Issues of Safety and Efficacy in Geriatric Prescribing. Objectives. Having completed the learning activities, the participant will be able to:

Transcription

1 Issues of Safety and Efficacy in Geriatric Prescribing Margaret Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC President, Fitzgerald Health Education Associates, Inc. North Andover, MA Family Nurse Practitioner, Greater Lawrence (MA) Family Health Center Editorial Board Member The Nurse Practitioner, Prescriber s Letter, American Nurse Today Member, Pharmacy and Therapeutics Committee Neighborhood Health Plan, Boston, MA Fitzgerald Health Education Associates, Inc. 1 Objectives Having completed the learning activities, the participant will be able to: Identify the effects of aging and disease state on pharmacokinetics and pharmacodynamics. Recognize safety issues with the use of select medications in the elderly. Fitzgerald Health Education Associates, Inc. 2 Prescribing in the Older Adult When compared to the younger adult, what is different in the elder? PD (pharmacodynamics) PK (pharmacokinetics) Both? Neither? Fitzgerald Health Education Associates, Inc. 3

2 General Pharm Rule in Prescribing for the Elder: Consider normative agerelated changes and subsequent impact on drug choice and dose. Fitzgerald Health Education Associates, Inc. 4 Summary of Age-related Changes Adults age y Adult age y % body weight as water 60% 53% Lean muscle mass Baseline =>20% reduction % body weight as fat 26-33% (women) 18-20% (men) 38-45% (women) 36-38% (men) Serum albumin (average) 4.7 g/dl (47 g/l) 3.8 g/dl (38 g/l) Relative kidney weight 100% 80% Relative hepatic blood flow 100% 55-60% Source: Katzung, BG. (2011) Basic and Clinical Pharmacology (12th ed.) New York: Lange Medical Books/ McGraw-Hill. Fitzgerald Health Education Associates, Inc. 5 Singla and Morrill: Warfarin Maintenance Dosages in the Very Elderly The mean daily warfarin dose was significantly lower with increasing age; the mean ± S.D. daily dose for patients younger than 75 years was 4.9 ± 2.6 mg/day, while that for patients 85 years or older was 3.5 ± 2.6 mg/day. Source: Fitzgerald Health Education Associates, Inc. 6

3 Avoiding the Unneeded Use of Sleep Aids Fitzgerald Health Education Associates, Inc. 7 Your patient is a 75-year-old man who is in general good health with well-controlled HTN and dyslipidemia. He presents today with a chief complaint of difficulty initiating and maintaining sleep for about the past year. He drinks about 5 cups of coffee a day but states, I really do not think this had anything to it. I have done this for years. Fitzgerald Health Education Associates, Inc. 8 Caffeine s PK T ½ range=1.5-9 h Cmax=~ mins Minimum first-pass effect CYP450 1A2 substrate Source: The National Academies Press: Caffeine for the Sustainment of Mental Task Performance, available at Fitzgerald Health Education Associates, Inc. 9

4 True or false? When compared with a healthy 40- year-old adult, CYP450 isoenzyme levels can drop by up to 30% in elders after age 70. CYP450 1A2 s activity is influenced by the presence or absence of estrogen in women. Fitzgerald Health Education Associates, Inc. 10 General Pharm Rule in Prescribing for the Elder: Is the medication you are considering prescribing listed in the Beers Criteria? Journal of the American Geriatrics Society American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults American Geriatrics Society: 2012 Beers Criteria Update Expert Panel J Am Geriatr Soc. 2012; 60(4): PIMs per Beers Potentially inappropriate medications (PIMs) continue to be prescribed and used as first-line treatment for the most vulnerable of older adults, despite evidence of poor outcomes from the use of PIMs in older adults. Fitzgerald Health Education Associates, Inc. 12

5 Avoid medications with systemic anticholinergic effect due to risk of confusion, urinary retention, constipation, visual disturbance, and hypotension. The adverse effects could lead to polypharmacy and risk of delirium. Fitzgerald Health Education Associates, Inc. 13 Medications with Significant Anticholinergic Effects 1 st -generation antihistamines Chlorpheniramine (Chlor-Trimeton ) Diphenhydramine (Benadryl ) Hydroxyzine (Atarax ) Cyproheptadine (Periactin ) Promethazine (Phenergan ) Fitzgerald Health Education Associates, Inc. 14 First-generation Antihistamines Additional comments from Beers Criteria Clearance reduced with advanced age Tolerance develops when these products used as hypnotic Fitzgerald Health Education Associates, Inc. 15

6 Commonly Used Meds in Elder with Anticholinergic Effect Examples Oxybutynin (Ditropan ) immediate release vs. sustained release SR form=better tolerance with similar therapeutic efficacy Examples Amitriptyline vs. nortriptyline Fitzgerald Health Education Associates, Inc. 16 Oxybutynin in a Sustained Release Patch Form Oxytrol for women Above=Full branded name for this indication Indication=OAB Identical dose as the Rx formulation Labeling restricted to women due to licensing Safety, efficacy data presented to FDA=Limited to women Fitzgerald Health Education Associates, Inc. 17 Avoid using medications where there is little evidence of benefit but evidence of risk. Fitzgerald Health Education Associates, Inc. 18

7 Antiarrhythmic Drugs (Class Ia, Ic, III) Per Beers Criteria Avoid antiarrhythmic drugs as first-line treatment of atrial fibrillation. Fitzgerald Health Education Associates, Inc. 19 Antiarrhythmic Drugs (Class Ia, Ic, III) Per Beers Criteria Data suggest that rate control yields better balance of benefits and harms than rhythm control for most older adults. Fitzgerald Health Education Associates, Inc. 20 Antiarrhythmic Drugs (Class Ia, Ic, III) Examples Amiodarone Dronedarone Flecainide Procainamide Propafenone Quinidine Sotalol Fitzgerald Health Education Associates, Inc. 21

8 Antiarrhythmic Drugs (Class Ia, Ic, III) per Beers Criteria Amiodarone use is associated with multiple toxicities, including thyroid disease, pulmonary disorders, and QT interval prolongation. Fitzgerald Health Education Associates, Inc. 22 In an older woman with recurrent UTI, consider alternative other than chronic antimicrobial therapy. Fitzgerald Health Education Associates, Inc. 23 Estrogens with or without Progestins per Beers Criteria Topical vaginal cream: Acceptable to use low-dose intravaginal estrogen for the management of dyspareunia, lower urinary tract infections, and other vaginal symptoms. Fitzgerald Health Education Associates, Inc. 24

9 Per Beers Criteria: True or false? There is evidence that vaginal estrogens for treatment of vaginal dryness is safe and effective in women with breast cancer, especially at dosages of estradiol dose <25 mcg twice weekly. Fitzgerald Health Education Associates, Inc. 25 General Pharm Rule in Prescribing for the Elder: While PD does not change with aging, some age-related physical changes will result in less drug effect. Fitzgerald Health Education Associates, Inc. 26 Age-related Changes Influencing Pharmacodynamics Age-related changes in vascular, pulmonary, cardiac tissue Decrease in effect of beta-adrenergic agents Beta2-agonists such as albuterol, salmeterol Beta antagonists such as metoprolol, carvedilol Fitzgerald Health Education Associates, Inc. 27

10 Additional Therapeutic Choices with Less Age-related Impact Inhaled anticholinergic Tiotropium, ipratropium bromide Calcium channel blockers Dihydropyridines (DHP) such as amlodipine Non DPH such as verapamil, diltiazem Some evidence of increased sensitivity to Non-DPH PR-prolonging effects in elder Fitzgerald Health Education Associates, Inc. 28 Discontinue medications that likely should not have been started in the first place. PPI Use: Third Leading Drug Class in Sales Risks vs. Benefits References: Proton Pump Inhibitors: Appropriate use and safety concerns. Pharmacist s Letter/Prescriber s Letter 2010 (Updated March 2011); 26(7):

11 Consequences of Long-term PPI Use Rebound hypersecretion 60% to 90% using PPIs for =>2 months Explains why reports increased GI symptoms with discontinuation Considering tapering medication with reducing dose, followed by every other day use, H2RA, antacid use for symptoms Fitzgerald Health Education Associates, Inc. 31 Consequences of Long-term PPI Use Potential decrease in absorption of select micronutrients requiring acid stomach environment Iron, vitamin B12 Supplementation needs not established Fitzgerald Health Education Associates, Inc. 32 Consequences of Long-term PPI Use Increased fracture risk in epidemiologic studies, noted in male and female Associated with 25% increase in overall fractures, 47% increase in spinal fractures in postmenopausal women Calcium citrate absorption less affected by altered gastric acidity Fitzgerald Health Education Associates, Inc. 33

12 Consequences of Long-term PPI Use Magnesium absorption Increase risk hypomagnesaemia noted with Mg depleting medication use such as thiazide and loop diuretics Digoxin toxicity risk increased with low Mg Fitzgerald Health Education Associates, Inc. 34 Lansoprazole Prevacid Omeprazole Prilosec Pantoprazole Protonix Rabeprazole AcipHex Esomeprazole Nexium PPI: CYP450 2C19 Inhibitors Source: Click on Clinically Relevant Table for useful summary of CYP450 drug interactions. Fitzgerald Health Education Associates, Inc. 35 And perhaps DC a med that might have been the trigger to go on a PPI? Source: y&selectedtitle=1%7e150#h Fitzgerald Health Education Associates, Inc. 36

13 Continuing Bisphosphonate Therapy For patients taking alendronate or risedronate for five years or who received zoledronic acid once yearly for three years, who have a stable BMD, no previous vertebral fractures, and who are at low risk for fracture in the near future, we suggest discontinuing the drug. Fitzgerald Health Education Associates, Inc. 37 Per Beers Criteria, Commonly Used Medication in Elder with Little Evidence of Benefit Aspirin for primary prevention of cardiac events Lack of evidence of benefit versus risk in individuals aged 80 Use with caution in adults aged 80 Fitzgerald Health Education Associates, Inc. 38 Avoid unneeded repeat therapy.

14 72-year-old Woman with UTI and Mild Renal Insufficiency Urine culture results=100k colonies E. coli What is the best therapeutic option? Sensitive Nitrofurantoin Ciprofloxacin Resistant TMP-SMX Ampicillin Fitzgerald Health Education Associates, Inc. 40 Antimicrobial Dose Adjustment in Renal Impairment: Nitrofurantoin If Cr Cl=>50 mg/dl (=>0.84 ml/s) Standard dosing according to indication If Cr Cl<50 mg/dl (<0.84 ml/s) Avoid use Fitzgerald Health Education Associates, Inc. 41 Medications with Dose Adjustment Required in Renal Impairment Ciprofloxacin Cr Cl=>30 ml per minute (0.5 ml/s): No change with doses mg BID Cr Cl<30 ml per minute (0.5 ml/s): Required dose q24h Fitzgerald Health Education Associates, Inc. 42

15 Medications with Dose Adjustment Required in Renal Impairment TMP SMX (Bactrim ) Cr Cl>30 ml/min (0.5 ml/s): No change, 1 DS tab BID Cr Cl ml/min ( ml/s): 1 DS tablet 24h OR 1 SS tablet q12h Cr Cl<15 ml/min (0.25 ml/s): Avoid if possible or use 1 tablet SS or DS q24h Fitzgerald Health Education Associates, Inc. 43 Keep abreast of new warnings about potential drug-drug interactions with long-used medications, particularly in the older adult. Fitzgerald Health Education Associates, Inc year-old Woman Health history HTN, T2DM, dyslipidemia, obesity, depression 4 days ago, treated for URI present X 3 days at local urgent care so this would not develop into a sinus infection since I have diabetes with an oral antibiotic Fitzgerald Health Education Associates, Inc. 45

16 Current Medications Metformin Glipizide Lisinopril HCTZ Pravastatin Low-dose ASA Fluoxetine Added 4 d ago Trimethoprimsulfamethoxazole for treatment of URI Fitzgerald Health Education Associates, Inc year-old Woman Labs approximately 2 months ago Cr=1.0 mg/dl (88.4 µmol/l) Calculated GFR=74 ml/min/1.71 m 2 Stage 2 CRF Patient states, My kidneys are fine. Na+=142 mmol/l ( ) K+=4.8 mmol/l ( ) A1C=6.8% (0.068 proportion) NL CBC with RBCs indices Lipids within acceptable range Fitzgerald Health Education Associates, Inc year-old Woman Presents today with the following Sudden onset inability to ambulate without assistance within p 12 hours Describes as my legs feel like Jell-O. I can hardly hold a cup of coffee. Generalized malaise, nausea without vomit, anorexia Fitzgerald Health Education Associates, Inc. 48

17 61-year-old Woman Clinical presentation Alert, oriented, no SOB Cardiac and respiratory exam=wnl Abdomen=Unremarkable Skin=WNL Unable to bear weight on legs Arm=Strength WNL Weak hand grasps bilaterally Fitzgerald Health Education Associates, Inc year-old Woman with New Onset Leg Weakness Today s labs BUN=38 mg/dl (8-20) [13.6 mmol/l ( )] Creatinine=1.2 mg/dl (0.44-1) [106.1 µmol/l ( )] BUN: Cr ratio=>20:1 Pre-, intra-, post renal azotemia? Glucose=148 mg/dl (74-118) [8.2 mmol/l ( )] Calcium=9.2 mg/dl ( ) [2.3 mmol/l ( )] Fitzgerald Health Education Associates, Inc year-old Woman with New Onset Leg Weakness Today s labs Na+=128 meq/l ( ) [128 mmol/l ( )] K=6.6 meq/l ( ) [6.6 mmol/l ( )] Cl=95 meq/l ( ) [95 mmol/l ( )] CO 2 =24 mmol/l (22-32) CBC with WBC diff=wnl Fitzgerald Health Education Associates, Inc. 51

18 Drug-induced Hyperkalemia TMP-SMX-induced hyperkalemia TMP structurally similar to potassiumsparing diuretic amiloride Principal site of action in kidney is the distal tubule, inhibits potassium secretion Fitzgerald Health Education Associates, Inc. 53 TMP-SMX-induced Hyperkalemia Among older patients treated with ACEIs or ARBs, the use of trimethoprim-sulfamethoxazole is associated with a major increase in the risk of hyperkalemia-associated hospitalization relative to other antibiotics. Source: Fitzgerald Health Education Associates, Inc. 54

19 TMP-SMX-induced Hyperkalemia Advice Avoid using TMP-SMX, if possible, in patients taking spironolactone, ACEI or ARB, especially if elderly or other chronic health problems Source: Fitzgerald Health Education Associates, Inc. 55 True or false? In providing care for an older adult with mild renal impairment who is taking an ACEI with K+=5-5.5 meq/l (5-5.5 mmol/l), aside from assuring adequate hydration, taking the once-daily ACEI dose in the morning should be considered so as to allow for overnight excretion of renal potassium to avoid hyperkalemia. Source: Hou FF et al. Efficacy and Safety of Benazepril for Advanced Chronic Renal Insufficiency. N Engl J Med 2006;354: Fitzgerald Health Education Associates, Inc. 56 Medications Used in Alzheimer-type Dementia Use of cholinesterase inhibitors is associated with increased rates of syncope, bradycardia, pacemaker insertion, and hip fracture in older adults with dementia. The risk of these previously under recognized serious adverse events must be weighed carefully against the drugs' generally modest benefits. Source: Arch Intern Med. 2009;169: Fitzgerald Health Education Associates, Inc. 57

20 General Pharm Rule in Prescribing for the Elder: Start low, go slow, but get to goal. Do not put patient in the situation of perhaps having some of the adverse effects but none of the benefit of a give medication. Fitzgerald Health Education Associates, Inc. 58 End of Presentation Thank you for your time and attention. Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC cs@fhea.com Fitzgerald Health Education Associates, Inc. 59 References Katzung, BG. (2014) Basic and Clinical Pharmacology (13th ed.) New York: Lange Medical Books/McGraw-Hill. Stringer, J. (2011) Basic Concepts in Pharmacology: All you need to know for each drug class (4th edition). New York: McGraw-Hill. Fitzgerald Health Education Associates, Inc. 60

21 All websites listed active at the time of publication. Fitzgerald Health Education Associates, Inc. 61

22 Acute Bacterial Rhinosinusitis: A focus on the latest treatment recommendations Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC President, Fitzgerald Health Education Associates, Inc., North Andover, MA Family Nurse Practitioner, Greater Lawrence (MA) Family Health Center Editorial Board Member The Nurse Practitioner, The Prescriber s Letter, American Nurse Today Member, Pharmacy and Therapeutics Committee Neighborhood Health Plan, Boston, MA Objectives Having completed the learning activities, the participant will be able to: Identify factors influencing the choice of an antimicrobial. Recognize the efficacy of select antimicrobials for the ABRS. Fitzgerald Health Education Associates, Inc. 2 Are the bugs winning? Is this a new problem? Fitzgerald Health Education Associates, Inc. 3

23 In Late 1920s Sir Alexander Fleming 1 st to suggest that penicillium mold must secrete antibacterial substance; 1 st to isolate active substance which he named penicillin Fitzgerald Health Education Associates, Inc. 4 Sir Alexander Fleming June 26, 1945, New York Times the microbes are educated to resist penicillin and a host of penicillin-fast (resistant organisms is bred out Fitzgerald Health Education Associates, Inc. 5 Sir Alexander Fleming June 26, 1945, New York Times In such cases the thoughtless person playing with penicillin is morally responsible for the death of the man who finally succumbs to infection with the penicillinresistant organism. I hope this evil can be averted. Fitzgerald Health Education Associates, Inc. 6

24 Empiric Antimicrobial Therapy The decisionmaking process where the clinician chooses the agent based on patient characteristics and site of infection. Fitzgerald Health Education Associates, Inc. 7 Questions to Ask Prior to Choosing an Antimicrobial What is/are the most likely pathogen(s) causing this infection? What is the spectrum of a given antimicrobial s activity? What is the likelihood of resistant pathogen? What is the danger if there is treatment failure? Fitzgerald Health Education Associates, Inc. 8 The Beta-lactam Ring: Vulnerable or Not? Penicillin Cephalosporin Fitzgerald Health Education Associates, Inc. 9

25 Without antibiotic: 2b 1 2x a 1 2z b 3 Actively growing S. pneumoniae: PBPs facilitate cell wall formation for new cell Alteration in Target Site Altered Penicillin-binding Proteins (PBPs) Antibiotic binds to PBPs PnPn 2b 1 2x a 1 2z b 3 Susceptible S. pneumoniae Cannot make adequate cell wall, growth stops Pn Pn 2b 1 2x a1 2z b 3 DRSP Antibiotic cannot bind to altered PBPs, growth continues (antibiotic resistance) Fitzgerald Health Education Associates, Inc. 10 Alteration in Ribosomal Target Sites S. pneumoniae vs. Macrolides: Methylation of Ribosomes Ribosomes Macrolide MM Protein Normal Macrolide MOA: Macrolide binds to ribosome of S. pneumoniae and inhibits bacterial protein synthesis Fitzgerald Health Education Associates, Inc. MM CH3 CH3 Macrolide unable to bind to ribosome Protein Macrolide Resistance: S. pneumoniae acquires gene that results in methylation of the ribosomes. Macrolide unable to bind to altered ribosomes and cannot interfere with protein synthesis 11 Predictors of Bacterial Eradication: PK/PD Profiles Time-Dependent Agents Concentration-Dependent Agents Includes: Penicillins Cephalosporins Clinical and bacteriologic success correlates with length of time bacteria are exposed to agent at concentration that exceeds MIC Peric M, et al. Clin Ther. 2003;25: Includes: Quinolones Macrolides Telithromycin Doxycycline TMP-SMX Successful therapy correlates with parameters that involve blood concentration of agent and MIC Fitzgerald Health Education Associates, Inc. 12

26 True or false? The macrolides, fluoroquinolones, and tetracyclines do not contain a betalactam ring and are therefore stable in the presence of beta-lactamase. Fitzgerald Health Education Associates, Inc. 13 True or false? S. pneumoniae occasionally exhibits resistance via betalactamase production. Fitzgerald Health Education Associates, Inc. 14 What facilitates resistance? Time Exposure Unnecessary doses Long tx period Under dosing Leaves behind more resistant bugs Fitzgerald Health Education Associates, Inc. 15

27 True or false? In a study of antimicrobial prescribing among primary care providers, physicians in high-volume practices and those who were in practice longer were more likely to prescribe antibiotics inappropriately. Source: CMAJ October 9, 2007; 177 (8). Fitzgerald Health Education Associates, Inc. 16 Updated Treatment Guidelines for ABRS in Children and Adults Chow, A., et al., IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Children and Adults, available at Patient_Care/PDF_Library/IDSA%20Clinical%20Practice%20G uideline%20for%20acute%20bacterial%20rhinosinusitis%20 in%20children%20and%20adults.pdf Fitzgerald Health Education Associates, Inc. 17 Is antimicrobial needed in ABRS therapy? Meta-analyses of antibiotic treatment vs. placebo in ABRS Number needed to treat (NNT) (95% CI) In adults=13 (9 22) In children=5 (4 15) Source: Chow, A., et al., IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Children and Adults Fitzgerald Health Education Associates, Inc. 18

28 Bacterial Pathogens Associated with ABRS Streptococcus pneumoniae Gram-positive diplococci DRSP rate nationally=25% Adults=38% Children=21 33% Source: Chow, A., et al., IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Children and Adults Fitzgerald Health Education Associates, Inc. 19 Bacterial Pathogens Associated with ABRS Haemophilus influenzae Gram-negative rod-shaped bacterium ~30% beta-lactamase production rate nationwide Nontypable strains cause ABRS Adults=36% Children=31 32% Source: Chow, A., et al., IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Children and Adults Fitzgerald Health Education Associates, Inc. 20 Bacterial Pathogens Associated with ABRS Moraxella catarrhalis Gram-negative with =>90% betalactamase production rate Adults=16% Children=8 11% Source: Chow, A., et al., IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Children and Adults Fitzgerald Health Education Associates, Inc. 21

29 Acute Rhinosinusitis Syndrome (ARS): Defining the terms Inflammation of the mucosal lining of nasal passage and paranasal sinuses lasting up to 4 weeks, caused by allergens, environmental irritants, and/or infection (viruses {majority}, bacteria and fungi). Fitzgerald Health Education Associates, Inc. 22 Acute bacterial rhinosinusitis (ABRS or ABS) Acute Rhinosinusitis (ARS): Defining the terms Secondary bacterial infection of paranasal sinuses usually following viral URI, relatively uncommon in adults and children. Less than 2% of viral URIs are complicated by ABRS. Fitzgerald Health Education Associates, Inc. 23 Empiric Antimicrobial Therapy in ABRS: Gram-positive with DRSP risk Gram-negative with beta-lactamase production risk Fitzgerald Health Education Associates, Inc. 24

30 Algorithm for the Management of Acute Bacterial Rhinosinusitis Signs and symptoms either: Risk for antibiotic resistance a) Persistent and not improving ( 10 days); Abbreviations: CT, computed b) Severe ( 3-4 days); or Age <2 y or >65 y, tomography; MRI, magnetic c) Worsening or double-sickening ( 3-4 days) daycare resonance imaging Prior antibiotics within the past month Risk for Resistance Prior hospitalization past 5 days No Yes Comorbidities Immunocompromised Symptomatic management Initiate first-line Initiate second-line antimicrobial therapy antimicrobial therapy Improvement after 3-5 days Worsening or no improvement after 3-5 days Improvement after 3-5 days Complete 5-7 days of antimicrobial therapy Improvement Complete 5-7 days of antimicrobial therapy Broaden coverage or switch to Complete 7-10 days of different antimicrobial class antimicrobial therapy Improvement Worsening or no improvement after 3-5 days Complete 7-10 days of Refer to specialist antimicrobial therapy CT or MRI to investigate noninfectious causes or Source: Clinical Infectious suppurative complications Diseases Advance Sinus or meatal cultures for pathogen-specific therapy Evidence-based Practice: Symptomatic treatment in ABRS Saline nasal irrigations Intranasal corticosteroids when ABRS is accompanied by allergic rhinitis Topical or systemic decongestants for patient sense of congestion relief Fitzgerald Health Education Associates, Inc. 26 Indication Initial empiric therapy Antimicrobial Regimens for Acute Bacterial Rhinosinusitis in Adults First-line (Daily dose) Second-line (Daily dose) Amoxicillinclavulanate Amoxicillin-clavulanate mg/125 mg mg/125 mg PO TID PO BID Or Or Amoxicillinclavulanate Doxycycline 100 mg 875 PO BID or 200 mg PO mg/125 mg PO BID daily Fitzgerald Health Education Associates, Inc. 27

31 Antimicrobial Regimens for Acute Bacterial Rhinosinusitis in Adults High dose (HD, 3-4 g/d) amoxicillin needed against DRSP Clavulanate as a beta-lactamase inhibitor, allows amoxicillin to have activity against beta-lactamase producing organisms such as H. influenzae, M. catarrhalis Fitzgerald Health Education Associates, Inc. 28 Antimicrobial Regimens for Acute Bacterial Rhinosinusitis in Adults Doxycycline- DRSP treatment failure risk, activity against gm negative organisms, stable in presence of beta-lactamase Pregnancy risk category D Fitzgerald Health Education Associates, Inc. 29 Antimicrobial Regimens for Acute Bacterial Rhinosinusitis in Adults β-lactam allergy (Allergy to antimicrobials with beta-lactam ring such as penicillins, cephalosporins) Doxycycline 100 mg PO BID Or Doxycycline 200 mg PO daily Or Levofloxacin 500 mg PO daily Or Moxifloxacin 400 mg PO daily Fitzgerald Health Education Associates, Inc. 30

32 Antimicrobial Regimens for Acute Bacterial Rhinosinusitis in Adults Respiratory fluoroquinolones (FQ)- Activity against DRSP, gramnegative organisms, stable in presence of beta-lactamase Fitzgerald Health Education Associates, Inc. 31 Antimicrobial Regimens for Acute Bacterial Rhinosinusitis in Adults Risk for antibiotic resistance or failed initial therapy Amoxicillin-clavulanate 2000 mg/125 mg PO BID Or Levofloxacin 500 mg PO daily Or Moxifloxacin 400 mg PO daily Fitzgerald Health Education Associates, Inc. 32 Antimicrobial Regimens for Acute Bacterial Rhinosinusitis in Adults All options with activity against DRSP, gram-negative organisms, stable in presence of and/or active against beta-lactamase Fitzgerald Health Education Associates, Inc. 33

33 Antimicrobial Regimens for Acute Bacterial Rhinosinusitis in Children Indication Initial empirical therapy First-line (Daily dose) Amoxicillinclavulanate 45 mg/kg/day PO BID Second-line (Daily dose) Amoxicillinclavulanate 90 mg/kg/day PO BID Source: Chow, A., et al., IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Children and Adults Fitzgerald Health Education Associates, Inc. 34 Antimicrobial Regimens for Acute Bacterial Rhinosinusitis in Children Risk for antibiotic resistance or failed initial therapy Amoxicillin-clavulanate 90 mg/kg/day PO BID Or Clindamycin a mg/kg/day PO TID plus cefixime 8 mg/kg/day PO BID or cefpodoxime 10 mg/kg/day PO BID Or Levofloxacin mg/kg/day PO every h a Resistance to clindamycin (~31%) is found frequently among Streptococcus pneumoniae serotype 19A isolates in different regions of the United States [94]. Source: Chow, A., et al., IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Children and Adults Antimicrobial Regimens for Acute Bacterial Rhinosinusitis in Children β-lactam allergy Type I hypersensitivity Non type I hypersensitivity Levofloxacin mg/kg/day PO every h Or Clindamycin a (30 40 mg/kg/day PO TID) plus cefixime (8 mg/kg/day PO BID) or cefpodoxime (10 mg/kg/day PO BID) a Resistance to clindamycin (~31%) is found frequently among Streptococcus pneumoniae serotype 19A isolates in different regions of the United States [94]. Source: Chow, A., et al., IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Children and Adults Fitzgerald Health Education Associates, Inc. 36

34 Where are the $4 drugs? Amoxicillin Clinical limitations? Ciprofloxacin Clinical limitations? TMP-SMX Clinical limitations? Cephalexin Clinical limitations? Fitzgerald Health Education Associates, Inc. 37 Antimicrobials Not Recommended Azithro-, clarithromycin DRSP treatment failure risk Fitzgerald Health Education Associates, Inc. 38 General Rule with Peds Antibiotic Dosing Safe products Easily metabolized Prescribe up to but do not exceed adult doses Source- Prescriber's Letter 2008; 15(4): Fitzgerald Health Education Associates, Inc. 39

35 Cross Allergy of PCN to Cephalosporins? How would you Prescribe Cephalosporins to Patients with Penicillin Allergies? FHEA News, Volume XII, Issue VIII, Page 13 Available at er/fheanews_volume12_issue8.pdf Fitzgerald Health Education Associates, Inc. 40 Type I Hypersensitivity Reaction AKA immediate or anaphylactic hypersensitivity Reaction involves preferential production of IgE in response to certain antigens (allergens) Fitzgerald Health Education Associates, Inc. 41 Type I Hypersensitivity Reaction Usually involves skin (urticaria eczema), eyes (conjunctivitis), nasopharynx (rhinorrhea, rhinitis), bronchopulmonary tissues (wheeze, cough) and/or GI tract (gastroenteritis) Fitzgerald Health Education Associates, Inc. 42

36 Type II Hypersensitivity AKA cytotoxic hypersensitivity Antigens normally endogenous Primarily mediated by IgM or IgG antibodies Reaction time Minutes to hours Fitzgerald Health Education Associates, Inc. 43 Clinical manifestations Drug-induced hemolytic anemia, granulocytopenia, thrombocytopenia Type II Hypersensitivity Fitzgerald Health Education Associates, Inc. 44 Conclusion Fitzgerald Health Education Associates, Inc. 45

37 End of Presentation Thank you for your time and attention. Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC Fitzgerald Health Education Associates, Inc. 46 All websites listed active at the time of publication. Fitzgerald Health Education Associates, Inc. 47

38 Drug Update: New Products, New Indications, New Warnings Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC President, Fitzgerald Health Education Associates, Inc., North Andover, MA Family Nurse Practitioner, Greater Lawrence (MA) Family Health Center Editorial Board Member The Nurse Practitioner, The Prescriber s Letter, American Nurse Today Member, Pharmacy and Therapeutics Committee Neighborhood Health Plan, Boston, MA Objectives Upon completion of the program, the participant will be able to: Describe characteristics of and recommendations for the use of new medications. Recognize new indications and cautions for established products. Fitzgerald Health Education Associates, Inc. 2 Drug Development: True or false? The average new drug developed by a major pharmaceutical company costs at least $4-11 billion to bring to market. Fewer than 1 drug or molecular entities that are considered to be therapeutic in 10 make it to market. Fitzgerald Health Education Associates, Inc. 3

39 For Answers to Questions Answers herper/2012/02/10/the-trulystaggering-cost-of-inventing-newdrugs Fitzgerald Health Education Associates, Inc. 4 How do medications reach the market? The Process of Drug Approval Fitzgerald Health Education Associates, Inc. 5 Fitzgerald Health Education Associates, Inc. 6

40 Fitzgerald Health Education Associates, Inc. 7 A wise prescriber avoids using new medications the first 6-12 months the product is on the market. Why? Is that consistently wise advice? Fitzgerald Health Education Associates, Inc. 8 If a significant problem 1/15,000 10/150, /1,500,000 Fitzgerald Health Education Associates, Inc. 9

41 Efinaconazole (JUBLIA ) Topical Solution, 10% Fitzgerald Health Education Associates, Inc. 10 Efinaconazole (JUBLIA ) Topical Solution, 10% What is it? An azole antifungal indicated for the topical treatment of onychomycosis of the toenails due to Trichophyton rubrum, Trichophyton mentagrophytes Fitzgerald Health Education Associates, Inc. 11 Efinaconazole (JUBLIA ) Efficacy Endpoints Efinaconazole (JUBLIA )vs. vehicle Complete cure 17.8% vs. 3.3% Complete or almost complete cure 26.4% vs. 7.0% Mycologic cure 55.25% vs. 16.8% Fitzgerald Health Education Associates, Inc. 12

42 Directions for Efinaconazole (JUBLIA ) Use Apply efinaconazole (JUBLIA ) to affected toenails once daily for 48 weeks using the integrated flow-through brush applicator. Not applied like nail polish When applying efinaconazole (JUBLIA ), ensure the toenail, toenail folds, toenail bed, hyponychium, and the undersurface of toenail plate, are completely covered. Fitzgerald Health Education Associates, Inc. 13 Comparison to Oral Antifungals Terbinafine 250 mg tab $4 for 30 tablets 3-6 months of therapy needed=$12-24 Terbinafine clinical efficacy endpoints Specifically cohort of elders Mycologic cure=64.0% Clinical cure=41.3% Complete cure=28.0% Source: Fitzgerald Health Education Associates, Inc. 14 Efinaconazole (JUBLIA )Cost, Amount Required Approximately $140 per ml 4 ml, 8 ml bottles Use instructions, daily requirement 1 drop to nail other than great toe 2 drops to great toe 2 nails plus 1 great toe=4 drops per day 4 ml bottle=about 3 weeks of therapy About $8,000+ for full course of therapy Fitzgerald Health Education Associates, Inc. 15

43 New Immunization for Prevention of a Devastating Disease Fitzgerald Health Education Associates, Inc. 16 Neisseria meningitidis Gram-negative diplococcus Largely droplet, saliva transmitted Normal nonpathogenic flora in nasopharynx of up to 5-15% of adults Major risk Children<5 years of age, adolescents Serogroups, A, B, C, Y, and W-135, cause almost all invasive disease. Fitzgerald Health Education Associates, Inc. 17 Meningococcal Disease: An Overview Burden of the disease per year in USA Approximately 1000 cases nationwide Most cases sporadic (97%), 3% associated with outbreaks 10-14% mortality 11-19% survive with significant sequelae including hearing loss, limb amputation, cognitive disability, other Fitzgerald Health Education Associates, Inc. 18

44 Fitzgerald Health Education Associates, Inc. 19 Meningococcal Vaccines Currently in Widespread Use Providing protection against serogroups A, C, Y, and W-135 Responsible for approximately 2/3 of invasive N. meningitidis disease in the USA MPSV4, Menomune Meningococcal polysaccharide vaccine MCV4-CRM, Menactra,Menveo Meningococcal conjugate vaccine Fitzgerald Health Education Associates, Inc. 20 Since Currently Recommended Use of MCV4 Vaccines Estimated annual number of cases of serogroups C and Y meningococcal disease Decreased 74% among persons aged 11 through 14 years Decreased 27% among persons aged 15 through 18 years Fitzgerald Health Education Associates, Inc. 21

45 Current MCV4 Vaccine Use Routinely in preteens and teens Additional select populations, see later in program Routine vaccination against meningococcal disease is not recommended for children aged 2 months through 10 years. Fitzgerald Health Education Associates, Inc. 22 Meningococcal Group B Vaccines (Bexero, Trumenba ) Filling in the Meningococcal Coverage Gap Fitzgerald Health Education Associates, Inc. 23 Meningococcal Group B Vaccine (Bexero, Trumenba ) Indication Prevention of invasive disease caused by Neisseria meningitidis serogroup B Coverage for 4 serogroup B strains representative of prevalent strains in USA Accounts for about 1/3 of all invasive N. meningitidis disease diagnosed annually in USA Approved for use in individuals 10 through 25 years of age Fitzgerald Health Education Associates, Inc. 24

46 Meningococcal Group B Vaccine (Bexero, Trumenba ) How delivered? 3-dose series (0.5 ml each) according to 0-, 2-, and 6-month schedule Routinely indicated? Not at this time, consider use in outbreak of meningococcal group B infection Fitzgerald Health Education Associates, Inc. 25 Meningococcal Group B Vaccine (Trumenba ) Guidance on use downloads/interim-guidance.pdf Fitzgerald Health Education Associates, Inc. 26 Additional Candidates for Immunization Against Meningococcal Disease with MCV4 Anticipated travel to a country in the meningitis belt of sub- Saharan Africa or other location of epidemic meningococcal disease, particularly if contact with the local population will be prolonged Fitzgerald Health Education Associates, Inc. 27

47 Additional Candidates for Immunization Against Meningococcal Disease with MCV4 Splenic dysfunction or splenectomy Persistent complement component deficiency Military recruits Planned travel to Mecca, Saudi Arabia, for annual Hajj In presence of community outbreak Fitzgerald Health Education Associates, Inc. 28 For full advisory on meningococcal vaccine, please see Fitzgerald Health Education Associates, Inc. 29 For advisory on meningococcal chemoprophylaxis, please see surv-manual/chpt08-mening.html Fitzgerald Health Education Associates, Inc. 30

48 Another Adult Immunization Recommendation in Select Population Reference at hepb_vaccination.pdf Fitzgerald Health Education Associates, Inc. 31 Hepatitis B Vaccination In unvaccinated adults with diabetes mellitus age years Provide hepatitis B series In unvaccinated adults with diabetes mellitus age=>60 years Consider administering hepatitis B Fitzgerald Health Education Associates, Inc. 32 Why the recommendation? Outbreaks of HBV in long-term care facilities At least 29 HBV outbreaks of HBV with the majority involving adults with diabetes receiving assisted blood glucose monitoring by healthcare professional with responsibility for more than one patient Fitzgerald Health Education Associates, Inc. 33

49 Why the recommendation? Where is HBV found? Stable for long periods lancing devices, blood glucose meters, even when no blood is visible Found in reservoirs of insulin pens Fitzgerald Health Education Associates, Inc. 34 Leading to a change in labeling via FDA mandate that really should not be needed but. Fitzgerald Health Education Associates, Inc. 35 Source: Insulin pens and pens for other injectable diabetes medicines should never be shared among patients, even if the needle is changed. Sharing pens can result in the spread of serious infections from one patient to another. Fitzgerald Health Education Associates, Inc. 36

50 Source: To promote safe use, we are requiring that pens and packaging containing multiple doses of insulin and other injectable diabetes medicines display a warning label stating For single patient use only. Fitzgerald Health Education Associates, Inc. 37 Inhaled Rapid-acting Insulin (Afrezza ) Fitzgerald Health Education Associates, Inc. 38 Insulin inhalation (Exubera ): No Longer Available But why? Fitzgerald Health Education Associates, Inc. 39

51 Insulin inhalation (Exubera ): Inhaler Fitzgerald Health Education Associates, Inc. 40 Inhaled Insulin (Afrezza ) What is it? Rapid-acting insulin with slightly shorter duration of action when compared to aspart, lispro (Humalog, Novolog ) When to use For mealtime insulin when injectable insulin not acceptable Cost=Approximately 2x RAI injectable Fitzgerald Health Education Associates, Inc. 41 Inhaled Insulin (Afrezza ) Do not use with COPD, asthma, lung cancer Current or <6 months quit smokers Bronchospasm risk Special recommendations Spirometry before starting, at 6 months, then annually Discontinue if 20% decline in FEV 1 from baseline Fitzgerald Health Education Associates, Inc. 42

52 PressAnnouncements/ucm htm, Afrezza has a Boxed Warning advising that acute bronchospasm has been observed in patients with asthma and chronic obstructive pulmonary disease (COPD). Afrezza should not be used in patients with chronic lung disease, such as asthma or COPD because of this risk Fitzgerald Health Education Associates, Inc. 43 Inhaled Insulin (Afrezza ) How supplied 4- or 8-unit cartridges Doses greater than this will require multiple cartridges and inhalations Switching from injected mealtime insulin Round up to nearest 4 units and convert unit-per-unit 6 units aspart=8 units inhaled insulin (Afrezza ), 8 units lispro=8 units inhaled insulin (Afrezza ) Fitzgerald Health Education Associates, Inc. 44 Inhaled Insulin (Afrezza ) Review inhalation technique Monitor glucose carefully with transition from one insulin form to another, especially with rounding up dose Fitzgerald Health Education Associates, Inc. 45

53 End of Presentation Thank you for your time and attention. Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC Fitzgerald Health Education Associates, Inc. 46 All websites listed active at the time of publication. Fitzgerald Health Education Associates, Inc. 47

54 Laboratory Monitoring During Drug Therapy Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC President, Fitzgerald Health Education Associates, Inc., North Andover, MA Family Nurse Practitioner, Greater Lawrence (MA) Family Health Center Editorial Board Member The Nurse Practitioner, The Prescriber s Letter, American Nurse Today Member, Pharmacy and Therapeutics Committee Neighborhood Health Plan, Boston, MA Objectives Having completed the learning activities, the participant is able to: Identify the appropriate use of laboratory diagnostics during select drug therapy. Discuss commonly monitored laboratory parameters such a hepatic enzymes, hematologic, and renal parameters and the role of these tests in laboratory monitoring during select drug therapy. Fitzgerald Health Education Associates, Inc. 2 Objectives Having completed the learning activities (cont.): Describe the use of laboratory monitoring for clinical effect and toxicity in select narrow therapeutic index medications. Fitzgerald Health Education Associates, Inc. 3

55 Lab Norms the normal range of serum laboratory test values is defined such that 2.5% of the normal population will have abnormally elevated laboratory values for a given test. Source: Fitzgerald Health Education Associates, Inc. 4 Why is lab monitoring during drug therapy needed? Potential ill effects from medication use Checking for elevated hepatic enzymes in a patient taking a statin or TZD (<0.5-1% likelihood) To see if underlying or comorbid disease worsens Checking renal function in a person with T2DM who is taking metformin Fitzgerald Health Education Associates, Inc. 5 Why is lab monitoring during drug therapy needed? To check for drug levels Checking theophylline or other narrow therapeutic index (NTI) drug level To check for drug effect Checking TSH, INR or drug level Fitzgerald Health Education Associates, Inc. 6

56 72-year-old Man Hx HTN, dyslipidemia, stroke Resides in long-term care facility Develops heart failure with CAP Hospitalized, meds adjusted Now back in your care for followup Fitzgerald Health Education Associates, Inc. 7 Prior to illness Atorvastatin 20 mg daily Lisinopril 40 mg daily HCTZ 12.5 mg daily ASA 81 mg daily 72-year-old Man Current medications Atorvastatin 20 mg daily Lisinopril 40 mg daily Furosemide 40 mg daily Spironolactone 25 mg daily ASA 325 mg daily Fitzgerald Health Education Associates, Inc year-old Man Prior to illness Cr=1.1 mg/dl (97.2 µmol/l) BUN=18 mg/dl (6.4 mmol/l) BUN: Cr=<20:1 K+=4.5 meq/l (4.5 mmol/l) GFR=66 ml/min/1.73 m 2 per NKF calculator Fitzgerald Health Education Associates, Inc. 9

57 72-year-old Man 1 mo post illness Cr=1.5 mg/dl (132.6 µmol/l) BUN=44 mg/dl (15.71 mmol/l) BUN:Cr>20:1 K+=6.3 meq/l (6.3 mmol/l) Fitzgerald Health Education Associates, Inc. 10 Fitzgerald Health Education Associates, Inc. 11 Aldosterone Antagonist: Spironolactone (Aldactone ), Eplerenone (Inspra ) Do not initiate Serum creatinine>2.5 mg/dl (221 µmol/l) in men or >2 mg/dl (176.8 µmol/l) in women or CrCl 30 ml/min (0.50 ml/s) Rationale- Increased risk of hyperkalemia Fitzgerald Health Education Associates, Inc. 12

58 When Adding a K+ Sparing Product in Person on ACEI/ARB Recheck K+ 3 and 7 days after initiation, then q month X 3 mo, then q 3 mo or sooner if clinically indicated Monitor Cr As indicated by clinical comorbid conditions Fitzgerald Health Education Associates, Inc. 13 Monitoring K+ in Person on ACEI/ARB with CKD If initial K+ is >5 meq/l (5 mmol/l) Do not initiate therapy If K+>5.5 meq/l (5.5 mmol/l) Discontinue K+ sparing product or reduce dose Source: Recommended Laboratory Monitoring for Common Medications, Prescriber's Letter; 13(11): Fitzgerald Health Education Associates, Inc. 14 Monitoring K+ in Person on ACEI/ARB with CKD Check K+ and SCr within 1 to 2 weeks of initiation (1 week in elderly) and after dosage increases Recheck in 3 to 4 weeks if stable, then 1-2 times per year or as dictated by patient comorbidities or status change Fitzgerald Health Education Associates, Inc. 15

59 Monitoring K+ in Person on ACEI/ARB without CKD Check K+ 3-4 weeks after initiation Consider K+ monitoring with aliskiren (Tekturna ) Fitzgerald Health Education Associates, Inc. 16 K+ Monitoring with Diuretic Use Loop without K+ sparing medication K+ wasting typically Dose dependent Worse in first weeks of use Check at least weekly for first month Thiazide without K+ sparing medication K+ usually at its lowest point 1 mo after starting or adjusting dose with intact renal function Fitzgerald Health Education Associates, Inc. 17 K+ Monitoring with Diuretic Use Add K+ monitoring Fluid, electrolyte disturbances symptoms particularly with at-risk situations Dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, myalgia, muscle cramps, hypotension, low urine output, rapid heart rate, confusion, seizures, gastrointestinal symptoms (nausea, vomiting) Fitzgerald Health Education Associates, Inc. 18

60 With Diuretic Use Check at Baseline, Monitor Periodically Loop Ca+ wasting Na+ wasting Mg+ wasting K+ wasting Thiazide Ca+ sparing Na+ wasting Mg+ wasting K+ wasting Fitzgerald Health Education Associates, Inc year-old Woman Presents 6 mo hx Increasing fatigue Worsening numbness of hands and feet Health history Type 2 DM, dyslipidemia, HTN, all at treatment goal Fitzgerald Health Education Associates, Inc year-old Woman Presents Current medications (daily doses) Metformin 2 g Glimepiride 4 mg Atorvastatin 20 mg ASA 81 mg Lisinopril 20 mg HCTZ 12.5 mg Fitzgerald Health Education Associates, Inc. 21

61 66-year-old Woman Presents Hg=11.2 g/dl (12-14 g/dl) (112 g/l { g/l}) Hct=33% (36-43%) (0.33 proportion { proportion}) 1:3 Ratio with NL hydration RBC=3.2 million ( mil) Proportionally decreased when compared with H and H Fitzgerald Health Education Associates, Inc year-old Woman Presents MCV=112 fl (81-96 fl) Does RBC size or color change over cell s life span? MCHC=34.8 g/dl (31-37 g/dl) (348 g/l { g/l}) What is the RBC lifespan? RDW=19% ( %) (0.19 proportion { proportion}) New cells different size (likely larger) when compared to old cells Fitzgerald Health Education Associates, Inc year-old Woman Presents Cobalamin=100 pg/ml ( pg/ml) (73.8 pmol/l { pmol/l}) Serum folate=8 ng/ml (3-20 ng/ml) (18 nmol/l { nmol/l}) Drug level, reflects dietary intake over p h Fitzgerald Health Education Associates, Inc. 24

62 66-year-old Woman Presents RBC folate=380 ng/ml (NL= ng/ml) (861 nmol/l { nmol/l}) Incorporated in erythrocytes during cell development, remain unchanged throughout RBC lifespan ( d), not influenced by diet Potentially falsely elevated in person with rapidly developing folate deficiency Also low in about 50% who have vit B12 (cobalamin) deficiency Fitzgerald Health Education Associates, Inc. 25 Vitamin B12 Deficiency and Metformin Use Dose dependent response Each 1 g/day metformin increment nearly triple vitamin B12 deficiency risk (odds ratio: 2.88; 95% CI, , P<0.001) Fitzgerald Health Education Associates, Inc. 26 Vitamin B12 Deficiency and Metformin Use Time dependent response On metformin for =>3 y had 2 X risk compared with those using the drug for less than three years (odds ratio: 2.4; 95% CI, , P=0.001) Source: Ting R Z-W, Szeto CC, Chan M H-M, et al. Risk factors of vitamin B12 deficiency in patients receiving metformin. Arch Intern Med 2006;166: Fitzgerald Health Education Associates, Inc. 27

63 Vitamin B12 Deficiency and Metformin Use Particular risk in vegetarians Adjusted risk of developing vitamin B12 deficiency vegetarians who use metformin =1600% Advice with metformin use Monitor for vitamin B12 deficiency Vitamin B12 and B complex supplementation Source: Ting R Z-W, Szeto CC, Chan M H-M, et al. Risk factors of vitamin B12 deficiency in patients receiving metformin. Arch Intern Med 2006;166: Fitzgerald Health Education Associates, Inc. 28 Pernicious Anemia vs. Vitamin B12 Deficiency due to Metformin Use Pernicious anemia Neurological findings typically more profound including absent DTR More profound anemia More marked macrocytosis Vit B12 deficiency due to metformin use Less profound neurological findings, DTR usually intact Milder anemia More modest macrocytosis Fitzgerald Health Education Associates, Inc. 29 Hepatic testing for what? Do LFTs exist? Is there hepatocellular damage? Alanine aminotransferase (ALT formerly known as SGPT), aspartate aminotransferase (AST, formerly known as SGOT) How severe is the injury? Fitzgerald Health Education Associates, Inc. 30

64 Monitor for, anticipate or avoid B12 deficiency? Monitor Annual vitamin B12 level Anticipate All on metformin receive vitamin B mcg injection annually Avoid Calcium carbonate 1.2 grams daily to correct loose stools associated with metformin therapy Source: Fitzgerald Health Education Associates, Inc. 31 Hepatic testing for what? Do LFTs exist? Is there cholestasis? γ-glutamyltransferase (GGT), alkaline phosphatase (ALP) Fitzgerald Health Education Associates, Inc. 32 Hepatic testing for what? Do LFTs exist? Can the liver synthesize plasma protein? Albumin (longer T ½), prothrombin (shorter T ½, reflected in INR) Perhaps best test of how liver actually functions How is the liver s excretion function? Bilirubin Fitzgerald Health Education Associates, Inc. 33

65 Drug-induced Hepatic Injury Most frequent reason for drug to be withdrawn from market Accounts for >50% cases of acute liver failure in US >75% of cases of idiosyncratic drug reactions result in liver transplantation or death Fitzgerald Health Education Associates, Inc. 34 Drug-induced Hepatic Injury Gender issues In one study, women accounted for 79% of reactions due to acetaminophen, 73% of idiosyncratic drug reactions Elders at particular risk of death from drug-induced hepatic injury Fitzgerald Health Education Associates, Inc. 35 Hepatotoxic Drug Reactions Usual response with moderate-tosevere injury Resembles viral hepatitis Rapid onset malaise, jaundice Elevated aminotransferase levels (=>5 X ULN) Source: Lee, W. Drug-Induced Hepatotoxicity, NEJM, July 31, 2003 Volume 349: Number 5. Fitzgerald Health Education Associates, Inc. 36

66 51-year-old Woman Yellow eyes that developed 1 week post termination of a 5-d course of antimicrobial therapy AST=930 unit/l (0 to 40 unit/l) ALT=730 unit/l (0 to 40 unit/l) GGT=250 unit/l (0 to 60 unit/l) ALP=188 unit/l (25 to 150 unit/l) Total bilirubin level=9.5 mg/dl ( µmol/l) Direct bilirubin level=3.35 mg/dl (57.29 µmol/l) INR=2.51 Fitzgerald Health Education Associates, Inc. 37 ALT=78 unit/l AST=40 unit/l ALT>AST GGT=32 unit/l ALP=155 unit/l MCV=82 fl What is the difference? NAFLD vs. AFLD ALT=50 unit/l AST=90 unit/l AST>ALT GGT=103 unit/l ALP=225 unit/l MCV=104 fl Fitzgerald Health Education Associates, Inc. 38 Antiepileptic Drug Use When should therapeutic levels be checked? Initial dose titration To establish target level in patient with good control and few adverse effects Suspected toxicity Starting or stopping an interacting drug Diseases or physiologic changes Poor control Fitzgerald Health Education Associates, Inc. 39

67 Does this apply to all AEDs? Narrow therapeutic index Phenytoin Carbamazepine Oxcarbazepine Valproate Wider therapeutic index Topiramate Gabapentin Fitzgerald Health Education Associates, Inc. 40 If AED Levels are Needed Check just before a dose is due Trough level If toxicity is suspected Consider checking peak level of rapidly absorbed, short T ½ drugs Carbamazepine at 6 to 8 hrs post-dose Valproic acid 1 to 4 hrs post-dose Divalproex 3 to 5 hrs post-dose Fitzgerald Health Education Associates, Inc. 41 True or false? Carbamazepine s T ½ when patients first take the medication is about h. Due to microsomal enzyme autoinduction, carbamazepine s T ½ is shorter (about h) in patients who take the medication more than 4 weeks. Fitzgerald Health Education Associates, Inc. 42

68 True or false? Carbamazepine induces the metabolism of other anticonvulsant drugs such as phenytoin, clonazepam, primidone, valproic acid, and ethosuximide, potentially causing levels of these medications to drop. Fitzgerald Health Education Associates, Inc. 43 True or false? The concurrent use of certain CYP450 inhibitors such as erythromycin, clarithromycin, and cimetidine results in an increase in carbamazepine levels. Fitzgerald Health Education Associates, Inc. 44 Hemopoiesis

69 22-year-old Well Woman on Anticonvulsant Hg=9.1 g/dl (91 g/l) Hct=28% (0.28 proportion) RBC=2.8 million ( ) Platelets=75 K ( K) Fitzgerald Health Education Associates, Inc year-old Well Woman on Anticonvulsant MCV=81 fl (81-99) NL size MCHC=34.8 g/dl (31-37) (348 g/l { }) NL color RDW=12.1% ( %) (0.121 proportion { }) New cells similar size to old cells Retics=1.8% (0.018 proportion) Fitzgerald Health Education Associates, Inc year-old Well Woman on Anticonvulsant WBC=3,300 ( K) Neutrophils=48% (60) Lymphs=40% (30) Eos=7% (6) Monos=4% (3) Baso=1% (1) Fitzgerald Health Education Associates, Inc. 48

70 Select Anticonvulsant Therapy: Recommended Monitoring CBC with WBC and platelets With carbamazepine use, due to bone marrow suppression potential Baseline, monthly for 2 or 3 months, then at least every two years Fitzgerald Health Education Associates, Inc. 49 Mechanism of Drug-induced Thrombocytopenia With isolated thrombocytopenia Likely caused by accelerated platelet destruction by drug-dependent, platelet-reactive antibodies With other cytopenias Look for underlying, unifying process such as aplastic anemia Fitzgerald Health Education Associates, Inc. 50 Thrombocytopenia 50, ,000 mm 3 (50, , /L) No bleeding risk 20,000-50,000 mm 3 (20,000-50, /L) Minor spontaneous or post op bleeding 5,000-20,000 mm 3 (5,000-20, /L) Potential for serious bleed <5,000 mm 3 (5, /L) Serious bleeding risk Fitzgerald Health Education Associates, Inc. 51

71 Drug-induced Thrombocytopenia UF heparin Less with LMWH Sulfonamides Thiazide diuretics Cimetidine Quinine Vancomycin Phenytoin Carbamazepine ẞ-lactams Cephalosporins, PCN Digoxin Valproic acid Fitzgerald Health Education Associates, Inc. 52 Drug-induced Thrombocytopenia Withdraw the agent Increase in platelet count typically seen in 2-7 days Fitzgerald Health Education Associates, Inc. 53 References Recommended lab monitoring for common medications. Pharmacist's Letter/Prescriber's Letter, Detail Document #300610, available at prescribersletter.therapeuticresearch.com Ferri, F. (2014) Ferri s Best Test: A practical guide to clinical laboratory medicine and diagnostic imaging (3d. ed). Philadelphia: Elsevier Mosby Available at fhea.com Fitzgerald Health Education Associates, Inc. 54

72 End of Presentation Thank you for your time and attention. Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC Fitzgerald Health Education Associates, Inc. 55 All websites listed active at the time of publication. Fitzgerald Health Education Associates, Inc. 56

73 Uncommon Drug Reactions: The zebra in your exam room Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC President, Fitzgerald Health Education Associates, Inc., North Andover, MA Family Nurse Practitioner, Greater Lawrence (MA) Family Health Center Editorial Board Member The Nurse Practitioner, The Prescriber s Letter, American Nurse Today Member, Pharmacy and Therapeutics Committee Neighborhood Health Plan, Boston, MA Objectives Upon completion of this session, the participant will be able to: Identify the risk factors for select uncommon drug reactions. Describe the clinical presentation of select uncommon drug reactions. Develop an initial plan of care for patients presenting with select drug reactions. Fitzgerald Health Education Associates, Inc. 2 A 56-year-old Man Longstanding hx HTN, dyslipidemia Current meds Lisinopril HCTZ Atorvastatin Presents with a 2-h hx increasing swelling of the tongue and lips Fitzgerald Health Education Associates, Inc. 3

74 ACEI-induced Angioedema Fitzgerald Health Education Associates, Inc. 4 Well demarcated, non-pitting edema that occurs as large erythematous areas in skin, subcutaneous tissues With ACEI use, mouth, tongue involved What is angioedema? Fitzgerald Health Education Associates, Inc. 5 ACEI-induced Angioedema Bramante RM, Rand M. N Engl J Med 2011;365:e4. Fitzgerald Health Education Associates, Inc. 6

75 Angioedema Risk with ACEI Use: Risk factors Several risk factors Not clearly established History of idiopathic angioedema Head and neck surgery Allergy to seafood African ancestry Male gender Source: Fitzgerald Health Education Associates, Inc. 7 ACEI-induced Angioedema Mechanism of reaction Not fully understood Likely bradykinin associated Not true allergic reaction No testing to predict who will have this reaction Can occur at any time during ACEI therapy Fitzgerald Health Education Associates, Inc. 8 ACEI-induced Angioedema As with standard angioedema Remove precipitating drug, if present Attention to airway patency Antihistamine Epinephrine Systemic corticosteroid Route dictated by degree of upper airway obstruction Source: Fitzgerald Health Education Associates, Inc. 9

76 How long will ACEI-induced angioedema last? Improves With acute treatment Full resolution Related to T½ of the offending medication Lisinopril, trandolapril=up to 3 days Captopril=1 2 days Fitzgerald Health Education Associates, Inc. 10 ARB: An acceptable substitute? ARB-related angioedema Reported 0.1% of ARB users Unclear if cross reaction Not considered safe ACEI alternative Fitzgerald Health Education Associates, Inc. 11 A 12-year-old with a 72-hour History of R-sided Otalgia Physical exam reveals bright red nonmobile TM, otherwise unremarkable Parent and child desire antimicrobial therapy Fitzgerald Health Education Associates, Inc. 12

77 A 12-year-old with a 72-hour History of R-sided Otalgia Past history Generally well, UTD with IZ Allergies Rash from amoxicillin when she was a baby. Went away in a couple of days. Parents deny difficulty breathing during rash, cannot recall how rash looked Fitzgerald Health Education Associates, Inc. 13 Antimicrobial to use to treat AOM with this history? A penicillin form? A macrolide? A cephalosporin? Questions? Fitzgerald Health Education Associates, Inc. 14 Type I Hypersensitivity Reaction AKA immediate or anaphylactic hypersensitivity Reaction involves preferential production of IgE in response to certain antigens (allergens) such as medications Fitzgerald Health Education Associates, Inc. 15

78 Type I Hypersensitivity Reaction Usually involves skin (urticaria eczema), eyes (conjunctivitis), nasopharynx (rhinorrhea, rhinitis), bronchopulmonary tissues (wheeze, cough) and/or GI tract (gastroenteritis) Fitzgerald Health Education Associates, Inc. 16 Type II Hypersensitivity Clinical manifestations Drug-induced hemolytic anemia, granulocytopenia, thrombocytopenia Fitzgerald Health Education Associates, Inc. 17 The Amoxicillin Drug Rash AKA amoxicillin-induced morbilliform rash Usually maculopapular rash, not particularly itchy Generally will start a number of days into therapy, often after 1 week of therapy Fitzgerald Health Education Associates, Inc. 18

79 The Amoxicillin Drug Rash Etiology Delayed cell-mediated immune reaction Not considered a true allergic reaction Future PCN use possible Fitzgerald Health Education Associates, Inc. 19 AAP Clinical Practice Guideline: The Diagnosis and Management of Acute Otitis Media Source: /content/131/3/e964.short Fitzgerald Health Education Associates, Inc. 20 Recommended Antibacterial Agents in AOM Temp 39 C ( F) or severe Otalgia No Yes At diagnosis for patients being treated initially with antibacterial agents OR clinically defined treatment failure at hours after initial management with observation option Recommended Amoxicillin mg/kg/day in 2 divided doses Amoxicillin-clavulanate 90 mg/kg/day of amoxicillin with 6.4 mg/kg/day of clavulanate [amoxicillin to clavulanate ratio, 14:1] in 2 divided doses Alternative for Penicillin Allergy Cefdinir (14 mg/kg per date in 1 or 2 doses) Cefuroxime (30 mg/kg per day in 2 divided doses) Cefpodoxime (10 mg/kg per day in 2 divided doses) Ceftriaxone (50 mg IM or IV per day for 1 or 3 d)

80 Recommended Antibacterial Agents in AOM Temp 39 C ( F) or severe Otalgia No Yes Clinically defined treatment failure at hours after initial management with antibacterial agents Recommended Alternative for Penicillin Allergy Amoxicillin-clavulanate 90 mg/kg/day of amoxicillin component with 6.4 mg/kg/day of clavulanate in 2 divided doses Ceftriaxone (50 mg IM or IV for 3 d) Ceftriaxone 3 days Clindamycin (30 40 mg/kg per day in 3 divided doses), with or without third generation cephalosporin Clindamycin (30 40 mg/kg per day in 3 divided doses), plus third generation cephalosporin Tympanocentesis, consult specialist Cross allergy of PCN to cephalosporins? How would you Prescribe Cephalosporins to Patients with Penicillin Allergies? FHEA News, Volume XII, Issue VIII, Page 13 Available at ter/fheanews_volume12_issue8.pdf Fitzgerald Health Education Associates, Inc year-old Woman Briefly hospitalized 2 d for a soft tissue infection, discharged yesterday, I and D done, wound now packed, draining, states she has not have a fever 24 h, wound less painful Culture=MRSA Fitzgerald Health Education Associates, Inc. 24

81 45-year-old Woman Concomitant health problems Migraine uses sumatriptan 3 6 tabs to manage this problem on a monthly basis Perimenopausal symptoms with hot flashes during week prior to menses, using a natural product to minimize vasomotor symptoms PMS, taking a robin s egg blue pill for 2 weeks prior to menses for last 3 months, finds this very helpful Fitzgerald Health Education Associates, Inc year-old Woman Newly added medicine when hospitalized A really strong and expensive antibiotic, was given IV now on same product PO Was told to report daily for wound checks for the next few days Fitzgerald Health Education Associates, Inc year-old Woman: Today s evaluation Hx I feel really jittery. I started having diarrhea last night. Afebrile, AP=110 BPM, RR=24 BPM, BP=140/95 mmhg I and D site with less redness and drainage Fitzgerald Health Education Associates, Inc. 27

82 PE General 45-year-old Woman: Today s evaluation Alert, cooperative, slightly tremulous PERLA, pupil size 5 mm bilateral Fundi WNL Neck Thyroid NL, carotids with brisk upstroke, no bruit Fitzgerald Health Education Associates, Inc year-old Woman: Today s evaluation PE (cont.) Cardiac Regular rhythm, no S3, S4, or extra systoles Chest No crackles or wheezing Fitzgerald Health Education Associates, Inc year-old Woman: Today s evaluation PE(cont.) Abdomen=+SL hyperactive bowel sounds, mild diffuse tenderness without rigidity, guarding or rebound Reflexes=2+ upper extremities, 4+ lower extremities Limb pulses, strength, sensation intake Fitzgerald Health Education Associates, Inc. 30

83 45-year-old Woman: Today s evaluation This patient s findings are most likely the result of: A. Impending sepsis. B. MRSA endotoxin production. C. A drug-drug interaction. D. Another health problem not mentioned here. Fitzgerald Health Education Associates, Inc. 31 What else? Additional health history? Additional labs or other diagnostics? Fitzgerald Health Education Associates, Inc year-old Woman: Today s Evaluation In asking her about the natural medicine, you discover that it contains: A. Kava kava. B. St. John s wort. C. Soy. D. Vitamin B6. Fitzgerald Health Education Associates, Inc. 33

84 45-year-old Woman: Today s evaluation In asking her about the prescription medicine for her PMS, you discover that it contains: A. Fluoxetine. B. Diazepam. C. Progesterone. D. Ethinyl estradiol. Fitzgerald Health Education Associates, Inc. 34 Spectrum of Clinical Findings in Serotonin Syndrome Boyer E and Shannon M. N Engl J Med 2005;352: Fitzgerald Health Education Associates, Inc. 35 Findings in a Patient with Moderately Severe Serotonin Syndrome Boyer E and Shannon M. N Engl J Med 2005;352: Fitzgerald Health Education Associates, Inc. 36

85 Intervention in Serotonin Syndrome Mildly ill Hyperreflexia, tremor, afebrile Supportive care Removal of precipitating drugs Benzodiazepines Source: Boyer E and Shannon M. N Engl J Med 2005;352: Fitzgerald Health Education Associates, Inc. 37 Intervention in Serotonin Syndrome Moderately ill Aforementioned findings, fever, cardiorespiratory abnormalities Aggressive correction of cardiorespiratory and thermal abnormalities Administration of 5-HT2A antagonists such as cyproheptadine (Periactin ) with a dose range=12 32 mg/24h so that up to 95% of serotonin receptor sites are occupied Source: Boyer E and Shannon M. N Engl J Med 2005;352: Fitzgerald Health Education Associates, Inc. 38 Linezolid PI DI Caution (Zyvox ) Coadministration of selective serotonin reuptake inhibitors and adrenergic drugs should be avoided because of central nervous system toxicity. Mechanism Reversible, nonselective inhibitor of monoamine oxidase Fitzgerald Health Education Associates, Inc. 39

86 A patient is on SSRI and needs linezolid. Is this a potential lifethreatening problem? What is the T½ of the SSRI? How many drug-free T½ would be needed prior to starting linezolid? Fitzgerald Health Education Associates, Inc. 40 Jason, 22-year-old 1-week hx intermittent frontal HA, photophobia, nausea, mild sore throat, body aches Really no better, might be getting worse. Tylenol does not help any more. Also weird noise in my ears, like a pumping or swishing sound Denies vomiting, fever, stiff neck Fitzgerald Health Education Associates, Inc. 41 Jason, 22-year-old Health history No recent or remote head trauma, no recent travel, noncontributory except for acne, using minocycline 6 mo Social history Cigarette use=5 pk-yr hx, currently smoking ½ PPD, smokes marijuana on the weekends, rare alcohol use, denies other substance use Fitzgerald Health Education Associates, Inc. 42

87 Jason, 22-year-old T=98.6 F (37 C), P=60 BPM, RR=16, BP=102/52 mmhg Cardiac, respiratory, abdomen=wnl Skin=Without unusual rash or lesions, a few papular acne lesions Fitzgerald Health Education Associates, Inc. 43 Jason, 22-year-old Neuro Alert but irritable, photophobic CN 2 12 intact, nuchal rigidity absent, DTR= +2/4 bilaterally with down going toes, no sensory defects, gait and balance NL Fitzgerald Health Education Associates, Inc. 44 Jason, 22-year-old Bilateral Papilledema Fitzgerald Health Education Associates, Inc. 45

88 Idiopathic Intracranial Hypertension What is it? AKA pseudotumor cerebri, benign intracranial hypertension Increased intracranial pressure in absence of brain tumor Variety of causes Fitzgerald Health Education Associates, Inc. 46 Idiopathic Intracranial Hypertension (IIH): Etiology Medication-induced High-dose vitamin A Vitamin A derivative such as isotretinoin Long-term tetracycline therapy Minocycline, doxycycline Combined oral contraceptives Obesity Potent risk factor Fitzgerald Health Education Associates, Inc. 47 IIH: Diagnostics Major diagnostic aim Rule out other causes of ICP Neuroimaging MRI or CT Lumbar puncture Diagnostic to rule in/out meningitis Treatment with temporary relief of symptoms Fitzgerald Health Education Associates, Inc. 48

89 IIH: Treatment Removal of offending medication Osmotic diuretic Acetazolamide (Diamox ) Surgical intervention Rarely indicated, largely when vision loss appears likely Fitzgerald Health Education Associates, Inc. 49 Reference Digre, K. Not so benign intracranial hypertension; Condition needs to be diagnosed before patients develop visual symptoms, available at articles/pmc / Fitzgerald Health Education Associates, Inc. 50 Information from an FDA Advisory: Phenytoin, fosphenytoin sodium, and carbamazepine associated with potential increased risk of serious skin reactions Fitzgerald Health Education Associates, Inc. 51

90 FDA Table of Pharmacogenomic Biomarkers in Drug Labels Available at areas/pharmacogenetics/ucm htm Fitzgerald Health Education Associates, Inc. 52 What is the reaction? Toxic epidermal necrolysis (TEN) Life-threatening skin disorder characterized by mucocutaneous reaction with widespread erythema, necrosis, epidermal and mucosal bullous detachment of the epidermis End result=skin exfoliation and resulting sepsis. With mucous membrane involvement, respiratory failure, GI bleed, ocular and GU complications Fitzgerald Health Education Associates, Inc. 53 Clinical Images of Patients With Toxic Epidermal Necrolysis Sheridan, R. L. et al. N Engl J Med 2005;353:

91 What is the reaction? Stephen-Johnson syndrome A TEN variant Fitzgerald Health Education Associates, Inc. 55 Reaction to Phenytoin with a Positive Nikolsky s Sign Fitzgerald Health Education Associates, Inc. 56 Who is at risk for these reactions? According to FDA advisory Note with phenytoin therapy in Asian patients positive for a particular human leukocyte antigen (HLA) allele, HLA- B*1502 HLA complex helps immune system distinguish the body's own proteins from proteins made by foreign invaders including bacteria and viruses. Fitzgerald Health Education Associates, Inc. 57

92 Who is at risk for these reactions? Presence of this genetic variation Occurs almost exclusively in patients with ancestry across broad areas of Asia, including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais, up to 10 15% of this population Uncommon in other south Asians, Japanese, Koreans Fitzgerald Health Education Associates, Inc. 58 Is this seen in other ethnic groups? With other alleles? The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P= ). Source: HLA-A*3101 and Carbamazepine-Induced Hypersensitivity Reactions in Europeans, N Engl J Med 2011; 364: Fitzgerald Health Education Associates, Inc. 59 Testing for the condition? HLA-B*1502 allele testing Recommendations to test at-risk ethnic groups prior to initiating therapy with these medications Fitzgerald Health Education Associates, Inc. 60

93 Is this a disease state? Not abnormal or a marker of a disease state Simply agenetic variation noted in aforementioned ethnic groups No other known risk from having the allele Fitzgerald Health Education Associates, Inc. 61 Other medication use implicated? Avoid use of the following in individual positive for this genetic variation Fosphenytoin, prodrug converted to phenytoin after administration Carbamazepine, as TEN noted in this risk group as well but continues to be investigated Fitzgerald Health Education Associates, Inc. 62 Time frame for the reaction? Discontinue drug in at-risk individual? With carbamazepine use >90% have this reaction within first few months of treatment Long-term users who have not developed these problems considered low risk for future development of this reaction Similar observation with phenytoin use Fitzgerald Health Education Associates, Inc. 63

94 FDA Table of Pharmacogenomic Biomarkers in Drug Labels Includes list of medication with pharmacogenomic warnings in prescribing information Currently approximately 100 medications on list Antiretrovirals, cancer chemotherapy, cardiovascular, psychiatric/neurological medications most often listed. Fitzgerald Health Education Associates, Inc. 64 References Ferri, F. (2014) Ferri s Best Test: A Practical Guide to Clinical Laboratory Medicine and Diagnostic Imaging, 3 rd Edition, St. Louis: Elsevier Health Sciences. Available at fhea.com Fitzgerald Health Education Associates, Inc. 65 End of Presentation Thank you for your time and attention. Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC cs@fhea.com Fitzgerald Health Education Associates, Inc. 66

95 All websites listed active at the time of publication. Fitzgerald Health Education Associates, Inc. 67

96 Hypertension Update: The latest treatment recommendations from JNC-8 Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC President, Fitzgerald Health Education Associates, Inc., North Andover, MA Family Nurse Practitioner, Greater Lawrence (MA) Family Health Center Editorial Board Member The Nurse Practitioner, The Prescriber s Letter, American Nurse Today Member, Pharmacy and Therapeutics Committee Neighborhood Health Plan, Boston, MA Objectives Upon completion of the learning activity the participant will be able to: Describe the clinical consequences of hypertension. Identify antihypertensive medications with compelling indications for use with select patients. Discuss JNC-8 Guidelines for treatment of hypertension. Fitzgerald Health Education Associates, Inc Evidence-based Guideline for the Management of High BP in Adults: Report from the Panel Members Appointed to the Eighth Joint National Committee (JNC-8) Source: The Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA. Doi: /jama Fitzgerald Health Education Associates, Inc. 3

97 BP=HR (Heart Rate) X SV (Stroke Volume) X PR (Peripheral Resistance, Also Known as Peripheral Vascular Resistance {PVR}) Peripheral Resistance Cardiac Output Age (years) 80 Fitzgerald Health Education Associates, Inc. 4 Definition of Hypertension Normal Prehypertension Hypertension <120/80 mm Hg / mm Hg 140/90 mm Hg Definition of HTN unchanged from through JNC-1, JNC-2, JNC-3, JNC-4, JNC-5, JNC-6, JNC-7, JNC-8 (one exception) Fitzgerald Health Education Associates, Inc. 5 HTN: A Complex Disease with a Core Defect of Vascular Dysfunction that Leads to Select Target Organ Damage (TOD) Treating HTN Goal=Reach BP goal while minimizing risk of HTN TOD Fitzgerald Health Education Associates, Inc. 6

98 HTN TOD Brain Stroke Vascular (multiinfarct) dementia Fitzgerald Health Education Associates, Inc. 7 HTN TOD Eye HTN retinopathy with risk of blindness Fitzgerald Health Education Associates, Inc. 8 HTN TOD Kidney HTN nephropathy Renal failure Fitzgerald Health Education Associates, Inc. 9

99 HTN TOD Cardiovascular system Atherosclerosis MI LVH HF Fitzgerald Health Education Associates, Inc. 10 Hypertension TOD: Atrial Fibrillation HTN=Major AF development risk factor New onset of AF approx 2% per year age =>65 years Evidence that HTN control prevents its development/recurrence Fitzgerald Health Education Associates, Inc. 12

100 Establishing the Diagnosis of HTN Fitzgerald Health Education Associates, Inc. 13 Key to Effective Practice: An Accurate BP Measurement =>2 measurements per visit Auscultatory method preferred Patient seated comfortably for =>5 minutes with back supported, feet on floor, arm supported in horizontal position BP cuff at heart level Technique for home or clinic Fitzgerald Health Education Associates, Inc. 14 Key to Effective Practice: An Accurate BP Measurement BP cuff size Covers more than 80% of upper arm Cuff s bladder approximately 40% of arm circumference Use of too small cuff can lead to a falsely elevated BP Source: Fitzgerald Health Education Associates, Inc. 15

101 Key to Effective Practice: An Accurate BP Measurement Additional measure Measured with patient standing for 1-3 minutes to evaluate for postural hypotension or hypertension Fitzgerald Health Education Associates, Inc. 16 When to initiate pharmacologic therapy, establishing treatment goals per JNC-8 Fitzgerald Health Education Associates, Inc. 17

102 Recommendations for Management of Hypertension General population<60 years of age Initiate pharmacologic treatment to lower BP at DBP 90 mmhg and treat to a goal DBP<90 mmhg, lower BP at SBP 140 mmhg and treat to a goal SBP<140 mmhg. Grade A evidence for ages years, Grade E evidence for ages years Fitzgerald Health Education Associates, Inc. 19 Recommendations for Management of Hypertension General population=>60 years of age (cont.) Threshold to start meds=150/90 mmhg (Grade A) BP goal with treatment goal SBP<150 mmhg and goal DBP<90 mmhg (Grade A) Yields reduction in stroke, HF, CHD Fitzgerald Health Education Associates, Inc. 20 Recommendations for Management of Hypertension Diabetes mellitus=>18 years of age Start pharmacologic treatment to lower BP at SBP 140 mmhg or DBP 90 mmhg and treat to this goal Expert opinion Grade E Insufficient evidence to support a lower threshold (or goal) based on outcomes Fitzgerald Health Education Associates, Inc. 21

103 Recommendations for Management of Hypertension Chronic kidney disease (CKD) =>18 years of age Start pharmacologic treatment to lower BP at SBP 140 mmhg or DBP 90 mmhg, treat to goal SBP<140 mmhg and goal DBP<90 mmhg Expert opinion Grade E Fitzgerald Health Education Associates, Inc. 22 Are there benefits of additional lowering BP? In adults<60 years of age DBP 90 mmhg based on evidence that DBP<85 or 80 mmhg=no additional benefit noted In adults=>60 years of age Lowering to <140/<90 mmhg showed no additional benefit, compared to or mmhg Fitzgerald Health Education Associates, Inc. 23 What if already at lower BP with current therapy? In general population Treatment is well tolerated without adverse effects to QoL (quality of life). Treatment does not need to be adjusted. Expert opinion Grade E Fitzgerald Health Education Associates, Inc. 24

104 JNC-7 vs JNC-8: Medication Recommendations JNC-7 5 drug classes to be considered as initial therapy, thiazide-type diuretics as initial therapy for most patients without compelling indication for another class, dose ranges mentioned JNC-8 4 specific medication classes and doses based on RCT evidence, racial, CKD, and diabetic subgroups, created table of drugs and doses used in the outcome trials Fitzgerald Health Education Associates, Inc. 25 How many medications? When BP is >20/10 mmhg above goal, consideration should be given to starting with 2 drugs. Fitzgerald Health Education Associates, Inc. 26 References Blood pressure reduction, persistence and costs in the evaluation of antihypertensive drug therapy, available at Combination therapy versus monotherapy in reducing blood pressure: Meta-analysis on 11,000 participants from 42 trials, available at Fitzgerald Health Education Associates, Inc. 27

105 The Major AntiHTN Drug Groups ACE-I, ARB CCB Thiazide-like diuretics Thiazide diuretics (HCTZ) chlorthalidone, indapamide Fitzgerald Health Education Associates, Inc. 28 The Major AntiHTN Drug Groups Why these drug classes? Comparable outcomes, particularly in general population Grade B evidence (moderate amount) Lower overall death rates Improved CV (with exception of heart failure), cerebrovascular, renal outcomes Fitzgerald Health Education Associates, Inc. 29 Ethnic Differences in Cardiovascular Drug Response: Potential Contribution of Pharmacogenetics Drug category Mean BP reduction (SBP/DBP) White-Black difference Whites Blacks Diuretics 11.5/ / /-1.5 CCBs 15.3/ / /-0.6 β-blockers 11.7/ / /2.9 ACEI/ARB 12.8/ / /3.0 Source: Fitzgerald Health Education Associates, Inc. 30

106 Fitzgerald Health Education Associates, Inc. 31 How often should you titrate medication? If goal BP is not reached within a month of treatment, increase the dose of the initial drug or add a second drug from one of the classes in recommendations. Expert opinion Grade E Fitzgerald Health Education Associates, Inc. 32 Dosing for Antihypertensive Drugs Per JNC-8, medications should be dosed adequately to achieve results similar to those seen in RCTs. These RCTs excluded certain patient groups including individuals with established CVD, heart failure. Fitzgerald Health Education Associates, Inc. 33

107 Effect of Adding BP Medications vs. Increasing Single Drug Comparison of our results with those of a published meta-analysis of different doses of the same drug showed that doubling the dose of 1 drug had approximately one fifth of the equivalent incremental effect (0.22 [95% CI, ]). Source: Fitzgerald Health Education Associates, Inc. 34 Medication Thiazide-like diuretics Examples- HCTZ, chlorthalidone, indapamide MOA- Low volume sodium depletion that leads to PVR reduction BP=HR x SV x PVR Comment Thiazide diuretic use is an independent risk factor of T2DM development. Monitor for K+, Na+, Mg+ depletion. Calcium sparing. Elders particularly sensitive to hyponatremia induced by thiazide diuretic use. Fitzgerald Health Education Associates, Inc. 35 Antihypertensive medication Chlorthalidone (Hygroton ) Hydrochlorothiazide (HydroDiuril ) Indapamide (Lozol ) Thiazide-type Diuretics Initial daily dose, mg Target dose in RCTs, mg/d No. of doses per day a a Current recommended evidence-based dose that balances efficacy and safety is mg daily. Fitzgerald Health Education Associates, Inc. 36

108 Thiazide Diuretic Use Less effective when GFR<30 ml/min/1.73 m 2 Loop diuretics will likely remain effective. Be vigilant for evidence of overdiuresis in older adult. Postural hypotension, BUN: Cr ratio=>20 Fitzgerald Health Education Associates, Inc. 37 K+ Monitoring with Diuretic Use Thiazide without K+ sparing medication K+ usually at its lowest point 1 mo after starting or adjusting dose Loop without K+ sparing medication K+ wasting typically Dose dependent Worse in first weeks of use Check at least weekly for first month Fitzgerald Health Education Associates, Inc. 38 Renin-angiotensin Cascade: What works where? Angiotensinogen Non-renin (e.g. tpa) Angiotensin I Non-ACE (e.g. chymase) Angiotensin II Renin ACE Bradykinin Inactive peptides AT 1 AT 2 AT n

109 Medication Angiotensin converting enzyme inhibitors (ACEI) ACEI examples- Lisinopril, enalapril, all with pril suffix Angiotensin receptor blockers (ARB) ARB examples- Losartan, telmisartan, all with sartan suffix Comments Adjust dose in renal insufficiency. Do not use in presence of bilateral renal artery stenosis. Hyperkalemia risk, especially with inadequate fluid intake, excessive diuresis, when used with aldosterone antagonist. Fitzgerald Health Education Associates, Inc. 40 Medication MOA- Attenuate angiotensin II (Ag II, a potent vasoconstrictor that stimulates adrenal catecholamine release) effect by minimizing its production (ACEI) or blocking its action (ARB) BP=HR x SV x PVR (without increase in HR, SV) Comments ACEI-induced cough- Can use ARB as alternative. Angioedema risk with ACEI use, less so with ARB use Do not use during pregnancy (category D). Fitzgerald Health Education Associates, Inc. 41 ACE Inhibitors Antihypertensive medication Initial daily dose, mg/d Target dose in RCTs reviewed, mg/d No. of doses per day Captopril Enalapril Lisinopril Abbreviations: ACE, angiotensin-converting enzyme; RCT, randomized controlled trial.. Fitzgerald Health Education Associates, Inc. 42

110 Angiotensin Receptor Blockers Antihypertensive medication Initial daily dose, mg Target dose in RCTs reviewed, mg No. of doses per day Eprosartan Candesartan Losartan Valsartan Irbesartan Abbreviations: ACE, angiotensin-converting enzyme; RCT, randomized controlled trial. Fitzgerald Health Education Associates, Inc. 43 Monitoring K+ in Person on ACEI/ARB with CKD Check K+ and SCr within 1 to 2 weeks of initiation (1 week in elderly) and after dosage increases Recheck in 3 to 4 weeks if stable, then 1-2 times per year or as dictated by patient comorbidities or status change Fitzgerald Health Education Associates, Inc. 44 Per JNC-8 ACEI or ARB improves kidney outcomes for patients with CKD. This recommendation applies to CKD patients with and without proteinuria, as studies using ACEIs or ARBs showed evidence of improved kidney outcomes in both groups. Fitzgerald Health Education Associates, Inc. 45

111 Medication Calcium channel blockers (CCB) Dihydropyridine (DHP) examples- Amlodipine, felodipine, others, all with -ipine suffix NonDHP CCB examples- Diltiazem, verapamil MOA- Causes vasodilatation BP=HR x SV x PVR Comment Use with caution in presence of heart failure, renal or hepatic impairment. NonDPH=CYP4503A4 inhibitors, potential for drug-drug interaction Fitzgerald Health Education Associates, Inc. 46 Calcium Channel Blockers Antihypertensive medication Initial daily dose, mg Target dose in RCTs reviewed, mg No. of doses per day Amlodipine Diltiazem extended release Abbreviations: ACE, angiotensin-converting enzyme; RCT, randomized controlled trial. a Current recommended evidence-based dose that balances efficacy and safety is mg daily. Fitzgerald Health Education Associates, Inc. 47 What does this mean in practice? 58-year-old African-American man with T2DM, HTN and dyslipidemia, BP=170/105 mmhg Clear need for 2+ meds JNC-7=Thiazide, ACEI, CCB BP goal=<130/<80 mmhg JNC-8=Thiazide, ACEI, CCB BP goal=<140/<90 mmhg Fitzgerald Health Education Associates, Inc. 48

112 What does this mean in practice? 66-year-old woman of European ancestry with HTN, BP=162/92 mmhg Possible control with 1 med JNC-7=Thiazide as 1 st line, BB, ACEI, CCB as 2d line Goal BP<140/<90 mmhg JNC-8=Thiazide, ACEI, CCB BP goal=<150/<90 mmhg Fitzgerald Health Education Associates, Inc. 49 Beta blockers as a 4 th line therapy? Fitzgerald Health Education Associates, Inc. 50 Meta-analysis Results: Beta Blockers in Uncomplicated HTN Stroke Significantly higher with beta blockers than with other antihtn (relative risk, 1.16; 95% CI, ) Most problematic w/ atenolol than w/ other non-beta blocker antihtn (RR, 1.26; 95% CI, ) Fitzgerald Health Education Associates, Inc. 51

113 Source Lindholm LH et al. Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005 Oct 29; 366: Fitzgerald Health Education Associates, Inc. 52 Beta Blockers Antihypertensive medication Initial daily dose, mg Target dose in RCTs reviewed, mg No. of doses per day Atenolol Metoprolol Abbreviations: ACE, angiotensin-converting enzyme; RCT, randomized controlled trial. a Current recommended evidence-based dose that balances efficacy and safety is mg daily. Fitzgerald Health Education Associates, Inc. 53 Aldosterone antagonist as a 4 th line drug? Fitzgerald Health Education Associates, Inc. 54

114 Medication Comment Aldosterone antagonist Hyperkalemia risk, Examples: Spironolactone particularly w/ ACEI, ARB (Aldactone ), eplerenone use or volume depletion, (Inspra ) including excessive MOA: Block effects of diuresis. Most often used aldosterone, therefore in heart failure treatment. better regulating of Na+ Gynecomastia risk with and water homeostasis prolonged use and maintenance of Use with caution in intravascular volume renal impairment, BP=HR x SV x PVR especially when GFR<30 ml/min/1.73 m 2 Fitzgerald Health Education Associates, Inc. 55 Anticipated BP Response with Spironolactone Use SBP reduction 22 mmhg DBP reduction 10 mmhg Average dose 25 mg per day Fitzgerald Health Education Associates, Inc. 56 You start a patient on spironolactone who is also on an angiotensin-converting enzyme inhibitor. You advise the patient to return in 4 weeks to check which of the following laboratory parameters? Fitzgerald Health Education Associates, Inc. 57

115 Why not check the labs sooner? A. Sodium B. Calcium C. Potassium D. Chloride Fitzgerald Health Education Associates, Inc. 58 Per JNC-8: Medications that are not Mentioned Centrally-acting agents Clonidine, methyldopa Direct renin inhibitor Aliskiren Fitzgerald Health Education Associates, Inc. 59 Conclusion Fitzgerald Health Education Associates, Inc. 60

116 End of Presentation Thank you for your time and attention. Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC Fitzgerald Health Education Associates, Inc. 61 All websites listed active at the time of publication. Fitzgerald Health Education Associates, Inc. 62

117 Dyslipidemia: The latest treatment recommendations Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC President, Fitzgerald Health Education Associates, Inc., North Andover, MA Family Nurse Practitioner, Greater Lawrence (MA) Family Health Center Editorial Board Member The Nurse Practitioner, The Prescriber s Letter, American Nurse Today Member, Pharmacy and Therapeutics Committee Neighborhood Health Plan, Boston, MA Fitzgerald Health Education Associates, Inc. 1 Objectives Having completed the learning activities, the participant will be able to: Identify the ACC/AHA recommendations for the treatment of dyslipidemia. Describe the classification of dyslipidemia goals per ACC/AHA. Fitzgerald Health Education Associates, Inc. 2 Objectives Having completed the learning activities, the participant will be able to: (cont.) Discuss select considerations in prescribing lipid-lowering therapies. Fitzgerald Health Education Associates, Inc. 3

118 Dyslipidemia Treatment Recommendations Stone NJ, Robinson J, Lichtenstein AH, et al. ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol Available at a.full.pdf Fitzgerald Health Education Associates, Inc. 4 Comparing the Guideline: How many adults are eligible for treatment? ATP-3=48.5 million adults ACC/AHA=56.7 million adults Fitzgerald Health Education Associates, Inc. 5 ATP3 vs. ACC/AHA Guidelines Moderate- or high-intensity statin therapy Individuals who fall into 4 categories No specific LDL cholesterol goals Rather degree of LDL cholesterol reduction with statin therapy Measure lipids during follow-ups Not to assess achievement of given LDL goal but rather adherence to therapy Fitzgerald Health Education Associates, Inc. 6

119 ACC/AHA Dyslipidemia Guidelines High- and moderateintensity statin treatment emphasized Low-intensity statin therapy nearly eliminated Fitzgerald Health Education Associates, Inc. 7 ACC/AHA Dyslipidemia Guidelines Atherosclerotic cardiovascular disease (ASCVD) broadly defined Includes stroke, coronary heart disease and peripheral arterial disease Fitzgerald Health Education Associates, Inc. 8 ACC/AHA Dyslipidemia Guidelines Nonstatin therapies deemphasized No guidelines provided for treating high triglyceride levels This program will cite separate recommendations on this issue later in program. Fitzgerald Health Education Associates, Inc. 9

120 Potential Limitations of ACC/AHA Guidelines Potential for overtreatment, particularly in elder Potential for under-treatment, particularly in elevated LDL-C whose 10-year ASCVD risk is less than 7.5% because of younger age Fitzgerald Health Education Associates, Inc. 10 Potential Limitations of ACC/AHA Guidelines Does not address patients younger than age 40 or older than 75 years Family history of ASCVD, triglyceride levels not considered Fitzgerald Health Education Associates, Inc. 11 AHA/ACC Disclaimer The results and recommendations provided by this application are intended to inform but do not replace clinical judgment. Therapeutic options should be individualized and determined after discussion between the patient and their care provider. Fitzgerald Health Education Associates, Inc. 12

121 CVD Risk Estimator Calculator from ACC/AHA Guidelines Available at Fitzgerald Health Education Associates, Inc. 13 HMG CoA Reductase Inhibitors: The Statins Simvastatin (Zocor ), atorvastatin (Lipitor ), pravastatin (Pravachol ), pitavastatin (Livalo ), others Fitzgerald Health Education Associates, Inc. 15

122 Mechanism of Action HMG-CoA Reductase Inhibitor: The Statins Inhibitor of HMG-CoA reductase Enzyme responsible for conversion of HMG-CoA to mevalonate, and decreases hepatic biosynthesis of cholesterol As a result Hepatocytes compensate by increasing the number of LDL surface receptors to increase LDL reuptake from the circulation. End result is reduction of serum LDL concentration. Fitzgerald Health Education Associates, Inc. 16 HMG CoA Reductase Inhibitor Check hepatic enzymes prior to initiation to establish baseline. No further routine hepatic enzyme monitoring warranted during statin use. Serious liver injury due to statins is usually idiosyncratic and not prevented with routine monitoring. Fitzgerald Health Education Associates, Inc. 17 HMG CoA Reductase Inhibitor T2DM risk is slightly increased with statin use, particularly with more potent statin in higher dose. Cardiovascular benefit outweighs small risk. Cognitive impairment while on statin rarely reported. If occurs, consider lowering dose or try another statin. Fitzgerald Health Education Associates, Inc. 18

123 Clinical Scenarios Fitzgerald Health Education Associates, Inc year-old Woman of European Ancestry with HTN and T2DM Total cholesterol: 185 mg/dl (4.8 mmol/l) HDL cholesterol: 35 mg/dl (0.9 mmol/l) Systolic blood pressure: 139 mm Hg Smoker: No 10-year ASCVD risk=11.5% Fitzgerald Health Education Associates, Inc. 20 Fitzgerald Health Education Associates, Inc. 21

124 High-intensity statin therapy examples LDL-C reduction approx. 50% Moderate-intensity statin therapy examples LDL-C reduction approx % Low-intensity statin therapy examples LDL-C reduction approx. <30% Daily dose Atorvastatin (40 )-80 mg Rosuvastatin mg Daily dose Atorvastatin mg Rosuvastatin 5-10 mg Simvastatin mg Pravastatin mg Lovastatin 40 mg Daily dose Pravastatin mg Lovastatin 20 mg *Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. Biologic basis for a less-than-average response possible. Evidence from 1 RCT only: Down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Incremental decrease through Aggressive Lipid Lowering study) Fitzgerald Health Education Associates, Inc year-old Woman with HTN and DM of Other Ancestry 10-year ASCVD risk=11.5% Unchanged from white designation Might underestimate risk for persons from some race/ethnic groups, Native American, south Asian ancestry, and some Latinos (Puerto Ricans), and might overestimate risk for others, including east Asian ancestry and Mexican Americans Fitzgerald Health Education Associates, Inc year-old Man of European Ancestry with HTN, T2DM Race: White/other Total cholesterol: 220 mg/dl (5.7 mmol/l) HDL cholesterol: 51 mg/dl (1.3 mmol/l) Systolic blood pressure: 122 mm Hg Smoker: Yes 10-year ASCVD risk=31.8% Fitzgerald Health Education Associates, Inc. 24

125 Fitzgerald Health Education Associates, Inc year-old African American Man, No DM, Nonsmoker Total cholesterol: 180 mg/dl (4.7 mmol/l) HDL cholesterol: 28 mg/dl (0.7 mmol/l) SBP: 148 mm Hg Hypertension treatment: No 10-year ASCVD risk=16.1% High intensity statin therapy recommended Fitzgerald Health Education Associates, Inc. 26 With a 68-year-old African American Man Add smoking 16.1% risk becomes 26.2% risk Take away smoking, add DM 16.1% becomes 28.4% risk Add smoking and DM 16.1% becomes 43.9% risk Fitzgerald Health Education Associates, Inc. 27

126 55-year-old White Woman with HTN, No DM, Nonsmoker Total cholesterol: 230 mg/dl (6 mmol/l) HDL: 55 mg/dl (1.4 mmol/l) SBP: 146 mm Hg, on meds Calculated 10-yr risk of ASCVD: 4% Fitzgerald Health Education Associates, Inc. 28 Fitzgerald Health Education Associates, Inc. 29 Additional Factors Considered in Dyslipidemia Therapy Moderate intensity statin therapy advised In individuals for whom after quantitative risk assessment a riskbased treatment decision is uncertain, additional factors may be considered to inform treatment decision making. Fitzgerald Health Education Associates, Inc. 30

127 Additional Factors Considered in Dyslipidemia Therapy LDL-C 160 mg/dl (4.1 mmol/l) Evidence of genetic hyperlipidemias Family history of premature ASCVD Onset <55 years of age in a first degree male relative or <65 years of age in a first degree female relative Fitzgerald Health Education Associates, Inc. 31 Additional Factors Considered in Dyslipidemia Therapy hs-c-reactive protein 2 mg/l CAC score 300 Agatston units or 75 th %tile for age, sex, ethnicity CAC=Coronary Artery Calcium Ankle-brachial index<0.9 Elevated lifetime risk of ASCVD Fitzgerald Health Education Associates, Inc. 32 Two 73-year-olds with Established ASCVD Male, GFR=84 ml/min/1.73 m2, BMI=27 kg/m2 Female, GFR=48 ml/min/1.73 m2, BMI=22 kg/m2 Fitzgerald Health Education Associates, Inc. 33

128 Fitzgerald Health Education Associates, Inc. 34 Individuals at Risk for Statin Adverse Effects Multiple or serious comorbidities, including impaired renal or hepatic function History of previous statin intolerance or muscle disorders History of hemorrhagic stroke Fitzgerald Health Education Associates, Inc. 35 Individuals at Risk for Statin Adverse Effects Unexplained ALT elevations>3 times ULN >75 years of age Asian ancestry Fitzgerald Health Education Associates, Inc. 36

129 Definitions National Lipid Association (NLA) Myopathy=Symptoms of myalgia in addition to an elevation in serum creatine kinase (CK) greater than 10 times the upper limit of normal (CK >10 ULN) Also known as myositis Fitzgerald Health Education Associates, Inc. 37 Statin-induced Myopathy Risk >50% FDA Reported=Drug-drug Interaction Risk Statins alone Usually in higher doses in advancing age (>75 years), particularly with renal impairment Select statins and interacting medications All due to CYP450 3A4 inhibition Lova-, simva-, atorvastatin=cyp450 3A4 substrates Cyclosporine Select oral antifungals Itraconazole, ketoconazole Fitzgerald Health Education Associates, Inc. 38 Statin-induced Myopathy Risk >50% FDA Reported=Drug-drug Interaction Risk Select statins w interacting medications Macrolides Erythromycin, clarithromycin but not azithromycin Select HIV protease inhibitors Select calcium channel blockers Amiodarone Grapefruit juice ingestion Fitzgerald Health Education Associates, Inc. 39

130 Simvastatin: When Compared to Ingestion with Water as Control With grapefruit juice C max and AUC increased 12.0-fold (P<0.001) and 13.5-fold (P<0.001) 24 hours after last grapefruit juice C max and AUC increased 2.4-fold (P<0.01) and 2.1-fold (P<0.001) 7 days after last grapefruit juice dose No change Source: Fitzgerald Health Education Associates, Inc. 40 CYP450 Substrates CYP450 3A4 Atorvastatin Lovastatin Simvastatin CYP450 2C9 Pitavastatin Rosuvastatin Not metabolized by CYP450 Pravastatin Fitzgerald Health Education Associates, Inc. 41 Recommendations for Managing Common Difficulties During Statin Therapy Per ACC/AHA Dyslipidemia Guidelines Fitzgerald Health Education Associates, Inc. 42

131 Statin Therapy During Mild to Moderate Muscle Symptoms Mild to moderate muscle symptoms develop during statin therapy In absence of clinically significant increase in serum creatine kinase Discontinue statin until the symptoms can be evaluated. Fitzgerald Health Education Associates, Inc. 43 Statin Therapy with Mild to Moderate Muscle Symptoms Evaluate for other conditions that increase the risk for muscle symptoms. Hypothyroidism Reduced renal or hepatic function Rheumatologic disorders such as polymyalgia rheumatica, steroid myopathy Vitamin D deficiency Primary muscle diseases Fitzgerald Health Education Associates, Inc. 44 Statin Therapy with Mild to Moderate Muscle Symptoms If muscle symptoms resolve off statin and no contraindication Start lower dose of same statin. Monitor for return of symptoms. Fitzgerald Health Education Associates, Inc. 45

132 Statin Therapy with Mild to Moderate Muscle Symptoms If symptoms return Discontinue current statin. Start low dose of another statin. Titrate up dose slowly to goal, monitoring for symptom recurrence. Fitzgerald Health Education Associates, Inc. 46 Statin Therapy with Mild to Moderate Muscle Symptoms Persistent symptoms for =>2 months post discontinuation of statin therapy Myalgia and/or elevated CK levels Consider cause other than statininduced myopathy. Fitzgerald Health Education Associates, Inc. 47 Therapeutic Options in Statin Intolerance in the Absence of Myopathy/ Myositis Source: An Update on Statin Alternatives and Adjuncts, Matthew J Sorrentino, Clin Lipidology. 2012;7(6): Fitzgerald Health Education Associates, Inc. 48

133 Options in Statin-intolerance Consider following options Every-other-day statin therapy Anecdotal evidence of helpfulness Aim for weekly total dose vs. getting some rather than no statin on board? Favors longer T½ statins Atorvastatin, rosuvastatin Fitzgerald Health Education Associates, Inc. 49 Options in Statin-intolerance Most commonly reported Myalgia without CK rise Use of more hydrophilic/less lipophilic statin Rosuvastatin, pravastatin most hydrophilic Simvastatin, lovastatin most lipophilic Other medications if statin use impossible Fitzgerald Health Education Associates, Inc. 50 The AIM-HIGH Investigators The role of niacin in raising high-density lipoprotein cholesterol to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally treated lowdensity lipoprotein cholesterol rationale and study design. The Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: Impact on global health outcomes (AIM-HIGH). Am Heart J 2011; 161: PL Detail-Document, Niacin: Who needs it? Pharmacist s Letter/Prescriber s Letter. February Fitzgerald Health Education Associates, Inc. 51

134 Niacin: AIM-HIGH The AIM-HIGH study goal To determine if a niacin/statin combination could further reduce the risk of cardiovascular events in patients with cardiovascular disease and wellcontrolled LDL but low HDL and high triglycerides vs a statin alone Fitzgerald Health Education Associates, Inc. 52 Niacin: AIM-HIGH Primary outcome measure Time from randomization to first CHD death, nonfatal MI, ischemic stroke, acute coronary syndrome hospitalization, or symptoms requiring coronary or cerebral revascularization (exclusive of revascularization of restenosis) Fitzgerald Health Education Associates, Inc. 53 Niacin: AIM-HIGH Interim analysis Demonstrated lack of benefit of simva/ niacin vs simva alone Small increase in ischemic stroke in the combination group (1.6% vs 0.7%) 1/3 of individuals in stroke group had discontinued niacin=>2 mo prior to stroke. 9 of the 28 stroke patients in the combination group had stopped taking niacin 2 months to 4 years prior to stroke. Fitzgerald Health Education Associates, Inc. 54

135 What to make of AIM-HIGH results? Coronary Drug Project study Prestatin study where most of niacin s advantage was seen AIM-HIGH Subjects with LDL well-controlled on and HPS2-THRIVE studies had well-controlled Fitzgerald Health Education Associates, Inc. 55 What to make of AIM-HIGH results? Statin non-ldl benefits Decreased inflammation Inability to lower CV risk further Beyond known reduction from statins HDL often have to be very low to get a benefit from niacin. Fitzgerald Health Education Associates, Inc. 56 Evaluation and Treatment of Hypertriglyceridemia: A Endocrine Society Clinical Practice Guideline Available at Fitzgerald Health Education Associates, Inc. 57

136 Classifying Hypertriglyceridemia Mild to moderate elevation Mild=triglycerides= mg/dl ( mmol/l) Moderate= mg/dl ( mmol/l) Risk factor for CVD Fitzgerald Health Education Associates, Inc. 58 Classifying Hypertriglyceridemia Severe and very severe elevation Severe=triglycerides= mg/dl ( mmol/l) Very severe=2000+ mg/dl (22.6+ mmol/l) Risk factor for acute pancreatitis Fitzgerald Health Education Associates, Inc. 59 Treatment Options in Hypertriglyceridemia Niacin Given results of AIM-HIGH and other studies, fibrates preferred Fibric acid derivatives (fibrates) Fenofibrate, fenofibric acid Gemfibrozil use not recommended Likely leader for triglyceride lowering Fitzgerald Health Education Associates, Inc. 60

137 Per ACC/ AHA Recommendations Fenofibrate With low- or moderate-intensity statin only if benefits from ASCVD risk reduction or when triglycerides are >500 mg/dl (5.65 mmol/l), are judged to outweigh the potential risk for adverse effects. Evidence E (Expert opinion) Fitzgerald Health Education Associates, Inc. 61 End of Presentation Thank you for your time and attention. Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC cs@fhea.com Fitzgerald Health Education Associates, Inc. 62 References John F. Keaney, Jr., M.D., Gregory D. Curfman, M.D., And John A. Jarcho, M.D. A Pragmatic View Of The New Cholesterol Treatment Guidelines. N Engl J Med 2014; 370: Fitzgerald Health Education Associates, Inc. 63

138 References Stone Nj, Robinson J, Lichtenstein Ah, Bairey Merz Cn, Lioyd-jones Dm, Blum Cb, Mcbride P, eckel Rh, Schwartz Js, Goldberg Ac, Shero St, Gordon D, Smith Sc Jr, Levy D, Watson K, Wilson Pw ACC/AHA Guideline On The Treatment Of Blood Cholesterol To Reduce Atherosclerotic Cardiovascular Risk In Adults: A Report Of The American College Of Cardiology/American Heart Association Task Force On Practice Guidelines. J Am Coll Cardiol Nov 7. Pii: S Fitzgerald Health Education Associates, Inc. 64 All websites listed active at the time of publication. Fitzgerald Health Education Associates, Inc. 65

139 Pharmacokinetics (PK), Pharmacodynamics (PD): In the choice of the best medication for a given patient Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC President, Fitzgerald Health Education Associates, Inc., North Andover, MA Family Nurse Practitioner, Greater Lawrence (MA) Family Health Center Editorial Board Member The Nurse Practitioner Journal, The Prescribers Letter, American Nurse Today Member, Pharmacy and Therapeutics Committee Neighborhood Health Plan, Boston, MA Objectives Having completed the learning activities, the participant will be able to: Identify principles of safe prescribing. Identify the basic principles of drug absorption, distribution, and elimination and their relationship to clinical pharmacokinetics. Fitzgerald Health Education Associates, Inc. 2 Objectives Having completed the learning activities (cont.): Recall the importance of drug bioavailability, T ½, clearance, steady state concentrations, T max, and AUC (area under the curve) in clinical pharmacokinetics drug interactions. Fitzgerald Health Education Associates, Inc. 3

140 Key Pharm Principles Fitzgerald Health Education Associates, Inc. 4 Pharmacology Defined The study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes. Source: Katzung, 2014 Fitzgerald Health Education Associates, Inc. 5 Pharmacodynamics (PD) Study of biochemical and physiological effects of drugs What the drug does to the body and/ or disease Fitzgerald Health Education Associates, Inc. 6

141 Pharmacodynamics: True or false? The pharmacodynamic profile of a medication is unchanged over the lifespan. Fitzgerald Health Education Associates, Inc. 7 Pharmacokinetics (PK) What the body does to the drug Includes Absorption Distribution Biotransformation (metabolism) Excretion of drugs Fitzgerald Health Education Associates, Inc. 8 Pharmacokinetics: True or false? Age and gender significantly impact a medication s pharmacokinetics. Fitzgerald Health Education Associates, Inc. 9

142 Fick s Law The tendency for molecules to move in the direction from higher concentration to lower concentration via random molecular motion Typically occurs across a membrane or other permeable barrier Fitzgerald Health Education Associates, Inc. 10 Examples of These Permeable Membranes Blood-brain Mammary Placenta Cell membrane Vessels Fitzgerald Health Education Associates, Inc. 11 Absorption Principles Passive diffusion From area of higher to lower concentration Most common form of drug diffusion Fitzgerald Health Education Associates, Inc. 12

143 Absorption Facilitated diffusion Passive process where solutes still move down concentration gradient Fitzgerald Health Education Associates, Inc. 13 Absorption Principles Why can t the following drugs be given orally? Even if you can protect the med from GI ph Unfractionated heparin MW=40,000-50,000 d Insulin MW=5,500 d LWMH MW=8,000 d Fitzgerald Health Education Associates, Inc. 14 For Oral Drug Absorption Proper molecular weight <1000, most daltons Lipid soluble substance To pass through gut wall Fitzgerald Health Education Associates, Inc. 15

144 For Oral Drug Absorption Small intestine functional Due to large surface area, major point of GI absorption Fitzgerald Health Education Associates, Inc. 16 Other Routes of Absorption (An issue we will revisit) GI tract Inhalation Sublingual Intranasal Rectal Intrathecal Parenteral Topical Intravascular Subcutaneous Transdermal Intramuscular Fitzgerald Health Education Associates, Inc. 17 Area Under the Curve (AUC) Area under the plot of drug plasma concentration against time after a single dose drug administration Fitzgerald Health Education Associates, Inc. 18

145 T max, C max T max Time to maximum drug level observed C max Maximum or peak concentration of a drug observed after its administration Clinical significance? Fitzgerald Health Education Associates, Inc. 19 AUC Single Dose of Glyburide Fitzgerald Health Education Associates, Inc. 20 Immediate vs. Sustained Release Morphine Fitzgerald Health Education Associates, Inc. 21

146 Insulin Effect Insulin PK Curves What is potential problem when insulin is at C max? Intermediate (NPH) adapted from R. Bergenstal, IDC Rapid (Lispro, glulisine, aspart) Short (Regular) Hours Long (Detemir, Glargine) Fitzgerald Health Education Associates, Inc. 22 You see a woman with a chief complaint of dysmenorrhea. You can give her one, dose appropriate tablet of any of the following: Which is the best choice? A. Naproxen (Naprosyn ) B. Naproxen sodium (Aleve, Anaprox ) C. Enteric coated naproxen Fitzgerald Health Education Associates, Inc. 23 In Healthy Volunteers Time to C max of naproxen forms Naproxen sodium=1 h Naproxen=1.9 h EC naproxen=4 h Fitzgerald Health Education Associates, Inc. 24

147 Volume of Distribution Total amount of drug in body Drug blood concentration Distribution of a medication between plasma and rest of body; the volume in which the amount of drug would need to be uniformly distributed to produce the observed blood concentration Fitzgerald Health Education Associates, Inc. 25 Factors Influencing Volume of Distribution Aging Less free water, more body fat even with unchanged weight Hydration status Lower circulating and interstitial fluid volume=less water distribution Fitzgerald Health Education Associates, Inc. 26 Factors Influencing Volume of Distribution Compartment and volume Total body water (0.6 L/Kg) Small, water soluble such as ethanol Extracellular water (0.2 L/Kg) Larger water soluble molecules such as gentamicin Fitzgerald Health Education Associates, Inc. 27

148 Factors Influencing Volume of Distribution Compartment and volume (cont.) Blood and plasma Strongly protein-bound molecules Warfarin, carbamazepine, phenytoin Large molecules Heparin (MW=>5000 d) Fitzgerald Health Education Associates, Inc. 28 Factors Influencing Volume of Distribution Compartment and volume (cont.) Fat ( L/kg) Highly lipid soluble molecules such as benzos, PCP, THC Think of meds that can be found in toxicologic testing for a number of days or weeks p last use. Bone (0.07 L/kg) Ions such as lead, fluoride Pb found in adult bone decades after last ingestion as a child Fitzgerald Health Education Associates, Inc. 29 Summary of Age-related Changes % body weight as water Adults age y Adult age y 60% 53% Lean muscle mass Baseline =>20% reduction % body weight as fat 26-33% (women) 18-20% (men) Serum albumin (average) 38-45% (women) 36-38% (men) 4.7 g/dl (47 g/l) 3.8 g/dl (38 g/l) Relative kidney weight 100% 80% Relative hepatic 100% 55-60% blood flow Source: Katzung, BG. (2014) Basic and Clinical Pharmacology 13th ed.) New York: Lange Medical Books/ McGraw-Hill. Fitzgerald Health Education Associates, Inc. 30

149 How Drugs Cross Cell Membranes Passive diffusion Across the gradient Water-soluble via aqueous channels in cell membrane Lipid-soluble through the membrane itself Fitzgerald Health Education Associates, Inc. 31 How Drugs Cross Cell Membranes Active transport Active movement of a drug or ion across a membrane against its concentration gradient This requires energy. Saturable Affected by competitive inhibitors Fitzgerald Health Education Associates, Inc. 32 Fitzgerald Health Education Associates, Inc. 33

150 Clearance Volume of body fluid from which the chemical is completely removed by biotransformation and/or excretion Renal clearance=water soluble Hepatic clearance=fat soluble Fitzgerald Health Education Associates, Inc. 34 What does the body want to do to drugs? Hang on to these foreign substances? Get rid of the invader as quickly as possible? Fitzgerald Health Education Associates, Inc. 35 Biotransformation Sites Primary Liver Less active but clinically important GI tract Lung Skin Kidney Fitzgerald Health Education Associates, Inc. 36

151 150 lb, 67 (68 kg, 170 cm), 45-year-old, 1 Male, 1 Female Who has Larger liver? More hepatic enzymes? Larger kidneys? More body fat? More lean muscle? Fitzgerald Health Education Associates, Inc lb, 67 (68 kg, 170 cm), 45-year-old, 1 Male, 1 Female One exercises One is sedentary Does this influence drug metabolism? Distribution? Biotransformation? Fitzgerald Health Education Associates, Inc. 38 Medications Parent Drug to Metabolite Amitriptyline ---> nortriptyline Codeine ---> morphine Primidone ---> phenobarbital Valacyclovir ---> acyclovir Fitzgerald Health Education Associates, Inc. 39

152 Clopidogrel Activation Fitzgerald Health Education Associates, Inc. 40 First Pass Effect Biotransformation and/or excretion of oral drug by hepatic mechanisms prior to entering GI tract then are transported to interact with receptors in target tissues Fitzgerald Health Education Associates, Inc. 41 First Pass Effect (AKA Presystemic Elimination) Drugs absorbed from the GI tract pass through the portal venous system then through the liver and finally into the systemic circulation. Extensive hepatic metabolism/ extraction result in minimal drug delivery to the systemic circulation for certain agents. Fitzgerald Health Education Associates, Inc. 42

153 First Pass Effect: True or false? Drugs with large first pass effect exhibit significant differences in pharmacological effects comparing oral vs. IV administration. Fitzgerald Health Education Associates, Inc. 43 Compare Oral vs. Parenteral Dose Sumatriptan Oral= mg Parenteral=6 mg Transdermal=6.5 mg Levofloxacin (CAP dose) Oral=750 mg Parenteral=750 mg Fitzgerald Health Education Associates, Inc. 44 True or false? Regardless of route of administration, all medications undergo first pass effect. Fitzgerald Health Education Associates, Inc. 45

154 Other Routes of Absorption: What is role of first pass effect? GI tract Sublingual Rectal Parenteral Intravascular Subcutaneous Intramuscular Inhalation Intranasal Intrathecal Topical Transdermal Fitzgerald Health Education Associates, Inc. 46 T ½ Time required for the amount of drug in the body to be reduced or eliminated by ½ Also known as elimination or biological T ½ 3-5 T ½ needed to reach steady state 3-5 drug-free T ½ needed to eliminate drug from body Fitzgerald Health Education Associates, Inc. 47 What % is left of original drug dose? 1 T ½ 50% left 2 T ½ 50% of 50%=25% left 3 T ½ 50% of 50% of 50%=12.5% left 4 T ½ 50% of 50% of 50% of 50%=6.25% left 5 T ½ 50% of 50% of 50% of 50% of 50%=3.125% left Fitzgerald Health Education Associates, Inc. 48

155 True or false? The T ½ of a medication is a predictable number regardless of the patient s age, gender, and overall state of health. Fitzgerald Health Education Associates, Inc. 49 Clinical Examples Levothyroxine T ½=7 d Average for euthyroid state, longer if hypothyroid, shorter if hyperthyroid 5 T ½=35 d Penicillin T ½=1-2 h 5 T ½=5-10 h Fitzgerald Health Education Associates, Inc. 50 Zaleplon Zolpidem Sonata Ambien 1 2 T ½ (hours) Triazolam Halcion 3 Eszopiclone Lunesta Temazepam Restoril 6 11 Estazolam Quazepam Prosom Doral Flurazepam Dalmane All brand names are the property of their respective owners. Dikeos DG, Soldatos. Prim Care Companion J Clin Psychiatry.. Lunesta PI.. 74 Fitzgerald Health Education Associates, Inc. 51

156 Does drug effect exceed 3-5 T ½? Aspirin T ½=0.25 h Effect on platelet function 8-9 d Fitzgerald Health Education Associates, Inc. 52 Bioavailability Percent of dose enter systemic circulation after administration of a given dosage form Lower bioavailability Simvastatin Higher bioavailability Atorvastatin Fitzgerald Health Education Associates, Inc. 53 Statin vs. Statin McTaggart F, et al. Am J Cardiol. 2001;87(suppl):28B-32B. T ½ Bioavailability Rosuvastatin 20 h 20% Simvastatin 1-2 h <5% Atorvastatin 14 h 14% Pravastatin 1-2 h 17% Fitzgerald Health Education Associates, Inc. 54

157 Statin vs. Statin LDL Lowering at Various Doses ( Lova Mevacor 20 mg=29% 40 mg=31% 80 mg=48% Prava Pravachol 10 mg=19% 20 mg=29% 40 mg=34% 80 mg=48% Simva Zocor 10 mg=28% 20 mg=35% 40 mg=40% 80 mg=48% Fluva Lescol 20 mg=17% 40 mg=23% 80 mg=33% Atorva Lipitor 10 mg=38% 20 mg=46% 40 mg=51% 80 mg=54% Rosuva Crestor 5 mg=43% 10 mg=50% 20 mg=53% 40 mg=62% Pitava Livalo 1 mg=30% 2 mg=36% 4 mg=45% Fitzgerald Health Education Associates, Inc. 55 Which statins are best taken at dinner or bedtime? Which statins can be taken anytime of day? Why? Fitzgerald Health Education Associates, Inc. 56 Bioavailability Dependent on Route of Administration IV 100% IM, SC % PO 5% to nearly 100% Hepatic first-pass effect, incomplete absorption Fitzgerald Health Education Associates, Inc. 57

158 Bioavailability Dependent on Route of Administration Rectal % Lost drug Inhalation 5-100% Lost drug Transdermal % Fitzgerald Health Education Associates, Inc. 58 Factors Influencing Ability for Medication to be Delivered Transdermally Molecular weight<1000 daltons ph range 5-9 in aqueous medium No histamine-releasing action Relatively low daily drug requirement Fitzgerald Health Education Associates, Inc. 59 Hormonal Contraception Daily Dose Ortho Evra Norelgestromin 150 mcg Metabolite of norgestimate EE 20 mcg Ortho Tri-Cyclen Norgestimate 0.25 mg 3d phase EE 35 mcg Fitzgerald Health Education Associates, Inc. 60

159 Ortho Evra Warning it has been found that users of ethinyl estradiol/norelgestromin (Ortho Evra ) are exposed to about 60% more total estrogen in their blood than if they were taking a typical birth control pill containing 35 micrograms of estrogen. However, the highest blood level of estrogen (peak blood levels) is about 25% lower with ethinyl estradiol/norelgestromin (Ortho Evra ) than with typical birth control pills. Fitzgerald Health Education Associates, Inc. 61 Does that make any sense? Patch 3 days to reach therapeutic level Levels remain steady until removed Oral Series of peaks and troughs Rapid decline during pill-free week Fitzgerald Health Education Associates, Inc. 62 Majority of drugs exhibit their effect via an interaction with a macromolecule or receptor site. Site of Drug Action Fitzgerald Health Education Associates, Inc. 63

160 Receptor Sites Proteins that selectively allow a substance to bind and cause action Receptor site characteristics Electrical charge Size Shape Fitzgerald Health Education Associates, Inc. 64 Where is the target receptor site? Beta-1 One heart Beta-2 Airways to two lungs Two arms, two legs Alpha-1 Vascular bed Fitzgerald Health Education Associates, Inc. 65 Agonist Binds to a receptor, causes an effect similar to endogenous compound Name reflects receptor Beta-2 adrenergic agonist Examples- Albuterol, salmeterol, others Fitzgerald Health Education Associates, Inc. 66

161 Agonist Example Decongestants Alpha-1, beta-1, beta-2 agonist Fitzgerald Health Education Associates, Inc. 67 Antagonist Endogenous regulatory compound action blocked by drug Name reflects receptor Beta-1 adrenergic antagonist Fitzgerald Health Education Associates, Inc. 68 All drugs referred to as blockers Alpha-1 adrenergic Doxazosin Beta-1 adrenergic Atenolol Non selective B-1, B-2 adrenergic Propranolol Examples Fitzgerald Health Education Associates, Inc. 69