Objectives Having completed the learning activities, the participant is able to: Laboratory Diagnostics: A focus on monitoring during drug therapies

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1 Laboratory Diagnostics: A focus on monitoring during drug therapies 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 is able to: Identify the appropriate use of laboratory testing as part of the clinical evaluation process during select drug therapy. Discuss the clinical utility of commonly ordered hematologic, renal, hepatic laboratory parameters during select drug therapy. 2 Objectives Having completed the learning activities (cont.): Identify the appropriate use of laboratory testing as part of the evaluation process of the person during select drug therapy. 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: 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 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 5 6 All rights reserved. Reproduction is prohibited. 1

2 72 Yo 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 follow up Prior to illness Atorvastatin 20 mg daily Lisinopril 40 mg daily HCTZ 12.5 mg daily ASA 81 mg daily 72 Yo Man Current medications Atorvastatin 20 mg daily Lisinopril 40 mg daily Furosemide 40 mg daily Spironolactone 25 mg daily KCl 40 meq BID ASA 325 mg daily Yo Man 72 Yo 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 m2 per NKF calculator 1 mo p 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) 9 10 Aldosterone Antagonist: Spironolactone (Aldactone ), Eplerenone (Inspra ) Mechanism of action Block effects of aldosterone therefore better regulating Na+ and water homeostasis and maintenance of intravascular volume Angiotensin II acts on adrenal cortex, causing it to release aldosterone, hormone that causes kidneys to retain sodium and lose potassium 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 12 All rights reserved. Reproduction is prohibited. 2

3 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 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): 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 Monitoring K+ in Person on ACEI/ARB without CKD Check K+ 3-4 weeks after initiation Consider K+ monitoring with aliskiren (Tekturna ) 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 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 All rights reserved. Reproduction is prohibited. 3

4 6 mo hx Increasing fatigue Worsening numbness of hands and feet Health history Type 2 DM, dyslipidemia, HTN, all at treatment goal Current medications (daily doses) Metformin 2 g Glimepiride 4 mg Atorvastatin 20 mg ASA 81 mg Lisinopril 20 mg HCTZ 12.5 mg Hg=11.2 g/dl (12-14 g/dl) (112 g/l { g/l}) Hct=33% (36-43%) (0.33 proportion { proportion}) 1: Ratio with NL hydration RBC=3.2 million ( mil) Proportionally decreased when compared with H and H 21 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 22 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 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 All rights reserved. Reproduction is prohibited. 4

5 Potentially falsely elevated in person with rapidly developing folate deficiency Also low in about 50% who have vit B12 (cobalamin) deficiency 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) 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: 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: Atypical Antipsychotics: Metabolic Monitoring Examples Aripiprazole (Abilify ), clozapine (Clozaril ), olanzapine (Zyprexa ), paliperidone (Invega ), quetiapine (Seroquel ), risperidone (Risperdal ), ziprasidone (Geodon ) Do atypical antipsychotic agents directly increase DM risk? Reported at International Society for Pharmacoepidemiology meeting 19,878 veterans with thought disorders treated with older typical antipsychotics or newer atypical antipsychotics for a period of three years All rights reserved. Reproduction is prohibited. 5

6 Do atypical antipsychotic agents directly increase DM risk? Reported at International Society for Pharmacoepidemiology meeting (cont.) Adjusted hazard ratios for DM risk Olanzapine (HR 1.50, 95% CI ) Risperidone (HR 1.47, 95% CI ) Quetiapine (HR 1.54, 95% CI ) Source: Palacioz K. Atypical antipsychotics and diabetes. Therapeutic Research Center. Pharmacist's Letter/Prescriber's Letter;19: Atypical Antipsychotics: Metabolic Monitoring Fasting glucose in absence of DM Baseline, at 12 weeks to four months, then annually Check more frequently if high diabetes risk Monitor patients with diabetes regularly for worsening glucose control Atypical Antipsychotics: Metabolic Monitoring Fasting lipid profile Baseline, at 12 weeks, then every two to every five years if normal More frequently if clinically indicated Reports of increased LDL, triglycerides, total cholesterol 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? Hepatic testing for what? Do LFTs exist? Is there cholestasis? γ-glutamyltransferase (GGT), alkaline phosphatase (ALP) Hepatic testing for what? Do LFTs exist? Can the liver synthesize plasma protein? Albumin (longer T ½, prothrombin (shorter T ½) Perhaps best test of how liver actually functions How is the liver s excretion function? Bilirubin All rights reserved. Reproduction is prohibited. 6

7 What is the difference? Drug-induced Hepatic Injury ALT=78 unit/l AST=40 unit/l ALT>AST GGT=32 unit/l ALP=155 unit/l MCV=82 fl ALT=50 unit/l AST=90 unit/l AST>ALT GGT=103 unit/l ALP=225 unit/l MCV=104 fl 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 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 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 Mr. S. is a 44-year-old man. Presents for a sick visit Recent URI, given antibiotic for acute sinusitis 5 days ago Now presents with a CC: Funny colored urine, fatigue, yellow eyes Mr. S. Alanine aminotransferase (ALT)=876 unit/l (reference range=0 to 40 unit/l) How many times ULN? Aspartate aminotransferase (AST)=200 unit/l (reference range=0 to 40 unit/l) How many times ULN? Ratio? All rights reserved. Reproduction is prohibited. 7

8 Mr. S. Alkaline phosphatase (ALP)=291 unit/l (reference range=0 to 40 unit/l) Marker of cholestasis Total bilirubin=3.2 mg/dl (54.7 µmol/l) (reference range= mg/dl { µmol/l}) Mr. S. Direct bilirubin=1.99 mg/dl (34.03 µmol/l) (reference range= mg/dl { µmol/l}) Excretion function, rises when capacity exceeded Albumin=48 g/l (reference range=35 to 55 g/l) Long T ½, days Mr. S. International normalized ratio=1.3 Short T ½, h Serologic evaluation for acute and chronic viral hepatitis=negative Yo Woman Yellow eyes that developed 1 week p 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= Now what? Antiepileptic Drug Use Additional dx? Different dx? 47 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 48 All rights reserved. Reproduction is prohibited. 8

9 Does this apply to all AEDs? If AED Levels are Needed Narrow therapeutic index Phenytoin Carbamazepine Oxcarbazepine Valproate Wider therapeutic index Topiramate Gabapentin 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 True or false? 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. 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 True or false? Hemopoiesis The concurrent use of certain CYP450 inhibitors such as erythromycin, clarithromycin, cimetidine, and propoxyphene results in an increase in carbamazepine levels All rights reserved. Reproduction is prohibited. 9

10 22 Yo 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) Yo 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) Yo Well Woman on Anticonvulsant WBC=3,300 ( K) Neutrophils=48% (60) Lymphs=40% (30) Eos=7% (6) Monos=4% (3) Baso=1% (1) 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 Mechanism of Drug-induced Thrombocytopenia 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 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 All rights reserved. Reproduction is prohibited. 10

11 Drug-induced Thrombocytopenia Drug-induced Thrombocytopenia UF heparin Less with LMWH Sulfonamides Thiazide diuretics Cimetidine Quinine Vancomycin Phenytoin Carbamazepine B-lactams Cephalosporins, PCN Digoxin Valproic acid Withdraw the agent Increase in platelet count typically seen in 2-7 days References Recommended lab monitoring for common medications. Pharmacist's Letter/ Prescriber's Letter 2010;26(7): Ferri, F. (2014) Ferri s Best Test: A practical guide to clinical laboratory medicine and diagnostic imaging (3 rd ed.). Philadelphia: Elsevier Mosby Available at End of Presentation Thank you for your time and attention. Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC Website: cs@fhea.com All websites listed active at the time of publication. 65 All rights reserved. Reproduction is prohibited. 11

12 Fitzgerald Health Education Associates, Inc. 26 All rights reserved. Reproduction is prohibited. 12