Peak Development for ...

Medication Administration

Vol. 16 Issue 10
October 2015

Promoting Safety:
Drugs with a Narrow Therapeutic Index
Peak Development Resources
P.O. Box 13267
Richmond, VA 23225
Phone: (804) 233-3707
Fax: (804) 233-3705
Email: editor@peakdev.com

Peak Development for Medication

Administration and Competency
Assessment Tool for Medication
Administration are components of
a site license for the Peak
Development Resources
Competency Assessment System
for Medication Administration
and may be reproduced for this
individual facility only. Sharing
of these components with any
other freestanding facility within
or outside the licensees corporate
entity is expressly prohibited.

The information contained in

Peak Development for Medication
Administration is intended only as
a guide for the practice of
licensed nursing personnel who
administer medications. Every
effort has been made to verify the
accuracy of the information
herein. Because of rapid changes
in the field of drug therapy, the
reader is advised to consult the
package insert, facility pharmacist
or patients physician for relevant
information. This is particularly
important for new or seldom used
drugs. Use of professional
judgment is required in all patient
care situations. It is the readers
responsibility to understand and
adhere to policies and procedures
set forth by the employing
institution. The editor and
publisher of this newsletter
disclaim any liability resulting
from use or misuse of
information contained herein.
Copyright 2015

After completion the learner should be able to:

1. Define therapeutic index and its implications.
2. Identify four NTI drugs and related
assessment for toxicity.
3. Discuss measures designed to decrease
the risk of adverse effects with NTI drugs.
4. Correctly calculate dosage of NTI drugs.
According to recent data from the US Centers
for Disease Control and Prevention (CDC),
prescription drug use in the US continues to
increase. Since 1994, the percentage of
Americans taking at least one prescription drug
in the past 30 days increased from 39.1% to
47.3%. Use of multiple prescription drugs has
also increased. The rate of those taking 5 or more
drugs has more than doubled in the last two
decades, from 4% of the population to over 10%.
Medication use has significant, and
sometimes life-saving, benefits for those who
need it. But it also carries the risk of adverse
drug events (ADEs), unwanted and undesirable
drug side effects. Over 700,000 Americans are
seen in the emergency department (ED) each
year for treatment of ADEs, and 17% of these
require hospitalization. Adults 65 years and older
are twice as likely to come to the ED with ADEs
as other age groups, and 7 times more likely to
be hospitalized as a result. Also, overall deaths
due to ADEs have increased, from 35,000 to
118,000 annually in the last 10 years.
Of the drugs causing these ADEs, the
majority had a narrow therapeutic index. This
means that the difference between a therapeutic
dose and a toxic dose is relatively small. The
therapeutic index of a drug is an important
characteristic that must be considered by
physicians, nurses, pharmacists and any other
healthcare providers involved in medication use.
Therapeutic index Definition & Significance
The therapeutic index is the range of doses
or blood levels at which the drug is effective
without signs of toxicity, and serves as a relative
measure of a drugs safety. It is calculated as a
ratio between a drugs average therapeutic dose

and its average lethal dose, or between the

drugs minimum effective and minimum toxic blood
concentrations. For example, if the average
effective dose of drug A is 2.5 mg, and the
average lethal dose is 150 mg, the ratio would be
150/2.5, for a therapeutic index of 60. Using
blood concentrations as an example, if drug B
has a lowest effective serum level of 20 mcg/ml
and lowest toxic serum level of 35 mcg/ml, the
therapeutic index is 35/20, or 1.75.
The higher the therapeutic index, the lower
the drugs risk for toxicity and adverse effects is
considered to be. Conversely, the lower the
therapeutic index number, the higher is the
drugs risk. Drugs having a low therapeutic index
are identified as narrow therapeutic index
(NTI) drugs. Other terms that may be used
include narrow therapeutic range, narrow
therapeutic window, narrow therapeutic ratio and
critical dose drugs.
The FDA defines NTI drugs as those with a
therapeutic index of less than 2, and that safe
and effective use of the drug products requires
careful dosage titration and patient monitoring.
The FDA also states that these are drugs where
small differences in dose or blood concentration
may lead to dose- and blood concentrationdependent, serious therapeutic failures or
adverse drug reactions. Serious events are
persistent, irreversible, slowly reversible, or lifethreatening, possibly resulting in hospitalization,
disability, or even death.
Characteristics of NTI drugs include:
little separation between therapeutic and toxic
doses or blood concentrations
sub-therapeutic concentrations lead to
serious therapeutic failure
subject to therapeutic drug monitoring (TDM)
have low-to-moderate within-subject variability,
meaning the drugs effects on an individual tend
to remain stable
in clinical practice, doses are often adjusted
in very small increments (<20%)

NTI Drugs
There are a number of drugs in common use having a
narrow therapeutic index. In a CDC study of adverse effects
that resulted in hospitalization in adults age 65 and over,
warfarin, a drug with a narrow therapeutic index, caused the
greatest percentage. While the FDA has not created a
comprehensive list of NTI drugs, selected drugs commonly
identified as having a NTI include:
Aminoglycosides: Antibiotics such as gentamicin, tobramycin
and amikacin are used for treatment of serious infections. Drug
serum levels, as well as BUN and creatinine, are evaluated to
reduce risk of nephrotoxicity and ototoxicity. This monitoring
may not be required in patients with normal renal function and
short duration of therapy, such as < 37 days. Peak and
trough drug levels are obtained for monitoring. Peak levels
help to ensure that the amount of drug is sufficient to kill the
bacteria. Trough levels help to ensure that the drug is being
adequately cleared by the kidneys, so that the risk of drug
build-up and toxicity is reduced. These levels vary, depending
on the drug used, severity of infection, and dosage.
Carbamazepine: This drug is indicated for treatment of
epilepsy and trigeminal neuralgia. It is monitored using serum
drug levels, with a target range of 412 mcg/ml, and toxicity
>15 mcg/ml. Signs of toxicity include drowsiness, tremors,
shock, respiratory depression and tachycardia.
Digoxin: Prescribed for treatment of heart failure and atrial
fibrillation, digoxin caused more than 1% of emergency visits
for ADEs in patients age 40 and over in a CDC study. Target
serum levels are 0.52 ng/ml; signs of toxicity have
commonly occurred at levels of 2 ng/ml and above. Signs
include nausea/vomiting, bradycardia and other dysrhythmias,
and visual changes, such as blurred or yellow vision.
Levothyroxine: Thyroid replacement drugs, such as
Synthroid, are dosed in very small amounts. Small changes in
dosage can cause significant under or over-medication. The
drug is monitored using levels of thyroid stimulating hormone
(TSH) and clinical signs/symptoms, such as heart rate, blood
pressure, and signs of hypo or hyperthyroidism. TSH levels
ranging from 0.454.12 mlU/L are recommended for adults.
Lithium: This drug is used as a mood stabilizer in treatment of
bipolar disorder. Target adult lithium levels may range from
0.61.2 mEq/L, depending on the individuals needs. Toxicity,
usually with levels above 1.5 mEq/L, may cause tremors,
slurred speech, seizures, renal damage and hypothyroidism.
Phenytoin: Target adult serum levels for this antiepileptic drug
are 1020 mcg/ml, with toxicity likely at levels above 30 mcg/
ml. Signs of toxicity include nystagmus, lethargy and
confusion.

Theophylline: Theophylline is a bronchodilator indicated for

treatment of asthma and other chronic lung diseases. Target
serum drug levels range from 1020 mcg/ml. Signs of toxicity
include nausea/vomiting, tachycardia and other dysrhythmias,
hypotension and seizures.
Warfarin: This commonly-used anticoagulant requires
frequent monitoring due to risk of clot formation and bleeding.
Prothrombin time is used to measure warfarin effects,
expressed as the International Normalized Ratio (INR). The
target range for most patients is an INR value of 23, possibly
higher for some patients. An INR >5 generally indicates
toxicity. Signs include bleeding, bruising, and tarry stools.
Nursing Implications
NTI drugs require ongoing monitoring to ensure that
optimum therapeutic effects are occurring and to prevent and
detect adverse effects. It is important to remember that drugs
have varying effects on individual patients. Even when a drug
dose or serum drug level is within the normal range, this may
be too much or too little drug for the individual. Toxicity or lack
of therapeutic effects can occur. So, in addition to verifying
recommended dosages and monitoring serum drug levels for
NTI drugs, continue to assess the patient closely for signs of
toxicity and therapeutic effects, even when other parameters
are within normal limits. If signs of toxicity occur, hold the drug
and notify the prescriber. Also, pay careful attention to possible
drug interactions, since altered serum levels of NTI drugs are
more likely to cause patient harm..
Because exact dosage is so important with NTI drugs,
tablets should preferably not be split. Even slight differences in
dose may result in an inadequate or excessive dosage. If splitting
is necessary, care should be used to obtain equal halves.
Use caution when generic NTI drugs are substituted for
the original branded medication, as some patients have had
adverse responses when switched to a generic version. For
example, the FDA reports that the majority of physicians
surveyed regarding anti-epileptic drugs had seen breakthrough
seizures occur with generic substitution of these drugs, and
therefore write prescriptions for brand name only. Some states
have laws regulating the substitution of NTI drugs with generic
equivalents, requiring that the prescriber and patient are
notified about and agree to the substitution. Be familiar with
the laws in your state. Patients switching manufacturers for
their NTI medications should be closely monitored for
therapeutic and adverse effects.
A thorough knowledge base, proper use of laboratory and
clinical assessment data, and careful administration practices
are all essential components to promote safe and therapeutic
use of NTI drugs.

Peak Development for Medication Administration

Promoting Safety: Drugs with a Narrow Therapeutic Index

Page 2

Peak Development for ...

Medication Administration
Competency Assessment Tool

Vol. 16 Issue 10
October 2015

Promoting Safety:
Drugs with a Narrow Therapeutic Index
NAME:

DATE:

UNIT:

Directions: Place the letter of the one best answer in the space provided.
_____1. Due to the current emphasis on disease prevention in the US, use of prescription drugs has
decreased significantly in the last 20 years.
A. True
B. False
_____2. The therapeutic index of a drug identifies the range of doses or blood levels at which:
A. the drug is effective without signs of toxicity
B. toxicity occurs
C. the drug is not effective in achieving therapeutic goals
D. either too much or too little drug is given
_____3. The lower the therapeutic index number, the higher is the drugs risk to the patient.
A. True
B. False
_____4. Which of the following drugs is LEAST likely to require monitoring of serum drug levels:
A. gentamicin
B. theophylline
C. furosemide
D. carbamazepine
_____5. Which of the following is used to monitor the effectiveness of levothyroxine therapy:
A. levothyroxine serum drug level
B. thyroid stimulating hormone level
C. serum prolactin level
D. all of the above

_____6. Drug toxicity cannot occur as long as the serum drug level is maintained within the
therapeutic range.
A. True
B. False
_____7. The INR (International Normalized Ratio) test is commonly used to monitor the effects of:
A. warfarin
B. heparin
C. lithium
D. digoxin
_____8. For most patients, the INR target range is:
A. less than 1
B. 12
C. 23
D. 56
_____9. Mrs. Adams is an 80-year old patient who takes digoxin as part of her drug therapy for atrial
fibrillation. When the nurse brings in her digoxin dose, Mrs. Adams complains of
severe nausea and my vision is blurryI cant see too well this morning. Her pulse is 60/
min and irregular, fairly typical for Mrs. Adams. The nurse checks the chart for her most
recent digoxin level, which is 1.8, within the normal laboratory range. The nurse should:
A. give Mrs. Adams the scheduled digoxin dose
B. wait a few hours to give the digoxin dose to see if her symptoms improve
C. call the prescriber to request an increased dose, since her a fib seems to be worsening
D. hold the dose and notify the prescriber of Mrs. Adams symptoms
_____10. Drug order: Phenytoin suspension 200 mg PO three times daily
Drug label: Phenytoin suspension 125 mg per 5 ml
Give:
A. 4 ml
B. 6 ml
C. 8 ml
D. 9 ml

Competency Assessment Tool

Promoting Safety: Drugs with a Narrow Therapeutic Index

Page 2

Peak Development for ...

Medication Administration

Month: October 2015

Issue:
Promoting Safety: Drugs with a
Narrow Therapeutic Index

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