Objectives Laboratory Diagnostics: A focus on monitoring ... · Laboratory Diagnostics: A focus on...

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, MAFamily Nurse Practitioner,

Greater Lawrence (MA) Family Health CenterEditorial Board Member

The Nurse Practitioner Journal, The Prescribers Letter, American Nurse Today

Member, Pharmacy and Therapeutics CommitteeNeighborhood 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.

© Fitzgerald Health Education Associates, Inc.2

●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.


Objectives (continued)

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: http://www.ncbi.nlm.nih.gov/pubmed/18436073


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?

(continued)

●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. All rights reserved. Reproduction is prohibited. Prior permission required for use of questions.

1

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


72 Yo Man (continued)

● Prior to illness– Atorvastatin

20 mg daily– Lisinopril 40 mg daily– HCTZ 12.5 mg daily– ASA 81 mg daily

● 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

8© Fitzgerald Health Education Associates, Inc.


●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)

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


Aldosterone Antagonist: Spironolactone (Aldactone®),

Eplerenone (Inspra®) (continued)

●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




2

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 onACEI/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):221250.


Monitoring K+ in Person onACEI/ARB with CKD

(continued)

●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 onACEI/ARB without CKD

●Check K+ – 3-4 weeks after initiation

●Consider K+ monitoring with aliskiren (Tekturna®)


K+ Monitoring withDiuretic 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




3

© Fitzgerald Health Education Associates, Inc.

66 Yo Woman Presents

6 mo hx – Increasing fatigue– Worsening numbness of hands and feet

Health history– Type 2 DM, dyslipidemia, HTN, all at

treatment goal

19 © Fitzgerald Health Education Associates, Inc. 20

66 Yo Woman Presents (continued)

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

Hg=11.2 g/dL (12-14 g/dL) (112 g/L {120-140 g/L})

Hct=33% (36-43%) (0.33 proportion {0.36-0.43 proportion})– 1: Ratio with NL hydration

RBC=3.2 million (4.2-5.4 mil)– Proportionally decreased when

compared with H and H



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 {310-370 g/L})– What is the RBC lifespan?

RDW=19% (11.5-15%) (0.19 proportion {0.115-0.15 proportion})– New cells different size (likely larger) when

compared to old cells



Cobalamin=100 pg/mL (190-914 pg/mL) (73.8 pmol/L {140.2-674.5 pmol/L})

Serum folate=8 ng/mL (3-20 ng/mL) (18 nmol/L {6.8-45.3 nmol/L})– “Drug” level, reflects dietary intake

over p 48-72 h



RBC folate=380 ng/mL (NL=280-790 ng/mL) (861 nmol/L {634.5-1790 nmol/L})̶ Incorporated in erythrocytes during cell

development, remain unchanged throughout RBC lifespan (90-120 d), not influenced by diet




4


Potentially falsely elevated in person with rapidly developing folate deficiency̶ 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, 2.2-3.9, P<0.001)

Vitamin B12 Deficiency and Metformin Use

(continued)

●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, 1.5-3.9, 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;166:1975-9.



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;166:1975-9

Vitamin B12 Deficiency and Metformin Use (continued)

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



5

●Reported at International Society for Pharmacoepidemiology meeting (cont.)– Adjusted hazard ratios for DM risk ●Olanzapine (HR 1.50, 95% CI 1.22-1.84)●Risperidone (HR 1.47, 95% CI 1.19-1.81)●Quetiapine (HR 1.54, 95% CI 0.98-2.43)

– Source: Palacioz K. Atypical antipsychotics and diabetes. Therapeutic Research Center. Pharmacist's Letter/Prescriber's Letter;19:191113.


Do atypical antipsychotic agents directly increase DM risk?

(continued)


●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.



(continued)

●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?

(continued)

● Is there cholestasis?– γ-glutamyltransferase

(GGT), alkaline phosphatase (ALP)


Hepatic testing for what?Do LFTs exist?

(continued)

●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




6

What is the difference?

● 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


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


Drug-induced Hepatic Injury (continued)

●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-to-severe 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 349:474-485. Number 5.


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”


●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?


Mr. S. (continued)



7

●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=0.3-1.2 mg/dL {5.13-20.5 µmol/L})


Mr. S. (continued)

●Direct bilirubin=1.99 mg/dL (34.03 µmol/L) (reference range=0.0-0.3 mg/dL {0.0-5.13 µmol/L})– Excretion function, rises when

capacity exceeded

●Albumin=48 g/L (reference range=35 to 55 g/L) – Long T ½, 19-21 days


Mr. S. (continued)

● International normalized ratio=1.3– Short T ½, 24-60 h

●Serologic evaluation for acute and chronic viral hepatitis=Negative


Mr. S. (continued)

46

51 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

(162.45 µmol/L)● Direct bilirubin level=3.35 mg/dL

(57.29 µmol/L)● INR=2.51

© Fitzgerald Health Education Associates, Inc.

Now what?

●Additional dx?●Different dx?


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




8

Does this apply to all AEDs?

●Narrow therapeutic index– Phenytoin– Carbamazepine– Oxcarbazepine – Valproate

●Wider therapeutic index– Topiramate– Gabapentin


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


True or false?

●Carbamazepine’s T ½ when patients first take the medication is about 31-35 h

●Due to microsomal enzyme autoinduction, carbamazepine’s T ½ is shorter (about 10-20 h) in patients who take the medication more than 4 weeks.


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.


True or false?

●The concurrent use of certain CYP450 inhibitors such as erythromycin, clarithromycin, cimetidine, and propoxyphene results in an increase in carbamazepine levels.


Hemopoiesis




9

22 Yo Well Woman on Anticonvulsant

●Hg=9.1 g/dL (91 g/L)●Hct=28% (0.28 proportion)●RBC=2.8 million (4.2-5.4)●Platelets=75 K (130-400 K)


22 Yo Well Womanon Anticonvulsant

(continued)● MCV=81 fl (81-99)

– NL size● MCHC=34.8 g/dL (31-37) (348 g/L

{310-370})– NL color

● RDW=12.1% (11.5-15%) (0.121 proportion {0.115-0.15})– New cells similar size to old cells

● Retics=1.8% (0.018 proportion)© Fitzgerald Health Education Associates, Inc.

56

22 Yo Well Womanon Anticonvulsant

(continued)

●WBC=3,300 (4.8-10.8 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

●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


Thrombocytopenia

● 50,000-150,000 mm3 (50,000-150,000 109/L)– No bleeding risk

● 20,000-50,000 mm3 (20,000-50,000 109/L)– Minor spontaneous or post op bleeding

● 5,000-20,000 mm3 (5,000-20,000 109/L)– Potential for serious bleed

● <5,000 mm3 (5,000 109/L)– Serious bleeding risk




10

Drug-induced Thrombocytopenia

● UF heparin– Less with LMWH

● Sulfonamides● Thiazide diuretics ● Cimetidine● Quinine

● Vancomycin● Phenytoin● Carbamazepine● B-lactams

– Cephalosporins, PCN

● Digoxin● Valproic acid


Drug-induced Thrombocytopenia (continued)

●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):260704.

● Ferri, F. (2014) Ferri’s Best Test: A practical guide to clinical laboratory medicine and diagnostic imaging (3rd ed.). Philadelphia: Elsevier Mosby– Available at www.fhea.com


End of PresentationThank you for your time and attention.

Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC

Website: www.fhea.com E-mail: [email protected]



All websites listed active at the time of publication.



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