions
- 1. Overview on Drug Interactions Dr Ananya Chakraborty Professor & HOD Pharmacology PHARMAQUEST-2021 1
- 2. Outline • Swiss cheese prescribing model • First reported drug interaction • Pandemic interactions • Mechanisms of drug interactions • Summary 2 PHARMAQUEST-2021
- 3. PHARMAQUEST-2021 3 Why are there holes in Swiss cheese?
- 4. The Swiss cheese prescribing model 4 PHARMAQUEST-2021
- 5. PHARMAQUEST-2021 5 The first reported drug interaction
- 6. A pandemic case report 6 PHARMAQUEST-2021 Manigaba K, Hawks J and Kima M. Remdesivir-Warfarin Interaction: A Case Report. HCA Healthcare Journal of Medicine, 2020; 1. Article 15.DOI: 10.36518/2689-0216.1164
- 8. Published case series 8 Reference: Landayan RP, Saint-Felix S, Williams A. Probable Interaction Between Warfarin and the Combination of Remdesivir With Dexamethasone for Coronavirus Disease 2019 (COVID-19) Treatment: A 2 Case Report. Journal of Pharmacy Practice. April 2021. doi:10.1177/08971900211008623 PHARMAQUEST-2021
- 9. INR results during hospitalization Case 1: 71 year old patient Case 2: 62 year old patient 9 Reference: Landayan RP, Saint-Felix S, Williams A. Probable Interaction Between Warfarin and the Combination of Remdesivir With Dexamethasone for Coronavirus Disease 2019 (COVID-19) Treatment: A 2 Case Report. Journal of Pharmacy Practice. April 2021. doi:10.1177/08971900211008623 PHARMAQUEST-2021
- 10. Which picture depicts the clinical scenarios? Picture 1 Picture 2 10 PHARMAQUEST-2021
- 12. From rat poison to clinical use 12 PHARMAQUEST-2021 • 1920s: Healthy cattle that gazed on sweet clover hay were dying from internal bleeding • 1941: Wisconsin Alumni Research Foundation (WARF), patent for dicoumarol • 1945: Rodenticide • 1954: Human use
- 13. More than 65 years of experience • Antiplatelet regimens (OR=1.74; 95% CI 1.56, 1.94) • Antimicrobials (OR=1.63; 95% CI 1.45, 1.83) • NSAIDs (OR=1.83; 95% CI 1.29, 2.59) • SSRIs (OR=1.62; 95% CI 1.42, 1.85) • Loop diuretics (OR=1.92; 95% CI 1.29, 2.86) 13 Still scope for broadening knowledge? Wang M, Zeraatkar D, Obeda M, Lee M, Garcia C, Nguyen L, Agarwal A, Al-Shalabi F, Benipal H, Ahmad A, Abbas M, Vidug K, Holbrook A. Drug-drug Interactions with Warfarin: A Systematic Review and Meta-analysis. Br J Clin Pharmacol. 2021 Mar 26. doi: 10.1111/bcp.14833. Epub ahead of print. PMID: 33769581. PHARMAQUEST-2021
- 14. Take home message • Why important? PATIENT SAFETY • Preventable in-hospital ADRs • Prevent emergency hospital visits • Good medication practices “AVOID MISTAKES” • Allergies/Vitamins/OTC • INTERACTIONS • Dependence/Mendel 14 PHARMAQUEST-2021
- 15. Pharmacodynamic drug interaction Dr Kevin Manohar Salis, M.B.B.S, P.G.C.B.I, M.D Associate Professor Department of Pharmacology, VIMS & RC 15 PHARMAQUEST-2021
- 17. Significance of drug interactions 17 PHARMAQUEST-2021
- 19. 1. Additive effects or summation 19 PHARMAQUEST-2021
- 20. Additive effects or summation 20 PHARMAQUEST-2021
- 21. 2. Supraadditive or synergism 21 PHARMAQUEST-2021
- 24. 4. Antagonistic physiological systems 24 PHARMAQUEST-2021
- 27. Drug Interactions Kinetics based Dr Shubhatara Swamy 27 PHARMAQUEST-2021
- 28. Pharmacokinetics relevant to drug interactions 28 PHARMAQUEST-2021
- 29. Interactions at the absorption level Drug A causes vasoconstriction at the site of administration and interferes with the systemic absorption of Drug B administered at the same site 29 PHARMAQUEST-2021
- 30. Interactions at the absorption level Drug A causes vasoconstriction at the site of administration and interferes with the systemic absorption of Drug B administered at the same site 30 PHARMAQUEST-2021
- 31. Interactions at the absorption level Drug A neutralises gastric acid (elevates gastric pH) and prevents the absorption of Drug B 31 PHARMAQUEST-2021
- 32. Interactions at the absorption level Drug A neutralises gastric acid (elevates gastric pH) and prevents the absorption of Drug B & 32 PHARMAQUEST-2021
- 33. Interactions at the absorption level Drug A delays gastric emptying and the systemic absorption of Drug B absorbed primarily in the intestine 33 PHARMAQUEST-2021
- 34. Interactions at the absorption level Drug A delays gastric emptying and the systemic absorption of Drug B absorbed primarily in the intestine 34 PHARMAQUEST-2021
- 35. Interactions at the absorption level Drug A forms chelates or complexes with Drug B and prevents its absorption 35 PHARMAQUEST-2021
- 36. Interactions at the absorption level Drug A forms chelates or complexes with Drug B and prevents its absorption 36 PHARMAQUEST-2021
- 37. Interactions at the absorption level— membrane transport Drug A blocks the transport of Drug B into hepatocytes and increases its plasma levels 37 PHARMAQUEST-2021
- 38. Interactions at the absorption level— membrane transport Drug A blocks the transport of Drug B into hepatocytes and increases its plasma levels 38 PHARMAQUEST-2021
- 39. Interactions at the distribution level Drug A competes for plasma protein binding with Drug B and increases its plasma level 39 PHARMAQUEST-2021
- 40. Interactions at the distribution level Drug A competes for plasma protein binding with Drug B and increases its plasma level 40 PHARMAQUEST-2021
- 41. Interactions at metabolic level Drug A induces a CYP450 isoenzyme responsible for the metabolism of Drug B and decreases its plasma levels 41 PHARMAQUEST-2021
- 42. Interactions at metabolic level Drug A induces a CYP450 isoenzyme responsible for the metabolism of Drug B and decreases its plasma levels 42 PHARMAQUEST-2021
- 43. Interactions at metabolic level Drug A inhibits a CYP450 isoenzyme responsible for the metabolism of Drug B and increases its plasma levels 43 PHARMAQUEST-2021
- 44. Interactions at metabolic level Drug A inhibits a CYP450 isoenzyme responsible for the metabolism of Drug B and increases its plasma levels 44 PHARMAQUEST-2021
- 45. Interactions at the elimination level— • Drug-induced reduction in GFR ( & ) • Reduced clearance and increase in plasma concentration ( & ) 45 PHARMAQUEST-2021
- 46. Interactions at the elimination level Drug A competes for renal tubular transport with Drug B and increases its elimination half life 46 PHARMAQUEST-2021
- 47. Interactions at the elimination level Drug A competes for renal tubular transport with Drug B and increases its elimination half life 47 PHARMAQUEST-2021
- 48. Case scenario 1. Probable Interaction Between Warfarin and the Combination of Remdesivir With Dexamethasone for Coronavirus Disease 2019 (COVID-19) Treatment: A 2 Case Report. First Published April 15, 2021 https://doi.org/10.1177/08971900211008623 2. Remdesivir-Warfarin Interaction: A Case Report. HCA Healthcare Journal of Medicine (2020) 1:COVID- 19 https://doi.org/10.36518/2689-0216.116 48 PHARMAQUEST-2021
- 49. Warfarin • Commonly used anticoagulant • Narrow therapeutic index • Severe bleeding or thrombosis formation • Regulated by hepatic concentrations of warfarin and vitamin K 49 PHARMAQUEST-2021
- 50. Warfarin & dexamethasone • Metabolism of Warfarin increased when combined with Dexamethasone • Mechanism of warfarin-dexamethasone interaction Inhibits vitamin K1 uptake Downregulates mRNA expression of NPC1L1 via glucocorticoid receptor α (GRα)-mediated mechanisms 50 PHARMAQUEST-2021
- 51. Warfarin & dexamethasone & remdesivir • Potential for interaction based on a calculated drug interaction probability scale score of 5 • Demonstrated by marked INR elevations within 24 to 48 hours of initiation of the combination in 2 cases • Patients with historically stable INR history 51 PHARMAQUEST-2021
- 53. Warfarin & remdesivir • Probable interaction between warfarin and remdesivir • On applying the Adverse Drug Reaction Probability Scale, Naranjo Scale • April 2021 53 PHARMAQUEST-2021
- 56. Take home message • As a general principle – drugs and with a carry a higher potential risk of interactions • Electronic prescribing systems can to possible interactions and can with drug selection and dosage 56 PHARMAQUEST-2021
- 58. Let’s discuss a case • A 68-year-old woman with type 2 diabetes mellitus and hypertension presents with 2 episodes of severe hypoglycaemia for last 2 days • She was discharged from the hospital for community acquired pneumonia one week back • The patient states that the only change in her medications is a “new medication” for her DM that she received when she was discharged. 58 PHARMAQUEST-2021
- 59. Why hypoglycemia? • Her regular medications • Glipizide 20mg daily • Lisinopril 10mg daily • Metformin 1000mg twice daily • On discharge Glimepiride, 2mg per day was added 59 PHARMAQUEST-2021
- 60. What is therapeutic duplication • Prescribing multiple drugs for the same indication • Increase patient safety risk and total health care costs • Leads to medication errors • Patient taking both omeprazole and esomeprazole • Duplication of albuterol: use of two different name inhalers 60 PHARMAQUEST-2021
- 61. Why is this a patient safety concern? • Overdose of medication and risk of toxicity • Increased risk of adverse drug reactions due to high concentration of drug in the body 61 PHARMAQUEST-2021
- 62. Duplication prescribing By doctor: Handwritten prescription Mostly PRN medication for pain, nausea and vomiting By patient: Multiple visit to different doctor or Pharmacies 62 PHARMAQUEST-2021
- 63. How does duplication occur? • 1. Polypharmacy: Simultaneous use of multiple medications in an individual patient • 2. Changes in drug therapy • One or multiple prescribers may lead to patient confusion • If a medication is proving ineffective and a prescriber decides to give the patient a different drug within the same drug class, the patient may inadvertently take the old drug in addition to the new drug, causing duplication of therapy 63 PHARMAQUEST-2021
- 64. How does duplication occur? 3. Lack of communication between patients & prescribers • A patient may be taking over-the-counter medications in addition to their prescribed medication, and this may not be communicated effectively between all relevant • A patient may also be visiting multiple prescribers who are unaware of the various drugs a patient is taking, and inadvertently prescribe drugs within the same class 64 PHARMAQUEST-2021
- 65. Methods to prevent therapeutic duplication 1.CPOE- Computerized provider order entry 2.CDS- Clinical decision support 3.EHR- Electronic Health Record 4.OMS- Order-management system 5.MEDICATION RECONCILIATION 6.PATIENT EDUCATION 65 PHARMAQUEST-2021
- 67. Medication reconciliation • Is a process of obtaining a list of the patient's current medications • Name of the drug • Dosage, route, frequency • Time of the last dose • Must be reconciled upon admission, transfer from operation theatre, intensive care unit, and at discharge PHARMAQUEST-2021 67
- 68. Why medication reconciliation • To prevent ADR’s • To eliminate medication discrepancies • To ensure patient receive appropriate medication • To improve communication at patients transfer 68 PHARMAQUEST-2021
- 70. PHARMAQUEST-2021 70 Patient education • Avoid multi doctors visit • Avoid different pharmacies • Avoid self medication • Inform your doctor about current medications or if on any alternative medicines • If any problem to recognize medication ask pharmacist before taking
- 71. Take home message • Proper knowledge of different brand names of same drugs: Look alike, sound alike drugs • Proper attention by in-house physicians, nurses during daily rounds and daily review of medication card by clinical pharmacists • Regular prescription audit 71 PHARMAQUEST-2021
- 72. Adverse drug reactions: Drug interactions Dr Nishith RS 72 PHARMAQUEST-2021
- 73. Outline Drug interactions – ADR: Is it common ? Warfarin – Ibuprofen (NSAIDs) Warfarin – Acetaminophen Warfarin – Steroids/Remdesivir 73 PHARMAQUEST-2021
- 77. 77 PHARMAQUEST-2021 Moore N et. al Adverse drug reactions and drug-drug interactions with over-the-counter NSAIDs. Ther Clin Risk Manag. 2015
- 78. “Lowest possible dose - shortest possible duration” 78 PHARMAQUEST-2021
- 81. 81 Warfarin & ibuprofen: CYP2C9 Increased bleeding time Moore N et. al Adverse drug reactions and drug–drug interactions with over-the-counter NSAIDs. Ther Clin Risk Manag. 2015 PHARMAQUEST-2021
- 85. 85 Oxidized vitamin K- hydroquinone (KH2) Directly inhibit vitamin K- dependent carboxylation Inhibition of vitamin K epoxide reductase (VKOR) activity PHARMAQUEST-2021
- 86. 86 Shek, K.L.A. et. al Warfarin-Acetaminophen Drug Interaction Revisited. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy (2012) > 1.3 g acetaminophen/day for > 2 weeks Increases risk substantially PHARMAQUEST-2021
- 87. 87 Lopes, Renato D et al. “Warfarin and acetaminophen interaction: a summary of the evidence and biologic plausibility.” Blood vol. 118,24 (2011) More than or equal to 2 g/day of acetaminophen for at least 3 consecutive days INR should be tested 3 to 5 days after the first acetaminophen dose PHARMAQUEST-2021
- 88. 88 Chronic warfarin therapy – stable INR Corticosteroids Remdesivir ? PHARMAQUEST-2021
- 89. Oral corticosteroids-chronic warfarin therapy 387 patients 62.5%: supratherapeutic INR No SAE One minor case of epistaxis 89 Hazlewood et.al Effect of oral corticosteroids on chronic warfarin therapy. Ann Pharmacother. 2006 Dec PHARMAQUEST-2021
- 90. 90 Warfarin dose reduction Close monitoring of INR values Significant change in INR value can be expected: drug interactions PHARMAQUEST-2021
- 92. Dr. Latha Kamath 92 PHARMAQUEST-2021 Drug Interactions: Resources To Update
- 93. DRUG INTERACTIONS • Drug interactions significant toxicity or loss of clinical effect. • Risks increase with the number of drugs the patient takes. PHARMAQUEST-2021 93
- 94. How to remember all????? PHARMAQUEST-2021 94
- 95. RESOURCES • Books & literature • Table of drugs • Electronic resources-Subscription software’s • Websites-Online drug interaction checkers • Phone based Apps 95 PHARMAQUEST-2021
- 96. BOOKS & LITERATURE •Pharmacology textbooks- Martindale •Stockley’s drug interactions •Primary literature (case reports and clinical papers) International & national product information Guidance from international & national regulatory bodies PHARMAQUEST-2021 96
- 97. Table of drugs SUBSTRATE INHIBITORS INDUCERS Digoxin Atorvastatin Aspirin Diltiazem Carvedilol Cyclosporin Losartan Nifedipine Reserpine Quinidine Spironolactone Tacrolimus Amiloride Substrates, inhibitors & inducers of P-gp PHARMAQUEST-2021 97
- 100. Electronic resources-Subscription software • Severity of interaction • Mechanism • Precautions & clinical effects PHARMAQUEST-2021 100
- 101. Subscription software 1. Lexicomp Interactions module 2. Micromedex Drug Interactions 3. Clinical Pharmacology Drug Interaction Report 4. Facts & Comparisons e Answers 5. Stockley’s Drug Interactions 6. Drug Interactions Analysis and Management 7. Drug Interaction Facts PHARMAQUEST-2021 101
- 102. Comparison Study Robert D. Beckett etal-Evaluation of resources for analyzing drug interactions PHARMAQUEST-2021 102
- 104. The Swiss cheese prescribing model 104 PHARMAQUEST-2021
- 105. PHARMAQUEST-2021 105
- 106. PHARMAQUEST-2021 106
- 107. 107 PHARMAQUEST-2021
- 109. Take home • Impossible to remember--- All Interactions • Resources --- Books--- Software's--- websites---Apps. • Resources + Clinical experience= Improved Therapy outcome PHARMAQUEST-2021 109
- 110. Q and A session 110