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P h a r m a c y P r a c t i c e n at i o n a l c o n t i n u i n g e d u c at i o n p r o g r a m

Approved BY CCCEP FOR

1.25 CEUs
CCCEP file #502-1206
This lesson has been approved
for 1.25 CEUs by the Canadian Council on Continuing
Education in Pharmacy. Approved for
1.25 CEUs by lOrdre des pharmaciens
du Qubec. Accreditation of this program
will be recognized by CCCEP until February 5, 2010.

Laboratory test
monitoring in
community practice

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

Learning objectives
Upon successful completion of this lesson, 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/laboratory 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).

Instructions
1. 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 individual 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.

answer online at pharmacygateway.ca

In addition to keeping abreast of the grow

ing number of available therapeutic
products and complicated disease states,
pharmacists are increasingly expected to
determine the appropriateness of drug
therapy, as well as monitor drugs for effi
cacy and toxicity. Responding to these
challenges requires a basic understanding
of the interpretation of laboratory values.1,2
Although most pharmacists will not be
independently ordering laboratory tests or
managing abnormal laboratory values,
many do play an important role in a
multidisciplinary 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 of
normal values. Furthermore, the utility of
a particular laboratory test in the diagnosis
of different disease states will be dictated
by 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 restricted

to those with the disease) for different
pathologic conditions.1 Assuming that
commercially available test kits are
reliable (i.e., reproducible with multiple
testing) and valid (i.e., accurate measure
ment of value), several important questions
should be considered before interpreting
any laboratory abnormality (Figure 1).

Supported by an unrestricted grant from

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Laboratory test monitoring in community practice

case A

A 46-year-old patient is sent for routine biochemistry blood work following an annual
checkup with his family doctor. The potassium level returns as 5.5 mmol/L (normal range:
3.55 mmol/L). All other blood work, including
the serum creatinine and bicarbonate, is normal. 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 patients
hyperkalemia be treated?

Is the abnormality clinically

significant?

The established normal range for any par

ticular laboratory value is based on the
mean value in a population of normal sub
jects plus or minus two standard deviations
below and above the mean.1 Therefore,
95% of any given population should fall
into this normal range. However, it is also
important to note that by using this defini
tion, 2.5% of the normal population will
actually fall above and 2.5% will fall below
this range. Different laboratories may
report different normal ranges due to
variability in the analytical methods or
reagents used for testing. Other factors
such as gender, age, race, concurrent
medications or disease states may also alter
this normal range. For example, it has been
noted that the normal range for the white
blood 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 test
value does return outside of the established
normal range, the significance of the abnor
mality must be assessed. The clinical sig
nificance is based on several factors
including the sensitivity of the specific test,
as well as other supporting clinical evi
dence such as signs and symptoms in the
patient or other corroborating abnormal
test values. For example, a potassium value
of 3.4 mmol/L (normal range:
3.55 mmol/L) may be deemed clinically
insignificant, unless the patient is com
plaining of palpitations and has a history
of cardiac arrhythmias.3
In general, the farther the value is from
the normal range, the greater the likelihood
of an abnormality.1 If there is a question of
validity of the abnormal value, the test can
either be repeated or another test that
would support the same diagnosis can be
done. For example, an elevation in both
CE2 pharmacypractice | march 2007

blood urea nitrogen (BUN) and serum

creatinine would more likely represent
renal dysfunction than an isolated eleva
tion in BUN.
Is the value consistent with
previous measurements and
the patients overall clinical
picture?

Every test is associated with day-to-day

variation, despite consistency within a
given patient.1 If routine blood work reveals
an abnormal value in an otherwise healthy
and stable patient, the possibility of
laboratory error must be considered.
Laboratory errors can include clerical
errors (the wrong patients blood work),
spoiled specimens (delays in analyzing,
wrong type of test tube, improper timing)
or analytical errors (technical error, faulty
reagent). In addition, certain foods, medi
cations and disease states can interfere
with laboratory tests, producing falsely
abnormal results.1,2 For example, spirono
lactone can interfere with certain digoxin
assays, producing artificially elevated
results.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 particular
patient. While abnormal values found upon
routine blood work may be disregarded

figure 1
Practical framework for
interpretation of abnormal
laboratory values
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?

response to case A
In this case, an abnormal laboratory value
was found on routine testing, rather than during a workup for specific signs and symptoms. 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 palpitations, 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 Therefore, the blood work should be repeated before
therapy or further investigation is initiated.

(or repeated), an abnormal value in a

patient with clinical signs and symptoms
of a particular disease provides additional
information to support the diagnosis of the
specific pathologic condition.
Does the abnormality require
management?

Once a valid abnormality has been

detected, a decision to institute manage
ment must then be made. This decision
will be dependent on the extent of the
abnormality, any associated clinical signs
and symptoms as well as the consequences
of not treating the abnormal test result. For
example, one would be more likely to treat
a modest hypokalemia in a patient receiv
ing digoxin since hypokalemia predisposes
to digoxin-induced cardiac arrhythmias.3

Common laboratory tests

The following is a discussion of laboratory

tests that may be commonly encountered
when 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 the

complete blood count (CBC) includes
hemoglobin (as well as other indices of red
blood cell quantity and morphology), WBC
and platelet count.
Hemoglobin, which reflects the oxygencarrying capacity of red blood cells, will
be decreased in patients with anemia.1,5
The normal range for hemoglobin differs
between men and women. Once anemia
has been established, additional informa
tion regarding the etiology of the anemia
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P h a r m a c y P r a c t i c e n at i o n a l c o n t i n u i n g e d u c at i o n p r o g r a m

Laboratory test monitoring in community practice

table 1
Common laboratory tests

1,2

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 cirrhosis
aminotransferase (ALT, formerly
dosage adjustment for drugs which are
SGPT) hepatically metabolized not well-defined

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

creatine kinase (CK)

skeletal muscle injury
< 195 IU/L
CK levels seen in rhabdomyolysis, status
epilepticus, neuroleptic malignant syndrome,
malignant hyperthermia

drugs which may CK (statins, neuroleptics)
creatinine (Scr)
renal function
44106 mol/L
renal dysfunction common in diabetes, heart
failure, long-standing hypertension

adjust drug doses for renal impairment

drugs which may Scr (ACEIs, ARBs, NSAIDs)

monitor potassium in patients with Scr
glucose

48 mmol/L

Hb, MCV
anemia
Hb (women): 115165 g/L
anemias (macrocytic) with MCV (folate or

Hb (men): 130180 g/L vitamin B12 deficiency)

MCV: 7698 fL
anemias (microcytic) with MCV (iron deficiency)

drugs which Hb: zidovudine
hemoglobin A1c

long-term glycemic
control (over 23 months)

6% (target usually 7%)

INR; replaces PT
coagulation
0.91.1
therapeutic target for most indications (deep vein
thrombosis, atrial fibrillation) is 23
platelet count
150400 x 10-9/L
drugs which platelet count: heparin, chemo-
therapy

drugs which platelet aggregation but not count
(ASA, NSAIDs, clopidogrel)
potassium
3.55 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
0.55 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 g/L
may be persistently elevated post-cardiac events
myocardial infarction in patients with renal failure

WBC count
411 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)

* 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 = Systme International (This is an international method of reporting clinical laboratory values in a standard metric format, used in most countries with the exception of
the United States.)2
ASA = acetylsalicylic acid; ACEI = angiotensin converting enzyme; ALT = alanine aminotransferase; ARB = angiotensin receptor blocker; AST = aspartate aminotransferase; CK = creatine kinase; Hb = hemoglobin; HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyne A reductase (statins); INH = isoniazid; MCV = mean corpuscular volume;
NSAID = nonsteroidal anti-inflammatory 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

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Laboratory test monitoring in community practice

is further investigated. The CBC also

includes the mean corpuscular volume
(MCV), which provides information on the
morphology of the red cells. The MCV will
be decreased in microcytic anemias (e.g.,
iron-deficiency anemia) and increased in
macrocytic anemias (e.g., folate or vitamin
B12 deficiencies).5 Iron-deficient anemia is
the most common nutritional deficiency in
developed countries.5 Although the hemo
globin in patients with iron-deficiency
anemia will respond quickly to iron sup
plements, therapy is often continued for
three to six months in order to replace the
iron 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 indicative
of infection, and less commonly, hemato
logic malignancies (e.g., leukemia).1 For
most infections in the community, however,
it would be expected that the WBC would
only be mildly elevated, and therefore
blood work is not usually sent off for a CBC.
Conversely, a low WBC (leukopenia) may
represent an immunocompromised state
and may predispose to infection.1 Patients
receiving drugs which cause leukopenia
(e.g., chemotherapy, clozapine) will have
routine CBCs done to monitor for this.
These patients are at high risk of serious
infection, but often do not mount typical
signs and symptoms of infection. Therefore,
these patients should be counselled to
monitor for fever and seek medical atten
tion should fever develop, even in the
absence of typical infectious symptoms.7
A low platelet count (thrombocytopenia)
may predispose patients to bleeding. Com
mon causes of thrombocytopenia include
autoimmune diseases (e.g., idiopathic
thrombocytopenic purpura), as well as
drugs (heparin, chemotherapy).1 There are
many drugs which decrease platelet
aggregation (e.g., acetylsalicylic acid,
nonsteroidal anti-inflammatory drugs
[NSAIDs], clopidogrel) but without altering
the actual platelet count.1 Patients receiv
ing these drugs should be counselled
appropriately on bleeding risks, but will
not 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
CE4 pharmacypractice | march 2007

in the community due to age-related

declines in renal function, as well as the
high prevalence of diabetes, hypertension
and heart failure, all of which predispose
to renal dysfunction. Once renal dysfunc
tion is established, more extensive tests
such as urinalysis, ultrasound and renal
biopsies may be performed in order to
investigate the etiology of the disorder.8
As pharmacists, renal function is impor
tant to monitor since many drugs have
nephrotoxic properties (e.g., NSAIDs,
ACEIs and ARBs) and the doses of drugs
that are renally excreted (e.g., digoxin,
allopurinol, many antibiotics) will need to
be reduced in these patients.8 Renal fail
ure patients also have difficulty excreting
potassium, so cautious use of drugs which
increase serum potassium (potassium
supplements, ACEIs, ARBs, spironolac
tone) is also warranted in these patients.8
The use of ACEIs in patients with renal
dysfunction can be difficult. While ACEIs
are contraindicated in patients with
bilateral renal artery stenosis (primarily
seen in patients with extensive athero
sclerois and peripheral vascular disease),
patients with renal dysfunction secondary
to hypertension and diabetes may actually
benefit from the use of ACEIs.9 ACEIs have
been shown to decrease the development
and progression of both hypertensive and
diabetic nephropathy.9 In heart failure, the
use of ACEIs improve both hemodynamics
and decrease progression of disease lead
ing to reduced morbidity and mortality.10
Careful initiation of ACEIs with slow dose
titration, however, may be required to avoid
significant increases in serum creatinine
following initiation of drug therapy. In gen
eral, up to a 30% rise in serum creatinine
would be tolerated prior to discontinuation
of the ACEI.10 It is also important to note
that most ACEIs are renally excreted, so
the target dose in patients with renal dys
function may be lower than in those with
normal renal function.11 In addition, mon
itoring of serum potassium becomes essen
tial in these patients since they are already
predisposed to hyperkalemia as a result of
their impaired renal function. While there
are less data to support the use of ARBs
in heart failure, renal dysfunction and
hyperkalemia are as likely to occur with
the ARBs and thus, similar precautions
should 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) and
alanine aminotransferase (ALT, formerly
SGPT). These tests, however, are more
indicative 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), albumin
and bilirubin.12 The AST and ALT, how
ever, are of importance to pharmacists due
to the number of drugs (including herbal
medications) implicated in inducing
hepatic injury (e.g., acetaminophen, metho
trexate, isoniazid).13 Other common causes
of hepatocellular injury include chronic
alcohol abuse, viral hepatitis, acute heart
failure and ischemia.1,2,14
With drug-induced liver injury, it is
important to remember that, while many
drugs can cause minor increases in liver
function tests (LFTs), significant injury is
rare. Asymptomatic patients with less than
a threefold increase in LFTs should be
monitored closely with investigation of
other causes.14 Drug therapy, however,
should be reassessed when the elevations
in LFTs are significant or persistent.
The adjustment of drug dosing in patients
with liver disease has been less defined
compared to patients with renal dysfunc
tion.12 Unlike the creatinine clearance
(calculated using the serum creatinine) in
renal disease, there does not appear to
be a biochemical test in patients with
liver disease that closely correlates to
the hepatic metabolism of drugs. Often,
dosages of drugs metabolized by the liver
are, therefore, not reduced until there
appears to be significant functional hepatic
impairment, as evidenced by an increased
INR and bilirubin, as well as a decreased
serum albumin.12
Common electrolytes

Disorders of potassium homeostasis are

likely to be the most common electrolyte
abnormalities seen by pharmacists. While
hypokalemia predisposes to cardiac
arrhythmias and muscle weakness, hyper
kalemia can also result in life-threatening
cardiac arrhythmias.3 In the absence of
renal dysfunction, however, hyperkalemia
is less commonly seen. Increasing use of
the combination of ACEIs, ARBs and
spironolactone in heart failure patients has
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lead to a recent rise in hospitalizations due

to hyperkalemia.15 Therefore, this combi
nation of drugs is only recommended for
patients under careful medical supervision
(e.g., in a heart failure clinic).10
As potassium is an intracellular ion,
hyperkalemia can also be seen when there
is evidence of significant tissue damage
(e.g., rhabdomyolysis, tumour lysis syn
drome post chemotherapy) and when red
blood cells are damaged during blood sam
pling (hemolysis).3
Hypokalemia is more commonly seen,
especially in patients who are receiving
diuretics. Replacement is particularly
important 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 in
total body potassium.3 Therefore, in
patients with ongoing potassium losses
(e.g., vomiting, diarrhea, aggressive diure
sis), large doses of potassium chloride may
be 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 glycosylated
hemoglobin (HbA1c), however, provides
better information on the level of glycemic
control over a longer period of time (i.e.,
23 months). Target HbA1c levels of less
than seven per cent generally reflect fast
ing BG in the 46 mmol/L range, and post
prandial BG (2 hours post meal) in the
range of 510 mmol/L.16
International Normalized Ratio

The INR has replaced the prothrombin

time (PT) as a monitoring tool for oral anti
coagulants such as warfarin. The INR was
developed in order to account for differ
ences in reagents used when conducting
the PT test. The normal INR is one, with
a target of two to three for most conditions
requiring anticoagulation.17 The INR is
measured routinely in patients receiving
warfarin to ensure adequacy of anticoagu
lation, without an increased risk of bleed
ing. Although intensive INR monitoring is
done when oral anticoagulation is initiated,
the frequency of monitoring decreases
(i.e., to monthly) as patients become sta
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bilized on therapy. As many drugs (e.g.,

antibiotics, amiodarone) 17 have the poten
tial to interact with warfarin, more frequent
monitoring of the INR is required when
new drugs are added or discontinued.
Thyroid function tests

Hypothyroidism is common, particularly

in 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 American
Thyroid Association.18 The usual screening
test is the Thyroid Stimulating Hormone
(TSH) test, which shows increased levels
in patients with hypothyroidism. Confirma
tory tests such as checking free T3 and T4
levels are usually completed if the TSH is
elevated. Once supplemental thyroxine has
been initiated, response to therapy will be
monitored by repeat TSH levels,
usually six to eight weeks following initia
tion of therapy.19

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 ratio
is < 4. Moderate-risk patients should be
treated if their LDL-C is > 3.5 mmol/L or
their TC:HDL-C ratio is > 5. Low-risk
patients should be treated if their LDL-C
is > 5 mmol/L or their TC:HDL-C ratio is
> 6. The target for both the low- and
moderate-risk patients is a 40% reduction
in their LDL-C.20
If therapy is instituted, repeat choles
terol levels are usually done every six
weeks, until the target levels are achieved.
Once the target cholesterol levels are
reached, periodic monitoring every four to
six months is recommended.22

Creatine kinase

With the increasing use of high-dose sta

tins to prevent cardiovascular morbidity
and mortality,20 monitoring of creatine
kinase (CK) levels has become more com
mon. CK is increased when muscle is
Lipids
injured and thus, can be increased even
With the aging population and the increas with strenuous exercise or intramuscular
ing prevalence of obesity and diabetes, injections.1,2 There are several subunits of
targeting high cholesterol has become an the CK enzyme, the most common being
important factor in the attempt to reduce the CK-MM isoenzyme found primarily in
the burden of cardiovascular disease. skeletal muscle. The CK-MB fraction, pri
There is also an abundance of evidence marily found in cardiac muscle, has tradi
that the use of drug therapy, in particu tionally been used in the diagnosis of
lar the HMG Co-A reductase inhibitors myocardial infarctions.1,2 The CK-MB has
(statins), significantly reduces the risk of now largely been replaced by the troponin
cardiovascular morbidity and mortality.20 level, which is a much more sensitive and
Cholesterol and triglycerides are trans earlier indicator of myocardial damage.2
ported in the body as lipoproteins. The two The statins, as well as other fibrates, how
major classes of lipoproteins are the low- ever, can cause myositis and increase the
density lipoproteins (LDL-C) and the high- total CK.20 Myalgias can occur in the
density lipoproteins (HDL-C). Elevated absence of a rise in CK. It is controversial
total and LDL cholesterol, as well as low whether patients receiving statin therapy
HDL cholesterol have been linked with should routinely have their CK measured.
the development of coronary heart disease, If patients develop myalgias, CK can be
specifically coronary atherosclerosis and measured; if significantly increased from
ischemic heart disease. The total choles baseline, the statin dose can be lowered or
terol (TC): HDL-C ratio appears to be a the drug can temporarily be held.23
more specific and sensitive predictor of
Total CK levels will also be increased
cardiovascular risk compared to the total in pathologic conditions affecting skeletal
cholesterol level.21
muscle including rhabdomyolysis, status
The current targets for the ratio of epilepticus, malignant hyperthermia and
LDL-C and TC: HDL-C ratio are based on neuroleptic malignant syndrome.1,2
a patients 10-year risk of coronary artery
disease-related death or nonfatal myocar Drug levels
dial infarction.20 Patients with risk factors As many factors may affect the response
for coronary artery disease (e.g., smoking, of drugs in different patients (e.g.,
diabetes, family history, hypertension, pharmacokinetics, genetics, concurrent
male > 40, female > 50) should therefore medical conditions, compliance), there is
be screened for hyperlipidemia and catego usually a good correlation between drug
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Laboratory test monitoring in community practice

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 several
factors:24 a reliable assay must be com
mercially available; there must be a cor
relation between drug concentrations in
the blood and efficacy and/or toxicity; and
the drug must have a narrow therapeutic
index (i.e., doses or concentrations which
produce toxicity are just above those which
are efficacious). The availability of drug
levels, 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 poor
correlation between drug response and the
concentration of the antidepressant in the
blood. Similarly, in a tricyclic antidepres
sant overdose, clinical signs and symptoms
(i.e., ECG changes) are more predictive of
toxicity than the serum concentration.25
For many drugs, the concentrations in the
blood do not necessarily reflect concentra
tions at the drugs site of action (e.g., cen
tral nervous system or cardiac tissue) and
therefore, in these cases, the use of a
therapeutic end point (e.g., INR, blood
pressure) is more valuable for dosage
individualization.
Provided the above criteria apply, thera
peutic drug monitoring is primarily done on
drugs with a narrow therapeutic range. Indi
cations for drug levels include suspicion of
toxicity, suspected drug interactions, chang
ing renal or hepatic function, monitoring of
patient compliance or investigation of a poor
response.24 Routine monitoring of levels, in
the absence of a valid indication, is costly
and unnecessary.

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: 1.02.6 nmol/L), and she would like to
know whether there is an antidote for digoxin.

Similar to abnormal laboratory results,

interpretation of drug levels requires
knowledge of the testing methods as well
as the pharmacokinetics of the particular
drug. Consideration must also be given to
substances that cross-react or interfere
with individual drug assays. Several
CE6 pharmacypractice | march 2007

pharmacokinetic parameters, including

distribution, metabolism, protein binding
and the elimination half-life, will also
influence the interpretation of drug levels.24
Levels drawn prior to the completion of the
distribution phase of the drug may be arti
ficially elevated. This is particularly impor
tant with digoxin, which has a distribution
phase of up to six to eight hours; levels
taken prior to completion of the distribu
tion phase will produce levels that
are alarmingly higher than the normal
reference range. Levels taken prior to dose
administration (i.e., trough levels) avoid
this problem.26

response to case B
In order to make a decision regarding the treatment of this patients high digoxin level, a couple 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 repeated, but prior to the administration of the
digoxin (i.e., trough level).

As most assays measure the parent drug,

therapeutic drug monitoring with drug
levels will be of little use if the metabolite
of a drug is responsible for the therapeutic
activity. Most assays also measure the total
concentration of drug, rather than the free
or unbound portions of the drug.24 Unfor
tunately, it is actually the unbound drug
that is responsible for therapeutic activity.
Therefore, for drugs that are highly protein
bound, 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 the
total drug concentration is measured. For
example, the target therapeutic concen
trations for phenytoin are between
4080 mol/L. Assuming that phenytoin
is 90% protein bound, these total concen
trations correlate with free concentra
tions of 48 mol/L (i.e., 10% of the total
concentration). In a patient with a low albu
min who now has a free fraction of 20%, a
phenytoin level (total drug) which returns
as 60 mol/L will now correlate to a free
concentration of 12 mol/L (20% of 60

mol/L). The level of 60 mol/L appears

to be in the therapeutic range of 4080
mol/L (for total drug) but actually exceeds
the free therapeutic range (48 mol/L).
As it is the free or unbound portion of the
drug that is active, this patient is, therefore,
at risk of toxicity, even though his total
level appears to be normal.27
Finally, for most drugs, levels taken at
steady state are most desirable.24 Thus,
knowledge of the elimination half-life is
required to determine the timing of the
drug level relative to the initiation of drug
therapy. For drugs with a short half-life
(e.g., theophylline), drug levels taken
within two to three days of dosage adjust
ment likely reflect steady-state concentra
tions.24 In contrast, for drugs with a long
half-life (e.g., digoxin), steady state is not
usually reached for five to seven days, and
levels taken before this time may under
estimate steady-state concentrations.24,26
While therapeutic drug monitoring with
the use of drug levels was very popular
several decades ago, its use has diminished
with the declining use of drugs that have
been traditionally assayed (e.g., theophyl
line, antiarrhythmics).

The pharmacists role

In order for pharmacists to play an integral

role in the multidisciplinary care of
patients, an understanding of common
laboratory tests is required. These labora
tory values may represent target end points
for drug therapy (e.g., INR, HbA1c, lipid
profile) or adverse effects secondary to drug
therapy (e.g., LFTs, CKs), or require modi
fication of drug therapy (e.g., reduction in
dose of drugs that are renally excreted).
With respect to end points of therapy, phar
macists can also play an important role in
promoting compliance with drug therapy
and empowering patients to take respon
sibility for achieving appropriate targets
(e.g., HbA1c, LDL-C).

Summary

In conclusion, interpretation of abnormal

laboratory results and drug levels requires
a systematic approach involving an under
standing of the test specifics, as well as
clinical insight. Abnormal results should
not always be taken at face value, and
evaluation of other relevant factors must
be completed prior to initiation of action
based on the test.

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Laboratory test monitoring in community practice

References

1. 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 therapeutics: the
clinical use of drugs, 8th ed. Baltimore, MD: Lippincot, Williams and
Wilkins; 2005: 2-12-22. 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: 31-131-22.
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, 4th 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, 6th 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 thyroid
dysfunction. 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 pharmacokinetics. In: Evans WE, Schentag JJ, Jusko WJ, eds. Applied
pharmacokinetics. Principles of therapeutic drug monitoring, 3rd ed.
Vancouver, WA: Applied Therapeutics Inc., 1992; 1-21-8.
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; 20-120-48. 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; 25-125-44.

Questions
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 doctors office called
him to say his potassium level returned as
high. All of the following could contribute to
hyperkalemia except:
a) ramipril
b) renal dysfunction
c) hemolysis of the blood sample
d) hydrochlorothiazide
5 The most appropriate management of
NBs 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.

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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 (115165 g/L)
MCV: 115 (7698 fL)
WBC: 12 (411 x 10-9/L )
platelet: 450 (150400 x 10-9/L )
Which of the following statements regarding
TKs 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 require
antibiotics.
d) TKs 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 following 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 admission, indicates the following: allopurinol 300
mg po daily, enalapril 10 mg po BID, hydrochlorothiazide 25 mg po daily, potassium chloride
20 mmol po BID. Which of the following statements regarding DBs medications is true?
a) T
 he 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 calculated 10-year risk of coronary artery disease.
b) CKs should be monitored every two weeks for
three 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 diagnosed with heart failure and is started on
furosemide and captopril. Which of the following statements is true regarding SGs 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

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Laboratory test monitoring in community practice

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 function, 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 indicator of long-term glycemic control than serial
blood glucose levels.
a) true
b) false
15 Which of the following statements regarding the use of INR monitoring in patients
receiving warfarin is false?
a) The prothrombin time (PT) is used for the monitoring 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.

a) length of distribution phase

b) elimination half-life
c) protein binding
d) all of the above

16 Which of the following statements regarding 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.

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

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 pharmacokinetic parameters is required in order
to appropriately interpret drug levels?

20 You are called by a family physician in your

medical building asking for advice on a
patients toxic digoxin level. Which of the following 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 relationship 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
This month
Laboratory test monitoring in community practice
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, hypothyroidism, diagnostic tests in adrenal diseases, fluid
and electrolyte imbalance, and electrolyte replacement protocols.

CE8 pharmacypractice | march 2007

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
honey.fisher@pharmacygroup.rogers.com

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This lesson is supported by an unrestricted grant
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