1. Lab Test Monitering

8/18/2019 1. Lab Test Monitering

1/8

In addition to keeping abreast of the grow-ing number of available therapeuticproducts and complicated disease states,pharmacists are increasingly expected todetermine the appropriateness of drugtherapy, as well as monitor drugs for effi-cacy and toxicity. Responding to thesechallenges requires a basic understandingof the interpretation of laboratory values.1,2

Although most pharmacists will not beindependently ordering laboratory tests ormanaging abnormal laboratory values,many do play an important role in amultidisciplinary team approach to opti-mizing patient medications.

Interpretation of laboratory abnorma-lities is much more complicated than com-paring a value against a reference range ofnormal values. Furthermore, the utility ofa particular laboratory test in the diagnosisof different disease states will be dictatedby how sensitive the test is (i.e., the ability

of a test to detect patients with disease),as well as how specific the test is (i.e.,

whether abnormal test values are restrictedto those with the disease) for differentpathologic conditions.1 Assuming thatcommercially available test kits arereliable (i.e., reproducible with multipletesting) and valid (i.e., accurate measure-ment of value), several important questionsshould be considered before interpretingany laboratory abnormality (Figure 1).

answer online at pharmacygateway.ca march 2007 | pharmacypractice CE1

LEARNING OBJECTIVESUpon successful completion of this les-

son, you should be able to:

1. outline a general framework for the

assessment of laboratory abnormalities

2. apply this practical framework to the

assessment of some common

laboratory abnormalities

3. interpret common drug levels/labora-

tory abnormalities for the purposes of

assessment of drug efficacy or toxicity

To successfully complete the post-test

for this lesson, you may need access to

the Compendium of Pharmaceuticals and

Specialties (CPS).

INSTRUCTIONS1. After carefully reading this lesson,

study each question and select the

one answer you believe to be correct.

2. To pass this lesson, a grade of at least

70% (14 out of 20) is required. If you

pass, your CEU(s) will be recorded with

the relevant provincial authority(ies).

(Note: some provinces require indi-vidual pharmacists to notify them.)

ANSWERING OPTIONS A. For immediate results, answer online

at www.pharmacygateway.ca.

B. Mail or fax the printed answer card

to (416) 764-3937. Your reply card

will be marked and you will be

advised of your results within six to

eight weeks in a letter from

Pharmacy Practice.

1.25 CEUs

APPROVED BY CCCEP FOR

CCCEP file #502-1206

This lesson has been approved

for 1.25 CEUs by the Cana-

dian Council on Continuing

Education in Pharmacy. Approved for

1.25 CEUs by l’Ordre des pharmaciens

du Québec. Accreditation of this program

will be recognized by CCCEP until Febru-

ary 5, 2010.

By Sharon Yamashita B.Sc.Phm., ACPR, Pharm.D., FCSHP

ce lessonP H A R M A C Y P R A C T I C E N A T I O N A L C O N T I N U I N G E D U C A T I O N P R O G R A M

Laboratory testmonitoring incommunity practice

Supported by an unrestricted grant from


2/8

ce lesson

answer online at pharmacygateway.caCE2 pharmacypractice | march 2007

Laboratory test monitoring in community practice

P H A R M A C Y P R A C T I C E N A T I O N A L C O N T I N U I N G E D U C A T I O N P R O G R A M

IS THE ABNORMALITY CLINICALLY

SIGNIFICANT?

The established normal range for any par-

ticular laboratory value is based on themean value in a population of normal sub-

jects plus or minus two standard deviationsbelow and above the mean.1 Therefore,95% of any given population should fallinto this normal range. However, it is alsoimportant to note that by using this defini-tion, 2.5% of the normal population willactually fall above and 2.5% will fall belowthis range. Different laboratories mayreport different “normal ranges” due tovariability in the analytical methods orreagents used for testing. Other factors

such as gender, age, race, concurrentmedications or disease states may also alterthis normal range. For example, it has beennoted that the normal range for the whiteblood cell (WBC) count in people of Afri-can descent is lower than that of the Cau-casian population.1

Regardless of these variables, if a testvalue does return outside of the establishednormal range, the significance of the abnor-mality must be assessed. The clinical sig-nificance is based on several factorsincluding the sensitivity of the specific test,as well as other supporting clinical evi-

dence such as signs and symptoms in thepatient or other corroborating abnormaltest values. For example, a potassium valueof 3.4 mmol/L (normal range:3.5–5 mmol/L) may be deemed clinicallyinsignificant, unless the patient is com-plaining of palpitations and has a historyof cardiac arrhythmias.3

In general, the farther the value is fromthe normal range, the greater the likelihoodof an abnormality.1 If there is a question ofvalidity of the abnormal value, the test caneither be repeated or another test that

would support the same diagnosis can bedone. For example, an elevation in both

blood urea nitrogen (BUN) and serumcreatinine would more likely represent

renal dysfunction than an isolated eleva-tion in BUN.

IS THE VALUE CONSISTENT WITH

PREVIOUS MEASUREMENTS AND

THE PATIENT’S OVERALL CLINICAL

PICTURE?

Every test is associated with day-to-dayvariation, despite consistency within agiven patient.1 If routine blood work revealsan abnormal value in an otherwise healthyand stable patient, the possibility oflaboratory error must be considered.Laboratory errors can include clerical

errors (the wrong patient’s blood work),spoiled specimens (delays in analyzing,wrong type of test tube, improper timing)or analytical errors (technical error, faultyreagent). In addition, certain foods, medi-cations and disease states can interferewith laboratory tests, producing falselyabnormal results.1,2 For example, spirono-lactone can interfere with certain digoxinassays, producing artificially elevatedresults.4 In addition, cimetidine and trim-ethoprim interfere with creatinine secre-tion, thereby elevating serum creatinine in

the absence of renal dysfunction.5

Abnormal values should also be con-sidered in the context of a particularpatient. While abnormal values found uponroutine blood work may be disregarded

(or repeated), an abnormal value in apatient with clinical signs and symptomsof a particular disease provides additionalinformation to support the diagnosis of thespecific pathologic condition.

DOES THE ABNORMALITY REQUIRE

MANAGEMENT?

Once a valid abnormality has beendetected, a decision to institute manage-ment must then be made. This decision

will be dependent on the extent of theabnormality, any associated clinical signsand symptoms as well as the consequencesof not treating the abnormal test result. Forexample, one would be more likely to treata modest hypokalemia in a patient receiv-ing digoxin since hypokalemia predisposesto digoxin-induced cardiac arrhythmias.3

Common laboratory testsThe following is a discussion of laboratorytests that may be commonly encounteredwhen dealing with patients in the phar-macy. A summary of these tests can be

found in Table 1.

THE COMPLETE BLOOD COUNT

Important information derived from thecomplete blood count (CBC) includeshemoglobin (as well as other indices of redblood cell quantity and morphology), WBCand platelet count.

Hemoglobin, which reflects the oxygen-carrying capacity of red blood cells, willbe decreased in patients with anemia.1,5 The normal range for hemoglobin differsbetween men and women. Once anemia

has been established, additional informa-tion regarding the etiology of the anemia

A 46-year-old patient is sent for routine bio-

chemistry blood work following an annualcheckup with his family doctor. The potas-

sium level returns as 5.5 mmol/L (normal range:

3.5–5 mmol/L). All other blood work, including

the serum creatinine and bicarbonate, is nor-

mal. The patient has no significant past medical

history and is not taking any medications. The

physical exam was normal, including a normal

electrocardiogram (ECG). Should this patient’s

hyperkalemia be treated?

In this case, an abnormal laboratory value

was found on routine testing, rather than dur-ing a workup for specific signs and symp-

toms. The patient is not receiving any medica-

tions that could account for hyperkalemia

(e.g., angiotensin converting enzyme inhibitors

[ACEIs] angiotensin receptor blockers [ARBs],

spironolactone, potassium supplements), and

common medical causes of hyperkalemia (e.g.,

renal failure, metabolic acidosis) have been ruled

out.3 The patient does not appear to have any

signs or symptoms of hyperkalemia (no palpita-

tions, normal electrocardiogram [ECG]). One

explanation for hyperkalemia in this patient may

be hemolysis of the blood sample, leading to an

artificially high serum potassium level.3 There-

fore, the blood work should be repeated before

therapy or further investigation is initiated.

figure 1

How abnormal is the value?

Is the value congruent with the clinical

picture?

Is the value consistent with the previous

measurements in this patient?

Is the abnormality clinically significant?

Does the abnormality require management?

Practical framework forinterpretation of abnormallaboratory values

response to case Acase A


3/8




table 1

LABORATORY PARAMETER MEASUREMENT “NORMAL RANGE*” (IN SI UNITS) COMMENTS

aspartate aminotransferase hepatic injury < 31 IU/L • hepatic dysfunction common in viral hepatitis,(AST, formerly SGOT)/alanine alcoholic cirrhosisaminotransferase (ALT, formerly • dosage adjustment for drugs which are SGPT) hepatically metabolized not well-defined

• drugs which may AST/ALT (acetaminophen,HMG-CoA, reductase inhibitors, macrolideantibiotics, azole antifungals, INH, rifampin)

creatine kinase (CK) skeletal muscle injury < 195 IU/L • CK levels seen in rhabdomyolysis, statusepilepticus, neuroleptic malignant syndrome,malignant hyperthermia

• drugs which may CK (statins, neuroleptics)

creatinine (Scr) renal function 44–106 µmol/L • renal dysfunction common in diabetes, heartfailure, long-standing hypertension

• adjust drug doses for renal impairment • drugs which may Scr (ACEIs, ARBs, NSAIDs) • monitor potassium in patients with Scr

glucose 4–8 mmol/L

Hb, MCV anemia Hb (women): 115–165 g/L • anemias (macrocytic) with MCV (folate or Hb (men): 130–180 g/L vitamin B

12 deficiency)

MCV: 76–98 fL • anemias (microcytic) with MCV (iron deciency) • drugs which Hb: zidovudine

hemoglobin A1c long-term glycemic ≤ 6% (target usually ≤ 7%)control (over 2–3 months)

INR; replaces PT coagulation 0.9–1.1 • therapeutic target for most indications (deep vein

thrombosis, atrial fibrillation) is 2–3

platelet count 150–400 x 10-9 /L • drugs which platelet count: heparin, chemo-therapy

• drugs which platelet aggregation but not count(ASA, NSAIDs, clopidogrel)

potassium 3.5–5 mmol/L • hypokalemia common in diarrhea, vomiting• hyperkalemia common in renal failure • drugs which may potassium (diuretics,

corticosteroids)• drugs which may potassium (ACEIs, ARBs,

potassium-sparing diuretics)

TSH thyroid function 0.5–5 mIU/L • screening test for thyroid function ( with hypo-thyroidism, with hyperthyroidism)

• often done in conjunction with free T3 and T4 levels • drugs which affect thyroid function: amiodarone

Tn T cardiac muscle injury, < 0.1 µg/L • may be persistently elevated post-cardiac events myocardial infarction in patients with renal failure

WBC count 4–11 x 10-9 /L • increased in infections, hematologic malignancies• decreased level may predispose to infection • drugs which may WBC (chemotherapy, clozapine) • drugs which may WBC (corticosteroids)

Common laboratory tests1,2

* Note that these values represent the normal range from the laboratory at Sunnybrook Health Sciences Centre. Each laboratory may establish their own normal range and,therefore, patient values should be compared against the normal range provided with the test value.

SI = Système International (This is an international method of reporting clinical laboratory values in a standard metric format, used in most countries with the exception ofthe United States.)2

ASA = acetylsalicylic acid; ACEI = angiotensin converting enzyme; ALT = alanine aminotransferase; ARB = angiotensin receptor blocker; AST = aspartate aminotrans-ferase; CK = creatine kinase; Hb = hemoglobin; HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyne A reductase (statins); INH = isoniazid; MCV = mean corpuscular volume;NSAID = nonsteroidal anti-inammatory drug; PT = prothombin time; Scr = creatinine; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic

transaminase; Tn T = troponin T; TSH = thyroid stimulating hormone; T3 = triiodothyronine; T4 = tetraiodothyronine; WBC = white blood cell


4/8


ce lessonLaboratory test monitoring in community practice


is further investigated. The CBC alsoincludes the mean corpuscular volume

(MCV), which provides information on themorphology of the red cells. The MCV willbe decreased in microcytic anemias (e.g.,iron-deficiency anemia) and increased inmacrocytic anemias (e.g., folate or vitaminB

12 deficiencies).5 Iron-deficient anemia is

the most common nutritional deficiency indeveloped countries.5 Although the hemo-globin in patients with iron-deficiencyanemia will respond quickly to iron sup-plements, therapy is often continued forthree to six months in order to replace theiron stores (measured by serum ferritin).Many patients with chronic diseases will

have a normocytic, normochromic anemia,which will not respond to typical replace-ment therapy.5

An elevated WBC is usually indicativeof infection, and less commonly, hemato-logic malignancies (e.g., leukemia).1 Formost infections in the community, however,it would be expected that the WBC wouldonly be mildly elevated, and thereforeblood work is not usually sent off for a CBC.Conversely, a low WBC (leukopenia) mayrepresent an immunocompromised stateand may predispose to infection.1 Patients

receiving drugs which cause leukopenia(e.g., chemotherapy, clozapine) will haveroutine CBCs done to monitor for this.These patients are at high risk of seriousinfection, but often do not mount typicalsigns and symptoms of infection. Therefore,these patients should be counselled tomonitor for fever and seek medical atten-tion should fever develop, even in theabsence of typical infectious symptoms.7

A low platelet count (thrombocytopenia)may predispose patients to bleeding. Com-mon causes of thrombocytopenia includeautoimmune diseases (e.g., idiopathic

thrombocytopenic purpura), as well asdrugs (heparin, chemotherapy).1 There aremany drugs which decrease plateletaggregation (e.g., acetylsalicylic acid,nonsteroidal anti-inflammatory drugs[NSAIDs], clopidogrel) but without alteringthe actual platelet count.1 Patients receiv-ing these drugs should be counselledappropriately on bleeding risks, but willnot have their platelet count monitored.

RENAL FUNCTION TESTS

The most common test to determine renal

function is the serum creatinine test. Ele-vations in serum creatinine are common

in the community due to age-relateddeclines in renal function, as well as the

high prevalence of diabetes, hypertensionand heart failure, all of which predisposeto renal dysfunction. Once renal dysfunc-tion is established, more extensive testssuch as urinalysis, ultrasound and renalbiopsies may be performed in order toinvestigate the etiology of the disorder.8

As pharmacists, renal function is impor-tant to monitor since many drugs havenephrotoxic properties (e.g., NSAIDs,ACEIs and ARBs) and the doses of drugsthat are renally excreted (e.g., digoxin,allopurinol, many antibiotics) will need tobe reduced in these patients.8 Renal fail-

ure patients also have difficulty excretingpotassium, so cautious use of drugs whichincrease serum potassium (potassiumsupplements, ACEIs, ARBs, spironolac-tone) is also warranted in these patients.8

The use of ACEIs in patients with renaldysfunction can be difficult. While ACEIsare contraindicated in patients withbilateral renal artery stenosis (primarilyseen in patients with extensive athero-sclerois and peripheral vascular disease),patients with renal dysfunction secondaryto hypertension and diabetes may actually

benefit from the use of ACEIs.9

ACEIs havebeen shown to decrease the developmentand progression of both hypertensive anddiabetic nephropathy.9 In heart failure, theuse of ACEIs improve both hemodynamicsand decrease progression of disease lead-ing to reduced morbidity and mortality.10 Careful initiation of ACEIs with slow dosetitration, however, may be required to avoidsignificant increases in serum creatininefollowing initiation of drug therapy. In gen-eral, up to a 30% rise in serum creatininewould be tolerated prior to discontinuationof the ACEI.10 It is also important to note

that most ACEIs are renally excreted, sothe target dose in patients with renal dys-function may be lower than in those withnormal renal function.11 In addition, mon-itoring of serum potassium becomes essen-tial in these patients since they are alreadypredisposed to hyperkalemia as a result oftheir impaired renal function. While thereare less data to support the use of ARBsin heart failure, renal dysfunction andhyperkalemia are as likely to occur withthe ARBs and thus, similar precautionsshould be taken when initiating these drugs

in heart failure patients.10

LIVER FUNCTION TESTS

The most commonly ordered tests to assess

hepatic function are the aspartate amino-transferase (AST, formerly SGOT) andalanine aminotransferase (ALT, formerlySGPT). These tests, however, are moreindicative of hepatocyte damage or destruc-tion rather than the function of the liver.12 More accurate tests that measure the func-tional ability of the liver include the Inter-national Normalized Ratio (INR), albuminand bilirubin.12 The AST and ALT, how-ever, are of importance to pharmacists dueto the number of drugs (including herbalmedications) implicated in inducinghepatic injury (e.g., acetaminophen, metho-

trexate, isoniazid).13 Other common causesof hepatocellular injury include chronicalcohol abuse, viral hepatitis, acute heartfailure and ischemia.1,2,14

With drug-induced liver injury, it isimportant to remember that, while manydrugs can cause minor increases in liverfunction tests (LFTs), significant injury israre. Asymptomatic patients with less thana threefold increase in LFTs should bemonitored closely with investigation ofother causes.14 Drug therapy, however,should be reassessed when the elevations

in LFTs are significant or persistent.The adjustment of drug dosing in patientswith liver disease has been less definedcompared to patients with renal dysfunc-tion.12 Unlike the creatinine clearance(calculated using the serum creatinine) inrenal disease, there does not appear tobe a biochemical test in patients withliver disease that closely correlates tothe hepatic metabolism of drugs. Often,dosages of drugs metabolized by the liverare, therefore, not reduced until thereappears to be significant functional hepaticimpairment, as evidenced by an increased

INR and bilirubin, as well as a decreasedserum albumin.12

COMMON ELECTROLYTES

Disorders of potassium homeostasis arelikely to be the most common electrolyteabnormalities seen by pharmacists. Whilehypokalemia predisposes to cardiacarrhythmias and muscle weakness, hyper-kalemia can also result in life-threateningcardiac arrhythmias.3 In the absence ofrenal dysfunction, however, hyperkalemiais less commonly seen. Increasing use of

the combination of ACEIs, ARBs andspironolactone in heart failure patients has


5/8




lead to a recent rise in hospitalizations dueto hyperkalemia.15 Therefore, this combi-

nation of drugs is only recommended forpatients under careful medical supervision(e.g., in a heart failure clinic).10

As potassium is an intracellular ion,hyperkalemia can also be seen when thereis evidence of significant tissue damage(e.g., rhabdomyolysis, tumour lysis syn-drome post chemotherapy) and when redblood cells are damaged during blood sam-pling (hemolysis).3

Hypokalemia is more commonly seen,especially in patients who are receivingdiuretics. Replacement is particularlyimportant in symptomatic patients, as well

as patients with a history of heart disease(e.g., ischemia, arrhythmias or heart fail-ure). As potassium is primarily an intracel-lular ion, small decreases in serum potas-sium likely represent large decreases intotal body potassium.3 Therefore, inpatients with ongoing potassium losses(e.g., vomiting, diarrhea, aggressive diure-sis), large doses of potassium chloride maybe required to correct the total body potas-sium deficit.

BLOOD GLUCOSE AND HBA1C

Daily monitoring of blood glucose (BG)levels has become popular due to the avail-ability of home glucose monitoring devices.Periodic monitoring of the glycosylatedhemoglobin (HbA1c), however, providesbetter information on the level of glycemiccontrol over a longer period of time (i.e.,2–3 months). Target HbA1c levels of lessthan seven per cent generally reflect fast-ing BG in the 4–6 mmol/L range, and post-prandial BG (2 hours post meal) in therange of 5–10 mmol/L.16

INTERNATIONAL NORMALIZED RATIO

The INR has replaced the prothrombintime (PT) as a monitoring tool for oral anti-coagulants such as warfarin. The INR wasdeveloped in order to account for differ-ences in reagents used when conductingthe PT test. The normal INR is one, witha target of two to three for most conditionsrequiring anticoagulation.17 The INR ismeasured routinely in patients receivingwarfarin to ensure adequacy of anticoagu-lation, without an increased risk of bleed-ing. Although intensive INR monitoring isdone when oral anticoagulation is initiated,

the frequency of monitoring decreases(i.e., to monthly) as patients become sta-

bilized on therapy. As many drugs (e.g.,antibiotics, amiodarone) 17 have the poten-

tial to interact with warfarin, more frequentmonitoring of the INR is required whennew drugs are added or discontinued.

THYROID FUNCTION TESTS

Hypothyroidism is common, particularlyin the elderly and in the female popula-tions. Routine screening for hypothyroid-ism in patients > 35 years of age is there-fore recommended by the AmericanThyroid Association.18 The usual screeningtest is the Thyroid Stimulating Hormone(TSH) test, which shows increased levelsin patients with hypothyroidism. Confirma-

tory tests such as checking free T3 and T4 levels are usually completed if the TSH iselevated. Once supplemental thyroxine hasbeen initiated, response to therapy will bemonitored by repeat TSH levels,usually six to eight weeks following initia-tion of therapy.19

LIPIDS

With the aging population and the increas-ing prevalence of obesity and diabetes,targeting high cholesterol has become animportant factor in the attempt to reduce

the burden of cardiovascular disease.There is also an abundance of evidencethat the use of drug therapy, in particu-lar the HMG Co-A reductase inhibitors(statins), significantly reduces the risk ofcardiovascular morbidity and mortality.20

Cholesterol and triglycerides are trans-ported in the body as lipoproteins. The twomajor classes of lipoproteins are the low-density lipoproteins (LDL-C) and the high-density lipoproteins (HDL-C). Elevatedtotal and LDL cholesterol, as well as lowHDL cholesterol have been linked withthe development of coronary heart disease,

specifically coronary atherosclerosis andischemic heart disease. The total choles-terol (TC): HDL-C ratio appears to be amore specific and sensitive predictor ofcardiovascular risk compared to the totalcholesterol level.21

The current targets for the ratio ofLDL-C and TC: HDL-C ratio are based ona patient’s 10-year risk of coronary arterydisease-related death or nonfatal myocar-dial infarction.20 Patients with risk factorsfor coronary artery disease (e.g., smoking,diabetes, family history, hypertension,

male > 40, female > 50) should thereforebe screened for hyperlipidemia and catego-

rized by risk (i.e., high, moderate or low).20 In high-risk patients, the target LDL-C is

< 2 mmol/L and the target TC:HDL-C ratiois < 4. Moderate-risk patients should betreated if their LDL-C is > 3.5 mmol/L ortheir TC:HDL-C ratio is > 5. Low-riskpatients should be treated if their LDL-Cis > 5 mmol/L or their TC:HDL-C ratio is> 6. The target for both the low- andmoderate-risk patients is a 40% reductionin their LDL-C.20

If therapy is instituted, repeat choles-terol levels are usually done every sixweeks, until the target levels are achieved.Once the target cholesterol levels arereached, periodic monitoring every four to

six months is recommended.22

CREATINE KINASE

With the increasing use of high-dose sta-tins to prevent cardiovascular morbidityand mortality,20 monitoring of creatinekinase (CK) levels has become more com-mon. CK is increased when muscle isinjured and thus, can be increased evenwith strenuous exercise or intramuscularinjections.1,2 There are several subunits ofthe CK enzyme, the most common beingthe CK-MM isoenzyme found primarily in

skeletal muscle. The CK-MB fraction, pri-marily found in cardiac muscle, has tradi-tionally been used in the diagnosis ofmyocardial infarctions.1,2 The CK-MB hasnow largely been replaced by the troponinlevel, which is a much more sensitive andearlier indicator of myocardial damage.2 The statins, as well as other fibrates, how-ever, can cause myositis and increase thetotal CK.20 Myalgias can occur in theabsence of a rise in CK. It is controversialwhether patients receiving statin therapyshould routinely have their CK measured.If patients develop myalgias, CK can be

measured; if significantly increased frombaseline, the statin dose can be lowered orthe drug can temporarily be held.23

Total CK levels will also be increasedin pathologic conditions affecting skeletalmuscle including rhabdomyolysis, statusepilepticus, malignant hyperthermia andneuroleptic malignant syndrome.1,2

Drug levelsAs many factors may affect the responseof drugs in different patients (e.g.,pharmacokinetics, genetics, concurrent

medical conditions, compliance), there isusually a good correlation between drug


6/8




level and efficacy or toxicity.24 Therefore,the use of drug levels allows for optimiza-

tion of drug therapy through the individu-alization of dosing in patients.Monitoring of drug levels to determine

efficacy or toxicity is dependent on severalfactors:24 a reliable assay must be com-mercially available; there must be a cor-relation between drug concentrations inthe blood and efficacy and/or toxicity; andthe drug must have a narrow therapeuticindex (i.e., doses or concentrations whichproduce toxicity are just above those whichare efficacious). The availability of druglevels, however, does not necessarily cor-respond to the usefulness of drug levels in

the management of disease. For example,while serum concentrations of antidepres-sants can be measured, there is a poorcorrelation between drug response and theconcentration of the antidepressant in theblood. Similarly, in a tricyclic antidepres-sant overdose, clinical signs and symptoms(i.e., ECG changes) are more predictive oftoxicity than the serum concentration.25 For many drugs, the concentrations in theblood do not necessarily reflect concentra-tions at the drug’s site of action (e.g., cen-tral nervous system or cardiac tissue) and

therefore, in these cases, the use of atherapeutic end point (e.g., INR, bloodpressure) is more valuable for dosageindividualization.

Provided the above criteria apply, thera-peutic drug monitoring is primarily done ondrugs with a narrow therapeutic range. Indi-cations for drug levels include suspicion oftoxicity, suspected drug interactions, chang-ing renal or hepatic function, monitoring ofpatient compliance or investigation of a poorresponse.24 Routine monitoring of levels, inthe absence of a valid indication, is costlyand unnecessary.

Similar to abnormal laboratory results,interpretation of drug levels requiresknowledge of the testing methods as wellas the pharmacokinetics of the particulardrug. Consideration must also be given to

substances that cross-react or interferewith individual drug assays. Several

pharmacokinetic parameters, includingdistribution, metabolism, protein binding

and the elimination half-life, will alsoinfluence the interpretation of drug levels.24 Levels drawn prior to the completion of thedistribution phase of the drug may be arti-ficially elevated. This is particularly impor-tant with digoxin, which has a distributionphase of up to six to eight hours; levelstaken prior to completion of the distribu-tion phase will produce levels thatare alarmingly higher than the normalreference range. Levels taken prior to doseadministration (i.e., trough levels) avoidthis problem.26

As most assays measure the parent drug,therapeutic drug monitoring with druglevels will be of little use if the metaboliteof a drug is responsible for the therapeuticactivity. Most assays also measure the totalconcentration of drug, rather than the freeor unbound portions of the drug.24 Unfor-tunately, it is actually the unbound drugthat is responsible for therapeutic activity.Therefore, for drugs that are highly proteinbound, small changes in binding may

result in large changes in the free concen-tration of the drug. These changes, how-ever, will not be detected when thetotal drug concentration is measured. Forexample, the target therapeutic concen-trations for phenytoin are between40–80 µmol/L. Assuming that phenytoinis 90% protein bound, these total concen-trations correlate with “free” concentra-tions of 4–8 µmol/L (i.e., 10% of the totalconcentration). In a patient with a low albu-min who now has a free fraction of 20%, aphenytoin level (total drug) which returns

as 60 mol/L will now correlate to a freeconcentration of 12 µmol/L (20% of 60

µmol/L). The level of 60 µmol/L appearsto be in the therapeutic range of 40–80

µmol/L (for total drug) but actually exceedsthe free therapeutic range (4–8 µmol/L).As it is the free or unbound portion of thedrug that is active, this patient is, therefore,at risk of toxicity, even though his totallevel appears to be normal.27

Finally, for most drugs, levels taken atsteady state are most desirable.24 Thus,knowledge of the elimination half-life isrequired to determine the timing of thedrug level relative to the initiation of drugtherapy. For drugs with a short half-life(e.g., theophylline), drug levels takenwithin two to three days of dosage adjust-

ment likely reflect steady-state concentra-tions.24 In contrast, for drugs with a longhalf-life (e.g., digoxin), steady state is notusually reached for five to seven days, andlevels taken before this time may under-estimate steady-state concentrations.24,26

While therapeutic drug monitoring withthe use of drug levels was very popularseveral decades ago, its use has diminishedwith the declining use of drugs that havebeen traditionally assayed (e.g., theophyl-line, antiarrhythmics).

The pharmacist’s roleIn order for pharmacists to play an integralrole in the multidisciplinary care ofpatients, an understanding of commonlaboratory tests is required. These labora-tory values may represent target end pointsfor drug therapy (e.g., INR, HbA1c, lipidprofile) or adverse effects secondary to drugtherapy (e.g., LFTs, CKs), or require modi-fication of drug therapy (e.g., reduction indose of drugs that are renally excreted).With respect to end points of therapy, phar-macists can also play an important role inpromoting compliance with drug therapy

and empowering patients to take respon-sibility for achieving appropriate targets(e.g., HbA1c, LDL-C).

SummaryIn conclusion, interpretation of abnormallaboratory results and drug levels requiresa systematic approach involving an under-standing of the test specifics, as well asclinical insight. Abnormal results shouldnot always be taken at face value, andevaluation of other relevant factors mustbe completed prior to initiation of action

based on the test.

case B A physician from your medical building calls

down to ask you a question regarding a

digoxin level that she just received for one of her

patients. The level is high (3.1 nmol/L; normal

range: 1.0–2.6 nmol/L), and she would like to

know whether there is an antidote for digoxin.

In order to make a decision regarding the treat-

ment of this patient’s high digoxin level, a cou-

ple of factors must be considered. The first is

the time that the level was taken relative to the

administration of the last dose, and the second

is whether the patient is exhibiting any signs or

symptoms of digoxin toxicity (e.g., bradycardia,

palpitations, ECG abnormalities).26 If the patient

is asymptomatic and it is determined that the

level was taken within eight hours of the patient

taking the last dose, the level was likely drawn

during the distribution phase and is therefore

clinically insignificant. The level should be re-

peated, but prior to the administration of the

digoxin (i.e., trough level).

response to case B


7/8

1 All laboratory values that fall outside of

the normal reference range represent

disease.

a) true

b) false

2 Factors which can affect the normal

reference range for any given laboratory test

include:a) day-to-day variability

b) race and gender

c) certain medications

d) all of the above

3 The decision to institute therapy for an

abnormal test result is based on which of the

following factors?

a) extent of the abnormality

b) concurrent signs and symptoms

c) consequences of not treating the abnormality

d) all of the above

4 NB tells you that his doctor’s office called

him to say his potassium level returned as

high. All of the following could contribute tohyperkalemia except :

a) ramipril

b) renal dysfunction

c) hemolysis of the blood sample

d) hydrochlorothiazide

5 The most appropriate management of

NB’s abnormal laboratory value may include:

a) Repeat the blood sample to confirm the high

result.

b) Change the ramipril to candesartan.

c) Change the hydrochlorothiazide to spironolactone.

d) Refer NB to the nearest emergency department

as NB needs to be dialyzed.

6 TK, a 41-year-old healthy female, comes

into your pharmacy complaining of fatigue,

and is looking for an iron supplement. She

appears pale and lethargic in appearance.

The most appropriate recommendation for her

would be:

a) Increase dietary sources of iron (e.g., spinach,

liver).

b) Take a multivitamin with iron and folic acid.c) Refer her to her family doctor for appropriate

blood work.

d) Take ferrous sulphate 150 mg TID.

7 TK is sent for a CBC which returns as:

Hb: 106 (115–165 g/L)

MCV: 115 (76–98 fL)

WBC: 12 (4–11 x 10-9 /L )

platelet: 450 (150–400 x 10-9 /L )

Which of the following statements regarding

TK’s condition is true?

a) TK may have an iron deficiency anemia and

may require iron supplementation.

b) TK has a macrocytic anemia; folate and B12

levels should be ordered.

c) TK has evidence of an infection and may requireantibiotics.

d) TK’s platelet count predisposes her to bleeding.

8 The most common type of anemia in a patient

with a history of rheumatoid arthritis would be:

a) iron deficiency anemia

b) macrocytic anemia due to vitamin B12

deficiency

c) normocytic, normochromic anemia

d) hemolytic anemia

9 In a patient with an elevated serum

creatinine due to diabetes, which of the fol-

lowing medications should be avoided?

a) ramipril c) naproxen

b) valsartan d) all of the above

10 DB was recently discharged from hospital

following a myocardial infarction. She tells you

that her course in hospital was complicated by

kidney failure and fluid in her lungs. Her

medication profile, prior to her hospital admis-

sion, indicates the following: allopurinol 300

mg po daily, enalapril 10 mg po BID, hydrochlo-

rothiazide 25 mg po daily, potassium chloride

20 mmol po BID. Which of the following state-ments regarding DB’s medications is true?

a) The allopurinol dose should be reduced as it is

renally cleared.

b) The enalapril should be discontinued due to the

risk of hyperkalemia.

c) Trbesartan should be initiated as it is less likely

to worsen her renal function.

d) The potassium chloride dose is likely too low as

DB is receiving hydrochlorthiazide.

11 DB is started on atorvastatin 80 mg po

daily. Which of the following statements is

correct ?

a) The target cholesterol will be based on her cal-

culated 10-year risk of coronary artery disease.

b) CKs should be monitored every two weeks forthree months, then monthly.

c) Once target cholesterol levels are achieved,

levels should be monitored every six weeks.

d) The atorvastatin dose should be reduced because

of her renal dysfunction.

12 SG comes into your pharmacy complaining

of shortness of breath. He has just been diag-

nosed with heart failure and is started on

furosemide and captopril. Which of the fol-

lowing statements is true regarding SG’s heart

failure therapy?

a) The captopril dose should be started at a low

dose and slowly titrated up to the target dose.

b) The serum creatinine should be monitored and

if it increases by 10%, the captopril should be

Questions




References1. Ravel R, ed. Clinical laboratory medicine: clinical application of

laboratory data. 6th

ed, Chicago, Year Book Medical Publishers, Inc.,1995. 2. Garrison MW, Young LY. Interpretation of clinical laboratory

tests. In: Koda-Kimble MA, Young LY, eds. Applied therapeut ics: the

clinical use of drugs, 8 th ed. Baltimore, MD: Lippincot, Williams and

Wilkins; 2005: 2-1–2-22. 3. Brophy DF, Gehr TWB. Disorders of

potassium and magnesium homeostasis. In: DiPiro JT, Talbert RL, Yee

GC, et al, eds. Pharmacotherapy: a pathophysiologic approach, 6th ed.

New York, NY: McGraw-Hill; 2005:967-82. 4. Huffman DH. The effect

of spironolactone and canrenone on the digoxin radioimmunoassy. Res

Commun Chem Pathol Pharmacol 1974; 9:787-90. 5. McEvoy GK, ed.

American hospital formulary service. Drug information 2005.

Bethesda, MD: American Society of Health-System Pharmacists Inc.,

2005. 6. Ineck B, Mason BJ, Thompson, G. Anemias. In: DiPiro JT,

Talbert RL, Yee GC, et al, eds. Pharmacotherapy: a pathophysiologic

approach, 6th ed., New York, NY: McGraw Hill, 2005; 1805-31. 7. Fish

DN, Goodwin SD. Infections in immunocompromised patients. In:

DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: a

pathophysiologic approach, 6th ed. New York, NY: McGraw-Hill; 2005:

2191-215. 8. Brophy DF. Acute renal failure. In: Koda-Kimble MA,

Young LY, eds. Applied therapeutics: the clinical use of drugs, 8th ed.

Baltimore, MD: Lippincot, Williams and Wilkins; 2005: 31-1–31-22.9. Bakris GL, Williams M, Dworkin L, et al for the National Kidney

Foundation Hypertension and Diabetes Executive Committees Working

Group Preserving renal function in adults with hypertension and

diabetes: a consensus approach.. Am J Kidney Dis 2000; 36: 646-61.

10. Arnold JM, Liu P, Demers C, et al. Canadian Cardiovascular Society

consensus conference recommendations on heart failure 2006:

diagnosis and management. Can J Cardiol 2006; 22:23-45.

11. Aronoff GR, Berns JS, Brier ME, et al. Drug prescribing in renal

failure. Dosing guidelines for adults, 4 th ed. Philadelphia, PA: American

College of Physicians; 1999. 12. Timm EG, Stragand JJ. Portal

hypertension and cirrhosis. In: DiPiro JT, Talbert RL, Yee GC, et al, eds.

Pharmacotherapy: a pathophysiologic approach, 6 th ed. New York, NY:

McGraw-Hill; 2005: 693-711. 13. Navarro VJ, Senior JR. Drug-related

hepatotoxicity. N Engl J Med 2006; 354:731-9. 14. Herrera JL.

Abnormal liver enzyme levels: the spectrum of causes. Postgrad Med

1993: 93: 113-16. 15. Juurlink DN, Mamdani MM, Lee DS, et al. Rates

of hyperkalemia after publication of the Randomized Aldactone

Evaluation Study. N Engl J Med 2004; 351: 2448-50. 16. Canadian

Diabetes Association Clinical Practice Guidelines Expert Committee.

Canadian Diabetes Association 2003 clinical practice guidelines for the

prevention and management of diabetes in Canada. Can J Diabetes.

2003;27(suppl 2):S18-S23. 17. Ansell J, Hirsh J, Poller L, et al. The

pharmacology and management of the vitamin K antagonists. The 7th

ACCP conference on antithrombotic and thrombolytic therapy. Chest

2004; 126: 204S-233S. 18. Ladenson PW, Singer, PA, Ain KB, et al.

American Thyroid Association guidelines for detection of thyroiddysfunction. Arch Intern Med 2000; 160: 1573-5. 19. Talbert RL.

Thyroid disorders. In: DiPiro JT, Talbert RL, Yee GC, et al, eds.

Pharmacotherapy. A pathophysiologic approach, 6th ed. New York, NY:

McGraw-Hill; 2005: 1369-90. 20. McPherson R, Frohlich J, Fodor G, et

al. Canadian Cardiovascular Society position statement.

Recommendations for the diagnosis and treatment of dyslipidemia

and prevention of cardiovascular disease. Can J Cardiol 2006; 22:

913-27. 21. Talbert RL. Hyperlipidemia. In: DiPiro JT, Talbert RL, Yee

GC, et al, eds. Pharmacotherapy: a pathophysiologic approach, 6th ed.

New York, NY: McGraw-Hill; 2005: 429-52.22. Third report of the

National Cholesterol Education Program (NCEP) Expert Panel on

Detection, Evaluation and Treatment of High Blood Cholesterol in

Adults. NIH publication No 02-5215. September 2002 available at

www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm 23. Law M,

Rudnicka AR. Statin safety: a systematic review. Am J Cardiol 2006;97:

S52-60. 24. Evans WE. General principles of of applied pharmaco-

kinetics. In: Evans WE, Schentag JJ, Jusko WJ, eds. Applied

pharmacokinetics. Principles of therapeutic drug monitoring, 3rd ed.

Vancouver, WA: Applied Therapeutics Inc., 1992; 1-2–1-8.

25. Boehnert MT, Lovejoy FG. Value of the QRS duration versus the

serum drug level in predicting seizures and ventricular arrhythmias

after an acute overdose of tricyclic antidepressants. N Engl J Med

1985; 313: 474-9. 26. Reuning RH, Geraets DR. Digoxin. In: Evans WE,

Schentag JJ, Jusko WJ, eds. Applied pharmacokinetics. Principles of

therapeutic drug monitoring, 3rd ed. Vancouver, WA: Applied

Therapeutics Inc., 1992; 20-1–20-48. 27. Winter ME, Tozer TN.Phenytoin. In: Evans WE, Schentag JJ, Jusko WJ, eds. Applied

pharmacokinetics. Principles of therapeutic drug monitoring, 3rd ed.

Vancouver, WA: Applied Therapeutics Inc., 1992; 25-1–25-44.


8/8

THIS MONTH


AUTHOR

Sharon Yamashita is the clinical co-ordinator in the

critical care unit of the Department of Pharmacy

at Sunnybrook Health Sciences Centre where,

on a daily basis, she deals with lab abnormalities.

She is also an assistant professor in the Faculty of

Pharmacy at the University of Toronto. She teaches

topics such as renal failure, liver disease, hypothy-

roidism, diagnostic tests in adrenal diseases, fluidand electrolyte imbalance, and electrolyte replace-

ment protocols.

All lessons are reviewed by a minimum of six

pharmacists for accuracy, currency and relevance

to current pharmacy practice.

CE CLINICAL EDITOR

Brenda McBean Cochran, B.S.P., M.Sc.(Phm)

Pharmacist consultant, Bedford, N.S.

CE MANAGING EDITOR

Honey Fisher

[email protected]

This lesson is published by Rogers Publishing Ltd.,

One Mount Pleasant Rd., Toronto, ON M4Y 2Y5.

Editorial office: Tel: (416) 764-3927 Fax: (416) 764-

3931. CE queries: Tel: (416) 764-3879 Fax: (416)

764-3937 [email protected]. No part of

this CE lesson may be reproduced, in whole or in

part, without the written permission of the publisher.

The authors, expert reviewers and provider state

that they have no real or potential conflict to disclose.

This lesson is supported by an unrestricted grant

from Genpharm Inc.




discontinued.

c) Potassium supplements should also be started

due to the risk of hypokalemia secondary to the

furosemide.d) If renal failure develops, the captopril should be

changed to candesartan.

13 More accurate assessment of liver func-

tion, rather than hepatocyte injury, can be

measured by which of the following tests?

a) the International Normalized Ratio (INR)

b) aspartate aminotransferase (AST)

c) alanine aminotransferase (ALT)

d) the AST:ALT ratio

14 Hemoglobin A1c levels are a better indica-

tor of long-term glycemic control than serial

blood glucose levels.

a) true

b) false

15 Which of the following statements regard-

ing the use of INR monitoring in patients

receiving warfarin is false?

a) The prothrombin time (PT) is used for the monitor-

ing of oral anticoagulation.

b) INRs < 2 are considered subtherapeutic for most

thromboembolic indications.

c) In general, the higher the INR, the higher the risk

of bleeding.

d) The INR should be monitored more frequently in

patients started on antibiotics.

16 Which of the following statements regard-

ing hypothyroidism is true?

a) It is more common in elderly males.

b) The free T3 is the most common screening test.

c) Routine screening is recommended in people

> 35 years of age.

d) Patients started on l-thyroxine will have their TSH

measured in six to eight days.

17 In order to individualize drug therapy

based on drug levels, the following criteria

must be met:

a) There must be a commercially available assay.

b) There must be a relationship between the drug

concentration and effect and/or toxicity.

c) The drug must possess a narrow therapeutic

index.

d) All of the above

18 Knowledge of which of the following phar-

macokinetic parameters is required in order

to appropriately interpret drug levels?

a) length of distribution phase

b) elimination half-life

c) protein binding

d) all of the above

19 Appropriate indications for ordering

digoxin levels in a heart failure patient include

all of the following except :

a) an interacting drug is added

b) weekly measurement to ensure level is therapeutic

c) if toxicity or noncompliance is suspected

d) when there is a change in renal function

20 You are called by a family physician in your

medical building asking for advice on a

patient’s toxic digoxin level. Which of the fol-

lowing responses is incorrect ?

a) Refer the patient to the nearest emergency

department for immediate administration of the

digoxin antidote.

b) Determine when the level was taken in relation-

ship to the last dose.

c) Determine whether the patient is exhibiting any

signs of toxicity.

d) Repeat the level prior to administration of the

next dose.

ce faculty

Documents

1. Lab Test Monitering