Polypharmacy, Drug/Drug Interactions

Practical Approach to Complex Pharmacological Needs: Polypharmacy, Drug/Drug Interactions

Rhonda Cooper-DeHoff, PharmD Eileen Handberg, PhD, ANP-BC Jane Linderbaum, ANP-BC David Parra, PharmD Case Study 1 Patient is a, 70 year old African American male, has HFrEF (EF 28%), exhibiting NYHA class III symptoms.

ADR: Lisinopril (angioedema) What is the best change in heart failure therapy for this patient? Vitals: BP: 120/70 mmHg HR: 70 bpm A. Switch valsartan to sacubitril/valsartan B. Add hydralazine/isosorbide dinitrate Labs: Scr: 0.9 mg/dL C. Add digoxin K+: 4.5 mEq/L D. Add ivabradine Medications (no changes since 2014): Furosemide 20mg daily (no significant edema presently) Metoprolol succinate 200mg daily Valsartan 180mg bid Spironolactone 50mg daily Case Study 2 Patient is a 63 year old white female, with HFrEF (EF 30% on Echo 12/2015) with NYHA class II symptoms. Patient took all her medications this morning. You have decided to switch lisinopril to ADR: Dizziness with high dose carvedilol sacubitril/valsartan. What should the next step be? Vitals: BP: 124/74 mmHg HR: 60 bpm A. Instruct patient to take sacubitril/valsartan tomorrow morning, replacing lisinopril. Labs: Scr: 1.2 mg/dL B. Instruct patient to discontinue lisinopril and K+: 4.8 mEq/L initiate sacubitril/valsartan the morning proBNP (NT-proBNP) 740 pg/mL after tomorrow.

Medications (no medication changes since 3/2016): C. Continue all medications as prescribed and Furosemide 40mg daily (no edema presently) add sacubitril/valsartan . Carvedilol 12.5mg bid (max tolerated dose) Lisinopril 20mg daily Spironolactone 50mg daily Case Study 3 A 68yowm with HFpEF, improved presents to clinic. After institution of GDMT his LVEF is now 49% (previously 30%). No symptoms and he feels well. Currently on carvedilol 25mg bid, sacubitril/valsartan 97/103mg bid, spironolactone 25mg daily, digoxin 0.125mg daily, furosemide 20mg prn

He complains he simply cannot stand taking this many medications nor afford it.

What do you think about reducing or discontinuing some of the above now that his LVEF has normalized? 4 Case Study 4

68 yo white male new to your clinic presents with a history of heart failure (EF 30%), AICD/PM, CAD (post MI 1999), HTN, Dyslipidemia, DM, PAD with intermittent claudication, CKD

Currently, quite stable with no complaints. Able to do ADL without symptoms and no changes in medications in the last 18 months. No edema. No PND/Orthopnea. No dizziness or lightheadedness. No chest pain.

5 Case Study 4

Medications: ASA 81mg daily, carvedilol 25mg bid, furosemide 80mg daily, KCL 20meq daily, enalapril 20mg bid, simvastatin 40mg qhs, digoxin 0.25mg daily, cilostazol 100mg bid

BP 110/70mmHg, BUN/Cr 30/1.6mg/dl, Digoxin level 1.4ng/ml, K+ 4.8meq/L

Do you want to make any changes?

6 Case 5 A primary care colleague inquires what to do with a patient (HFrEF in NSR) who has a digoxin level of 2.8ng/ml. Level was obtained at 10am, patient takes all medications at one time upon arising at 7am.

Your options: A. Continue current dose B. Reduce dose to target a level < 1ng/ml and repeat level in 1-2 weeks C. Reduce dose to target a level < 1ng/ml and repeat level in 1-2 days D. Repeat level Case 6

A 52 year old female with chronic heart failure with reduced ejection fraction (EF 15%) awaiting heart transplant. Patient is currently NYHA Class III/IV, and not responding with an adequate diuresis/relief of congestive symptoms despite furosemide 80mg bid. Patient has no prescription coverage.

What may help overcome diuretic resistance? A. Review low salt diet B. Change to torsemide 40-80mg daily C. Have patient lay down after taking furosemide D. Instruct patient to take furosemide on an empty stomach E. A, C, & D Case 7 An 65 y/o woman with CAD, s/p anterior wall MI, with left ventricular dysfunction with an EF of 30%, and chronic kidney disease stage 3 (eGFR 35 ml/min/1.73m2) is found to be in heart failure during routine office visit.

She has been taking ibuprofen for arthritic pain. Her medications include: furosemide 40 mg daily, lisinopril 5 mg daily, metoprolol tartrate 25 mg BID, aspirin 81 mg daily, atorvastatin 10 mg daily. Chest X-ray reveals pulmonary vascular congestion. She also has bilateral lower extremity edema. Case 7

What actions would you take?

A. Discontinue ibuprofen B. As the GFR becomes severe at 20 ml/min the dose of lisinopril should be decreased C. Furosemide reduces intravascular lung pressure and the dose should be increased D. Spironolactone 25 mg daily would be a good drug to add at this time E. A, B, & C F. A, C, & D G. A & C Case 7

What would you recommend for arthritic pain control? A. Nonacetylated salicylate (i.e. salsalate) B. Tramadol C. Naproxen D. Celecoxib E. A, B, or D F. Any of the above are acceptable AHA Scientific Statement Use of Nonsteroidal Antiinflammatory Drugs

Stepped approach to pharmacologic therapy for musculoskeletal symptoms in patients with known CVD or risk factors for IHD (in order of preference)
Acetaminophen, ASA, tramadol, or narcotic analgesics (short term)
Nonacetylated salicylates
Non COX-2 selective NSAIDs
NSAIDs with some COX-2 selectivity
COX-2 selective NSAIDs

Circulation. 2007;115:1634-1642 Case 8 You are asked to recommend antithrombotic therapy for a 76 year old male with permanent non-valvular atrial fibrillation who presented 8 weeks ago with an ischemic CVA. He is currently recovering in a rehab center and has a feeding tube placed as a residual effect of the stroke.

PMH: Permanent atrial fibrillation, CVA, hypertension, s/p total colectomy for colon cancer 2011

Which is the best option(s)? A. Warfarin B. Apixaban C. Dabigatran D. Rivaroxaban Case 9

76 year old male with hypertension, heart failure, diabetes mellitus, prior MI, PM/AICD, and transient ischemic attack presents with atrial fibrillation on 3 month AICD interrogation (6 episodes > 15 minutes). He has also fallen 3 times in the last month secondary to a gait imbalance.

Do you anticoagulate him and with what? Audience Response Question How often should a patient replace their bottle of SL NTG once they have opened it?

1. 3 months 2. 6 months 3. 12 months 4. Expiration date Audience Response Question Which of the following pose a significant drug- drug interaction when administered with ranolazine? A. Digoxin B. Atorvastatin C. Verapamil D. Digoxin and verapamil Drug Interactions with Ranolazine

Select drug-drug interactions with ranolazine – Substrate of P-gp, CYP3A, CYP2D6 (lesser) – Weak inhibitor CYP3A, moderate inhibitor of CYP2D6 and P-gp, inhibitor of OCT2 – Limit doses of simvastatin to 20mg daily – Adjust digoxin dose if needed (increases concentrations by 50%) – Limit ranolazine to 500mg twice daily if receiving moderate CYP3A inhibitors (e.g. diltiazem, verapamil) Audience Response Question

Which of the following statements is true? A. Drugs must physically interact with each other to cause a drug-drug interaction B. If food slows down the rate of absorption of a drug, but not the extent, it is not considered a drug interaction C. If a drug can worsen a patient’s comorbid medical condition, one can say a drug interaction exists Audience Response Question

Which of the following oral anticoagulants has/have a drug-nutrient interaction I. Warfarin II. Rivaroxaban 10mg dose III. Rivaroxaban 20mg dose IV. Dabigatran A. I and II B. I and III C. I, II, III D. I, III, ad IV Audience Response Question

Which of the following is true about amiodarone? I. Amiodarone is a weak CYP3A4 inhibitor II. Amiodarone is a strong CYP3A4 inhibitor III. Amiodarone is a P-gp inhibitor A. I only B. II only C. I and III D. II and III Amiodarone and Drug Interactions

Selected drug-drug interactions with amiodarone (a combined P-gp and weak-moderate CYP3A4 inhibitor) – Digoxin (reduce dose by 50%) – Statins • Limit dose of simvastatin to 20mg • Consider non CYP3A4 metabolized statins – Warfarin (reduce dose by up to 50%) – Target specific oral anticoagulants? Audience Question Which of the following oral anticoagulants has/have a drug-nutrient interaction I. Warfarin II. Rivaroxaban 10mg dose III. Rivaroxaban 20mg dose IV. Dabigatran A. I and II B. I and III C. I, II, III D. I, III, and IV Drug-nutrient interactions with oral anticoagulants •Green Leafy Vegetables Warfarin •Vitamin K •Bioavailability is dose-dependent Rivaroxaban •Doses > 10mg affected by food •15-20mg doses should be taken with evening meal

Dabigatran •Take with a full glass of water Audience Question Which of the following statements is true? A. Carvedilol does not have a significant drug-nutrient interaction B. Vorapaxar and prasugrel BOTH have the same drug-disease state interaction C. Cilostazol does not have a drug-disease interaction with heart failure Select drug interactions with carvedilol

• Drug-nutrient • Administer with food to reduce risk of hypotension • Food slows rate, but not extent, of absorption • Drug-drug • Digoxin trough concentrations increase by about 15% Audience Question • Which of the following is correct? 1. Entresto is not associated with any drug-drug interactions 2. Entresto could be administered with aliskiren 3. Entresto should not be administered to a patient with ACE inhibitor angioedema 4. Entresto could be administered with spironolactone Selected drug-drug interactions with Entresto (sacubitril, valsartan) • Avoid combo with aliskiren especially in diabetics • Absolute contraindication in anyone with hx of angioedema (ACE I or ARB or other) • Concomitant use with K+sparing diuretics or K+ supplement can result in hyperkalemia • Caution with NSAID use – risk worsening renal fxn (sacubitril) • Lithium toxicity observed (ARB) Case Presentation • 70 yo african american man seen on house call by NP and consultant pharmacist • PMH: hypertension, CHF, osteoarthritis hip, neuropathy, depression, anxiety, BPH, gastritis • CC: light headedness and worsening hip pain, feeling depressed • Exam: orthostatic hypotension, elevated pulse • Meds: EC ASA, methadone, enalapril, furosemide, pantoprazole, doxazosin, travoprost eye drops, sertraline Case Presentation • Prevention Magazine – Herbal Medications can help conditions, improve overall QOL – St John Wart, Bilberry, Zing (gingko biloba, ginseng etc), Hawthorne extract, CoQ10, Cata- clear (bilberry, vitamins), Colon-Helper (aloe, gentian, goldenseal, etc), Valerian, Saw Palmetto

Cappuzzo K. Consultant Pharmacist 2006;11:911-915 Audience Response Which of the following are potential drug-herb interactions in this patient? A) St John Wart – Methadone (decreased activity) B) St John Wart – SSRI (serotonin syndrome) C) Ginkgo Biloba – ASA (platelet inhibition) D) All of the above Case Presentation • At end of visit patient asked about whether he could take Viagra to reduce stress on his heart……..

• He had heard about it on the news……… Case Presentation • 61 yo man w/ hx of hypercholesterolemia x 11 yrs, tx with multiple different statins (all at 10mg dose) which was unsuccessful due to muscle intolerance (w/in 1 week). Normal CK, moderate LFT bumps. Patient drank 3 cups of green tea everyday “to reinforce his health”. Case Presentation

Active Prodrug Metabolite

Werba et al. Annals of Int Med 2008;149:286-288 Audience Response The likely underlying mechanism for the green tea – simvastatin interaction is

A) CYP3A4 induction B) CYP3A4 inhibition C) Unknown mechanism Case Presentation

• DSB is a 42 yo police officer. He weighs 260 lbs, BP 143/92, TC 200, LDL 130mg/dl, glucose 105 mg/dl • He takes a weight loss supplement (imported from Brazil) and loses 10 lbs • Label: vitamin E, centella, senna, cascara, other “natural ingredients” • He undergoes routine, random drug screen • He loses his job

NEJM 2009;361:1523-1525 Audience Response • Which of the following could have contributed to his losing his job? 1.“Natural Ingredient” 2.Cascara 3.Vitamin E Natural Ingredient……..

AMPHETAMINE Case Presentation

• 65yo wm with HTN hyperlipidemia and knee osteoarthritis presents with chief complaint of fatigue, decreased exercise tolerance and worsening bilateral leg swelling • For 5 years he had been prescribed lisinopril, simvastatin and meloxicam as needed for pain. • He was traveling oversees, fell in the airport upon arrival and experienced worsening knee pain during his vacation • He ran out of the meloxicam he brought with him and bought some diclofenac at the local drug store (OTC) • Over the next 3 months his pain continues, his mobility is limited and lisinopril dose was doubled to 20mg daily because his BP is slowly rising. Case Presentation

• Basic chemistry and UA reveal creatinine level of 3.51 mg/dl and BUN of 61 mg/dl (6 months prior 0.96 mg/dl, 18 mg/dl) • Lisinopril and meloxicam / diclofenac held, BP monitored • After 3 months, swelling and fatigue decreased, creatinine 2.17 mg/dl • Amlodipine started and referred to nephrology for probably NSAID induced nephropathy Teaching Points • NSAIDs – one of most commonly used drug classes – ~19% of US adult population using at least one on a regular bases • ~75% of US adult population have HTN • NSAID use increases BP ~ 5 mm Hg (~14 mm Hg in those with HTN) • NSAIDs increase aldosterone level – render ACE inhibitors and ARBs less effective – Combination of NSAIDs, ACE inhibitor and diuretic can increase risk of acute kidney injury by 30% • Need to individualize pain management – Physical therapy – Acetaminophen – Topical agents (capsaicin, diclofenac) – Monitor closely