718 Unit 6 Pharmacology of Body Defenses
Table 40.2 Selected Chemical Mediators of Inflammation
Mediator Description
Bradykinin Protein present in an inactive form in plasma and mast cells; increases vascular permeability and causes pain; effects are similar
to those of histamine; broken down by angiotensin-converting enzyme (ACE).
Complement
Series of at least 20 proteins that combine in a cascade fashion to neutralize or destroy an antigen; stimulates histamine release
C-reactive protein by mast cells; causes cell lysis.
Cytokines
Occurs as an early response to acute inflammation; activates complement; used as a biomarker to gauge the extent of inflammation.
Histamine
Leukotrienes Proteins produced by macrophages, leukocytes, and dendritic cells that mediate and regulate immune and inflammatory reactions;
examples include interleukins and tumor necrosis factor (TNF)
Prostaglandins
Stored and released by mast cells; causes vasodilation, smooth muscle constriction, tissue swelling, and itching.
Lipids stored and released by mast cells; effects are similar to those of histamine; synthesized from arachidonic acid; responsible
for some symptoms of asthma and allergies.
Lipid present in most tissues and stored and released by mast cells; increase capillary permeability, attract white blood cells to the site
of inflammation, cause pain, and induce fever; aspirin inhibits their synthesis; some are available as medications.
and associated repair processes by raising the temperature autoimmune disorders such as lupus and rheumatoid
of the body. When excessive, however, fever can harm the arthritis (RA), inflammation may persist for years, with
body and must be treated with drugs known as antipyretics symptoms becoming progressively worse over time. Other
(see Chapter 41). From a pharmacologic perspective, one of disorders such as seasonal allergy arise at predictable times
the most important nonspecific defenses is inflammation. during each year, and inflammation may produce only
Because of its significance, inflammation is presented sepa- minor, annoying symptoms.
rately in Sections 40.3 and 40.4.
40.4 Inflammation proceeds with the release
Interferons (IFNs) are antimicrobial proteins that are of chemical mediators.
crucial components of the innate body defense system.
Released by infected macrophages and lymphocytes, IFNs During inflammation, pathogens, chemicals, or physical
protect uninfected cells from pathogens. IFNs have been trauma cause the damaged tissue to release chemical
isolated and are now available as medications for the treat- mediators that act as alarms to notify the surrounding area
ment of immune disorders (see Chapter 42), viral infections of the injury. Chemical mediators of inflammation include
(see Chapter 54), and cancer (see Chapter 57). histamine, leukotrienes, bradykinin, complement, and
prostaglandins. These inflammatory mediators, some of
Inflammation which are listed in Table 40.2, are called proinflammatory
substances. Several inflammatory mediators are important
40.3 Inflammation is a nonspecific defense targets for anti-inflammatory drugs. For example, aspirin
mechanism that neutralizes or destroys foreign and ibuprofen are prostaglandin inhibitors that are effec-
substances and microbes. tive at treating fever, pain, and inflammation.
Inflammation occurs in response to many different stim- The rapid release of the chemical mediators of inflam-
uli, including physical injury, exposure to toxic chemicals, mation on a large scale throughout the body is responsible
extreme heat, invading microorganisms, or death of cells. for anaphylaxis, a life-threatening allergic response that
Inflammation is considered a nonspecific defense mecha- may result in shock and death. A number of chemicals,
nism because it proceeds in the same manner regardless of insect stings, foods, and some therapeutic drugs can cause
the cause. this widespread release of histamine from mast cells if the
individual has an allergy to these substances.
The central purposes of inflammation are to contain
the injury, destroy the pathogen, and initiate repair of the Histamine is a key chemical mediator of inflamma-
area. The repair of the injured area can proceed at a faster tion. It is stored primarily within mast cells located in tis-
pace by neutralizing the foreign agent and removing cel- sue spaces under epithelial membranes such as the skin,
lular debris and dead cells. Signs of inflammation include bronchial tree, and digestive tract and along blood vessels.
swelling, pain, warmth, and redness of the affected area. Mast cells detect foreign agents or injury and respond by
releasing histamine, which initiates the inflammatory
Inflammation may be classified as acute or chronic. response within seconds. In addition to its role in inflam-
During acute inflammation, such as that caused by minor mation, histamine also directly stimulates pain receptors
physical injury, 8 to 10 days are normally needed for the and is a primary agent responsible for the symptoms of
symptoms to resolve and for repair to begin. If the body seasonal allergies.
cannot neutralize the damaging agent, inflammation may
continue for long periods and become chronic. In chronic
Chapter 40 Review of Body Defenses and the Immune System 719
Vasodilation
(redness, heat)
Cellular Release of Vascular
injury chemical permeability
mediators (edema)
Mast cell • histamine
• bradykinin Cellular
• complement infiltration
• leukotrienes (pus)
Thrombosis
(clots)
Stimulation of
nerve endings
(pain)
Figure 40.2 Steps in acute inflammation.
When released at an injury site, histamine dilates Specific (Adaptive) Body Defenses
nearby blood vessels, causing the capillaries to become
more permeable. Plasma, complement proteins, and phago- 40.5 The specific body defenses include the
cytes can then enter the area to neutralize microbes or their humoral and cell-mediated immune systems.
toxins. The affected area may become congested with blood,
which can lead to significant swelling and pain. Figure 40.2 The body also has the ability to mount a third line of
illustrates the fundamental steps in acute inflammation. defense that is specific to certain threats. For example, a
specific defense may act against only a single species of
Histamine interacts with two different receptors to bacteria and be ineffective against all others. These are
elicit an inflammatory response. H1 receptors are present in known as adaptive defenses or, more commonly, the
the smooth muscle of the vascular system, the respiratory immune response. The primary cell of the immune
passages, and the digestive tract. Stimulation of these response is the lymphocyte.
receptors results in itching, pain, edema, vasodilation, bron-
choconstriction, and the characteristic symptoms of inflam- Microbes and foreign substances that elicit an immune
mation and allergy. In contrast, H2 receptors are present response are called antigens. Foreign proteins, such as
primarily in the stomach, and their stimulation results in those present on the surfaces of pollen grains, bacteria,
the secretion of large amounts of hydrochloric acid. nonhuman cells, and viruses, are the strongest antigens.
Typically, only a small fragment or piece of a foreign pro-
Drugs that act as specific antagonists for H1 and H2 tein is required to activate the immune system. It is esti-
receptors are in widespread therapeutic use. H1-receptor mated that the immune system is able to recognize and
antagonists, which are used to treat allergies and inflamma- react to over a billion different antigens.
tion, are discussed in Chapter 45. H2-receptor antagonists are
used to treat peptic ulcers and are discussed in Chapter 59. The immune response is extremely complex. Several
important aspects of the immune response are discussed next.
CONNECTION Checkpoint 40.1
Specificity: Each aspect of the immune response recog-
In addition to being a mediator of inflammation, bradykinin is respon- nizes only particular pathogens and not others. Recogni-
sible for one of the most common adverse effects of ACE inhibi- tion of the antigen is dependent on the immune cells
tors. From what you learned in Chapter 31, describe this adverse interacting with specific foreign proteins. Once an immune
effect. Answers to Connection Checkpoint questions are available on response is mounted, it generally only affects the one spe-
the faculty resources site. Please consult with your instructor. cific antigen that was recognized.
720 Unit 6 Pharmacology of Body Defenses
Systemic: Despite being specific to a particular antigen, It is important to remember that the body contains mil-
the immune response is systemic. Thus antigens that exist lions of different B cells, each programmed to react to a spe-
in remote regions beyond the initial site of infection will be cific antigen. These B cells, in turn, are able to construct
neutralized. millions of different types of antibodies, each specific to a
particular antigen. The body is preprogrammed with the
Memory: After an antigen interaction occurs, cells of the genetic information to defend against millions of different
adaptive immune system remember the immune response. antigens. Although it is unlikely that an individual will
This is different from the components of nonspecific ever be infected during a lifetime with all the different anti-
defenses, which have no memory. Upon subsequent expo- gens, the body is waiting for the challenge.
sures to the same antigen, the body is able to mount a stron-
ger and more rapid response. PharmFACT
The basic steps of the immune response involve recog- Once generated, a single plasma cell is capable of
nition of the antigen, communication and coordination manufacturing antibodies at an astounding rate, as many as
with other defense cells, and destruction or suppression of 2000 antibodies each second. The cell dies after about 4 to
the antigen. A large number of chemical messengers and 5 days (Marieb & Hoehn, 2016).
complex interactions are involved in the immune response,
many of which have yet to be discovered. The two primary Cell-Mediated Immune Response
divisions of the immune response are antibody-mediated
(humoral) immunity and cell-mediated immunity. 40.7 The cell-mediated immune response is
mediated by T lymphocytes and includes the
Humoral Immune Response secretion of cytokines.
40.6 The humoral immune response is mediated A second branch of the immune response involves T lym-
by B lymphocytes and includes the secretion of phocytes, or T cells. Two major types of T cells are called
antibodies. helper T cells and cytotoxic T cells. These cells are named
after a protein receptor on their plasma membrane. The
The humoral immune response is triggered when an anti- helper T cells have a CD4 receptor, and the cytotoxic T cells
gen encounters a B lymphocyte, more simply known as a have a CD8 receptor. The helper (CD4) T cells are particu-
B cell. The activated B cell divides to form millions of larly important because they are responsible for activating
identical copies of itself in a process known as clonal divi- most other immune cells, including B cells and other types
sion. Most cells in this clone are called plasma cells, and of T cells. Cytotoxic (CD8) T cells travel throughout the
their primary function is to secrete antibodies specific to body, directly killing certain bacteria, parasites, virus-
the antigen that initiated the challenge. Each plasma cell is infected cells, and cancer cells.
capable of manufacturing antibodies at an astounding rate,
as many as 2000 each second. PharmFACT
Circulating through body fluids are antibodies, also T cells move quickly throughout the body. In a typical day, a
known as immunoglobulins (Ig), which physically interact T cell may spend 30 minutes in the blood, 5 to 6 hours in the
with antigens to neutralize or mark them for destruction by spleen, and 15 to 20 hours in a lymph node (Martini, Nath,
other cells of the immune response. The activation of com- & Bartholomew, 2015).
plement, with subsequent inflammation and enhanced
phagocytosis, is a major defense mechanism resulting from T cells rapidly form clones after they are activated or
the formation of antigen–antibody complexes. Peak pro- sensitized following an encounter with their specific anti-
duction of antibodies occurs about 10 days after an initial gen. Unlike B cells, however, T cells do not produce anti-
antigen challenge. The important functions of antibodies bodies. Instead, activated T cells produce huge amounts of
are illustrated in Figure 40.3. cytokines, which are hormone-like proteins that regulate
the intensity and duration of the immune response and
After the antigen challenge, memory B cells are formed mediate cell-to-cell communication. Some cytokines kill for-
that will remember the specific antigen–antibody interac- eign organisms directly, whereas others induce inflamma-
tion. Should the body be exposed to the same antigen in the tion or enhance the killing power of macrophages. Specific
future, the humoral immune system will manufacture even cytokines released by activated T cells include interleukins,
higher levels of antibodies in a shorter period, approxi- gamma interferon, tumor necrosis factor (TNF), and perfo-
mately 2 to 3 days. For some antigens, such as those for mea- rin. Some cytokines are used therapeutically to stimulate
sles, mumps, or chickenpox, memory can be retained for an the immune system (see Chapter 42). Small amounts of
entire lifetime. Vaccines are sometimes administered to pro-
duce these memory cells in advance of exposure to the anti-
gen, so that when the body is exposed to the actual organism
it can mount a fast, effective response (see Chapter 43).
Chapter 40 Review of Body Defenses and the Immune System 721
6 Activates complement Antigen 1 Activates B
Complement binding lymphocytes
site
Antigen binds
to antibody
5 Triggers mast cell Antibody Memory Plasma
degranulation cells cells
Secrete
antibodies
NK cell or eosinophil 2 Acts as opsonins
4 Activates antibody-
Bacterial
dependent cellular toxins
activity
3 Causes antigen clumping
and inactivation of
bacterial toxins
Enhanced
phagocytosis
Figure 40.3 Functions of antibodies.
From Human Physiology: An Integrated Approach (5th ed.), by D. U. Silverthorn, 2010. Printed and electronically reproduced by permission. Upper Saddle River,
NJ: Pearson Education, Inc.
cytokines are also secreted by certain macrophages, B lym- CONNECTION Checkpoint 40.2
phocytes, mast cells, endothelial cells, and the stromal cells
of the spleen, thymus, and bone marrow. Proinflammatory cytokines such as interleukin-1 and TNF have been
associated with a higher risk of Alzheimer’s disease and progres-
Like B cells, some sensitized T cells become memory sion of this disorder. From what you learned in Chapter 21, describe
cells. If the patient encounters the same antigen in the the primary drug classes for treating Alzheimer’s disease. Answers
future, the memory T cells assist in mounting a more rapid to Connection Checkpoint questions are available on the faculty
immune response. resources site. Please consult with your instructor.
Understanding Chapter 40
Key Concepts Summary 40.2 Innate body defenses are the body’s first line
of defense against pathogens.
40.1 The lymphatic system is the primary organ system
that protects the body from invasion by foreign agents.
722 Unit 6 Pharmacology of Body Defenses 40.6 The humoral immune response is mediated by
B lymphocytes and includes the secretion of
40.3 Inflammation is a nonspecific defense mechanism antibodies.
that neutralizes or destroys foreign substances and
microbes. 40.7 The cell-mediated immune response is mediated
by T lymphocytes and includes the secretion of
40.4 Inflammation proceeds with the release of chemical cytokines.
mediators.
40.5 The specific body defenses include the humoral
and cell-mediated immune systems.
References Marieb, E. & Hoehn, K. N. (2016). Human anatomy and
physiology (10th ed.). Hoboken, NJ: Pearson.
Dieterich, L. C., & Detmar, M. (2016). Tumor
lymphangiogenesis and new drug development. Martini, F. H., Nath, J. L., & Bartholomew, E. F. (2015).
Advanced Drug Delivery Reviews, 99, 148–160. Fundamentals of human anatomy and physiology (10th ed.).
doi.org/10.1016/j.addr.2015.12.011 San Francisco, CA: Benjamin Cummings.
Krogh, D. (2014). Biology: A guide to the natural world,
technology update (5th ed.). San Francisco, CA: Benjamin
Cummings.
Selected Bibliography Silverthorn, D. U. (2016). Human physiology: An integrated
approach (7th ed.). Hoboken, NJ: Pearson.
DiPiro, J. T., Talbert, R. L., Yee, G. C., Matzke, G. R., Wells,
B. G., & Posey, L. M. (Eds.). (2014). Pharmacotherapy:
A pathophysiologic approach (9th ed.). New York, NY:
McGraw-Hill.
“I haven’t been feeling good this
week. It’s probably just the flu
like all my friends have. I’ll just
take some of the aspirin my mom
uses for her arthritis so I don’t
miss school and I’ll be fine.”
Patient “Joycee Layne”
Chapter 41
Pharmacotherapy
of Inflammation and Fever
Chapter Outline Learning Outcomes
cc Pathophysiology of Inflammation and Fever After reading this chapter, the student should be able to:
cc Pharmacotherapy of Inflammation
cc Nonsteroidal Anti-Inflammatory Drugs 1. Explain the pathophysiology of inflammation and
fever.
Salicylates
PROTOTYPE Aspirin (Acetylsalicylic Acid), p. 728 2. Identify drug classes used to treat inflammation and
Ibuprofen-Like Drugs fever.
PROTOTYPE Ibuprofen (Advil, Motrin,
Others), p. 731 3. Explain how aspirin damages the gastrointestinal
Cyclooxygenase-2 Inhibitors mucosa.
PROTOTYPE Celecoxib (Celebrex), p. 734
cc Antipyretic and Analgesic Drugs 4. Describe the symptoms and treatment of salicylism.
PROTOTYPE Acetaminophen (Tylenol), p. 735
5. Compare the actions and adverse effects of aspirin to
ibuprofen and ibuprofen-like drugs.
6. Compare the actions and adverse effects of the
cyclooxygenase-2 inhibitors to other nonsteroidal
anti-inflammatory drugs.
7. Describe the nurse’s role in the pharmacologic
management of inflammation and fever.
8. For each of the classes shown in the chapter outline,
identify the prototype and representative drugs and
explain the mechanism(s) of drug action, primary
indications, contraindications, significant drug
interactions, pregnancy category, and important
adverse effects.
9. Apply the nursing process to care for patients
receiving pharmacotherapy for fever or
inflammation.
723
724 Unit 6 Pharmacology of Body Defenses
Key Terms cyclooxygenase (COX), 726 salicylates, 725
prostaglandins, 725 salicylism, 729
anaphylaxis, 724
antipyretics, 725
Inflammation is a response to injury that destroys agents new tissue. Regeneration processes may replace normal
that could damage human tissue. A large number of condi- cells with scar tissue, especially in nerve, cardiac, and mus-
tions can trigger inflammation, including physical trauma, cle tissues. Replacement with fibrotic tissue can impair the
burns, chemical injury, infections, hypersensitivity reac- function of the inflamed tissue.
tions, or tissue necrosis (death). Although it is a natural
defense mechanism, excessive inflammation causes symp- Chronic inflammation: Chronic inflammation has a
toms that range from minor discomfort to severe, disabling slow onset and may lack the distinct stages characteristic
pain, fever, and limitation of mobility. This chapter exam- of acute inflammation. Whereas acute inflammation is the
ines drugs used to diminish the inflammatory response result of an influx of neutrophils, chronic inflammation is
and reduce fever. caused primarily by lymphocytes and macrophages. The
chronic invasion of an area by macrophages and the resul-
Pathophysiology tant chemical reaction at the tissue site activates fibroblasts
of Inflammation and Fever and generates scar tissue, which may limit mobility or nar-
row vessel lumens. Lymphocytes sometimes surround
41.1 Inflammation is a nonspecific body macrophages, resulting in granulomas. For example,
response to antigens and tissue injury. chronic inflammation from Mycobacterium tuberculosis in
the lung may occur over many years and yield the devel-
The basic process of inflammation and the proinflammatory opment of granulomas. The granulomas serve as a means
chemical mediators involved are described in Chapter 40. of protection, walling off the agent from the rest of the
The student should review that chapter before proceeding. body. In the event that the host’s immune response dimin-
ishes, the host is susceptible to the reemergence of inflam-
Acute inflammation: Acute inflammation has an imme- mation and the possible onset of active infection.
diate onset and lasts 1 to 2 weeks. The inflammatory pro-
cess is initiated when the body is exposed to a foreign When acute or chronic inflammation is caused by an
substance, or antigen. The antigen may be anything from infection, the patient is at risk for the development of a
ragweed pollen to a microorganism; it may even be a nor- febrile episode, which is characterized by an increase in
mal cell that has been damaged or changed. Once the body temperature due to cytokine-induced changes in the
inflammation process is initiated, nearby blood vessels hypothalamus. The systemic manifestations of inflamma-
become permeable, allowing phagocytic cells to reach and tion associated with an infection are elevated temperature
neutralize the antigen. The increased permeability causes above 39°C (102°F), pulse rate greater than 90 beats/min,
edema of the surrounding tissue, which often leads to acute respirations greater than 20 breaths/min, and a white
pain and, possibly, joint immobility. The greater the tissue blood cell count greater than 12,000/mm3.
damage from the antigen or the inflammation, the greater
the edema and the greater the immobility at the site. Pharmacotherapy of Inflammation
Occasionally, acute inflammation is initiated by a 41.2 Treatment of inflammation includes
rapid, massive release of inflammatory chemical mediators nonpharmacologic therapies and the
throughout the entire body. This condition, known as ana- administration of anti-inflammatory drugs.
phylaxis, is a life-threatening allergic response that may
cause cardiovascular shock and death. A number of chemi- Because inflammation is a nonspecific process and may be
cals, insect stings, foods, and some therapeutic drugs can caused by a variety of physical and infectious etiologies, it
cause this widespread release of histamine from mast cells may occur in virtually any tissue or organ system. When
if an individual has hypersensitivity to these substances. treating the patient with inflammation, the following gen-
eral principles apply:
The resolution of acute inflammation occurs when
damaged tissue begins the process of regeneration and • Inflammation is not a disease but a symptom of an
may conclude within a matter of weeks or continue underlying disorder. Whenever possible, the cause of
throughout the individual’s life with the regeneration of the inflammation is identified and treated.
Chapter 41 Pharmacotherapy of Inflammation and Fever 725
• Inflammation is a natural process for ridding the PharmFACT
body of antigens, and it is usually self-limiting.
Nonpharmacologic treatments such as ice packs and In the United States, approximately 70 million NSAID
rest should be used for mild symptoms whenever prescriptions are written each year. If over-the-counter
applicable. (OTC) use is included, more than 30 billion NSAID doses are
consumed each year (Wiegand, 2016).
• Topical drugs should be used when applicable because
they cause few adverse effects. Inflammation of the Nonsteroidal
skin and mucous membranes of the mouth, nose, rec- Anti-Inflammatory Drugs
tum, and vagina are best treated with topical drugs.
These include creams, ointments, patches, supposito- The NSAIDs consist of three major classes: salicylates, ibu-
ries, and intranasal sprays. Inhalation drugs may be profen (including ibuprofen-like drugs), and cyclooxygen-
used for pulmonary inflammation. ase-2 (COX-2) inhibitors. These drug classes are sometimes
grouped as first-generation NSAIDs (salicylates and
The goal of pharmacotherapy with anti-inflammatory ibuprofen-like drugs) and second-generation NSAIDs
drugs is to prevent or decrease the intensity of the (COX-2 inhibitors). This is not a particularly useful means
inflammatory response and reduce fever, if present. Most of grouping the drugs because there are over 20 first-
anti-inflammatory drugs are nonspecific; that is, whether generation NSAIDs and only one second-generation
the inflammation is caused by an injury, autoimmune NSAID. The ibuprofen-like NSAIDs are described in Section
disease, or allergy, the drug will exhibit the same inhibi- 41.4 and the COX-2 inhibitors are presented in Section 41.5.
tory actions. Common diseases that benefit from anti-
inflammatory medications include allergic rhinitis, Salicylates
anaphylaxis, ankylosing spondylitis, contact dermatitis,
Crohn’s disease, glomerulonephritis, Hashimoto’s 41.3 Aspirin is an inexpensive, effective, first-
thyroiditis, peptic ulcer disease (PUD), rheumatoid generation nonsteroidal anti-inflammatory drug
arthritis (RA), systemic lupus erythematosus, and ulcer- commonly used by adults.
ative colitis.
The first NSAID to be discovered was originally
If fever is associated with the inflammation, medica- extracted from the bark of the common willow tree. The
tions used to reduce body temperature, or antipyretics, medical uses of willow bark, especially for pain relief
may be administered. The goal of antipyretic therapy is to and fever reduction, had been known for centuries but it
lower body temperature while treating the underlying was not until 1828 that the active ingredient, called sali-
cause of the fever, which is usually an infection. Many of cin, was identified and converted to salicylic acid. Quite
the drugs used for inflammation also reduce fever and toxic in concentrated amounts, salicylic acid was con-
relieve mild to moderate pain. verted into its most useful form, known as aspirin or ace-
tylsalicylic acid, by a scientist at the Bayer Pharmaceutical
Two major drug classes are used for nonspecific Company in 1897. The chemical family to which aspirin
inflammation: nonsteroidal anti-inflammatory drugs belongs is known as the salicylates. Since its discovery,
(NSAIDs) and the corticosteroids. For mild to moderate aspirin has become one of the most highly used thera-
pain, inflammation, and fever, NSAIDs are the preferred peutic drugs in the world. Aspirin has the following
class of drugs. Should inflammation become severe or dis- indications for use:
abling, corticosteroid therapy is begun. Due to the poten-
tial for serious long-term adverse effects, oral or parenteral • Analgesic. The ability to relieve mild to moderate pain
corticosteroids are usually used for only 1 to 3 weeks to • Anti-inflammatory. The ability to decrease mild to
bring inflammation under control. The patient is then
switched to NSAIDs. Corticosteroids are used for a large moderate inflammation
number of conditions, and their pharmacotherapy is pre- • Antipyretic. The ability to lower body temperature
sented in Chapter 68. • Suppression of platelet aggregation. The ability to
A few anti-inflammatory drug classes are specific to prevent or treat cardiovascular conditions such as
certain disorders. For example, the 5-aminosalicylic acid acute myocardial infarction (MI) and stroke.
drugs such as sulfasalazine (Azulfidine) are specific to
treating inflammatory bowel disease (see Chapter 60). Col- Understanding the mechanism of action of aspirin is
chicine and allopurinol (Zyloprim) are used for the inflam- important because it explains both the therapeutic actions
mation specifically caused by gouty arthritis (see of the drug as well as its adverse effects. All NSAIDs act by
Chapter 72). These specific anti-inflammatory drugs are inhibiting the synthesis of prostaglandins. Prostaglandins
less widely prescribed because they are more toxic than the are local hormones found in virtually every tissue that have
NSAIDs. many diverse functions depending on their location.
726 Unit 6 Pharmacology of Body Defenses 5GNGEVKXG %1:
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Figure 41.1 Inhibition of cyclooxygenase-1 and -2. Nonselective NSAIDs block the cytoprotective effects as well as
inflammation. Selective COX-2 inhibitors block only the inflammation effects.
Several prostaglandins are available as drugs, including inhibition of COX is responsible for the therapeutic and
carboprost (Hemabate, prostaglandin F2 alpha), dinopros- adverse effects of these drugs, depending on the location
tone (Cervidil, prostaglandin E2), and misoprostol (Cytotec, and function of the prostaglandin that is being blocked. For
prostaglandin E1). The physiologic properties of prostaglan- example, the inhibition of COX in peripheral tissues will
dins include the following: reduce the pain and inflammation caused by prostaglan-
dins. The inhibition of COX in the stomach, however, will
• Mediation of inflammation. Cause vasodilation and remove the protective effect of prostaglandins and result in
pain, and increase capillary permeability damage to the gastrointestinal (GI) mucosa. The mecha-
nism by which aspirin produces its effects is illustrated in
• GI protection. Increase bicarbonate and mucus pro- Figure 41.1.
duction to protect the stomach mucosa from acid
Aspirin is a potent inhibitor of thromboxane, a sub-
• Renal protection. Help maintain blood flow through stance secreted by platelets. The inhibition of thromboxane
the kidneys in platelets is especially prolonged and may last for the
entire 8- to 11-day lifespan of the platelet. This antithrom-
• Smooth muscle. Help regulate smooth muscle tone in botic action inhibits platelet aggregation and reduces the
blood vessels; increase smooth muscle tone in the uterus; risk of adverse cardiovascular events, including MI and
may cause bronchodilation or bronchoconstriction stroke. The antipyretic effect of aspirin results from a sup-
pression of prostaglandin synthesis in the hypothalamus of
• Blood clotting. Increase platelet aggregation to pro- the brain. It lowers temperature by indirectly causing cen-
mote clot formation. trally mediated peripheral vasodilation and sweating. The
principal analgesic effect of aspirin occurs in the peripheral
Aspirin blocks the synthesis of prostaglandins by areas of the body and in the central nervous system (CNS).
inhibiting the enzyme cyclooxygenase (COX). Aspirin and
the ibuprofen-like NSAIDs block both forms of the enzyme,
known as COX-1 and COX-2, by changing their structures
and preventing the formation of prostaglandins. This
Chapter 41 Pharmacotherapy of Inflammation and Fever 727
Table 41.1 Salicylates
Drug Route and Adult Dose Adverse Effects
(Maximum Dose Where Indicated)
Tinnitus, deafness, urticaria, nausea, vomiting,
aspirin (acetylsalicylic acid, ASA) Mild to moderate pain or fever: confusion, drowsiness, prolonged bleeding time,
PO: 350–650 mg, q4h (max: 4 g/day) dyspepsia, stomach pain
Arthritic conditions:
PO: 3.6–5.4 g/day in 4–6 divided doses Bronchospasm, anaphylactic shock, laryngeal
TIA prophylaxis: edema, hemolytic anemia, salicylism,
PO: 5–325 mg/day angioedema, Reye’s syndrome, metabolic
MI or thromboembolic disorder prophylaxis: acidosis, severe GI bleeding, hepatotoxicity
PO: 80–325 mg/day
choline magnesium trisalicylate (Trilisate) PO: 1.0–2.5 g/day in 1–3 divided doses (max: 4.5 g/day)
magnesium salicylate (Doan’s Pills) Analgesic/antipyretic:
PO: 650 mg tid or qid
Arthritic conditions:
PO: 9.6 g/day in divided doses (max: 4.8 g/day)
salsalate (Mono-Gesic, Salsitab) PO: 325–3000 mg/day in divided doses (max: 4 g/day)
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
Doses for aspirin and the other salicylates are listed in • After aspirin is absorbed systemically, it inhibits
Table 41.1. COX-1 and depletes the GI mucosa of prostaglandins.
Prostaglandins normally provide a protective function
Aspirin is sometimes combined with prescription and in the GI mucosa by directing the secretion of mucus
OTC medications, and its presence is not always obvious and bicarbonate and promoting cellular repair of
unless the label is carefully inspected. This is especially mucosal damage.
important for patients with aspirin allergy, which is present
in about 1% of the population. Patients with asthma or • If GI damage or active ulcers are already present, the
food allergies are most likely to be allergic to aspirin. Aspi- antiplatelet effects of aspirin will prolong bleeding.
rin allergy symptoms include rash, urticaria, dyspnea,
wheezing, rhinorrhea, and cough. To prevent aspirin In addition to GI bleeding, aspirin can cause dyspep-
allergy, the patient should be instructed to read labels care- sia, nausea, and ulcer perforation. For patients who must
fully and avoid products containing salicylates. This is not take high doses of aspirin, proton pump inhibitors (PPIs),
always possible because salicylates are naturally found in such as omeprazole, may provide some degree of protec-
certain foods and are used as preservatives in others. tion against GI damage by reducing acid secretion in the
Patients with aspirin allergies should consult with a dieti- stomach. PPIs are effective and relatively safe drugs (see
tian regarding which food sources to avoid. Allergists may Chapter 59). An alternative therapy for GI protection is oral
be able to desensitize a patient if exposure to the drug is misoprostol (Cytotec), which is a prostaglandin. Misopros-
unavoidable or if the patient’s allergy is severe. Patients tol is a pregnancy category X drug, which limits its use in
who are hypersensitive to aspirin will likely be sensitive to women with childbearing potential.
other NSAIDs. For pain or fever relief, acetaminophen may
be an option for these adult patients. The antiplatelet effects of aspirin can promote bleeding
at sites other than the GI tract. Because it irreversibly inhib-
The most significant adverse effect of aspirin and other its COX-1 in platelets, the antiplatelet action of aspirin can
NSAIDs is GI bleeding, which is shown in Pharmacother- be prolonged. It may take longer for minor cuts and inju-
apy Illustrated 41.1. Although the risk is dose related, even ries to stop bleeding. Patients undergoing surgical or den-
low doses of aspirin (75–325 mg/day) may double the risk tal procedures should discontinue aspirin use a week prior
of GI bleeding. Risk factors for aspirin-induced GI bleeding to the procedure. Patients with known bleeding disorders
include history of peptic ulcers, age greater than 60, use of should not take aspirin at all.
anticoagulants or corticosteroids, Helicobacter pylori infec-
tion, smoking, and use of alcohol. Aspirin has the follow- Children under age 19 should never be administered
ing adverse effects on the GI mucosa: products that contain aspirin when they have flu symp-
toms, fever, or chickenpox due to the risk of Reye’s syn-
• As aspirin is absorbed across the stomach mucosa, it drome, a potentially fatal disease. It is unclear how aspirin
causes direct cellular injury. This topical damage to the contributes to Reye’s syndrome, because the condition can
stomach may be lessened by the use of enteric-coated appear without aspirin use. The incidence of Reye’s syn-
formulations. drome is now very rare due to public awareness of the risk
associated with aspirin use.
728 Unit 6 Pharmacology of Body Defenses
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PharmFACT an extremely versatile and widely used drug. It is used to
reduce pain and inflammation that is mild to moderate
More than 24,000 salicylate poisonings occur each year, of in intensity. The doses of aspirin needed to control severe
which about 5000 are intentional overdoses. Approximately pain or inflammation often result in a high incidence of
15 deaths from acute salicylate overdose occur each year adverse effects.
(Waseem, 2016).
Aspirin is approved by the FDA for the prevention of
PROTOTYPE DRUG Aspirin (Acetylsalicylic Acid) thromboembolic events. Aspirin is a first-line treatment
for stroke prophylaxis in patients with a history of tran-
Classification Therapeutic: Nonnarcotic analgesic, sient ischemic attacks (TIAs) or who have persistent or
antipyretic, antiplatelet paroxysmal atrial fibrillation. It is approved for MI pro-
phylaxis in patients who are at risk for a cardiac event and
Pharmacologic: Salicylate, NSAID who are not already taking warfarin or an antiplatelet
drug, including those with coronary artery disease who
Therapeutic Effects and Uses: Approved by the have already experienced an MI. To lower the risk of
U.S. Food and Drug Administration (FDA) in 1939, aspi- thromboembolic events, emergency medical services pro-
rin is one of the best known medications. The ability of fessionals administer aspirin to patients with a suspected
aspirin to reduce pain, inflammation, and fever makes it coronary thrombosis prior to hospital arrival. Patients
Chapter 41 Pharmacotherapy of Inflammation and Fever 729
with a high risk for arterial thromboembolism may receive agranulocytosis, head trauma, increased intracranial
low-dose aspirin therapy. pressure, history of GI bleeding, hypoprothrombinemia,
vitamin K deficiency, heart failure (HF), pregnancy, and
An off-label use of aspirin is to prevent colorectal can- lactation. Children and teenagers should not be adminis-
cer. Regular, long-term aspirin use has been determined to tered aspirin or products containing aspirin if they have
reduce the risk of colorectal cancer in certain populations a fever or a flulike illness. Patients over age 60 are espe-
(Dehmer, Maciosek, Flottemesch, LaFrance, & Whitlock, cially prone to GI ulceration and bleeding due to aspirin.
2016). Researchers are still unclear whether the reduction It should be used cautiously in patients with hypothyroid-
in the incidence of colorectal cancer from the drug is worth ism, immunosuppression, asthma, and gout. It should
the increased risk of GI bleeding. The effectiveness of aspi- also be used cautiously in patients with chronic kidney
rin in preventing cancer is an area of active research. disease (CKD), hepatic impairment, G6PD deficiency,
anemia, preoperatively, and in the presence of Hodgkin’s
Mechanism of Action: The anti-inflammatory action disease. Aspirin should not be taken during pregnancy,
of aspirin is caused by the inhibition of COX-1 and COX-2 especially in the third trimester; it may prolong bleeding
that leads to reduced prostaglandin synthesis. The analge- and inhibit natural contractions caused by prostaglandins
sic action of aspirin occurs peripherally with limited action in the uterus.
in the CNS on the hypothalamus. The suppression of pros-
taglandin synthesis in or near the hypothalamus results in Drug Interactions: Concurrent administration of
the lowering of body temperature. Aspirin acts indirectly, aspirin with other salicylates such as 5-aminosalicylic
causing centrally mediated peripheral vasodilation and acid increases the risk of salicylate toxicity. The combined
sweating. use of aspirin with acetaminophen may cause additive
nephrotoxicity. Ammonium chloride and other acidifying
Pharmacokinetics: agents decrease the renal elimination of aspirin, result-
ing in salicylate toxicity. The administration of aspirin
Route(s) Oral (PO), rectal with anticoagulants, thrombolytics, or antiplatelet drugs
increases the patient’s risk for bleeding. When oral anti-
Absorption 80–100% absorbed diabetic drugs are administered concurrently with high
doses of aspirin, hypoglycemic activity increases. Patients
Distribution Widely distributed; crosses the who consume three or more alcoholic drinks per day may
experience additive GI ulceration. Corticosteroids increase
placenta; secreted in breast milk; the risk of gastric irritation and result in ulcerogenic effects
when administered with aspirin. Methotrexate admin-
80–90% bound to plasma protein istered with aspirin results in methotrexate toxicity. Low
doses of salicylates may antagonize the uricosuric effects
Primary metabolism Hepatic; metabolized to salicylic of probenecid and sulfinpyrazone. The antihypertensive
effects of beta blockers may decrease if administered con-
acid, an active metabolite, in currently with aspirin. Herbal/Food: The administration
of feverfew, garlic, ginger, horse chestnut, and red clover
the GI mucosa, plasma, and will increase the patient’s risk for bleeding. Taking aspirin
with caffeine will increase the rate of aspirin absorption.
erythrocytes St. John’s wort may increase sedation.
Primary excretion Renal Pregnancy: Categories C (first and second trimester)
and D (third trimester).
Onset of action PO: 5–30 min; rectal: 1–2 h
Treatment of Overdose: Acute or chronic overdose
Duration of action PO: 1–4 h; rectal: 7 h of aspirin is known as salicylism, which is defined as
a serum salicylate level above 200 mcg/mL. The symp-
Adverse Effects: A major adverse effect of aspirin is toms depend on the dose but include tinnitus, metabolic
the risk of a serious hypersensitivity reaction, which is acidosis, hyperventilation, respiratory alkalosis (second-
noted with symptoms such as bronchospasm, laryngeal ary to stimulation of the respiratory center), dehydra-
edema, and anaphylaxis. It also causes significant stom- tion, agitation, CNS depression, nausea, and vomiting.
ach irritation, heartburn, nausea, vomiting, diarrhea, and Emesis, gastric lavage, and alkalinization of urine are
stomach pain in 10% to 30% of patients. The risk of GI indicated. Hemodialysis is of benefit in severe salicylate
bleeding increases with dose. The hematologic adverse poisonings.
effects of aspirin administration include thrombocytope-
nia, hemolytic anemia, and occult bleeding. Long-term
administration of aspirin may produce nephrotoxic effects
and hepatotoxicity. Tinnitus and hearing loss are common
adverse effects with high doses.
Contraindications/Precautions: Patients who
have a hypersensitivity to any salicylate (including that
found in foods) should not be administered aspirin or
other NSAIDs. Patients who have the “aspirin triad,”
which includes aspirin allergy, nasal polyps, and asthma,
should not be administered aspirin. Aspirin is also con-
traindicated in chronic rhinitis, acute bronchospasm,
730 Unit 6 Pharmacology of Body Defenses
Nursing Responsibilities: Key nursing implications Ibuprofen-Like Drugs
for patients receiving aspirin are included in the Nursing
Practice Application for Patients Receiving Pharmacother- 41.4 Ibuprofen and similar nonsteroidal anti-
apy for Inflammation and Fever. inflammatory drugs are the most common
medications for treating mild to moderate pain
Drugs Similar to Aspirin and inflammation.
(Acetylsalicylic Acid)
In the 1950s researchers began searching for safer alterna-
Drugs that produce similar actions to aspirin include cho- tives to aspirin or corticosteroids for treating the severe
line magnesium trisalicylate, magnesium salicylate, and inflammation of RA. An exhaustive search of over 600
salsalate. potential compounds over a 15-year period resulted in the
discovery of ibuprofen, one of the safest and most widely
Choline magnesium trisalicylate (Trilisate): Approved in prescribed NSAIDs in the world. The drug was intro-
1938, this drug combines choline salicylate and magne- duced in the United States in 1974, and it became one of
sium salicylate. It is an oral drug approved for fever and the first prescription-only drugs to be changed to OTC
mild to moderate pain and inflammation associated with status in 1984.
osteoarthritis, RA, bursitis, and other muscle or joint con-
ditions. This drug causes less GI irritation than aspirin, Since the discovery of ibuprofen, over 20 other non-
and it exhibits less antiplatelet activity. Choline magne- aspirin NSAIDs have been approved by the FDA. Although
sium trisalicylate should not be administered to patients their chemical structures vary, they are grouped as “ibu-
with known hypersensitivity to other salicylates. Other profen-like” because they share very similar actions and
contraindications and adverse effects are similar to those adverse effects with the original drug. Doses for the
of aspirin. This drug is pregnancy category C; category D if NSAIDs are listed in Table 41.2. When used at recom-
used for prolonged periods or near term. mended doses, NSAIDs have the following similarities:
Magnesium salicylate (Doan’s Pills): Approved in 1938, • All have the same mechanism of action: They inhibit
magnesium salicylate is an oral drug approved for fever both COX-1 and COX-2.
and mild to moderate pain and inflammation associated
with osteoarthritis, RA, bursitis, and other muscle or joint • All have analgesic properties: They are widely pre-
conditions. It inhibits prostaglandin synthesis in the same scribed to treat patients with mild to moderate pain.
manner as aspirin, but it is less potent, causes less GI irrita-
tion, and has less effect on platelet aggregation than aspi- • All have anti-inflammatory properties: Most are spe-
rin. Magnesium salicylate should not be administered to cifically approved for osteoarthritis and RA.
patients with known hypersensitivity to other salicylates.
Other contraindications and adverse effects are similar to • All have antipyretic properties, although not all of
those of aspirin. This drug is pregnancy category C for the them are approved for this indication.
first and second trimesters and D for the third trimester.
• Most are weak acids that are readily absorbed in the
Salsalate (Mono-Gesic, Salsitab): Approved in 1977, sal- GI tract.
salate has analgesic properties similar to those of aspirin
but it causes less gastric irritation. It is an oral drug • Most are strongly bound to albumin in the blood.
approved to treat mild and moderate pain due to osteoar- • Most are metabolized in the liver to inactive metabo-
thritis and RA. Like other salicylates, salsalate produces its
effects by inhibiting prostaglandin synthesis. It has little lites, which are excreted by the kidneys.
antipyretic activity and has less effect on platelet aggrega- • All have the ability to damage the GI mucosa, includ-
tion than aspirin. Salsalate should not be administered to
patients with known hypersensitivity to other salicylates. ing bleeding and ulcer formation.
Other contraindications and adverse effects are similar to • Many pose an increased risk of cardiac events, such as
those of aspirin. This drug is pregnancy category C.
heart failure and MI.
CONNECTION Checkpoint 41.1 • Many are nephrotoxic at high doses.
Aspirin is classified as an antiplatelet drug in Chapter 38. Name the From the preceding list, it should be obvious that the
other two classes of drugs that are antiplatelets and state the prototype available nonaspirin NSAIDs share many properties. There
drug for each class. Answers to Connection Checkpoint questions are are, however, some differences in pharmacokinetic profiles.
available on the faculty resources site. Please consult with your instructor. For example, some have longer half-lives or are available in
sustained release formulations that permit once-daily dos-
ing. Some are available by the parenteral route, and a few
are formulated for children. Some are enteric coated, which
may reduce stomach pain but does not appear to be protec-
tive against the formation of ulcers. Another consideration
that is important to many consumers is cost. A month’s
supply of generic ibuprofen 200 mg or naproxen 220 mg
costs less than $25 and is available OTC. At the opposite
extreme are prescription-only celecoxib (Celebrex) 200 mg
Chapter 41 Pharmacotherapy of Inflammation and Fever 731
Table 41.2 Nonaspirin NSAIDs and Acetaminophen
Drug Route and Adult Dose Adverse Effects
acetaminophen (Tylenol) (Maximum Dose Where Indicated)
Epigastric pain, abdominal pain
celecoxib (Celebrex) PO: 325–650 mg q4–6h (max: 4 g/day for all products containing
this drug) Hepatotoxicity, acute renal failure
Rectal: 650 mg q4–6h
Back pain, peripheral edema, abdominal pain,
PO: 100–400 mg bid (max: 800 mg/day) dyspepsia, flatulence, dizziness, headache,
insomnia, hypertension,
diclofenac PO: 25–100 mg/day in one or more doses
(Cataflam, Voltaren, others) Increased risk of cardiovascular events, acute
renal failure
diflunisal PO: 250–500 mg bid (max: 1500 mg/day)
Dyspepsia, dizziness, headache, drowsiness,
etodolac PO: 200–1200 mg/day in 2–4 divided doses (max: 1200 mg) tinnitus, rash, pruritus, increased liver enzymes,
prolonged bleeding time, edema, nausea,
fenoprofen (Nalfon) PO: 200–600 mg tid or qid (max: 3200 mg/day) vomiting, occult blood loss
flurbiprofen PO: 200–300 mg in 2–4 divided doses (max: 300 mg/day and Peptic ulcer, GI bleeding, anaphylactic reactions
100 mg/dose) with bronchospasm, blood dyscrasias, CKD, MI,
HF, hepatotoxicity
ibuprofen (Advil, Motrin, others) PO: 400–800 mg tid to qid (max: 3200 mg/day)
indomethacin (Indocin, Tivorbex) PO (immediate release): 25–50 mg bid or tid
PO (extended release): 75–100 once daily or bid
ketoprofen PO (immediate release): 25–75 mg tid or qid (max: 300 mg/day)
PO (extended release): 200 mg once daily
ketorolac (Sprix, Toradol) IM/IV: 30–60 mg qid (max: 120 mg/day)
PO: 10–20 mg qid (max: 40 mg/day)
Intranasal: 1 spray (15.75 mg) in each nostril q4–6h
meclofenamate PO: 200–400 mg/day in 3–4 divided doses (max: 400 mg/day)
mefenamic acid (Ponstel) PO: 500-mg loading dose followed by 250-mg maintenance dose
qid (max: 1250 mg/day for no longer than 7 days)
meloxicam (Mobic) PO: 7.5–15 mg once daily (max: 15 mg/day)
nabumetone (Relafen) PO: 1000 mg/day as a single dose (max: 2000 mg/day)
naproxen (Naprosyn) and PO: 250–500 mg bid (naproxen/naproxen controlled release max:
naproxen sodium (Aleve, 1500 mg/day; naproxen sodium max: 1650/day; nonprescription
Anaprox, others) max: 660 mg/day)
oxaprozin (Daypro) PO: 600–1200 mg daily (max: 1800 mg/day)
piroxicam (Feldene) PO: 10–20 mg once daily (max: 20 mg/day)
sulindac (Clinoril) PO: 150–200 mg bid (max: 400 mg/day)
tolmetin (Tolectin) PO: 400 mg tid (max: 1800 mg/day)
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
and flurbiprofen 100 mg, which cost $150 to $240 for a NSAIDs are considered equivalent to aspirin in their
monthly supply. Indications for each of the NSAIDs are effectiveness for treating pain, inflammation, and fever. For
listed in Table 41.3. the occasional user who takes the medications at recom-
mended doses and who has no risk factors, the drugs are
There are important differences between aspirin and very safe and rarely produce any significant adverse effects.
the ibuprofen-like drugs in their effects on the blood and For patients who must take high doses for a chronic illness,
heart. Although ibuprofen-like drugs affect blood coagula- ibuprofen appears to cause less GI bleeding than aspirin,
tion, their inhibitory effects on platelets are reversible and although both drugs place patients at high risk for GI
short lived. Because they have less antiplatelet effect than adverse effects.
aspirin, the ibuprofen-like drugs are not used for the pro-
phylaxis of adverse cardiovascular events. In fact, some of PROTOTYPE DRUG Ibuprofen (Advil, Motrin, Others)
the nonaspirin NSAIDs such as indomethacin and sulindac
significantly increase the risk of cardiovascular events. Classification Therapeutic: Analgesic, anti-inflammatory
Caution should be used with all the nonaspirin NSAIDs drug, antipyretic
when they are given for prolonged periods to patients with
a history of cardiac disease. Pharmacologic: NSAID
732 Unit 6 Pharmacology of Body Defenses
Table 41.3 Indications for Selected Nonsteroidal Anti-Inflammatory Drugs
NSAID Arthritis Mild to Fever Dysmenorrhea Other Approved Indications
Moderate Pain Ankylosing spondylitis; familial adenomatous
polyposis
celecoxib (Celebrex) A A A Ankylosing spondylitis; actinic keratosis
(topical); ocular pain and inflammation
diclofenac (Cataflam, A A A (ophthalmic)
Voltaren, others)
Miosis inhibition (ophthalmic)
diflunisal A A A Acute migraine
A A A Ankylosing spondylitis; close patent ductus
etodolac A A arteriosus (IV)
A Allergic conjunctivitis; reduce ocular pain
fenoprofen (Nalfon) A AA and inflammation (ophthalmic)
flurbiprofen A A Ankylosing spondylitis
ibuprofen (Advil, Motrin, A AA Ankylosing spondylitis; acute painful shoulder
others) A
indomethacin (Indocin,
Tivorbex)
ketoprofen
ketorolac (Sprix, Toradol)
meclofenamate A A A
A A
mefenamic acid (Ponstel) A
A AA A
meloxicam (Mobic) A
nabumetone (Relafen) A
A
naproxen (Naprosyn) and A
naproxen sodium (Aleve, A
Anaprox, others)
oxaprozin (Daypro)
piroxicam (Feldene)
sulindac (Clinoril)
tolmetin (Tolectin)
A = FDA approved.
Therapeutic Effects and Uses: Approved in 1974, the ductus. By blocking prostaglandin synthesis with ibu-
ibuprofen was the first nonaspirin NSAID marketed in profen, the ductus closes.
the United States. Like aspirin, it possesses analgesic, anti-
inflammatory, and antipyretic properties. It is indicated for Mechanism of Action: Ibuprofen inhibits COX-1 and
the relief of fever and mild to moderate pain associated COX-2, which block prostaglandin synthesis and modulate
with chronic symptomatic RA and osteoarthritis, myal- T-cell function. Ibuprofen inhibits inflammatory cell che-
gia, headache, dental pain, and dysmenorrhea. Chewable motaxis, decreases the release of superoxide radicals, and
tablets, drops, and solutions are available in low doses for increases the scavenging of these products at the inflam-
administration to children. matory sites.
Unlike aspirin, ibuprofen is not indicated to treat or Pharmacokinetics: PO
prevent any cardiovascular conditions. Ibuprofen inhibits Route(s) 80% absorbed
platelet aggregation and prolongs the bleeding time with- Absorption Crosses the placenta; unknown
out affecting the prothrombin time (PT) or whole-blood Distribution if secreted in breast milk; highly
clotting times. Its effects on platelets are reversible within protein bound
24 hours after discontinuation of the drug. Primary metabolism Hepatic
Primary excretion Renal; small amount biliary
Ibuprofen lysine (NeoProfen) is an intravenous (IV) Onset of action 1h
form of the drug that was approved in 2006 to close patent Duration of action 6–8 h
ductus arteriosus in premature infants. The drug has a 75%
success rate in infants who are no more than 32 weeks ges-
tational age. Although the mechanism of action is not
known, it is believed that prostaglandins delay closing of
Chapter 41 Pharmacotherapy of Inflammation and Fever 733
Adverse Effects: In low to moderate doses, ibuprofen and includes the administration of activated charcoal and
is well tolerated and serious adverse effects are uncom- nasogastric suction.
mon. The most frequent adverse events are GI related
and include bleeding, anorexia, heartburn, nausea, vom- Nursing Responsibilities: Key nursing implications
iting, and constipation or diarrhea. Adverse CNS effects for patients receiving ibuprofen are included in the Nurs-
include dizziness, headache, drowsiness, and tinnitus. ing Practice Application for Patients Receiving Pharmaco-
Rare, though serious, adverse effects include peripheral therapy for Inflammation and Fever.
edema, aplastic anemia, leukopenia, and anaphylaxis.
Chronic use of ibuprofen may lead to polyuria, azote- Drugs Similar to Ibuprofen
mia, hematuria, and increased creatinine and blood urea (Advil, Motrin, Others)
nitrogen (BUN) levels. Black Box Warnings: Ibuprofen
may increase the risk of serious and potentially fatal car- There are a number of subclasses of NSAIDs that are
diovascular thrombotic events, MI, and stroke. This risk based on the chemical structures of the molecules. These
may increase with duration of use and in patients with subclasses include the propionic acids (e.g., ibuprofen),
cardiovascular risk factors. Ibuprofen also increases the phenylacetic acids (e.g., diclofenac), indole acetic acids
risk of serious GI adverse effects including bleeding, (e.g., indomethacin), fenamates (e.g., mefenamic
ulcer, and stomach or intestine perforation. These GI acid), ketones (e.g., nabumetone), and oxicams (e.g.,
events may occur at any time during use and without piroxicam). From a clinical perspective, the nonaspirin
prior warning. Older adults are at greater risk for serious NSAIDs are remarkably similar to ibuprofen. Doses and
GI events. indications for these drugs differ, as listed in Tables 41.2
and 41.3.
Contraindications/Precautions: Patients who
have a known allergy to aspirin or other NSAIDs should PharmFACT
not be administered ibuprofen. In addition, patients who
have been diagnosed with PUD, bleeding abnormalities, It is estimated that NSAID use is associated with about
and perioperative pain related to coronary artery bypass 100,000 hospitalizations and 16,000 deaths annually in the
graft (CABG) should not receive ibuprofen. The drug United States, largely as a result of GI complications
should be used cautiously in patients with hypertension (Wiegand, 2016).
(HTN), history of GI bleeding, diabetes mellitus, and
impaired renal or hepatic function. It should also be used Cyclooxygenase-2 Inhibitors
cautiously in patients who have HF or a history of stroke
or MI. Children with asthma may experience dimin- 41.5 Celecoxib is an effective second-generation
ished respiratory function when administered ibuprofen. nonsteroidal anti-inflammatory drug, but its use
Patients with severe hepatic impairment should not is limited due to an increased risk of myocardial
receive ibuprofen because the drug can accumulate to infarction and stroke.
toxic levels.
Celecoxib (Celebrex) is a second-generation NSAID that
Drug Interactions: Oral anticoagulants and anti- blocks COX-2 without inhibiting COX-1. The selective
platelet drugs taken with ibuprofen increase the risk of inhibition of COX-2 produces the analgesic, anti-inflam-
bleeding. Ibuprofen may increase the toxicity of digoxin, matory, and antipyretic effects typical of other NSAIDs,
lithium, or methotrexate if taken concurrently. Use with but without causing platelet aggregation or GI irritation.
other NSAIDs, alcohol, or corticosteroids may cause The primary advantage of celecoxib is that it causes less GI
serious adverse GI events. The antihypertensive action bleeding and ulcer formation than aspirin or ibuprofen.
of diuretics, beta blockers, and angiotensin-converting This medication is the newest and most controversial of
enzyme (ACE) inhibitors may be reduced if taken with the NSAIDs.
ibuprofen. Herbal/Food: Ibuprofen combined with fever-
few, garlic, ginger, and ginkgo may result in an increased The ability to treat arthritis without adverse effects
risk of bleeding. caused excitement throughout the medical field in the
1990s, and the three drugs originally in this class were
Pregnancy: Categories B (first and second trimesters) widely prescribed. This elation quickly ended when
and D (third trimester). postmarketing data revealed that rofecoxib (Vioxx) dou-
bled the risk of MI and strokes in patients taking the
Treatment of Overdose: Overdose may lead to acute drug for extended periods. At that time, more than
renal failure, apnea, cyanosis, drowsiness, GI bleeding, 84 million people had used rofecoxib since its approval.
nausea, vomiting, and sweating. Treatment is supportive Based on the research data, the drug manufacturer vol-
untarily removed rofecoxib from the market. Shortly
afterward a second COX-2 inhibitor, valdecoxib (Bextra),
734 Unit 6 Pharmacology of Body Defenses
was also voluntarily withdrawn, leaving celecoxib (Cele- Celecoxib carries the same warnings as the ibuprofen-
brex) the sole drug in this class. A large number of law- like drugs. It may increase the risk of serious and poten-
suits were subsequently filed, and the development of tially fatal cardiovascular thrombotic events, MI, and
new COX-2 inhibitors has stopped in the United States. stroke. This risk may increase with duration of use and
Other COX-2 inhibitors are still available outside the in patients with cardiovascular risk factors. Celecoxib
United States. also increases the risk of serious GI adverse effects includ-
ing bleeding, ulcer, and stomach or intestine perforation.
PROTOTYPE DRUG Celecoxib (Celebrex) These GI events may occur at any time during use and
without prior warning. Older adults are at greater risk for
Classification Therapeutic: Anti-inflammatory serious GI events.
Pharmacologic: COX-2 inhibitor, NSAID
Contraindications/Precautions: Celecoxib should
Therapeutic Effects and Uses: Initially approved not be administered to patients with hepatic insufficiency
in 1998, celecoxib is used to treat mild to moderate pain because the primary site of drug metabolism is the liver.
and inflammation associated with RA, osteoarthritis, dys- It is also contraindicated in patients with chronic kidney
menorrhea, dental procedures, headache, and ankylosing disease (CKD). Celecoxib is contraindicated in patients
spondylitis. It is also an effective antipyretic drug. The with anemia or in the postoperative phase of a CABG.
effectiveness of celecoxib at reducing pain and inflamma- Celecoxib is administered cautiously in patients who are
tion is equivalent to that of other NSAIDs. poor CYP2C9 metabolizers. This drug is contraindicated
in patients with a history of GI bleeding or PUD, and it
In addition to its anti-inflammatory indications, cele- should be administered with caution to patients receiv-
coxib also is used for the prophylaxis of adenomas or ing anticoagulants. Patients with a history of asthma,
colorectal polyps in adults with familial adenomatous pol- bone marrow suppression, stroke, peripheral vascular
yposis (FAP). Patients with this condition have an inherited disease, elevated liver function tests, heart failure, kid-
mutation in a gene that results in hundreds of polyps and ney disease, and fluid retention should be administered
an almost 100% risk of colon cancer. Although celecoxib celecoxib cautiously.
reduces the number of polyps in these patients, it has not
been proven to reduce the risk of malignancies. Drug Interactions: If taken with celecoxib, oral
coagulation modifiers such as clopidogrel or warfarin
Mechanism of Action: Celecoxib selectively inhibits may cause an increased risk of bleeding. Celecoxib may
the enzyme COX-2. It inhibits prostaglandin synthesis to increase the toxicity of lithium if taken concurrently. Use
reduce inflammation. This action relieves pain and inflam- with alcohol, corticosteroids, aspirin, or other NSAIDs
mation in the joints and smooth muscle tissue. may cause serious adverse GI events. The antihyperten-
sive action of diuretics or ACE inhibitors may be reduced
Pharmacokinetics: if taken with celecoxib. Concurrent use with flucon-
azole may increase serum celecoxib levels. Herbal/Food:
Route(s) PO Feverfew, garlic, ginger, ginkgo, horse chestnut, and red
clover may increase the risk of bleeding if used during
Absorption Well absorbed celecoxib therapy.
Distribution Widely distributed; is likely Pregnancy: Category C; category D in the third
trimester.
secreted in breast milk;
Treatment of Overdose: Overdose may cause acute
97% protein bound renal failure, apnea, cyanosis, drowsiness, GI bleeding,
nausea, vomiting, and sweating. Treatment is supportive
Primary metabolism Hepatic by CYP2C9 and includes the administration of activated charcoal and
nasogastric suction.
Primary excretion Primarily feces (57%), with some
Nursing Responsibilities: Key nursing implications
in urine (27%) for patients receiving celecoxib are included in the Nurs-
ing Practice Application for Patients Receiving Pharmaco-
Onset of action Peak: 3 h therapy for Inflammation and Fever.
Duration of action Half-life: 11.2 h Drugs Similar to Celecoxib (Celebrex)
Adverse Effects: Common adverse effects include Celecoxib (Celebrex) is the sole medication in this class.
headache, HTN, fever, dyspepsia, upper respiratory tract
infection, arthralgia, cough, vomiting, and diarrhea. CNS
adverse effects include headache, dizziness, and insom-
nia. Adverse effects of the integumentary system are gen-
erally rare and include erythema multiforme, exfoliative
dermatitis, rash, Stevens–Johnson syndrome, and toxic
epidermal necrolysis. The long-term use of celecoxib may
cause CKD and hepatic impairment. Black Box Warnings:
Chapter 41 Pharmacotherapy of Inflammation and Fever 735
CONNECTIONS: Preparing for Advanced Practice
Intravenous Acetaminophen—Is it Worth the Cost?
Case up to 20%, a decreased length of hospital stay, and a reduction
in opioid-related complication rates (Jibril, Sharaby, Mohamed,
Sarah is a 27-month-old who had a surgical reduction of intus- & Wilby, 2015; Shaffer et al., 2017).
susception (telescoping of the intestines). The surgery was
uncomplicated and the patient has been brought into the pedi- The cost of IV acetaminophen is significantly higher than
atric postoperative area on IV morphine prn. Her parents are that of oral or rectal acetaminophen. On average, IV acetamino-
with her and she has already received 2 doses of IV morphine phen costs more than $10 per dose compared to less than $1
but continues to cry out in pain. Her parents are distraught, and for the oral and rectal routes. The clinician must weigh its bene-
they ask you, the pediatric nurse practitioner (NP) hospitalist, to fits against the risk of increased overall healthcare costs due to
evaluate Sarah for pain management. IV acetaminophen has adverse events related to increased opioid consumption by
recently become available at your institution, and you wonder if patients. The IV route should primarily be used for patients who
it could be added to her pain plan. Would this help minimize the cannot tolerate oral and rectal acetaminophen, such as those
potential for adverse opioid effects for this patient? who are NPO (nothing by mouth) or who cannot receive NSAIDs
due to risk of bleeding or opioid complications.
Discussion
IV acetaminophen is administered over 15 minutes and
IV acetaminophen (Ofirmev) was approved by the FDA in may be given as a single or repeated dose. The maximum daily
November 2010 for the management of mild to moderate pain, dose of acetaminophen is based on all routes of administration
the management of moderate to severe pain (along with opioid (IV, oral, and rectal) and all products (prescription and nonpre-
analgesics), and the reduction of fever in patients ages 2 years scription) containing acetaminophen.
and older. Ofirmev has been advertised as an opioid-sparing
analgesic with a potential for reducing opioid-related side The recommended dosage of Ofirmev is 15 mg/kg every
effects. Recent studies have shown several benefits in using IV 6 hours or 12.5 mg/kg every 4 hours, with a maximum single dose
acetaminophen such as a reduction in opioid administration by of 15 mg/kg, a minimum dosing interval of 4 hours, and a maximum
daily dose for all routes of acetaminophen of 75 mg/kg per day.
CONNECTION Checkpoint 41.2 per tablet, capsule, or dosing unit to lower the potential for
acetaminophen-induced hepatotoxicity.
Several NSAIDs are approved to treat mild migraines. From what you
learned in Chapter 25, what non-NSAID drug classes are used to Acetaminophen has no effect on platelet aggregation
terminate severe migraine episodes? Answers to Connection Check- and does not exhibit cardiotoxicity. Most importantly, it
point questions are available on the faculty resources site. Please consult does not cause GI bleeding or ulcers, as do the NSAIDs.
with your instructor.
PROTOTYPE DRUG Acetaminophen (Tylenol)
Antipyretic and Analgesic Drugs
Classification Therapeutic: Nonopioid analgesic,
41.6 Acetaminophen is administered for pain antipyretic
relief and to reduce fever, but it has no anti-
inflammatory properties. Pharmacologic: Para-aminophenol
derivative
Acetaminophen (Tylenol) is administered for pain relief and
to reduce fever. Unlike aspirin, ibuprofen, and celecoxib, Therapeutic Effects and Uses: Approved in 1950,
acetaminophen has no anti-inflammatory properties, and acetaminophen relieves mild to moderate pain but has no
therefore is not classified as an NSAID. Acetaminophen has effect on inflammation. Acetaminophen is approved to
equal effectiveness to the NSAIDs in reducing pain and treat pain associated with osteoarthritis of the hip or knee,
fever, and it is often a preferred drug for treating noninflam- dysmenorrhea, dental procedures, headache, and myalgia.
matory pain. It is the primary alternative to NSAIDs when It is a preferred drug for reducing fever. Acetaminophen is
patients have a contraindication to taking aspirin or ibupro- administered as a substitute for aspirin when NSAIDs are
fen. Acetaminophen is frequently combined with other OTC contraindicated due to age, allergy, or gastric irritation. It
drugs in treating severe flu symptoms. It is often combined is not linked with Reye’s syndrome, as is aspirin; thus it
with opioid analgesics; adding acetaminophen provides is safe to administer to infants, children, and adolescents
additive pain relief and allows for lower doses of the nar- who have flulike symptoms or chickenpox.
cotic (see Chapter 25). Due to a safety recommendation from
the FDA, drug manufacturers now limit the strength of acet- Acetaminophen is available for the oral (suspension, tab-
aminophen in prescription combination products to 325 mg lets, chewable tablets, extended release tablets, and oral gran-
ules) or rectal route. Childhood and infant preparations are
available. Ofirmev is an IV formulation of acetaminophen.
736 Unit 6 Pharmacology of Body Defenses
Mechanism of Action: Acetaminophen acts cen- alcohol with regularity because this greatly increases the risk
trally in the CNS by inhibiting COX. It has no effect on of hepatotoxicity. Alcohol-induced hepatotoxicity can occur at
COX in peripheral tissues. It also may inhibit the chemical therapeutic doses of acetaminophen. Due to additive hepato-
mediators of pain, but its mechanism is unclear. The reduc- toxic effects, acetaminophen should not be administered with
tion of fever occurs by its direct action on the heat-regulating barbiturates, carbamazepine, diphenylhydantoin, isoniazid,
center of the hypothalamus to produce peripheral vasodila- rifampin, and sulfinpyrazone. Long-term use of acetamino-
tion, sweating, and dissipation of heat. phen will increase the anticoagulant actions of warfarin. Zid-
ovudine administered with acetaminophen may increase the
Pharmacokinetics: risk of bone marrow suppression. Herbal/Food: Caffeine will
enhance the analgesic effects of acetaminophen. Hepatotoxic-
Route(s) PO, rectal, IV ity has been reported with concurrent echinacea use.
Absorption Rapid and complete absorption Pregnancy: Category B.
Distribution Distributed to all body fluids; Treatment of Overdose: Acetaminophen overdose is
treated with oral or IV acetylcysteine (Acetadote). For max-
crosses the placenta; secreted imum effectiveness, the antidote should be administered
within 8 hours of acetaminophen ingestion. The IV form
in breast milk; 25% bound to (Acetadote) is administered by the “three-bag method”:
plasma protein • Loading dose. Dilute 150 mg/kg in 200 mL of 5% dex-
trose and administer over 60 minutes.
Primary metabolism Hepatic
• Second dose. Dilute 50 mg/kg in 500 mL of 5% dex-
Primary excretion Renal trose and administer over 4 hours.
Onset of action PO: 30–60 min; IV: 15 min • Third dose. Dilute 100 mg/kg in 1,000 mL of 5% dex-
trose and administer over 16 hours.
Duration of action 3–8 h
Nursing Responsibilities: Key nursing implications
Adverse Effects: At recommended doses, acetamino- for patients receiving acetaminophen are included in the
phen is well tolerated and serious adverse effects are rare. Nursing Practice Application for Patients Receiving Phar-
The risk for adverse effects is dose related and increases macotherapy for Inflammation and Fever.
with long-term use. Acute acetaminophen poisoning is very
serious, and symptoms include anorexia, nausea, vomiting, Drugs Similar to Acetaminophen (Tylenol)
dizziness, lethargy, diaphoresis, chills, epigastric or abdom-
inal pain, and diarrhea. Excessive acetaminophen use is Acetaminophen is the only medication in this class.
the number one cause of acute hepatic failure in the United
States. The onset of hepatotoxicity is noted with elevated CONNECTIONS: Treating the
transaminases (alanine aminotransferase [ALT], aspartate Diverse Patient
aminotransferase [AST]) and bilirubin. The patient may
also experience hypoglycemia, hepatic coma, and acute Ethnic Differences in Acetaminophen
renal failure. Chronic ingestion of acetaminophen results Metabolism
in neutropenia, pancytopenia, leukopenia, thrombocytope-
nic purpura, hepatotoxicity in alcohol-dependent patients, Certain ethnic populations, including patients of Asian, African
and CKD. In 2013, the FDA issued a safety alert that recom- American, or Middle Eastern descent, may have higher rates of
mended the drug be immediately discontinued if skin reac- an enzyme deficiency that affects how they metabolize certain
tions or blisters develop. These skin lesions may indicate drugs. More than 200 million people worldwide are believed to
the development of rare, though serious, disorders such have a hereditary deficiency of the enzyme glucose-
as Stevens–Johnson syndrome. Black Box Warning: Acet- 6-phosphate dehydrogenase (G6PD). Patients with G6PD defi-
aminophen has the potential to cause severe liver injury ciency are at risk for developing hemolysis after ingesting
and may cause serious allergic reactions with symptoms of certain drugs, including acetaminophen. In patients with the
angioedema, difficulty breathing, itching, or rash. deficiency, therapeutic dosages of acetaminophen may cause
hemolysis. Because acetaminophen is one of the most com-
Contraindications/Precautions: Patients who are mon drugs used for fever, pain control, and in many OTC cough
allergic to acetaminophen should not be administered this and cold medicines, and because patients may not know that
medication. It should be used cautiously in patients with they have the deficiency, healthcare providers should recom-
anemia, G6PD deficiency, or hepatic disease. Acetamino- mend that ethnically diverse patients exercise caution when
phen should be administered cautiously to patients with using acetaminophen and report any signs or symptoms asso-
rheumatoid or osteoarthritis, malnutrition, bone marrow ciated with anemia. Patients with known G6PD deficiency
depression, and immunosuppression. Chronic administra- should avoid this drug. Patients receiving IV forms of acetamin-
tion of acetaminophen should be avoided in patients with ophen should have frequent CBC laboratory monitoring.
CKD because this drug can worsen kidney function.
Drug Interactions: Acetaminophen should not be
administered with alcohol or to patients who consume
Chapter 41 Pharmacotherapy of Inflammation and Fever 737
CONNECTIONS: NURSING PRACTICE APPLICATION
Patients Receiving Pharmacotherapy for Inflammation and Fever
Assessment
Baseline assessment prior to administration:
• Obtain a complete health history including hepatic, renal, respiratory, cardiovascular or neurologic disease, pregnancy, or breastfeeding. Obtain a
drug history including allergies, current prescription and OTC drugs, herbal preparations, caffeine, nicotine, and alcohol use. Be alert to possible drug
interactions.
• Obtain baseline vital signs and weight.
• Evaluate appropriate laboratory findings (e.g., complete blood count [CBC], coagulation panels, bleeding time, electrolytes, glucose, lipid profile, and
hepatic or renal function studies).
• Assess the patient’s ability to receive and understand instructions. Include family and caregivers as needed.
Assessment throughout administration:
• Assess for desired therapeutic effects (e.g., temperature returns to within normal range, pain is decreased or absent, signs and symptoms of
inflammation such as redness or swelling are decreased).
• Continue periodic monitoring of CBC, coagulation studies, bleeding time, electrolytes, glucose, lipids, hepatic, and renal function studies.
• Assess vital signs and weight periodically or if symptoms warrant. Report any weight gain over 1 kg (2 lb) in a 24-h period or more than 2 kg (5 lb) in 1 wk.
• Assess for and promptly report adverse effects: symptoms of GI bleeding (dark or tarry stools, hematemesis, coffee-ground emesis, or blood in the
stool), abdominal pain, severe tinnitus, dizziness, drowsiness, lightheadedness, palpitations, tachycardia, HTN, increased respiratory rate and depth,
pulmonary congestion, or edema.
Implementation
Interventions and (Rationales) Patient-Centered Care
Ensuring therapeutic effects: • Teach the patient to supplement drug therapy with nonpharmacologic
• Continue assessments as above for therapeutic effects. (Diminished fe- measures (e.g., RICE: rest, ice or cool compresses, compression
bandage [e.g., ACE wrap], elevation of the inflamed joint or limb);
ver, pain, or signs and symptoms of infection should begin after taking increased fluid intake for fever; positioning for comfort; diversionary
the first dose and continue to improve. The provider should be notified distractions (e.g., television or music).
if fever remains present after 3 days or if increasing signs of infection
are present.)
Minimizing adverse effects: • Teach the patient to immediately report a fever that does not diminish
• Continue to monitor vital signs, especially temperature if fever is below 37.8°C (100°F) or per established parameters, febrile seizures,
changes in behavior or LOC, tachycardia, palpitations, or increased
present, and blood pressure and pulse for patients on ibuprofen and blood pressure to the healthcare provider.
similar drugs. Immediately report undiminished fever, changes in level
of consciousness (LOC), febrile seizures, tachycardia, blood pressure • Teach the patient on ibuprofen or similar drugs how to monitor the
over 140/90 mmHg, or per parameters as ordered by the healthcare pulse and blood pressure. Ensure proper use and functioning of any
provider. (Fever should begin to diminish within 1–3 h after taking the home equipment obtained.
drug. Ibuprofen and similar drugs may increase the risk for cardiovas-
cular thrombotic events such as MI and stroke.)
• Continue to monitor periodic laboratory work: hepatic and renal func- • Instruct the patient on the need to return periodically for laboratory
tion tests, CBC, electrolytes, glucose, lipid levels, coagulation studies, work.
or bleeding time. Lifespan: Monitor the older adult frequently because
age-related physiologic changes increase the risk of adverse renal • Teach the patient to abstain from alcohol while taking acetaminophen.
and hepatic effects. (Aspirin and salicylates affect platelet aggregation Men who consume more than two alcoholic beverages per day or
and should be monitored if used long term or if excessive bleeding or women who consume more than one alcoholic beverage per day
bruising is noted. Acetaminophen can be hepatotoxic in large doses or should consult their healthcare provider before taking acetaminophen.
if taken when hepatic dysfunction is present.)
• Monitor for abdominal pain, black or tarry stools, blood in the stool, • Instruct the patient to immediately report any signs or symptoms of GI
hematemesis, coffee-ground emesis, dizziness, lightheadedness, bleeding.
and hypotension, especially if associated with tachycardia. Lifespan:
Monitor the older adult frequently for GI irritation or bleeding because • Teach the patient to take the drug with food or milk to decrease GI
age-related physiologic changes increase the risk of adverse effects. irritation. Enteric-coated tablets should be swallowed whole without
(NSAIDs may cause GI irritation and bleeding.) chewing, crushing, or breaking. Alcohol use should be avoided or
eliminated.
• Monitor for tinnitus, difficulty hearing, lightheadedness, or difficulty with • Instruct the patient to immediately report any signs or symptoms of
balance, and report promptly. (NSAIDs and salicylates may be ototoxic ringing, humming, buzzing in ears, difficulty with balance, dizziness or
and cause hearing loss.) vertigo, or nausea.
• Monitor urine output and renal function studies periodically. Weigh • Instruct the patient on NSAIDs and salicylates to report promptly any
patient on corticosteroids daily, and report weight gain of 1 kg (2 lb) or changes in the quantity of urine output, darkening of urine, or edema.
more in a 24-h period or more than 2 kg (5 lb) per week, or increas-
ing peripheral edema. (NSAIDs and salicylates may be nephrotoxic • Teach the patient on NSAIDs and salicylates to increase fluid intake,
and patients on long-term or high-dose therapy should monitor urine especially if fever is present.
output and have periodic renal function studies. Daily weight is an
accurate measure of fluid status and takes into account intake, output, • Instruct the patient to weigh self daily, ideally at the same time of day.
and insensible losses.) The patient should report a weight gain of more than 1 kg (2 lb) in a
24-h period or more than 2 kg (5 lb) per week, or increasing peripheral
edema.
• Periodically monitor vision in patients on NSAIDs. Immediately report • Teach the patient on NSAIDs to obtain eye exams twice yearly or more
unusual changes in visual acuity, blurred or diminished vision, reports frequently as instructed by the provider. Immediately report any eye
of spots in vision, or changes in color sense to the provider. (NSAIDs pain, diminished or blurred vision, or changes in color sense.
may cause blurred or diminished vision, decreased color sense,
diplopia, or scotomas.) (continued )
738 Unit 6 Pharmacology of Body Defenses
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
• Lifespan: Avoid the use of aspirin or salicylates in children under age • Instruct parents to use NSAIDs or acetaminophen in children under
19 unless explicitly ordered by the healthcare provider. (Aspirin has age 19 for fever or pain control, unless otherwise ordered by the pro-
been associated with an increased risk of Reye’s syndrome in children vider. Do not use aspirin or salicylates in children under age 19 unless
under age 19, particularly associated with the flu virus and varicella ordered by the provider or within 2–3 wk after the varicella vaccination
infections.) has been administered to these children.
• Teach parents to read labels on all OTC medications and to avoid
formulations with aspirin or salicylate on the label.
• Lifespan: Assess for the possibility of pregnancy before beginning the • Instruct women who may be considering pregnancy, or are pregnant,
drug. (Many NSAIDs are pregnancy category C or D.) to notify their provider before starting the drug.
Patient understanding of drug therapy: • The patient, family, or caregiver should be able to state the reason for
• Use opportunities during administration of medications and during the drug, appropriate dose and scheduling, what adverse effects to
observe for and when to report them, and the anticipated length of
assessments to discuss the rationale for drug therapy, desired medication therapy.
therapeutic outcomes, most commonly observed adverse effects,
parameters for when to call the healthcare provider, and any necessary
monitoring or precautions. (Using time during nursing care helps to
optimize and reinforce key teaching areas.)
Patient self-administration of drug therapy: • The patient, family, or caregiver is able to discuss appropriate dosing
• When administering the medication, instruct the patient, family, or and administration needs, including:
• NSAIDs should be taken with food or milk to decrease GI upset.
caregiver in proper self-administration, e.g., with food or milk. (Utilizing • Liquid doses of acetaminophen or NSAIDs should be measured
time during nurse administration of these drugs helps to reinforce with the dosage cup, dropper, or spoon enclosed with the pre-
teaching. Household measuring devices such as teaspoons differ scription. If that measuring device is no longer available, do not use
significantly in size and amount and should not be used for pediatric or a household spoon. Obtain another calibrated measuring cup or
liquid doses.) dropper.
Understanding Chapter 41
Key Concepts Summary medications for treating mild to moderate pain and
inflammation.
41.1 Inflammation is a nonspecific body response to
antigens and tissue injury. 41.5 Celecoxib is an effective second-generation
nonsteroidal anti-inflammatory drug, but its use
41.2 Treatment of inflammation includes is limited due to an increased risk of myocardial
nonpharmacologic therapies and the administration infarction and stroke.
of anti-inflammatory drugs.
41.6 Acetaminophen is administered for pain relief and
41.3 Aspirin is an inexpensive, effective, first-generation to reduce fever, but it has no anti-inflammatory
nonsteroidal anti-inflammatory drug commonly properties.
used by adults.
41.4 Ibuprofen and similar nonsteroidal anti-
inflammatory drugs are the most common
CASE STUDY: Making the Patient Connection
Remember the patient “Joy- Joycee Layne is a 17-year-old high school student in her
cee Layne” at the beginning senior year. She is an honors student, works hard to get
of the chapter? Now read the good grades, and hates to miss school. For the past 3 days,
remainder of the case study. she has not been feeling well. This morning her temperature
Based on the information is 39°C (102.2°F), and she has chills and a headache. Several
presented within this chapter, of her friends at school have the flu. She has taken ibupro-
respond to the critical think- fen for fevers and menstrual cramps in the past, but Joycee
ing questions that follow. cannot find any in the house as she prepares to leave for
Chapter 41 Pharmacotherapy of Inflammation and Fever 739
school. Her parents have already left for work, and they 2. Why is aspirin administered for fever?
trust her to check with you, the nurse who lives next door,
before taking any medication. Joycee calls you to ask “Is it 3. Should Joycee take the aspirin? Why or why not?
okay to take the aspirin that my mom uses for her arthritis
so I can go to school?” As the nurse, this presents an oppor- 4. What will you teach Joycee about aspirin and the
tunity for you to teach Joycee about aspirin and her fever. flulike symptoms she is having? What additional
patient teaching will she need?
Critical Thinking Questions
Answers to Critical Thinking Questions are available on the
1. Describe the pathophysiology of fever and faculty resources site. Please consult with your instructor.
inflammation.
Additional Case Study 2. What pain medications should be avoided while the
patient is receiving acetaminophen (Tylenol) for fever
Tameeka Jones has a postoperative infection following a reduction?
vaginal hysterectomy. The infection is noted at the site of
the laparoscopic incision of the lower abdomen. She has 3. What patient teaching is important for the patient
developed a fever of 38.8°C (102°F). The healthcare pro- who has a fever related to infection?
vider has ordered acetaminophen (Tylenol) 650 mg PO
every 4 to 6 h as needed for the fever. Answers to Additional Case Study questions are available on
the faculty resources site. Please consult with your instructor.
1. What is the action of acetaminophen (Tylenol)?
Chapter Review 4. An 80-year-old woman, who is scheduled for a total
knee replacement next month, currently takes ibupro-
1. A 30-year-old patient with depression has attempted fen (Motrin, Advil) 600 mg 3 times per day. Which
suicide by overdosing on acetaminophen (Tylenol). patient teaching intervention is most important?
The nurse in the emergency department will antici-
pate that the patient’s treatment will consist of: 1. Continue ibuprofen (Motrin, Advil) until surgery.
2. Stop ibuprofen (Motrin, Advil) today.
1. An intravenous infusion with normal saline to 3. Decrease ibuprofen (Motrin, Advil) to 2 times per day.
infuse at 1000 mL per hour. 4. Stop ibuprofen (Motrin, Advil) 7 to 14 days before
2. The administration of acetylcysteine (Acetadote) surgery.
by intravenous infusion.
5. The nurse should question the order of acetamino-
3. Preparation for cardioversion due to the phen (Tylenol) for which patient?
impending arrhythmia.
1. A patient with cirrhosis of the liver
4. The assessment of liver hepatic enzymes to 2. A patient with chronic obstructive pulmonary
determine hepatotoxicity.
disease
2. A patient has a fever and is allergic to aspirin. Which 3. A patient with breast cancer
medication will the nurse anticipate administering to 4. A patient who is taking warfarin (Coumadin)
reduce the patient’s fever?
6. A patient takes aspirin (acetylsalicylic acid) daily for
1. Ibuprofen (Motrin, Advil) pain in the right knee. Which toxic effects may be
2. Ketorolac (Toradol) present with aspirin overdosage? (Select all that apply.)
3. Acetaminophen (Tylenol)
4. Celecoxib (Celebrex) 1. Tinnitus
2. Hyperventilation
3. An anti-inflammatory drug is ordered to be given 3. Gastrointestinal bleeding
intravenously to the patient for pain. Which anti- 4. Decreased urinary output
inflammatory drug is administered parenterally? 5. Peripheral neuropathy
1. Ketorolac (Toradol) See Answers to Chapter Review in Appendix A.
2. Ketoprofen
3. Ibuprofen (Motrin, Advil)
4. Celecoxib (Celebrex)
740 Unit 6 Pharmacology of Body Defenses
References Shaffer, E. E., Pham, A., Woldman, R. L., Spiegelman, A.,
Strassels, S. A., Wan, G. J., & Zimmerman, T. (2017).
Dehmer, S. P., Maciosek, M. V., Flottemesch, T. J., Estimating the effect of intravenous acetaminophen for
LaFrance, A. B., & Whitlock, E. P. (2016). Aspirin for the postoperative pain management on length of stay and
primary prevention of cardiovascular disease and inpatient hospital costs. Advances in Therapy, 33, 2211.
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Preventive Services Task Force. Annals of Internal
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http://emedicine.medscape.com/article/1009987-
Jibril, F., Sharaby, S., Mohamed, A., & Wilby, K. (2015). overview#a0156
Intravenous versus oral acetaminophen for pain:
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v68i3.1458
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W., & Brost, B. (2015). Effect of acetaminophen on fetal
Chung, E. Y., & Tat, S. T. (2016). Nonsteroidal anti- activity. American Journal of Perinatology, 32, 1277–1280.
inflammatory drug toxicity in children: A clinical doi:10.1055/s-0035-1555126
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R. (2016). Evolution to low-dose NSAID therapy. Pain
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overview#aw2aab6b2b4 Purssell, E., & Collin, J. (2016). Fever phobia: The impact
of time and mortality—a systematic review and meta-
Guirguis-Blake, J. M., Evans, C. V., Senger, C. A., analysis. International Journal of Nursing Studies, 56,
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systematic evidence review for the U.S. Preventive Tran-Duy, A., Vanmolkot, F. H., Joore, M. A., Hoes, A. W.,
Services Task Force. Annals of Internal Medicine, 164, & Stehouwer, C. D. A. (2015). Should patients
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pump inhibitors? A systematic review and meta-
Lancaster, E. M., Hiatt, J. R., & Zarrinpar, A. (2015). analysis. International Journal of Clinical Practice, 69,
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s00204-014-1432-2 Wong, T., Stang, A. S., Ganshorn, H., Hartling, L.,
Maconochie, I. K., Thomsen, A. M., & Johnson, D. W.
Mallick-Searle, T. (2016). Over-the-counter analgesics: (2013). Combined and alternating paracetamol and
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McCarberg, B. H., & Cryer, B. (2015). Evolving therapeutic Yuan, J. Q., Tsoi, K. K. F., Yang, M., Wang, J. Y.,
strategies to improve nonsteroidal anti-inflammatory Threapleton, D. E., Yang, Z. Y., ... Chan, F. K. L. (2016).
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“I don’t know what’s worse—
the symptoms or the treatment.
I feel terrible.”
Patient “Carole Banks”
Chapter 42
Immunostimulants
and Immunosuppressants
Chapter Outline Learning Outcomes
cc Immunostimulants After reading this chapter, the student should be able to:
Interferons
PROTOTYPE Interferon Alfa-2b (Intron A), p. 743 1. Compare and contrast the therapeutic applications
Interleukins of the immunostimulants and immunosuppressants.
PROTOTYPE Aldesleukin (Proleukin), p. 746
2. Describe the roles of interferons, interleukins, and
cc Immunosuppressants other cytokines in modulating the immune response.
Calcineurin Inhibitors
PROTOTYPE Cyclosporine (Gengraf, Neoral, 3. Explain how pegylation of the interferon molecule
Sandimmune), p. 751 allows for less frequent dosing.
Cytotoxic Drugs and Antimetabolites
PROTOTYPE Azathioprine (Azasan, Imuran), p. 753 4. Explain why therapy with immunosuppressant
Antibodies medications is necessary following organ
PROTOTYPE Basiliximab (Simulect), p. 755 transplants.
Corticosteroids
5. Identify the classes of drugs used as
immunosuppressants.
6. Compare and contrast polyclonal and monoclonal
antibodies.
7. For each of the classes shown in the chapter outline,
identify the prototype and representative drugs and
explain the mechanism(s) of drug action, primary
indications, contraindications, significant drug
interactions, pregnancy category, and important
adverse effects.
8. Apply the nursing process to care for patients
receiving pharmacotherapy with immunostimulants
and immunosuppressants.
741
742 Unit 6 Pharmacology of Body Defenses
Key Terms immunostimulants, 742 pegylation, 743
immunosuppressants, 743 polyclonal antibodies, 755
biologic response modifiers, 743 interleukins (ILs), 746 transplant rejection, 749
calcineurin, 750 monoclonal antibody (MAB), 755
capillary leak syndrome, 746
cytokine release syndrome, 756
The immune system and other body defenses are truly for- specific to a single species of microbe, whereas others are
midable deterrents to invading microorganisms. A healthy nonspecific and provide the same response or protection
defense system can protect the body from life-threatening regardless of the invading pathogen. The student should
infections caused by thousands of different species of review the components of body defenses in Chapter 43
organisms often over an entire lifetime. In addition, body before proceeding.
defenses can protect against internal invaders such as can-
cer cells. In certain circumstances, however, drugs may be Immunomodulator is a general term referring to any
necessary to modulate the body’s defenses. This chapter drug or therapy that affects body defenses. An overview of
examines pharmacotherapy with drugs that either stimu- the immunomodulators is given in Figure 42.1. Two basic
late or suppress immune function. types of immunomodulators are used for pharmacotherapy:
42.1 Immunomodulators are substances that • Immunostimulants are drugs that increase the ability
either enhance or suppress the ability of the of the immune system to fight infection and disease.
body to fight infection and disease. In most cases, these drugs are used to treat patients
with cancer. The use of immunostimulants to treat
Body defenses are composed of a complex system of cells, cancer is called immunotherapy. Some immunostimu-
tissues, and processes designed with a single goal: to pro- lants are also used to treat hepatitis. The use of colony-
tect the body from invasion by foreign substances, or anti- stimulating factors to treat neutropenia was presented
gens, that may cause harm. Some of these defenses are in Chapter 39 and the application of vaccines to boost
the immune response is presented in Chapter 43.
Immunostimulants Immunosuppressants
Interferons Calcineurin Inhibitors
• Interferon alfa-2b • Cyclosporine
(Intron A) (Gengraf, Neoral, Sandimmune)
Interleukins Cytotoxic Drugs and
• Aldesleukin Antimetabolites
(Proleukin)
• Azathioprine
Colony-Stimulating Factors (Azasan, Imuran)
• Filgrastim
(Neupogen) Antibodies
• Basiliximab
Vaccines (Simulect)
• Hepatitis B vaccine
(Energix, Recombivax) Corticosteroids
• Hydrocortisone
Figure 42.1 Overview of immunomodulators.
Chapter 42 Immunostimulants and Immunosuppressants 743
• Immunosuppressants are drugs that diminish the Many different cell types produce IFNs. Although their
ability of the immune system to fight infection and functions are nearly identical, each IFN has a slightly dif-
disease. Immunosuppressants are used to prevent ferent structure, and some have different receptors. To dis-
transplant rejection and to dampen hyperactive tinguish among the different IFNs, each type is assigned
immune responses, such as those that may occur dur- numbers and a Greek letter. The most common types are
ing exacerbations of systemic lupus erythematosus IFN alfa-2b, IFN beta-1a, IFN beta-1b, and IFN gamma-1a.
(SLE) or rheumatoid arthritis (RA). When the drug consists of a mixture of IFNs, the letter “n”
is assigned. For example, IFN alfa-n3 is a mixture of IFN
Immunostimulants alfa subtypes. The alfa IFNs have the greatest clinical util-
ity. The formulations available are shown in Table 42.1.
42.2 Interferons are biologic response modifiers
that have antiviral and antineoplastic activity. The two “peg” formulations have the molecule poly-
ethylene glycol (PEG) bonded to the IFN. PEG is a polymer
When challenged by antigens, certain cells of the immune with low toxicity that can be found in skin creams, laxa-
system secrete cytokines, which are substances that help tives, lubricants, toothpastes, and many other products.
the body mediate and intensify the immune response. The addition of PEG to another molecule, known as
Because cytokines have powerful actions on the immune pegylation, increases the molecule’s solubility and extends
system, the body generally only produces them when chal- its stability. The addition of PEG to an IFN extends the half-
lenged by an antigen; their production is rapid though life of the drug to allow for once-weekly dosing. Indica-
transient. Although cytokines are essential components of tions for IFN alfa therapy include hairy cell leukemia,
body defenses, a chronic high level of cytokines can greatly non-Hodgkin’s lymphoma, acquired immunodeficiency
worsen symptoms of disorders such as psoriasis, Crohn’s syndrome (AIDS)–related Kaposi’s sarcoma, and chronic
disease, or RA. hepatitis B or C. The use of IFN alfa in the pharmacother-
apy of hepatitis is presented in Chapter 54. Doses of the
Cytokines exhibit multiple complex actions. A single IFNs are listed in Table 42.1.
cytokine can affect multiple target cells, each resulting in a
different action. There is also considerable overlap or redun- IFN beta consists of two different formulations, beta-1a
dancy among the cytokines in that different cytokines can and beta-1b, which are primarily reserved for the treatment
produce the same biologic actions. In addition to affecting of severe multiple sclerosis (MS) (see Chapter 21). A third
their target cells, cytokines interact with each other by turn- drug in this class, called IFN gamma-1b, has limited clini-
ing the synthesis of other cytokines on or off. The physiol- cal application in the treatment of chronic granulomatous
ogy of cytokines is complex and is an active research field. disease and severe osteoporosis.
Natural cytokines have been identified and, through PROTOTYPE DRUG Interferon Alfa-2b (Intron A)
recombinant deoxyribonucleic acid (DNA) technology,
enough quantity has been made available to treat certain Classification Therapeutic: Immunostimulant
disorders. Also called biologic response modifiers, some Pharmacologic: Interferon, biologic
of these drugs have been approved to boost specific func-
tions of the immune system. response modifier
Interferons (IFNs) are cytokines secreted by lympho- Therapeutic Effects and Uses: Approved in 1986,
cytes and activated macrophages that have been infected IFN alfa-2b is a biologic response modifier prepared by
with a virus. IFNs are unable to protect the infected cell, recombinant DNA technology. Indications include neo-
but they warn surrounding cells that a viral infection has plastic conditions such as hairy cell leukemia, malignant
occurred. IFNs attach to nearby uninfected cells, inducing melanoma, non-Hodgkin’s lymphoma, and AIDS-related
the production of protective antiviral proteins. When the Kaposi’s sarcoma as well as viral infections (chronic hepa-
virus attempts to attack the protected cell, the pathogen is titis virus B and C). IFN alfa-2b is also indicated for the
inactivated. intralesional treatment of condylomata acuminata, which
are genital warts caused by the human papillomavirus.
IFNs are part of the body’s nonspecific defense system. Off-label indications include chronic myelogenous leu-
Their actions slow the spread of viral infections, stimulate kemia, bladder cancer, herpes simplex virus, multiple
the activity of existing leukocytes, increase phagocytosis, myeloma, renal cell carcinoma, human immunodeficiency
and enhance the cytotoxic ability of T cells. Interestingly, virus (HIV), varicella-zoster virus (VZV), and West Nile
IFNs promote apoptosis in infected cells, which is a form of virus. It is available for intravenous (IV), intramuscular
programmed cell death in which the infected cell kills itself (IM), and subcutaneous administration.
to limit the replication and spread of the virus. In addition
to their antiviral actions, IFNs have antineoplastic and anti- Mechanism of Action: IFN alfa-2b has both antiviral
inflammatory properties. and antineoplastic activities. It is a nonspecific inhibitor of
744 Unit 6 Pharmacology of Body Defenses
Table 42.1 Immunostimulants
Drug Route and Adult Dose (Maximum Dose Where Indicated) Adverse Effects
aldesleukin (Proleukin)
IV: 600,000 units/kg (0.037 mg/kg) q8h by a 15-min IV infusion for Flulike symptoms, rash, anemia, nausea,
a total of 14 doses vomiting, diarrhea, confusion, dyspnea
bacillus Calmette-Guérin (BCG) Interdermal (Tice): 0.1 mL as vaccine Cardiac arrest, hypotension, tachycardia,
vaccine (TheraCys, Tice) Intravesical (TheraCys): Bladder instillation for bladder carcinoma thrombocytopenia, oliguria, anuria, pulmonary
edema, capillary leak syndrome
Interferons
Flulike symptoms, dysuria, hematuria, anemia,
IFN alfa-2b (Intron A) IM/Subcutaneous: Hairy cell leukemia: 2 million units/m2 3 times/wk lymphadenopathy
for up to 6 months
Thrombocytopenia, cystitis, urinary tract
Kaposi’s sarcoma: 30 million units/m2 3 times/wk for 16 wk infection (UTI), disseminated mycobacteria
Chronic hepatitis B: 30–35 million units/wk for 16 wk Flulike symptoms, myalgia, fatigue, headache,
anorexia, diarrhea, nausea
IFN alfa-n3 (Alferon N) Intralesion: 0.05 mL (250,000 international units) per wart twice/wk
for up to 8 wk Myelosuppression, thrombocytopenia,
neutropenia, suicide ideation, severe
IFN beta-1a (Avonex, Rebif) IM (Avonex): 30 mcg/wk depression, seizures (IFN beta), myocardial
Subcutaneous (Rebif): 44 mcg 3 times/wk infarction (MI) (IFN gamma), anaphylaxis,
hepatotoxicity
IFN beta-1b (Betaseron, Extavia) Subcutaneous: 0.25 mg (8 million units) every other day
IFN gamma-1b (Actimmune) Subcutaneous: 50 mcg/m2 3 times/wk
pegIFN alfa-2a (Pegasys) Subcutaneous: 180 mcg once weekly for 48 wk
pegIFN alfa-2b (Pegintron, Sylatron) Subcutaneous (Pegintron): 1.5 mcg/kg once weekly for 48 wk
Subcutaneous (Sylatron): 6 mg/kg/wk for 8 doses followed by
3 mg/kg/wk for up to 5 years
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
viral replication. It affects cancer cells by two mechanisms. the drug is discontinued. With prolonged therapy, serious
First, it enhances the general functions of the immune sys- adverse effects such as immunosuppression, hepatotoxic-
tem: IFNs increase the phagocytic activity of macrophages ity, and neurotoxicity may be observed. Black Box Warn-
and monocytes, resulting in enhanced cytotoxicity against ing: IFNs may cause or aggravate fatal or life-threatening
tumor cells. Second, this drug suppresses the growth of neuropsychiatric, autoimmune, ischemic, or infectious
cancer cells. disorders. The drug should be discontinued if these symp-
toms are persistent or severe.
Pharmacokinetics:
Contraindications/Precautions: Contraindica-
Route(s) IV, IM, subcutaneous tions include hypersensitivity to IFNs, autoimmune hep-
atitis, or hepatic decompensation. Neonates and infants
Absorption 80% absorbed should not receive this drug because it contains benzyl
alcohol, which is associated with an increased incidence
Distribution Unknown if secreted in breast of neurologic and other serious complications in this age
group. If infection occurs during therapy, anti-infectives
milk should be started immediately. Hepatic enzymes may
become elevated during IFN therapy and may require
Primary metabolism Minimal hepatic metabolism discontinuation of the drug. This effect is worse in
patients with preexisting hepatic impairment. IFN alfa-
Primary excretion Renal 2b should be used with caution in patients with cardiac
disease, herpes zoster, and recent exposure to chicken-
Onset of action Peak: 3–12 h pox. Triglycerides should be monitored during therapy
because elevated levels have resulted in symptoms of
Duration of action Half-life: 2–3 h pancreatitis in some patients.
Adverse Effects: The most common adverse effect of Drug Interactions: IFN alfa-2b may increase theophyl-
IFN therapy is a flulike syndrome of fever, chills, dizzi- line levels. Zidovudine may increase hematologic toxicity
ness, weight loss, and fatigue that occurs in about 50% of and cause immunosuppression. Herbal/Food: Unknown.
patients and that usually diminishes as therapy progresses.
Fatigue may be severe at higher doses. Neutropenia occurs
in most patients and headache, nausea, vomiting, diar-
rhea, and anorexia are common. Hair loss may occur with
prolonged therapy. Depression and suicidal ideation have
been reported and may be severe enough to require dis-
continuation of the drug. The depression may persist after
Chapter 42 Immunostimulants and Immunosuppressants 745
Pregnancy: Category C. If used with ribavirin, the CGD is an inherited disorder of phagocytic cells that leads
combination is category X. to recurrent life-threatening bacterial and fungal infec-
tions. A second characteristic of CGD is the development
Treatment of Overdose: Overdose with IFN may of nodular granulomas in the skin, gastrointestinal (GI)
cause lethargy and coma. Treatment is by general support- tract, and genitourinary (GU) tract due to chronic infec-
ive measures. tions at these sites. IFN gamma-1b reduces the frequency
and severity of infections in patients with CGD. Off-label
Nursing Responsibilities: Key nursing implications indications include infections by Mycobacterium avium
for patients receiving IFN alfa-2b are included in the Nurs- complex (MAC), pulmonary fibrosis, and ovarian cancer.
ing Practice Application for Patients Receiving Pharmaco- The most common adverse effects include flulike symp-
therapy with Immunomodulators. toms, nausea, vomiting, diarrhea, rash, and elevated
hepatic enzymes. Because of the potential for neutropenia
Drugs Similar to Interferon alfa-2b (Intron A) and thrombocytopenia, periodic CBCs are required. This
drug is pregnancy category C.
Other available IFNs include IFN alfa-n3, IFN beta-1a, IFN
beta-1b, IFN gamma-1b, pegIFN alfa-2a, and pegIFN alfa- PegIFN alfa-2a (Pegasys): PegIFN alfa-2a is a biologic
2b. IFN alfa-n1 (Wellferon) and IFN alfa-2a are no longer response modifier that has a molecule of PEG attached to
available in the United States. IFN alfacon-1 was discontin- IFN alfa-2a, which is identical to the natural IFN produced
ued in 2013. by human lymphocytes and macrophages. Approved in
2002, it is prepared through recombinant DNA technology
IFN alfa-n3 (Alferon N): Approved in 1989, IFN alfa-n3 is and is available as single-use prefilled syringes and admin-
a mixture of IFN alfa subtypes purified from human leuko- istered by the subcutaneous route. Approved indications
cytes. Indications include genital warts caused by human for pegIFN alfa-2a include chronic hepatitis B and
papillomavirus. Two injections per week for 8 weeks are hepatitis C virus infections that show evidence that the
usually sufficient to cause warts to disappear. Unlike the virus is replicating. Off-label uses include renal cell carci-
other IFNs, this drug is injected directly into lesions (intral- noma and chronic myelogenous leukemia. Patients should
esionally). Its off-label indications include treatment of hep- be monitored for serious depression and suicidal ideation.
atitis C, herpes simplex, and other viral infections by the Neutropenia and thrombocytopenia are uncommon but
subcutaneous route. This product may contain egg protein may be severe. Other potential adverse effects include coli-
and is contraindicated in patients with egg sensitivity. IFN tis, pancreatitis, hyper- or hypothyroidism, hypertension
alfa-n3 exhibits few adverse effects when administered (HTN), and dysrhythmias. A black box warning for IFNs
intralesionally. This drug is pregnancy category C. states that these drugs may cause or aggravate fatal or life-
threatening neuropsychiatric, autoimmune, ischemic, or
IFN beta-1a (Avonex, Rebif) and IFN beta-1b (Betaseron, infectious disorders. This drug is pregnancy category C.
Extavia): The beta interferons are first-line drugs for the
pharmacotherapy of MS. These medications decrease the PegIFN alfa-2b (Pegintron, Sylatron): Approved in 2001,
frequency of clinical exacerbations and slow the progres- pegIFN alfa-2b (Pegintron) is indicated for the treatment of
sion to physical disability, which is characteristic of MS. chronic hepatitis C in patients ages 3 years and older with
Both beta interferons are available by the subcutaneous compensated liver disease. It may be used off-label to treat
route; beta-1b can also be administered. Adverse effects are chronic hepatitis B infections and neoplastic disease.
similar to those of other IFNs, with flulike symptoms being Pegintron is usually given in combination with the antivi-
observed in the majority of patients. Patients should be ral ribavirin over a period of 24 to 48 weeks. It is important
monitored for depression and suicidal ideation. Additional to note that ribavirin can cause fetal injury and death and
details on the pharmacotherapy of MS and a drug proto- is a possible carcinogen. Sylatron was approved in 2011 for
type feature for IFN beta-1b are presented in Chapter 21. the adjunctive treatment of melanoma that has lymph
The beta interferons are pregnancy category C. node involvement.
IFN gamma-1b (Actimmune): Approved in 1999, IFN PegIFN alfa-2b has a molecule of PEG attached to the
gamma-1b is produced by recombinant DNA technology IFN molecule, which gives the drug an extended half-life.
and is very similar to natural IFN gamma. IFN gamma-1b Peak concentrations can be sustained for 48 to 72 hours,
has both direct and indirect antiviral activity. This drug which results in greater antiviral activity. The most fre-
activates macrophages to increase the production of inter- quently reported adverse effects with pegIFN alfa-2b are
leukin-12 and tumor necrosis factor (TNF), which increases injection-site reactions, fatigue, headache, rigors, fever,
the killing ability of these cells. IFN gamma-1b also pro- nausea, myalgia, and emotional lability. A black box warn-
motes the recruitment of leukocytes to the sites of infection ing for IFNs states that these drugs may cause or aggravate
or inflammation. IFN gamma-1b is the only IFN indicated fatal or life-threatening neuropsychiatric, autoimmune,
for the treatment of chronic granulomatous disease (CGD).
746 Unit 6 Pharmacology of Body Defenses
ischemic, or infectious disorders. This drug is pregnancy length of neutropenia in patients with cancer and in those
category C (category X if used with ribavirin). who have had a bone marrow transplant and whose bone
marrow has been suppressed by drugs. Filgrastim, the pro-
42.3 Interleukins, vaccines, and colony- totype, and other colony-stimulating factors are presented
stimulating factors are used to boost in Chapter 39.
the immune system.
CONNECTION Checkpoint 42.1
Interleukins (ILs) are a class of cytokines synthesized by
lymphocytes, monocytes, macrophages, and certain other From what you learned in Chapter 39, what is the primary indication
cells in response to antigen exposure. Like IFNs, ILs are of oprelvekin (Neumega) therapy, and what is its most important ad-
signaling molecules that enable cells of the immune sys- verse effect? Answers to Connection Checkpoint questions are avail-
tem to communicate with each other. The ILs, however, able on the faculty resources site. Please consult with your instructor.
work by different mechanisms than the IFNs. The ILs have
widespread effects on immune function that include the PROTOTYPE DRUG Aldesleukin (Proleukin)
following:
Classification Therapeutic: Immunostimulant
• Stimulation of cytotoxic T-cell activity against tumor Pharmacologic: Interleukin, biologic
cells
response modifier
• Activation and increased production of natural killer
(NK) cells Therapeutic Effects and Uses: Approved in 1992,
aldesleukin has a structure very similar to natural IL-2,
• Increased B-cell and plasma cell production and it has identical actions in the body. It is approved by
• Increased neutrophil chemotaxis the U.S. Food and Drug Administration (FDA) for the
• Promotion of inflammation. pharmacotherapy of metastatic renal cell carcinoma and
metastatic malignant melanoma. It has been designated by
More than 30 different ILs have been identified, though the FDA as an orphan drug for the chemotherapy of non-
only a few are available as medications. IL-2, which is Hodgkin’s lymphoma and acute myelogenous leukemia. It
derived from helper T cells, promotes the proliferation of is used off-label to treat leprosy.
both T cells and activated B cells. It is available as aldes-
leukin (Proleukin), which is indicated for the treatment of Aldesleukin is a very toxic drug that should be admin-
metastatic renal cell carcinoma and metastatic melanoma. istered only by personnel familiar with its use. It must be
IL-11, which is derived from bone marrow cells, is a growth administered in multiple, brief IV infusions because of its
factor with multiple hematopoietic effects. It is marketed as short half-life.
oprelvekin (Neumega) for its ability to stimulate platelet
production in patients with immunosuppression. Oprelve- Mechanism of Action: The mechanism of action of
kin is featured as a prototype drug in Chapter 39. Some aldesleukin is identical to that of endogenous IL-2. It initi-
interleukins are used in the pharmacotherapy of RA. ates a series of actions that activate IFNs, TNF, and other
ILs. The drug promotes proliferation of both B cells and
Bacillus Calmette-Guérin (BCG) vaccine (TheraCys, T cells, macrophages, and NK cells, which in turn increase
Tice) is a biologic response modifier that is available to the body’s ability to fight cancer cells.
enhance the immune system. BCG is an attenuated strain
of Mycobacterium bovis used for the pharmacotherapy of Pharmacokinetics: IV
certain types of bladder cancer. Route(s) N/A
Absorption Widely distributed; unknown if
Vaccines are types of immunostimulants that have the Distribution secreted in breast milk
ability to mobilize the body against specific antigens. A Renal
small amount of an inactivated antigen is administered Primary metabolism Renal
and the patient develops a subclinical immune reaction. If Primary excretion Unknown
reexposed to the antigen in future years, memory B or Onset of action Half-life: 85 min
T cells will develop a rapid response, eliminating the anti- Duration of action
gen before it causes disease. Vaccines are presented in
Chapter 43. Adverse Effects: Aldesleukin is a toxic drug that has
the potential to cause serious adverse effects in virtu-
The final type of immunostimulant includes the ally any organ system. Many of the adverse effects are
colony-stimulating factors, which are drugs that promote caused by capillary leak syndrome, a serious condition
the production of white blood cells (WBCs). For example, in which plasma proteins and other substances leave the
filgrastim (Neupogen) stimulates the production of granu-
locytes, and sargramostim (Leukine) activates multiple
types of leukocytes. These drugs are used to shorten the
Chapter 42 Immunostimulants and Immunosuppressants 747
blood and enter the interstitial spaces because of porous Treatment of Overdose: Dexamethasone may be
capillaries. If not monitored carefully, capillary leak used to reverse some of the toxicities observed from an
syndrome can result in death. Over 70% of patients tak- overdose of aldesleukin.
ing aldesleukin will experience hypotension, which can
sometimes be severe enough to cause tissues and organs Nursing Responsibilities: Key nursing implications
to receive an insufficient blood supply to function for patients receiving aldesleukin are included in the Nurs-
properly. Tachycardia and other dysrhythmias occur ing Practice Application for Patients Receiving Pharmaco-
in a significant number of patients. Diarrhea, nausea, therapy with Immunomodulators.
or vomiting may occur in as many as half the patients
taking the drug. Other common adverse effects include Drugs Similar to Aldesleukin (Proleukin)
confusion, drowsiness, oliguria, stomatitis, anorexia,
hyperbilirubinemia, hypothyroidism, elevated hepatic The only other IL approved by the FDA is IL-11, a platelet
enzymes, weight gain, dyspnea, and pulmonary conges- enhancer marketed as oprelvekin (Neumega), which is fea-
tion. Common changes in blood values include throm- tured as a prototype in Chapter 39. BCG vaccine is a mis-
bocytopenia, anemia, and leukopenia. Flulike symptoms cellaneous biologic response modifier.
such as fever and malaise occur frequently. Black Box
Warnings: Aldesleukin can cause severe capillary leak Bacillus Calmette-Guérin vaccine (TheraCys, Tice):
syndrome. Death may result from infection that can BCG vaccine is a live, attenuated vaccine that is available
spread throughout the body because of impaired neu- in two distinct strains with different indications. Both
trophil function. If moderate to severe fatigue develops, forms are pregnancy category C.
the drug should be withheld. The drug should be used
with extreme caution in patients with a history of car- TheraCys: TheraCys is approved for the prophylaxis and
diac or pulmonary disease. treatment of patients with superficial bladder cancer. This
drug is instilled into the urinary bladder for 2 hours, after
Contraindications/Precautions: There are many which the patient voids the medication. The treatment
contraindications to using aldesleukin, and a thorough may be repeated at 3-month intervals. TheraCys produces
baseline assessment of health status is required. If the a nonspecific immune reaction in the bladder that attracts
assessment indicates a preexisting bacterial infection, lymphocytes, macrophages, and NK cells to the site of the
this should be treated prior to initiating therapy with cancer. Adverse effects include local reactions such as blad-
aldesleukin. Aldesleukin should not be administered to der irritability, hematuria, dysuria, cystitis, incontinence,
patients with developing moderate to severe lethargy and nocturia. A flulike syndrome may occur. This drug
because the drug may induce coma. Patients with sig- contains a black box warning that intravesical instillation
nificant cardiac, central nervous system (CNS), pulmo- may cause disseminated infections because the drug con-
nary, renal, or hepatic impairment should not receive tains live attenuated mycobacteria.
this drug. Aldesleukin may cause seizures and should
be used with caution in patients with epilepsy. This drug Tice: Tice is used to stimulate immunity against Mycobac-
may worsen the condition of patients with autoimmune terium tuberculosis. Vaccination with BCG simulates expo-
disease, including those with scleroderma, RA, diabetes sure to tuberculosis and induces an immune response
mellitus, and thyroiditis. against the organism. This drug is used to prevent tuber-
culosis and is not given to treat active infections. It is the
Drug Interactions: Aldesleukin has the potential to only FDA-approved treatment for tuberculosis prophy-
interact with nearly any other drug. Given concurrently laxis. The drug is not 100% effective and its length of
with aldesleukin, drugs that affect mental status such as protection is variable. Flulike symptoms often develop 1 to
many antianxiety drugs, opioids, sedatives, or antipsy- 2 days after administration. Minor skin papules appear at
chotic medications may cause mood disturbances and the site of percutaneous puncture.
drowsiness. Concurrent administration with drugs that
are hepatotoxic or nephrotoxic may cause additive organ Immunosuppressants
damage. Caution should be practiced when using drugs
that modify coagulation such as aspirin, nonsteroidal anti- 42.4 Immunosuppressants are used to prevent
inflammatory drugs (NSAIDs), or platelet inhibitors due to transplant rejection and for the treatment of
an increased risk of bleeding. Antihypertensive drugs may autoimmune disorders.
cause additive hypotension when used with aldesleukin.
Herbal/Food: None known. Used to inhibit the immune response, immunosuppressants
are prescribed for patients who are receiving transplanted
Pregnancy: Category C. tissues or organs and to treat autoimmune disorders. Doses
for these medications are listed in Table 42.2.
748 Unit 6 Pharmacology of Body Defenses
Table 42.2 Immunosuppressants
Drug Route and Adult Dose Adverse Effects
Antibodies (Maximum Dose Where Indicated)
antithymocyte globulin Local reactions at the injection site (pain, erythema, myalgia),
(Atgam, Thymoglobulin) IV (Atgam): 10–30 mg/kg daily flulike symptoms (malaise, fever, chills), headache, dizziness
IV (Thymoglobulin): 1.5 mg/kg daily infused over 4–6 h
basiliximab (Simulect) for 7–14 days Anaphylaxis, HTN, serious infections, thrombocytopenia,
IV: 20 mg times 2 doses (first dose 2 h before surgery; leukopenia, kidney impairment (basiliximab), antithymocyte
belatacept (Nulojix) second dose 4 days after transplant) globulin, post-transplant lymphoproliferative disorder (PTLD)
Calcineurin Inhibitors IV: 5–10 mg/kg using enclosed silicone-free disposable syringe (belatacept)
cyclosporine (Gengraf,
Neoral, Sandimmune) Transplants: Hirsutism, tremor, nausea, vomiting
PO: 5–15 mg/kg/day
tacrolimus (Astagraf XL, Autoimmune disorders: HTN, MI, nephrotoxicity, hyperkalemia, seizures, paresthesia,
Prograf, others) PO: 1.25–2.5 mg/kg/day (max: 4 mg/day) hepatotoxicity
PO (immediate release): 0.1–0.15 mg/kg/day in 2 divided
doses q12h; give first PO dose 8–12 h after discontinuing Oliguria, nausea, constipation, diarrhea, headache, abdominal
IV therapy pain, insomnia, peripheral edema, fever
IV: 0.03–0.05 mg/kg/day as continuous infusion
Infections, HTN, nephrotoxicity, neurotoxicity (tremors,
Cytotoxic Drugs and Antimetabolites paresthesia, psychosis), hyperkalemia, anemia, hyperglycemia,
malignancy, thrombocytopenia, seizures
anakinra (Kineret) Subcutaneous: 100 mg (0.67 mL) once daily
Injection-site reactions, UTI, headache, nausea, diarrhea,
azathioprine (Azasan, PO/IV: 3–5 mg/kg/day initially; may be able to reduce to sinusitis, arthralgia, flulike symptoms
Imuran) 1–3 mg/kg/day
Leukopenia, infections, malignancy, anaphylaxis
cyclophosphamide PO: 2.5–3 mg/kg daily for a period of 60–90 days Nausea, vomiting, anorexia
(Cytoxan) (higher doses are used for malignant disease)
Severe nausea and vomiting, bone marrow suppression,
etanercept (Enbrel) Subcutaneous: 50 mg once/wk thrombocytopenia, serious infections, malignancy, hepatotoxicity
Nausea, vomiting, anorexia, neutropenia, alopecia
ibrutinib (Imbruvica) PO: 420 mg once daily
Anaphylaxis, leukopenia, pulmonary emboli, interstitial
methotrexate PO/IM/IV: 15–30 mg/day for 5 days; repeat every 12 wk pulmonary fibrosis, toxic epidermal necrolysis, Stevens–Johnson
(Rheumatrex, Trexall) for three courses syndrome, hemorrhagic cystitis, oligospermia
Injection-site reactions (pain, erythema, myalgia), abdominal
mycophenolate PO/IV: 720 mg bid in combination with corticosteroids pain, vomiting, headache
(CellCept, Myfortic) and cyclosporine; start within 24 h of transplant
Infections, pancytopenia, leukopenia, anemia, MI, heart failure,
Kinase Inhibitors (Rapamycins) malignancy
Fatigue, bruising, diarrhea, muscle spasms
everolimus (Afinitor, PO (Afinitor): 10 mg once daily
Zortress) Hemorrhage, fetal toxicity, thrombocytopenia, anemia, infections
PO (Zortress): Begin with 0.75 mg bid and adjust to achieve Headache, glossitis, gingivitis, mild leukopenia, nausea, alopecia
a trough concentration of 3–8 ng/mL
Ulcerative stomatitis, myelosuppression, aplastic anemia,
sirolimus (Rapamune) PO: 6–15 mg loading dose immediately after the transplant, hepatic cirrhosis, nephrotoxicity, sudden death, pulmonary
then 2–5 mg/day maintenance dose fibrosis, or pneumonia
Peripheral edema, diarrhea, headache, tremor, dyspepsia,
temsirolimus (Torisel) IV: 25 mg once weekly infused over 30–60 min abdominal pain
UTI, leukopenia, anemia, thrombocytopenia, sepsis, HTN
Peripheral edema, hyperlipidemia, nausea, HTN, UTI, asthenia,
weight changes (loss or gain), elevated serum creatinine,
hyperglycemia and fever
Leukopenia, anemia, thrombocytopenia, sepsis, secondary
infections, malignancy, anaphylaxis, interstitial lung disease or
pneumonia, birth defects
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
Transplantation: Transplants may include specific donors (allografts). Most transplantation procedures use
cells, parts of tissues, or complete organs. They may origi- allografts.
nate from the patient’s own body (autografts), genetically
identical donors (isografts), or genetically dissimilar Typing for transplanted tissues attempts to match, as
closely as possible, donor and recipient human leukocyte
Chapter 42 Immunostimulants and Immunosuppressants 749
CONNECTIONS: Community- as cytomegalovirus (CMV), hepatitis B and C viruses,
Oriented Practice Epstein-Barr virus (EBV), VZV, HIV, and herpes simplex
virus (HSV). If an active infection is discovered, it should
Fever in the Patient on Immunosuppressant be treated prior to transplantation. In addition, patients
Drugs should be screened for the presence of cancer prior to sur-
gery because immunosuppression will allow preexisting
Immunosuppressant drugs are now given to treat a variety of cancers to grow rapidly.
conditions, and more uses are being discovered. Patients tak-
ing immunosuppressants are at greater risk for infection but During immunosuppressant therapy the patient is sus-
may not always exhibit symptoms to the same degree that ceptible to infection from all types of pathogens: viral, bac-
patients with competent immune systems do. The patient must terial, fungal, or protozoan. Infections in immunosuppressed
be assessed for subtle signs of infection including low-grade patients are called opportunistic infections. Opportunistic
fevers (less than 37.8°C [100°F]), unusual skin lesions with or pulmonary infections are the leading cause of morbidity
without drainage, excessive fatigue, malaise, arthralgias, cough, and mortality in patients receiving a transplant. Many
headache, diarrhea, or nausea. Any of these symptoms should patients receive antibiotics for the prophylaxis of opportu-
be immediately reported to the healthcare provider so that nistic infections for 4 to 12 months following surgery. Six
appropriate follow-up examination can be conducted. months following the transplant, 80% of patients will
return to their baseline risk of infection, but the remainder
Before going home with an immunosuppressant drug, will remain at high risk indefinitely.
the patient should receive explicit instructions on when to call
the provider for a fever and how often the temperature should Long-term survivors of transplants are also at high risk
be taken when fever is present or symptoms such as those of developing cancers. These include non-Hodgkin’s lym-
listed above are present. Self-administration of antipyretics phoma, squamous and basal cell skin cancer, cervical can-
such as acetaminophen and ibuprofen is usually not appropri- cer, and Kaposi’s sarcoma. Regular follow-up monitoring
ate because they can mask the symptoms of a significant for cancer is required in these patients.
infection. Fevers that fall outside of the parameters set by the
healthcare provider need to be evaluated. PharmFACT
Many patients on immunosuppressant drugs are able to More than 119,000 patients are waiting for organ transplants.
live active, normal lives. However, they should be taught mea- About 83% of these are waiting for a kidney, 12% for a liver,
sures to reduce their exposure to infections, and should always and 3.5% for a heart (Organ Procurement and Transplantation
receive appropriate instruction for fever management before Network, 2017).
they begin to take the medication.
antigen (HLA) and ABO blood-type antigens. Despite Autoimmune disorders: Autoimmune disorders are those
accurate tissue matching, allografts always contain certain in which the body creates antibodies against normal tissues.
antigens that have the potential to trigger the patient’s The body attacks its own cells as if they were foreign, resulting
immune defenses. This response, called transplant rejec- in tissue injury. Examples of autoimmune disorders include
tion, is often acute; antibodies sometimes destroy the trans- RA, SLE, myasthenia gravis, and Hashimoto’s thyroiditis.
planted tissue within 48 hours after a transplant. The
cell-mediated branch of the immune system responds more Autoimmune diseases are characterized by symptom-
slowly to the transplant, attacking it about 2 weeks follow- atic periods alternating with remissions. Although the
ing surgery. Chronic rejection of the transplant may occur remissions may last many months or even years, relapses
months or even years after surgery. are often progressive, with symptoms worsening as the
disease progresses. During acute relapses, fever and signs
Successful transplantation requires the use of immu- of widespread inflammation may be present. Virtually any
nosuppressant drugs. One or more immunosuppressants tissue or organ may be affected, depending on the specific
are administered at the time of transplantation and are con- autoimmune disease.
tinued for several months following surgery. In some cases,
they are continued indefinitely at low doses. Transplanta- Unlike transplant recipients who may receive immu-
tion would be impossible without the use of effective nosuppressants indefinitely, patients with autoimmune
immunosuppressant drugs. Although immunosuppres- disease are usually given these drugs for brief periods in
sant therapies have proven very successful at preventing high doses to control relapses. In some cases, however,
acute transplant rejection, they have been less successful at these patients may receive low doses for longer periods for
preventing chronic rejection. prophylaxis.
Prior to the initiation of immunosuppressant therapy, The immunosuppressant class includes drugs that
it is critical that the patient be carefully assessed to rule out block the immune response by several different mecha-
active infections. This includes screening for viruses such nisms, as shown in Pharmacotherapy Illustrated 42.1. These
include blocking the receptors and production of IL-2,
750 Unit 6 Pharmacology of Body Defenses
Pharmacotherapy Illustrated 42.1
Mechanism of Action of Immunosuppressants
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6* $CUKNKZKOCD DKPFU VQ
VCETQNKOWU DNQEM +. TGEGRVQT
ECNEKPGWTKP KPFWEGF %CNEKPGWTKP
UGETGVKQP QH +. +. RTGXGPVKPI 6 EGNN
RTQNKHGTCVKQP
+.
6* EGNN RTQNKHGTCVKQP
%NQPCN ITQYVJ
QH 6 EGNNU
%NQPCN ITQYVJ %[VQVQZKE FTWIU
QH $ EGNNU CPVKOGVCDQNKVGU CPF
EQTVKEQUVGTQKFU DNQEM
ENQPCN ITQYVJ QH
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r C\CVJKQRTKPG
r OGVJQVTGZCVG
r O[EQRJGPQNCVG
inhibiting the proliferation of T cells, and using antibodies As described in Section 42.3, IL-2 is an important chemical
specific to certain receptors or cells of the immune response. mediator in promoting the proliferation of B cells, T cells,
The drugs may be classified into the following categories: macrophages, and NK cells. Blocking IL-2 suppresses the
immune response.
• Calcineurin inhibitors and similar drugs
• Cytotoxic drugs and antimetabolites Two of the most important drugs in transplant medi-
• Antibodies cine, cyclosporine (Gengraf, Neoral, Sandimmune) and
• Corticosteroids (glucocorticoids). tacrolimus (Astagraf XL, Prograf), are calcineurin inhibi-
tors. These drugs revolutionized the pharmacotherapy of
42.5 Calcineurin inhibitors are preferred drugs transplant rejection and have been the mainstay of trans-
for the prophylaxis of transplant rejection. plant therapy since the 1980s. Although newer medications
have been developed, the calcineurin inhibitors remain
When a T cell encounters an antigen, calcineurin is acti- critical drugs for transplant recipients. They allow the doses
vated. Calcineurin is an enzyme that acts as an intracellu- of corticosteroids to be lowered, thereby reducing the inci-
lar messenger, telling the T cell to begin synthesizing IL-2. dence of opportunistic infections following transplants.
Chapter 42 Immunostimulants and Immunosuppressants 751
Approved in 1983, cyclosporine was the first calcineu- Pharmacokinetics:
rin inhibitor and remains the prototype for this class. Some
data suggest that tacrolimus may be more effective in pre- Route(s) PO, IV, ophthalmic
venting transplant rejection and reducing the mortality
associated with transplants. It is the most common immu- Absorption Oral absorption is highly
nosuppressant used in certain types of transplants. In addi-
tion to their use in preventing transplant rejection, the variable
calcineurin inhibitors are also of value in treating the acute
inflammation associated with RA and psoriasis, an inflam- Distribution Widely distributed; crosses the
matory disorder of the skin.
placenta; secreted in breast milk;
Everolimus (Afinitor, Zortress), sirolimus (Rapa-
mune), and temsirolimus (Torisel) produce immunosup- 90% bound to lipoproteins
pressant effects similar to the calcineurin inhibitors.
They prevent the activation of T cells by inhibiting a key Primary metabolism Hepatic (CYP3A), extensive
regulatory protein kinase called mTOR. Thus, these
drugs are sometimes called mTOR inhibitors or kinase first-pass metabolism
inhibitors. The kinase inhibitors used to treat cancer
(see Chapter 57) inhibit a different cellular kinase than Primary excretion Bile and feces
the mTOR inhibitors.
Onset of action Peak: 3–4 h
PROTOTYPE DRUG Cyclosporine (Gengraf, Neoral,
Sandimmune) Duration of action Half-life: 16–27 h
Classification Therapeutic: Immunosuppressant Adverse Effects: The primary adverse effect of cyclo-
Pharmacologic: Calcineurin inhibitor sporine is nephrotoxicity, with up to 75% of patients expe-
riencing a reduction in urine flow. Over half the patients
Therapeutic Effects and Uses: Cyclosporine is a taking the drug will experience HTN and tremor. Hir-
complex chemical obtained from a soil fungus. It is FDA sutism occurs in many patients. Other common adverse
approved for the prophylaxis of kidney, heart, and liver effects are elevated hepatic enzymes, mild to moderate
transplant rejection; psoriasis; severe RA; and xeroph- HTN, headache, and gingival hyperplasia. Infections are
thalmia, an eye condition of diminished tear produc- common during cyclosporine therapy, including reactiva-
tion caused by ocular inflammation. Off-label indications tion of latent herpes or varicella infections. Periodic blood
include a number of autoimmune and inflammatory con- counts are necessary to ensure that leukocytes do not fall
ditions such as ulcerative colitis, SLE, myasthenia gravis, below 4000, or platelets below 75,000. Anaphylaxis has
aplastic anemia, Crohn’s disease, psoriatic arthritis, and been reported with IV administration. Long-term therapy
graft-versus-host disease (GVHD). increases the risk of malignancy, especially lymphomas
and skin cancers. Black Box Warning: This drug should
Cyclosporine may be administered as capsules, oral only be administered by healthcare providers experienced
solution, or IV or as an ophthalmic solution (Restasis) for in immunosuppressive therapy. Use may result in serious
xerophthalmia. Due to the risk of anaphylaxis, the IV route infections and possible malignancies. Kidney damage may
is used only when patients are unable to take oral (PO) occur, thus renal function should be monitored during
medications. Cyclosporine (modified) refers to the capsule, therapy. Patients with psoriasis who are taking cyclospo-
microemulsion dosage formulation of cyclosporine (Gen- rine with other psoriasis medications are at an increased
graf, Neoral). Cyclosporine (modified) has increased bio- risk of developing skin malignancies.
availability compared to that of cyclosporine (nonmodified)
and cannot be used interchangeably without close Contraindications/Precautions: Patients who are
monitoring. taking cyclosporine should avoid direct exposure to the
sun due to an increased risk of skin cancer. Because cyclo-
Unlike some of the more cytotoxic immunosuppres- sporine is nephrotoxic, the drug is either contraindicated
sants, cyclosporine is less harmful to bone marrow cells. or should be used with extreme caution in patients with
When prescribed for transplant recipients, it is often used chronic kidney disease: Renal laboratory function should
in combination with a corticosteroid such as prednisone. be regularly evaluated. The drug should not be used dur-
ing pregnancy or lactation. Because cyclosporine is primar-
Mechanism of Action: Cyclosporine inhibits the ily eliminated via the bile, its dose should be reduced in
function of calcineurin. This diminishes the activity of patients with hepatic or biliary impairment. Patients with
T cells and B cells and suppresses the immune response. active infections should be treated with anti-infectives
prior to cyclosporine therapy. Caution should be used
in patients with preexisting HTN because the drug may
worsen this condition.
Drug Interactions: Cyclosporine is a major substrate
of CYP3A4 and may interact with drugs that inhibit or
induce this enzyme. Drugs that may decrease cyclosporine
levels include phenytoin, phenobarbital, carbamazepine,
752 Unit 6 Pharmacology of Body Defenses
and rifampin. Azole antifungal drugs, oral hypoglyce- Sirolimus (Rapamune): Approved in 1999, sirolimus is a
mics, and macrolide antibiotics may increase cyclospo- PO drug isolated from a soil bacterium that shares a similar
rine levels. Because cyclosporine increases blood pressure, structure and potent immunosuppressant properties with
the doses of antihypertensives will require adjustment. tacrolimus. Sirolimus, however, acts by a unique mecha-
Potassium-sparing diuretics should be avoided because nism; that is, it binds to a protein known as FKBP that pre-
their concurrent use with cyclosporine causes hyperka- vents T-cell activation and proliferation and the production
lemia. Cyclosporine should be given with caution with of antibodies by B cells. Sirolimus does not exhibit the seri-
other nephrotoxic drugs due to the potential for additive ous organ toxicity characteristic of tacrolimus. This drug
kidney damage. Statins should not be used concurrently appears to be less effective than the calcineurin inhibitors,
with cyclosporine due to the potential for myopathy or but it does exert synergistic immunosuppression when
rhabdomyolysis. Herbal/Food: Food decreases the absorp- used with other immunosuppressive drugs. Sirolimus is
tion of the drug. Grapefruit juice can raise cyclosporine only approved for use in the prophylaxis of kidney trans-
levels by 50% to 200%. The immune-enhancing effects of plant rejection in combination with cyclosporine and corti-
astragalus and echinacea may interfere with the action of costeroids for the first year after transplantation. At 2 to
immunosuppressants. 4 months post-transplantation, the cyclosporine may be
gradually withdrawn over a 4- to 8-week period. The
Pregnancy: Category C. serum levels of sirolimus must be adjusted upward when
cyclosporine is withdrawn. Adverse effects include hyper-
Treatment of Overdose: An overdose of cyclospo- lipidemia, hypercholesterolemia, peripheral edema, tremor,
rine can result in significant nephrotoxicity and hepatotox- azotemia, elevated serum creatinine, HTN, diarrhea, and
icity. General supportive measures are indicated. anemia. Like most immunosuppressants, the drug carries a
black box warning regarding its potent immunosuppres-
Nursing Responsibilities: Key nursing implications sive actions and the possible development of serious infec-
for patients receiving cyclosporine are included in the tions and malignancies. In addition, the black box warning
Nursing Practice Application for Patients Receiving Phar- states that the use of this drug is not recommended in
macotherapy with Immunomodulators. patients with liver transplants (excess mortality and graft
loss) or lung transplants (bronchial rupture). This drug is
Drugs Similar to Cyclosporine (Gengraf, pregnancy category C.
Neoral, Sandimmune)
Tacrolimus (Astagraf XL, Prograf, others): Approved by
The only other calcineurin inhibitor is tacrolimus. the FDA in 1994, tacrolimus is available in PO capsule or
Although not calcineurin inhibitors, everolimus, sirolimus, IV forms for the prophylaxis of heart and liver transplant
and temsirolimus are immunosuppressants similar to rejection. Envarsus XR and Astagraf XL are extended
tacrolimus. release forms approved as once-daily oral drugs to pre-
vent rejection of kidney transplants. A topical form of
Everolimus (Afinitor, Zortress): Everolimus was initially tacrolimus (Protopic) is approved for the short-term treat-
approved in 2009 (Afinitor) to treat advanced renal cell ment of eczema and atopic dermatitis. The topical form
carcinoma, astrocytoma, and other forms of cancer. Subse- contains a black box warning of possible lymphoma and
quently, Zortress was approved for the prophylaxis of skin cancer. Tacrolimus is also used off-label for other
organ rejection in patients receiving a kidney or liver trans- transplants as well as for GVHD, nephritic syndrome,
plant. When used as an antineoplastic, the dose is much psoriasis, and uveitis. Tacrolimus is 100 times more potent
higher than that when used in transplant patients (see than cyclosporine and appears to be more effective in
Table 42.2). In transplant medicine, the drug is given in some patients at preventing transplant rejection. Nephro-
combination with basiliximab and concurrently with toxicity may occur in half the patients taking this drug.
reduced doses of cyclosporine and corticosteroids. To pre- Neurotoxicity symptoms are common and include head-
vent potential toxicity, therapeutic drug monitoring is ache, tremor, paresthesias, insomnia, and dizziness.
recommended. Hypertension, anemia, hyperglycemia, and GI complaints
occur in a significant number of patients who are taking
Everolimus is functionally similar to sirolimus and tacrolimus. Like cyclosporine, an increased incidence of
temsirolimus and blocks a key kinase enzyme that acti- infections and malignancies may occur with tacrolimus
vates B and T cells. Like most immunosuppressants, the use. This drug is pregnancy category C.
drug carries a black box warning regarding its potent
immunosuppressive actions and the possible development Temsirolimus (Torisel): Approved in 2007, temsirolimus is
of serious infections and malignancies. In addition the metabolized in the liver to sirolimus. It is approved to treat
black box warning includes an increased risk of kidney patients with advanced renal cell carcinoma that has not
damage, including renal arterial and venous thrombosis.
The drug is pregnancy category C.
Chapter 42 Immunostimulants and Immunosuppressants 753
responded to other therapies. This drug is administered Pharmacokinetics:
only by the IV route. Temsirolimus is toxic to the hemato-
logic system; 94% of patients will experience anemia, 53% Route(s) PO, IV
will experience lymphopenia, and 32% will experience leu-
kopenia. Hyperglycemia occurs in most patients; thus Absorption Well absorbed
patients with diabetes require close monitoring. Most
patients who are taking the drug will also experience hyper- Distribution Crosses the placenta; secreted
lipidemia that may be serious enough to require pharmaco-
therapy. Interstitial lung disease is a rare though potentially in breast milk; 30% bound to
fatal adverse effect. This drug is pregnancy category D.
plasma proteins
PharmFACT
Primary metabolism Hepatic; metabolized to mercap-
Each day in the United States about 22 people die waiting
for transplants. One organ donor can save up to eight lives topurine, an active metabolite
(organdonor.gov, 2015).
Primary excretion Renal
42.6 Cytotoxic drugs and antimetabolites are
used to suppress proliferating B cells and T cells. Onset of action 7–14 days
Cytotoxic drugs are immunosuppressive medications used Duration of action Half-life: 3 h
to kill B cells and T cells. Antimetabolites do not kill
directly, but instead severely restrict the replication of Adverse Effects: Azathioprine causes bone marrow
B cells and T cells. Each of these medications acts by a dif- suppression that can result in pancytopenia, agranulocy-
ferent mechanism. Some of the drugs resemble essential tosis, leukopenia, and thrombocytopenia. Serious infec-
chemical building blocks needed for the biosynthesis of tions may occur secondary to immunosuppression, and
DNA and block replication. Others inhibit protein synthe- latent herpes or varicella infections may become reacti-
sis. Most of the cytotoxic and antimetabolite immunosup- vated during azathioprine therapy. Hepatotoxicity has
pressants are nonspecific, affecting many different cells of been reported with this drug. Nausea and vomiting are
the immune response. They have similar indications and common, especially during the first few weeks of therapy.
adverse effects as the calcineurin inhibitors. Patients who have received a kidney transplant and who
are being treated with azathioprine have an increased
PROTOTYPE DRUG Azathioprine (Azasan, Imuran) risk of developing skin and lymphoid malignancies. The
toxicities of azathioprine are dose related and occur more
Classification Therapeutic: Immunosuppressant frequently in patients who have received a kidney trans-
Pharmacologic: Cytotoxic drug plant compared with those who are treated for RA. Black
Box Warning: Use may result in serious or fatal infections
Therapeutic Effects and Uses: An older immuno- and possible malignancies. Complete blood counts (CBCs)
suppressant approved in 1968, azathioprine is indicated should be monitored during therapy.
for the prophylaxis of kidney transplant rejection and for
the treatment of severe RA. Off-label indications include Contraindications/Precautions: Azathioprine should
other inflammatory disorders such as Crohn’s disease, be used with extreme caution in patients with preexisting
autoimmune hepatitis, myasthenia gravis, SLE, and ulcer- hematologic disease or hepatic impairment. Blood counts
ative colitis. When treating nontransplant conditions, it is and hepatic enzymes must be regularly monitored. Azathio-
generally prescribed only when standard treatments fail. prine is contraindicated during pregnancy and lactation.
Azathioprine is usually given PO, but it may be given Drug Interactions: Additive bone marrow suppres-
by the IV route to patients who are unable to take the drug sion is expected if azathioprine is given concurrently
by mouth. When used to prevent transplant rejection, it is with other immunosuppressants. Concurrent use of allo-
usually administered in combination with other purinol with azathioprine can result in a large increase
immunosuppressants. in azathioprine activity and hematologic toxicity. The use
of angiotensin-converting enzyme (ACE) inhibitors with
Mechanism of Action: Azathioprine inhibits DNA azathioprine may induce anemia and severe leukopenia.
synthesis, resulting in DNA damage and chromosome Herbal/Food: None known.
breakage. The drug is metabolized to mercaptopurine in
the liver, an active substance marketed as an antineoplastic Pregnancy: Category D.
drug for leukemia.
Treatment of Overdose: Hemodialysis may be of
value in removing some azathioprine from the blood
following an overdose. Other treatment measures are
supportive.
Nursing Responsibilities: Key nursing implications
for patients receiving azathioprine are included in the
Nursing Practice Application for Patients Receiving Phar-
macotherapy with Immunomodulators.
754 Unit 6 Pharmacology of Body Defenses
Drugs Similar to Azathioprine than binding to its receptors on T cells, TNF binds with
the etanercept. This inhibition of TNF activity reduces the
(Azasan, Imuran) levels of damaging cytokines responsible for causing
inflammation and joint destruction in patients with RA.
Other cytotoxic and antimetabolite drugs indicated for The drug is FDA approved to treat RA, psoriatic arthritis,
immunosuppression include anakinra, cyclophosphamide, plaque psoriasis, and ankylosing spondylitis. It is used
etanercept, methotrexate, and mycophenolate. off-label to prevent transplant rejection. It is administered
only by the subcutaneous route. The most common
Anakinra (Kineret): Approved in 2001, anakinra is an IL-1 adverse effects are injection-site reactions and infections.
receptor antagonist that prevents the formation of certain Etanercept has a black box warning regarding the possi-
inflammatory cytokines. The only indication for anakinra is bility of malignancy and serious infections during ther-
for the treatment of moderate to severe RA that has not apy, including tuberculosis and bacterial sepsis. This drug
responded to first-line drugs. It is administered only by the is pregnancy category B.
subcutaneous route, and injection-site reaction is the most
frequent adverse effect. Because the drug lowers WBC Methotrexate (Rheumatrex, Trexall): Methotrexate is an
counts, secondary infections occur in almost 40% of patients older antimetabolite approved in 1953 that acts by inhibit-
taking anakinra. This drug is pregnancy category B. ing the enzyme responsible for folic acid metabolism. Like
cyclophosphamide, it is indicated for various cancers as
Cyclophosphamide (Cytoxan): Cyclophosphamide is one well as serious inflammatory disorders such as RA, psoria-
of the most commonly prescribed antineoplastic medica- sis, SLE, and ulcerative colitis. Methotrexate is used off-
tions for patients with malignancies. It acts by forming label to prevent transplant rejection. The most frequently
cross-links in DNA, which prevents cancer cell replication. reported adverse reactions include nausea, vomiting, sto-
It is a powerful immunosuppressant, affecting both B cells matitis, esophagitis, oral ulceration, and abdominal dis-
and T cells. It is used off-label for SLE, GVHD, and RA, tress. Hematologic adverse reactions are common. The
and for the transplant prophylaxis of solid organs. Hema- drug carries a black box warning regarding the possibility
tologic toxicity (pancytopenia, leukopenia, anemia, and of malignancy and serious hematologic, GI, hepatic, pul-
thrombocytopenia) is a major dose-limiting adverse effect. monary, and dermatologic toxicity. Methotrexate is a pro-
Cyclophosphamide is a prototype antineoplastic drug dis- totype antineoplastic drug discussed in Chapter 57. This
cussed in Chapter 57. This drug is pregnancy category D. drug is pregnancy category X.
Etanercept (Enbrel): Approved in 1998, etanercept is a
protein that mimics the natural receptor for TNF. Rather
CONNECTIONS: Complementary and Alternative Therapies
Echinacea
Description Evidence
Nine species of echinacea have been identified, and all are native The quality and doses of echinacea used in research studies
to the midwestern United States and central Canada. Echinacea have varied widely, which makes comparisons and conclu-
purpurea (purple coneflower) and Echinacea angustifolia (narrow- sions extremely difficult. Echinacea is claimed to boost the
leaf coneflower) are the two most commonly studied species. All immune system by increasing IFN levels, increasing phagocy-
portions of the plant contain chemicals that have potential phar- tosis, and inhibiting the bacterial enzyme hyaluronidase.
macologic activity. Some substances in echinacea appear to have antiviral activ-
ity; thus the herb is sometimes taken to treat the common
History and Claims cold and influenza—indications for which it has received offi-
cial approval in Germany. No large-scale studies have dem-
Echinacea was used by Native Americans to treat various wounds onstrated significant differences between research participants
and injuries. Until the widespread manufacture of antibiotics in the taking echinacea and those taking a placebo (National Center
late 1940s, echinacea was commonly used as an anti-infective. for Complementary and Integrative Health, 2016), although
some evidence demonstrates that echinacea may reduce the
Standardization odds of getting a cold (University of Maryland Medical Center,
2016). Adverse effects are rare, although it may cause allergic
The flowers, leaves, and stems of this plant are harvested and reactions in patients who are allergic to plants in the daisy
dried. Preparations include dried powder, tincture, fluid extracts, family such as ragweed, marigolds, daisies, and chrysanthe-
and teas. No single ingredient seems to be responsible for the mums. It may also interfere with drugs that have immunosup-
herb’s activity. A large number of potentially active chemicals pressant effects.
have been identified from the extracts. Recommended doses
include 300 mg dry powdered extract (standardized to 3.5%
echinacoside) or 0.5 to 1 g dried root or tea.
Chapter 42 Immunostimulants and Immunosuppressants 755
Mycophenolate (CellCept, Myfortic): Approved in 1995, In the 1980s a technique was developed to harvest anti-
mycophenolate is a potent immunosuppressant that acts bodies produced by a single B cell. Because a single B cell
by inhibiting the DNA synthesis of B cells and T cells. produces a single antibody, it is called a monoclonal anti-
There are two forms of mycophenolate. Mycophenolate body (MAB). A MAB is very specific, targeting a single
mofetil (CellCept) is a prodrug that is converted in the type of target cell or receptor. This allows greater effects on
body to its active form, mycophenolic acid. It is given IV or the target cell or receptor at lower doses and with fewer
PO, usually in combination with other immunosuppres- adverse effects than using polyclonal antibodies.
sants such as cyclosporine and corticosteroids. Mycophe-
nolate sodium (Myfortic) is a delayed release tablet. The first MABs were derived from mouse cells and had
short half-lives. The human immune system quickly recog-
Indications for mycophenolate include the prophy- nized them as foreign when they were injected in patients.
laxis of heart, kidney, or liver transplant rejection. Myco- Through genetic engineering, scientists have been able to
phenolate also was given orphan drug status for the replace the mouse portions of the antibody with human
treatment of patients with myasthenia gravis and pem- sequences, thus allowing it to escape detection by the
phigus vulgaris. Off-label indications include SLE, immune system for longer periods and extending its
GVHD, and atopic dermatitis. GI adverse effects such as half-life.
nausea, vomiting, constipation, diarrhea, dyspepsia, and
abdominal pain are common. Other relatively frequent Scientists have created approximately 30 different
adverse effects include tachycardia, tremor, back pain, MABs to attack a diverse number of targets. The majority
sinusitis, increased urinary frequency, and blood dyscra- of the MABs are designed to attack specific types of cancer
sias. Weekly CBCs should be obtained and the drug with- cells. Others are used to treat autoimmune or inflammatory
held if the absolute neutrophil count (ANC) falls below disorders such as RA or psoriasis by attacking specific cells
1.3 × (10)3 cells/mcL. Mycophenolate carries a black box of the immune system that secrete proinflammatory medi-
warning regarding the possibility of malignancy, serious ators. The FDA-approved MABs are listed in Table 42.3.
infections, and embryofetal toxicity. This is a pregnancy Those used exclusively for cancer are found in Chapter 57.
category D drug.
The MABs are challenging to learn because many have
42.7 Antibodies are used to prevent acute similar names that end in -mab (for monoclonal antibody).
transplant rejection, autoimmune disorders, There is, however, some consistency to the names—they
and malignancies. reflect the origin of the antibody:
Recall from Chapter 40 that antibodies are proteins that are • MABs that have 75% human sequences are called chi-
produced following an antigen challenge. B cells become meric and have -xi in the name (e.g., basiliximab).
plasma cells, which subsequently produce massive
amounts of antibodies that help rid the body of the antigen • MABs that have 90% human sequences are called human-
through multiple mechanisms. Antibodies that are pro- ized and have -zu in their name (e.g., trastuzumab).
duced by a plasma cell are very specific to the antigen. For
example, exposure to Streptococcus would result in differ- • MABs that are 100% human have -mumab in their
ent antibodies than would Escherichia coli. In this example, name (e.g., golimumab).
antibodies boost the immune system. It may seem puzzling
then to learn that certain antibodies may be administered PROTOTYPE DRUG Basiliximab (Simulect)
to patients to suppress the immune response. How is this
possible? Classification Therapeutic: Immunosuppressant
Pharmacologic: Monoclonal antibody
The answer is to create antibodies against human
immune cells. A simple method is to inject animals (usually Therapeutic Effects and Uses: Basiliximab is a
horses, rabbits, or mice) with human T cells, B cells, or thy- monoclonal antibody approved in 1998 for the prophylaxis
mocytes. The animal forms antibodies against the human of acute kidney transplant rejection. The drug dampens
immune cells, which can be collected and purified. When the immune response by inhibiting CD25, a receptor on the
injected in humans, the animal’s antibodies will attack the surface of activated T cells. By binding to CD25, basilix-
T cells (or T-cell receptors). These are called polyclonal imab stops IL-2 from activating the T cell, and the immune
antibodies because they contain a wide mixture of response is prevented. This drug does not lower the total
different antibodies. This polyclonal drug product, called number of circulating T cells; it does, however, lower their
antithymocyte globulin (Atgam, Thymoglobulin), is a ability to respond to an antigen challenge.
potent immunosuppressant and is available for the prophy-
laxis of kidney transplant rejection and aplastic anemia. Administered by IV infusion, the standard regimen is
two doses; one is given 2 hours prior to transplantation and
the other is given 4 days later. Following the two infusions,
the actions of basiliximab may last for 4 to 6 weeks. It is
administered in combination with other immunosuppres-
sants, usually cyclosporine and corticosteroids.
756 Unit 6 Pharmacology of Body Defenses
Table 42.3 Selected Monoclonal Antibodies for Immunosuppression
Drug/Antibody Approval Date Target Approved Indication(s)
adalimumab (Humira) 2002 Inhibition of TNF-a signaling Inflammatory diseases (mostly autoimmune disorders)
basiliximab (Simulect) 1998 IL-2 receptor blocker Transplant rejection
belatacept (Nulojix) 2011 Inhibition of T-cell CD28 activation Kidney transplant rejection
belimumab (Benlysta) 2011 B lymphocytes Systemic lupus erythematosus
certolizumab pegol (Cimzia) 2008 TNF blocker Crohn’s disease, ankylosing spondylitis, and RA
eculizumab (Soliris) 2007 Blocks complement protein C5 Atypical hemolytic uremic syndrome and paroxysmal
nocturnal hemoglobinuria
golimumab (Simponi) 2009 TNF blocker Psoriatic arthritis, ankylosing spondylitis, and RA
infliximab (Remicade) 1998 Inhibition of TNF-a signaling Inflammatory diseases (mostly autoimmune disorders)
natalizumab (Tysabri) 2006 T-cell VLA4 receptor Inflammatory diseases (mainly autoimmune-related MS
therapy)
siltuximab (Sylvant) 2014 IL-6 receptor blocker Castleman disease (rare blood disorder)
tocilizumab (Actemra) 2010 IL-2 receptor blocker RA and cytokine release syndrome
tofacitinib (Xeljanz) 2012 JAK enzyme inhibitor RA
Mechanism of Action: Basiliximab inhibits the bind- Nursing Responsibilities: Key nursing implications
ing of IL-2 to CD25 on the surface of activated T cells. This for patients receiving basiliximab are included in the Nurs-
prevents the rapid proliferation of T cells that would nor- ing Practice Application for Patients Receiving Pharmaco-
mally release cytokines to attack transplanted tissue. therapy with Immunomodulators.
Pharmacokinetics: IV Drugs Similar to Basiliximab (Simulect)
Route(s) N/A
Absorption Unknown The other antibody drugs used in transplant medicine are
Distribution Unknown antithymocyte globulin and belatacept. The MABs used
Primary metabolism Unknown for RA such as adalimumab (Humira) and infliximab
Primary excretion 30 min (Remicade) are discussed in Chapter 72.
Onset of action 7.2-day half-life
Duration of action Antithymocyte globulin (Atgam, Thymoglobulin):
Approved in 1981, antithymocyte globulin consists of poly-
Adverse Effects: Basiliximab causes few adverse effects clonal antibodies obtained from the serum of horses
compared to the calcineurin inhibitors or the cytotoxic (Atgam) or rabbits (Thymoglobulin) exposed to human
immunosuppressants. The most common adverse effects are T cells. Doses of the two are not interchangeable. The drug
GI related such as nausea, vomiting, abdominal pain, and is a potent immunosuppressant used for the prophylaxis
diarrhea. Anaphylaxis has been reported. Black Box Warn- and management of transplant rejection and for the treat-
ing: Basiliximab should be administered only by healthcare ment of moderate to severe aplastic anemia in patients who
providers experienced in immunosuppressive therapy. are unable to have bone marrow transplantation. It is used
off-label to treat GVHD and myelodysplastic syndrome.
Contraindications/Precautions: The only contra- Given by the IV route, a single infusion may lower the lym-
indication to the use of basiliximab is hypersensitivity to phocyte count by 85% to 90%. After discontinuation of ther-
the drug. Because patients receiving this drug have sup- apy, T-cell counts take several months to return to baseline
pressed immune systems, vaccinations are normally post- levels. The most common adverse effects are fever, chills,
poned until immune function returns. malaise, headache, diarrhea, itching, and other flulike
symptoms. Corticosteroids, antihistamines, and acetamino-
Drug Interactions: Basiliximab does not interact phen may be administered 1 hour prior to antithymocyte
significantly with the major drugs used in transplant globulin therapy to prevent cytokine release syndrome.
medicine. However, caution must always be used when Anaphylaxis has been reported. Like other immunosup-
administering multiple drugs that suppress immune func- pressants, an increased incidence of infections and malig-
tion. Herbal/Food: None known. nancies is expected. A black box warning states that
antithymocyte globulin should be administered only by
Pregnancy: Category B. healthcare providers experienced in immunosuppressive
therapy. This drug is pregnancy category C.
Treatment of Overdose: Overdose with this drug is
very rare, since only 2 doses are administered.
Chapter 42 Immunostimulants and Immunosuppressants 757
Belatacept (Nulojix): Belatacept is a MAB approved in 2011 They intervene at multiple steps in the immune response,
for the prophylaxis of organ rejection in patients receiving including antigen presentation, production of cytokines,
kidney transplants. The drug blocks specific receptors on and the proliferation of lymphocytes.
T lymphocytes, inhibiting their proliferation and stopping
the production of cytokines that could damage a newly • Lymphocyte effect. A single dose of corticosteroid
transplanted organ. The drug acts by the same mechanism reduces circulating lymphocyte counts within a few
as abatacept (Orencia), which is approved to treat RA. hours. This inhibits the ability of the body to react to
Belatacept is always used in combination with basiliximab, an antigen challenge.
mycophenolate mofetil, and corticosteroids. The drug car-
ries a black box warning that it may increase the risk for • Monocyte effect. Corticosteroids quickly deplete the
developing post-transplant lymphoproliferative disorder body of monocytes and macrophages. Macrophages are
(PTLD). PTLD is a serious condition in which B cells prolif- responsible for presenting antigens to lymphocytes.
erate unchecked and may cause B-cell tumors. Recipients
who have never been exposed to the Epstein-Barr virus are • Neutrophil effect. Corticosteroids cause neutrophils
especially susceptible to PTLD. The warning also states that to move from the bone marrow into the general circu-
the drug may increase the risk for malignancies and that it lation, resulting in increased numbers of circulating
should not be used for liver transplants due to possible graft neutrophils. The drug then prevents the neutrophils
rejection. Belatacept is pregnancy category C. from migrating out of the circulation to sites of
inflammation.
CONNECTION Checkpoint 42.2
• Other effects. Corticosteroids block the production of
Basiliximab (Simulect) binds to CD25 and an immune response is prostaglandins and ILs. This results in T cells being
prevented. From what you learned in Chapter 40, which type of unable to react to antigens and proliferate.
immunity—humoral or cell mediated—does this drug affect? Answers
to Connection Checkpoint questions are available on the faculty resources Two common drugs in this class, prednisone and
site. Please consult with your instructor. methylprednisolone, have been widely used to prevent
transplant rejection since the 1960s. When used for a few
42.8 Corticosteroids are widely used as weeks, the corticosteroids are safe and effective immuno-
immunosuppressants but have significant suppressants. The long-term adverse effects of corticoste-
long-term adverse effects. roids, however, are serious and include osteoporosis,
cataract formation, mental status changes, fluid and salt
The corticosteroids, or glucocorticoids, are potent inhibi- retention, HTN, hyperglycemia, obesity, and adrenal atro-
tors of inflammation and are discussed in detail in Chap- phy. Because of their long-term effects, healthcare provid-
ters 41 and 68. They are often the preferred drugs for the ers have begun to look at the possibility of eliminating
short-term therapy of severe inflammation. corticosteroids from the transplant regimen. Some regi-
mens call for the initial use of corticosteroids, with their
In addition to their anti-inflammatory effects, cortico- gradual withdrawal at some point, usually within 3 to
steroids affect nearly every aspect of the immune response. 6 months following the transplant. The issue remains unre-
solved and an active area of research.
CONNECTIONS: NURSING PRACTICE APPLICATION
Patients Receiving Pharmacotherapy with Immunomodulators
Assessment
Baseline assessment prior to administration:
• Obtain a complete health history including previous history or current case of cancer; fever; active infections (especially herpes, varicella, and CMV);
hepatic, renal, cardiovascular, neurologic, or autoimmune disease; dermatologic conditions; HIV infection; pregnancy or breastfeeding. Obtain a drug
history, especially the use of corticosteroids.
• Obtain a dietary history, especially the intake of grapefruit or grapefruit juice.
• Obtain baseline vital signs, especially blood pressure and temperature, height, and weight.
• Assess oral and dental health.
• Evaluate appropriate laboratory findings (e.g., CBC, platelets, electrolytes, glucose, hepatic and renal laboratory values, and lipid levels).
• Assess the patient’s ability to receive and understand instructions. Include family and caregivers as needed.
Assessment throughout administration:
• Assess for desired therapeutic effects (e.g., no signs or symptoms of transplant rejection, no severe inflammatory response; suppression of autoim-
mune responses).
• Continue monitoring CBC, platelets, electrolytes, glucose, liver and renal function studies, and lipid levels.
• Assess vital signs, especially blood pressure and temperature.
• Assess for and immediately report adverse effects: fever, chills, visible signs of infection, nausea, vomiting, dizziness, confusion, muscle weakness,
tremors, tachycardia, HTN, angina, syncope, dyspnea, pulmonary congestion, skin rashes, bruising or bleeding, decreased urine output.
(continued )
758 Unit 6 Pharmacology of Body Defenses
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
Ensuring therapeutic effects: • Advise the patient on the treatment and condition-specific monitoring
• Continue assessments as above for therapeutic effects. (Monitoring will requirements (e.g., urine output, improvement of movement in joints
with lessened swelling).
be specific to the transplant, e.g., maintenance of urine output, or spe-
cific patient condition. Severe inflammatory conditions and autoimmune
disorders should show gradually lessening inflammation and pain.)
Minimizing adverse effects: • Teach the patient how to monitor blood pressure. Ensure proper use and
• Continue to monitor vital signs, especially blood pressure and tempera- functioning of any home equipment obtained. The patient should report
blood pressure over 140/90 mmHg or parameters set by the healthcare
ture. (Immunosuppressant drugs may cause HTN and increase the provider. Chest pain or pressure should be reported immediately.
risk of infections. Immunostimulants may cause hypotension.
Lifespan: Be particularly cautious with older adults who are at • Teach the patient to report any fever over 38.3°C (101°F) or as
increased risk for hypotension and at greater risk for falls.) instructed by the healthcare provider.
• Instruct the patient taking immunostimulants to rise from lying to sitting
or standing slowly to avoid dizziness or falls. If dizziness occurs, the
patient should sit or lie down and not attempt to stand or walk until the
sensation passes.
• Observe for signs and symptoms of infection: fever over 38.3°C • Teach the patient to immediately report signs and symptoms of infec-
(101°F) or parameters set by the healthcare provider, sore throat, tion such as wounds with redness or drainage, increasing cough,
diarrhea, malaise, white patches in the oral cavity, painful or vesicu- increasing fatigue, white patches on oral mucous membranes, white
lar rashes, reddened or warm areas at the site of injury, or lethargy. and itchy vaginal discharge, or itchy blister-like vesicles on the skin.
(Immunosuppressants increase the risk of infections, especially with
opportunistic infections such as herpes, varicella, CMV, and fungal • Instruct the patient, family, and caregivers on infection control
infections. Diverse Patients: Because some drugs such as cyclospo- measures, including:
rine [Gengraf, Neoral, Sandimmune] metabolize through the CYP450 • Washing hands frequently. Use lotion afterward to prevent exces-
system pathways, monitor ethnically diverse patients to ensure optimal sive drying and cracking of the skin.
therapeutic effects and to minimize adverse effects.) • Avoiding large crowds, especially indoors.
• Avoiding people with known infection or young children because
they have a higher risk of having an infection.
• Cooking food thoroughly, allowing the family or caregiver to pre-
pare raw meat or fish and clean up, and not consuming raw fruits
or vegetables.
• Assess for changes in level of consciousness, disorientation, confu- • Instruct the patient, family, or caregiver to immediately report increas-
sion, or tremors. (Neurologic changes may indicate adverse drug ing lethargy, disorientation, confusion, changes in behavior or mood,
effects.) slurred speech, tremors, or ataxia.
• Continue to monitor CBC, platelets, electrolytes, glucose, liver and • Instruct the patient on the need to return frequently for follow-up labo-
renal function studies, and lipid levels. (Immunosuppressants may ratory work.
cause leukopenia, anemia, thrombocytopenia, hyperglycemia, and
hyperkalemia. Lifespan: Monitor the older adult frequently because • Advise the patient to carry a wallet identification card or wear medical
age-related physiologic changes increase the risk of adverse renal and identification jewelry indicating immunosuppressant therapy.
hepatic effects.)
• Inspect oral mucous membranes, and schedule dental appointments • Teach the patient to maintain excellent oral hygiene, inspecting the oral
prior to starting drug therapy and frequently thereafter. (Immunosup- cavity daily. Keep regular dental visits, and consult the dentist about
pression increases the risk of oral candidiasis and gingivitis. Oral the required frequency.
antifungal rinses may be required.)
• Assess diet and consumption of grapefruit or grapefruit juice. (Grape- • Teach the patient to avoid grapefruit and grapefruit juice while on
fruit juice significantly increases cyclosporine levels and should be cyclosporine. Flavored beverages without juice are permissible.
avoided or eliminated while on immunosuppressant therapy.)
• Lifespan: Assess for pregnancy. (Pregnancy should be avoided • Discuss pregnancy and family planning with women of childbearing
during and for up to 4 months after discontinuing immunosuppres- age. Explain the effect of medications on pregnancy and breastfeeding
sive therapy. Women who become pregnant while on the drug should and the need to discuss any pregnancy plans with the healthcare pro-
consult with their healthcare provider.) vider. Discuss the need for additional forms of contraception, including
barrier methods, with patients taking immunosuppressants.
• Assess for development of hirsutism or alopecia. (Hirsutism is revers- • Advise the patient to notify the provider of changes to hair growth or
ible when the drug is discontinued. Alopecia may indicate significant texture.
immunosuppression.)
• Continue to monitor neurologic and mental status in patients receiving • Instruct the patient, family, or caregiver to immediately report increas-
IFN therapy. (Psychosis, depression, and suicidal ideations are poten- ing lethargy, disorientation, confusion, changes in behavior or mood,
tial adverse effects of IFN use.) agitation or aggression, slurred speech, or ataxia.
Patient understanding of drug therapy: • The patient, family, or caregiver should be able to state the reason for
• Use opportunities during administration of medications and during the drug, appropriate dose and scheduling, what adverse effects to
observe for and when to report them, and the anticipated length of
assessments to discuss the rationale for drug therapy, desired thera- medication therapy.
peutic outcomes, commonly observed adverse effects, parameters
for when to call the healthcare provider, and any necessary monitoring
or precautions. (Using time during nursing care helps to optimize and
reinforce key teaching areas.)
Chapter 42 Immunostimulants and Immunosuppressants 759
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
Patient self-administration of drug therapy: • Teach the patient to take the medication by:
• When administering medications, instruct the patient, family, or • Using the enclosed equipment to measure or mix the drug.
• Using a glass, and not paper or plastic cups, unless the package
caregiver in proper self-administration techniques followed by return directions indicate they are to be used.
demonstration. (Utilizing time during nurse administration of these • Mixing the drug with milk, chocolate milk, or orange juice, and stir-
drugs helps to reinforce teaching.) ring well. After taking the drug, rinse the cup with additional liquid
and drink it to ensure the entire dose is taken.
• Taking the medication at the same time each day.
Understanding Chapter 42
Key Concepts Summary 42.5 Calcineurin inhibitors are preferred drugs for the
prophylaxis of transplant rejection.
42.1 Immunomodulators are substances that either
enhance or suppress the ability of the body to fight 42.6 Cytotoxic drugs and antimetabolites are used to
infection and disease. suppress proliferating B cells and T cells.
42.2 Interferons are biologic response modifiers that 42.7 Antibodies are used to prevent acute transplant
have antiviral and antineoplastic activity. rejection, autoimmune disorders, and malignancies.
42.3 Interleukins, vaccines, and colony-stimulating 42.8 Corticosteroids are widely used as
factors are used to boost the immune system. immunosuppressants but have significant
long-term adverse effects.
42.4 Immunosuppressants are used to prevent
transplant rejection and for the treatment of
autoimmune disorders.
CASE STUDY: Making the Patient Connection
Remember the patient hospital, a full hepatitis panel found that she was positive
“Carole Banks” at the for hepatitis C virus (HCV).
beginning of the chapter?
Now read the remainder During the initial interview with Carole, she discloses
of the case study. Based that she was addicted to illegal IV drugs for 15 years and
on the information pre- was an alcohol abuser for 20 years. However, Carole
sented within this chap- claims that she has abstained from substance abuse for the
ter, respond to the critical thinking questions that past 5 years. She resides with her husband and three chil-
follow. dren and is employed as a clerk in a local retail conve-
nience store.
Carole Banks is a 42-year-old woman diagnosed with hep-
atitis C who was recently seen by her healthcare provider As part of the treatment for Carole’s hepatitis she is
at an office visit. She reported having right upper quad- prescribed IFN alfa-2b (Intron A). She is taught to self-
rant pain, fatigue, anorexia, nausea, and vomiting. She has administer (subcutaneously) the standard dose of IFN,
been feeling progressively worse for the past year but did 3 million units, 3 times weekly.
not seek medical care for her problem. She has lost 5.4 kg
(12 lb) over the past 6 months. Critical Thinking Questions
Carole was initially hospitalized to receive IV fluids for 1. Discuss the rationale for the use of IFN alfa-2b
dehydration and to be further evaluated. Once in the (Intron A) in the treatment of hepatitis C.
760 Unit 6 Pharmacology of Body Defenses 3. Identify the patient education that Carole will need
concerning her drug therapy.
2. What adverse effects might Carole experience with
this drug therapy? How can the nurse assist Carole to Answers to Critical Thinking Questions are available on the
cope with the related adverse effects? faculty resources site. Please consult with your instructor.
Additional Case Study 2. Describe the patient teaching that the nurse should
give to Gordon concerning this drug therapy.
Gordon Sharp had been on kidney dialysis since his car
crash 2 years ago. He sustained severe traumatic injuries 3. What dietary precautions would be indicated for this
and subsequently developed renal failure. Gordon has patient?
recently received a kidney transplant and is currently on
cyclosporine (Sandimmune). Answers to Additional Case Study questions are available on
the faculty resources site. Please consult with your instructor.
1. How does cyclosporine work and why is Gordon
receiving the drug?
Chapter Review 4. Azathioprine (Imuran) is prescribed to a patient who
had a kidney transplant. A nurse reviews the patient’s
1. The nurse is monitoring the laboratory findings of a medical record and would question the medication
patient who is taking interferon alfa-2b (Intron A). order for the patient with a history of:
Which findings would indicate that the patient is
experiencing common adverse effects? 1. Benign prostatic hyperplasia.
2. Cataracts.
1. Flulike symptoms of fever, chills, fatigue, and 3. Varicella zoster.
weight loss 4. Rheumatoid arthritis.
2. Depression with thoughts of suicide 5. A nurse is instructing a patient who is receiving tacro-
3. Edema, hypotension, and tachycardia limus (Prograf) following a liver transplant. Which
4. Fluid volume overload, hypertension, renal point should be included in the teaching plan?
insufficiency 1. Take a “baby” strength aspirin every day.
2. Increase physical activity to avoid weight gain.
2. The patient is receiving basiliximab (Simulect) and 3. Record radial pulse rate every morning in a
cyclosporine (Sandimmune) after a kidney transplant
to prevent organ rejection. The patient develops a journal.
high fever and chills, with a temperature of 39.4°C 4. Avoid raw fruits and vegetables and eat only fully
(103°F). The nurse interprets that the patient is most
likely experiencing: cooked meats.
1. Capillary leak syndrome. 6. A nurse is particularly cautious in monitoring the
2. A significant infection related to immunosuppression. patient who is prescribed aldesleukin (Proleukin). To
3. Graft-versus-host rejection. monitor for the development of capillary leak syn-
4. Androgen-insensitivity syndrome. drome, the nurse would frequently assess:
3. The nurse who is caring for a patient receiving cyclo- 1. Skin condition and rashes.
sporine (Sandimmune) will discontinue the medica- 2. Laboratory values for increasing amylase and
tion immediately and call the provider if which of the
following occurs? lipase.
3. Blood pressure and urine output.
1. Red blood cell count above 8.5 million/mm3 4. Vision and hearing.
2. White blood cell count below 4000/mm3
3. Platelet count above 100,000/mm3 See Answers to Chapter Review in Appendix A.
4. Serum creatinine level less than 1.0 mg/100 mL
Chapter 42 Immunostimulants and Immunosuppressants 761
References organdonor.gov. (2015). Organ donation statistics. Retrieved
from http://www.organdonor.gov/statistics-stories/
National Center for Complementary and Integrative statistics.html
Health. (2016). Echinacea. Retrieved from https://nccih.
nih.gov/health/echinacea/ataglance.htm University of Maryland Medical Center. (2016). Echinacea.
Retrieved from http://umm.edu/health/medical/
Organ Procurement and Transplantation Network. (2017). altmed/herb/echinacea
Data. Retrieved from http://optn.transplant.hrsa.gov/
data
Selected Bibliography Petty, M. (2016). Antibody-mediated rejection in solid
organ transplant. AACN Advanced Critical Care, 27,
Bamoulid, J., Staeck, O., Halleck, F., Dürr, M., Paliege, A., 316–323. doi:10.4037/aacnacc2016366
Lachmann, N., … Budde, K. (2015). Advances in
pharmacotherapy to treat kidney transplant rejection. Pfeil, A. M., Allcott, K., Pettengell, R., von Minckwitz, G.,
Expert Opinion on Pharmacotherapy, 16, 1627–1648. Schwenkglenks, M., & Szabo, Z. (2015). Efficacy,
doi:10.1517/14656566.2015.1056734 effectiveness and safety of long-acting granulocyte
colony-stimulating factors for prophylaxis of
Freeman, R., Koerner, E., Clark, C., & Halabicky, K. (2016). chemotherapy-induced neutropenia in patients with
Cardiac transplant postoperative management and cancer: A systematic review. Supportive Care in Cancer,
care. Critical Care Nursing Quarterly, 39, 214–226. 23, 525–545. doi:10.1007/s00520-014-2457-z
doi:10.1097/CNQ.0000000000000116
Williams, A., Low, J. K., Manias, E., & Crawford, K. (2016).
Jani, A. A. (2017). Infections after solid organ transplantation. The transplant team’s support of kidney transplant
Retrieved from http://emedicine.medscape.com/ recipients to take their prescribed medications: A
article/430550-overview collective responsibility. Journal of Clinical Nursing, 25,
2251–2261. doi:10.1111/jocn.13267
Pelligrino, B. (2016). Immunosuppression. Retrieved from
http://emedicine.medscape.com/article/
432316-overview#a1
“I don’t think these
immunizations are necessary.
They made her so sick last time!”
Mother of patient “Samantha Abbott”
Chapter 43
Immunizing Agents
Chapter Outline Learning Outcomes
cc Discovery of Vaccines After reading this chapter, the student should be able to:
cc Vaccines and the Immune System
cc Types of Vaccines 1. Explain why the development of vaccines was one
cc General Principles of Vaccine Administration of the most significant discoveries of modern
cc Active Immunity: Bacterial Immunizations medicine.
cc Active Immunity: Viral Immunizations
2. Compare and contrast active and passive immunity.
PROTOTYPE Hepatitis B Vaccine
(Engerix-B, Recombivax HB), p. 770 3. Explain the immune response that leads to the
cc Passive Immunity development of active immunity.
PROTOTYPE Rho(D) Immune Globulin
(RhoGAM), p. 776 4. Prepare a table listing the types of vaccines, their
indications, and potential adverse effects.
762
5. Explain why it is important to administer childhood
vaccines at specific ages.
6. Identify contraindications for vaccine
administration.
7. Describe the pathogenesis and immunization of
bacterial infections, including diphtheria, pertussis,
tetanus, pneumococcus, and meningococcus.
8. Describe the pathogenesis and immunization of
viral infections, including hepatitis A and B,
influenza, rabies, measles, mumps, rubella, polio,
varicella zoster, human papillomavirus, and
rotavirus.
9. Explain the rationale for administering antibodies to
establish passive immunity.
10. For each of the major vaccines and patient age
groups, identify the schedule for the recommended
dosage sequence established by the Centers for
Disease Control and Prevention.
11. Apply the nursing process to care for patients
receiving immunizing agents.
Chapter 43 Immunizing Agents 763
Key Terms incubation period, 763 shingles, 774
inoculation, 763 toxoids, 765
active immunity, 763 passive immunity, 764 vaccination, 763
attenuated, 764 postherpetic neuralgia, 774
boosters, 763
immunization, 763
The earliest attempts at treatments to prevent infection Vaccines and the Immune System
were reported in ancient Indian and Chinese literature
when dried, powdered scabs from infected individuals 43.2 Vaccines are used to activate the immune
were administered to healthy people. Vaccinations have system for the purpose of disease prevention.
since become one of the most important medical inter-
ventions for the prevention of serious infectious An immune response occurs when an antigen is recog-
disease. Routine vaccinations for polio, pertussis, nized by the B or T lymphocytes. Antigens are microbes
diphtheria, tetanus, and measles are estimated to pre- and foreign substances that elicit an immune response.
vent 3 million deaths annually. This chapter examines Most microbes, nonhuman proteins, bacterial or plant tox-
the role of vaccines in promoting the health of both chil- ins, and normal cells that become damaged or cancerous
dren and adults and the potential adverse effects of are considered antigens. Following the first exposure to an
these drugs. antigen, sufficient time is needed for the body to process
the antigen and mount an effective response. It is during
Discovery of Vaccines this time, known as the incubation period, that the symp-
toms of infection and tissue injury develop. During this
43.1 The eradication of smallpox was a great first antigen exposure, memory B cells or T cells are
triumph in modern medicine. formed. Should a second or subsequent exposure to the
same antigen occur, the memory cells react quickly to pro-
In the 1790s, Dr. Edward Jenner was experimenting duce a more rapid immune response with fewer (or no)
with the use of inoculation, the placement of a foreign symptoms of infection. The student should review
substance on or in an individual for the purpose of dis- Chapter 40 for a summary of the humoral and cell-
ease prevention. Inoculation uses live virus particles mediated immune responses before proceeding.
obtained from an infected patient. Jenner used the cow-
pox virus, a benign pathogen in humans, because he Edward Jenner was the first to use the term vaccina-
predicted that exposure to that virus would provide tion. Vaccination is the process of introducing foreign pro-
immunity to smallpox, which was one of the most teins or inactive cells (vaccines) into the body to trigger
dreaded human diseases of that era. Case fatality rates immune activation before the patient is exposed to the real
of 30% or more were reported with smallpox infections. pathogen. As a result of the vaccination, memory B cells
In the 18th century, the disease was a frequent cause or T cells are formed. When later exposed to the real infec-
of blindness and death for 400,000 people worldwide tious organism, these cells will react quickly by producing
annually. large quantities of antibodies and cytokines that help to
neutralize or destroy the antigen. Whereas some vaccina-
Jenner’s inoculation of a single 8-year-old boy ulti- tions are needed only once, most require follow-up doses,
mately led to one of the greatest triumphs in disease pre- known as boosters, to provide prolonged protection. The
vention. On May 8, 1980, the World Health Assembly type of response induced by the real pathogen, or its vac-
certified that global medical interventions had actually cine, is called active immunity. During this response the
eradicated smallpox infections from the planet. Although body produces its own antibodies in response to expo-
this announcement was heralded by the scientific com- sure. The active immunity induced by vaccines closely
munity as proof of the success of routine immunization, resembles that caused by natural exposure to the antigen,
it also has presented new challenges. With the last known including the generation of memory cells. The term
case of the disease, the need for smallpox immunization immunization is considered equivalent to the term vacci-
ceased, resulting in a growing, nonimmune population. nation, and either one may be used to describe this process
The widespread reappearance of the pathogen in of disease prevention.
an unvaccinated population could have disastrous
consequences. The effectiveness of most vaccines can be assessed by
measuring the amount of antibodies produced after the
vaccine has been administered, a quantity called titer. If the
764 Unit 6 Pharmacology of Body Defenses
Table 43.1 Vaccine Types
Type of Vaccine Immune System Response Vaccine Examples Remarks
Attenuated (live) virus B-cell response; T-cell response Polio (oral), measles, mumps, rubella, Risk for disease in individuals with
varicella reduced immune function
Inactivated (killed) virus B-cell response Does not confer lifelong immunity
Salk polio (injectable), influenza, rabies,
Toxoid B-cell response hepatitis A Large quantities of antigen needed
Recombinant technology vaccine B-cell response Contains no viral genetic material
Tetanus toxoid, diphtheria toxoid
Hepatitis B, human papillomavirus
titer falls below a specified, protective level over time, a Types of Vaccines
booster dose is indicated. Antibodies are a product of the
humoral immune system. The cell-mediated immune sys- 43.3 Four traditional methods are used
tem is also important in producing immunity, but its cellu- to produce vaccines.
lar responses are less readily measured.
The goal of vaccine administration is to induce long-last-
Passive immunity occurs when preformed antibodies ing immunity to a pathogen without producing an illness
are transferred or “donated” from one person to another. in an otherwise healthy individual. Therefore, the microor-
For example, maternal antibodies cross the placenta and ganisms and other substances used as vaccines must be
provide protection for the fetus and newborn. Other exam- able to strongly activate the immune system but be modi-
ples of passive immunity include the administration of fied to pose no significant risk of disease development.
immune globulin following exposure to hepatitis, antiven- The vaccine must be economical to develop and be stable
ins for snakebites, and sera to treat botulism, tetanus, and for storage and administration. For long-standing disease
rabies. The drugs for passive immunity are administered protection, the vaccine must be able to stimulate the pro-
when the patient has already been exposed to a virulent duction of memory B cells and T cells. Four traditional
pathogen, or when the patient is at very high risk for expo- methods are used to produce safe and effective vaccines,
sure and there is not sufficient time to develop active immu- as listed in Table 43.1. All four methods are capable of
nity. Patients who are immunosuppressed may receive inducing active immunity.
these drugs to prevent infections. Because these medica-
tions do not stimulate the patient’s immune system, no Attenuated (live) vaccines: Live vaccine products con-
memory cells are produced and protective effects last only 2 tain microorganisms that are capable of replicating and
to 3 weeks. Passive immunity is presented in Section 43.7. causing disease. Live vaccines are very effective at induc-
ing immunity but are not used for vaccination because of
Most vaccines are administered with the goal of pre- their risk. However, effective vaccines can be developed
venting illness. Common vaccines include those used to from organisms that are attenuated or rendered less able
prevent patients from acquiring measles, influenza, diph- to cause disease through the application of heat or chemi-
theria, polio, pertussis (whooping cough), tetanus, and cals. Attenuated (live) vaccines cause the development of a
hepatitis B. Anthrax vaccine has been used to immunize mild or subclinical case of the disease while still inducing
people who are at high risk for exposure to anthrax from a lasting immunity. The type of immune response obtained
potential bioterrorism incident (see Chapter 75). In the from the administration of a live or attenuated organism is
case of infection by the human immunodeficiency virus the same as if the patient had been exposed to the natural,
(HIV), experimental HIV vaccines are given after infection nonattenuated organism. There must, however, be ade-
has occurred for the purpose of enhancing the immune quate immune functioning for the vaccine to work. The
response, rather than preventing the disease. Unlike other use of attenuated (live) vaccines is dangerous for individu-
vaccines, experimental vaccines for HIV have thus far als who are immunosuppressed because the organism may
been unable to prevent acquired immunodeficiency syn- retain some residual ability to replicate and cause disease.
drome (AIDS). In very rare cases, the attenuated virus may mutate to an
infectious form in patients who received the vaccine. An
CONNECTION Checkpoint 43.1 example of a live or attenuated vaccine is the measles,
mumps, and rubella (MMR) vaccine.
The humoral and cell-mediated immune responses are components
of the specific (adaptive) body defenses. From what you learned in Inactivated (killed) vaccines: Inactivated or killed vac-
Chapter 40, compare and contrast the humoral and cell-mediated cines are of two types: whole agent and subunit. Whole-
responses to an antigen. Answers to Connection Checkpoint ques- agent vaccines consist of microbes killed by heat or
chemicals. Subunit vaccines consist of specific segments of
tions are available on the faculty resources site. Please consult with your
instructor.
Chapter 43 Immunizing Agents 765
a cell membrane, foreign proteins, or sequences of a chro- Many of the vaccine-preventable diseases are rare in
mosome rather than the whole microbe. the United States, but endemic to specific regions of the
world. The nurse should advise patients traveling to these
Inactivated or killed vaccines are safer than live vac- regions to check that their vaccinations are current. The
cines because the organism is unable to replicate, mutate, CDC provides updated country-specific health informa-
or cause disease. Subsequent booster doses are required to tion for those traveling abroad.
maintain immunity if inactivated or killed vaccines are
used. Examples of inactivated or killed vaccines include Dose and timing: The total dose of a vaccine is impor-
the influenza and hepatitis A vaccines. Examples of sub- tant for the development of immunity. For some vaccina-
unit vaccines are the human papillomavirus (HPV) vaccine tions, multiple doses are required to achieve immunity.
and the acellular pertussis vaccine. Omitting subsequent doses could result in less-than-full
disease protection.
Toxoid vaccines: Some pathogens secrete toxins, which
are responsible for the symptoms of the infection. Toxoids To prevent childhood diseases, certain vaccinations
are bacterial toxins that have been chemically modified to should begin at birth and proceed with booster doses at
be incapable of causing disease. When injected as a type of specific ages according to the schedule recommended by
immunization, toxoids induce the formation of antibodies the CDC. The timing established by the CDC allows the
that are capable of neutralizing the real toxins. Toxoids vaccine to be given prior to the expected exposure to the
attack the bacterial toxin, not the invading pathogen itself. pathogen. For example, the pertussis vaccine is begun in
Examples include the diphtheria and tetanus toxoids. the first few months of life because infection by Bordetella
pertussis often occurs by age 1 or 2 years. On the other hand,
Recombinant technology vaccines: Modern biologic vaccination for HPV is recommended at 11 to 12 years of
techniques have allowed the development of vaccines that age because this virus is spread by sexual contact, which
contain viral subunits or proteins that are generated in the often occurs during the teen years. Vaccination outside the
laboratory. Two examples of the use of this form of bio- guidelines of the vaccination schedule is permitted, but its
technology are immunizations for the hepatitis B virus effectiveness may be reduced.
(HBV) and HPV. These vaccines do not contain viral
genetic material; therefore, the viruses cannot multiply or Route of administration: Vaccines must be adminis-
become infectious. tered by the specific route indicated for each product. Fail-
ure to follow administration protocol may result in an
General Principles of Vaccine insufficient immune response. For example, hepatitis B
Administration vaccine elicits a satisfactory response when administered
into the deltoid muscle but not the gluteus muscle. Injec-
43.4 Vaccines should be administered by an tion into the gluteus muscle also risks injury to the sciatic
established schedule with precautions taken nerve. Varicella vaccine is given subcutaneously.
for patients who are immunosuppressed or
pregnant. Precautions and contraindications: There are few
absolute contraindications for the use of vaccines. How-
The effective use of vaccines requires that they be deliv- ever, caution must be used in immunocompromised
ered according to a specified schedule at the proper dose. patients, such as those with cancer, recent tissue transplant
Childhood vaccines have a specific age range at which recipients, or those infected with HIV. Patients receiving
they should be administered. Should a child miss the rec- high-dose, systemic corticosteroid therapy may also have
ommended vaccination date, “catch-up” doses can some- suppressed immune systems. Vaccinations in an immuno-
times be administered to provide adequate protection. In compromised patient should be avoided if the patient is
addition, comorbid health conditions sometimes cause the having an exacerbation of his or her disorder. In some
delay of vaccinations in certain patients. Although each cases, only inactivated (killed) vaccines are indicated for
vaccine has different indications, certain general principles these patients. Because it is suppressed, the patient’s
apply to the administration of most immunizations. immune system may not be able to develop effective
immunity in response to the vaccine, and subsequent labo-
In the United States, the Centers for Disease Control ratory results should be assessed to confirm that immunity
and Prevention (CDC) is the government agency that has actually occurred.
establishes immunization schedules. Immunization pro-
tocols are reviewed on a regular basis by the CDC’s The CDC provides guidelines for receiving vaccines
Advisory Committee on Immunization Practices, and during pregnancy (CDC, 2016b). Inactivated (killed) vac-
revisions are frequently made based on current research. cines may be administered to pregnant patients if the ben-
The practicing nurse should refer often to the CDC web- efits of disease prevention outweigh the possible risk to the
site for updates. mother and fetus. For example, the CDC recommends
766 Unit 6 Pharmacology of Body Defenses
vaccination for influenza (inactivated) and Tdap (tetanus, Table 43.2 summarizes the epidemiology and immuniza-
diphtheria, and pertussis booster vaccine). A woman tions associated with these pathogens. Immunizations
should be vaccinated for HBV if she is at risk for HBV infec- against viruses are presented in Section 43.6.
tion during pregnancy. Some vaccines, including those for
HPV, varicella, and MMR, should not be administered to Many bacterial infections cause host cellular injury by
pregnant women due to the potential risk to the fetus. For releasing toxic substances. Vaccination for bacterial infec-
other vaccines, the pregnant patient should consult with tions, therefore, may be achieved by exposing the immune
her healthcare provider. system to inactive bacterial toxins. When later faced with
the actual bacterial infection, the immune system will
Anaphylaxis and allergy: The most common adverse remember the protein-based toxin and respond rapidly by
effects of vaccination are pain, swelling, and redness at the producing antibodies to neutralize it.
injection sites. Allergy or anaphylaxis following vaccina-
tion is extremely rare. Some preparations may contain pre- It is common practice to combine several childhood
servatives such as gelatin or the mercury compound vaccines for a single administration. For example, DTaP
thimerosal, which could trigger an allergic response. combines diphtheria, tetanus, and pertussis into a single
Patients with confirmed vaccine anaphylaxis should not injection. Combining vaccines is less traumatic for the child
receive subsequent doses of that vaccine. and is more convenient and efficient for the caregiver and
the healthcare provider.
Adverse event reporting: Healthcare providers are
required to report all vaccine-related adverse events Diphtheria
requiring medical attention to the Vaccine Adverse Event
Reporting System (VAERS). The VAERS is a postmarketing Pathophysiology: Diphtheria is an infection of the
surveillance program conducted by the CDC and the U.S. upper respiratory tract caused by the gram-positive bac-
Food and Drug Administration (FDA). Voluntary reports terium Corynebacterium diphtheriae. The bacterium releases
may be submitted to the VAERS by patients and parents as a potent toxin that causes a low-grade fever, malaise, and
well as healthcare providers. Vaccine manufacturers are a painful oropharynx. The organism causes the formation
required to report any adverse effects of which they are of a thick, gray coating across the membranes of the soft
aware. palate, tonsillar areas, and uvula. The thickened mem-
branes can partially occlude the airway and cause diffi-
VAERS has a number of limitations. VAERS merely culty swallowing or a feeling of choking. Attempts to
collects data and reports incidences of adverse events; it remove the membrane result in pain and bleeding. If
does not attempt to confirm that the reported event was untreated, the membrane softens and gradually disap-
actually caused by the vaccine. Reports are not checked by pears approximately 1 week following its appearance. A
the FDA or CDC for accuracy or completeness. Despite its majority of deaths associated with diphtheria are related
limitations, VAERS serves as an important, central reposi- to toxin escape, leading to acute systemic toxicity or myo-
tory of information for identifying potential adverse effects carditis. Because of effective immunization programs, the
of vaccines. disease has almost been entirely eradicated from the
United States.
CONNECTION Checkpoint 43.2
Diphtheria toxoid: Diphtheria toxin is produced by
Vaccines are sometimes contraindicated in patients who are receiv- organisms in culture that are rendered inactive by the
ing immunosuppressant drugs. From what you learned in Chapter 42, addition of formalin. The diphtheria toxoid triggers
identify the following drugs as being either an immunosuppressant immune memory without producing disease in the upper
or an immunostimulant: aldesleukin (Proleukin), cyclosporine (Gen- airways. Currently diphtheria toxin is available as a com-
graf, Neoral, Sandimmune), basiliximab (Simulect), and hydrocorti- bination immunization with tetanus toxoid and acellular
sone. Answers to Connection Checkpoint questions are available on pertussis (DTaP) as well as in combination with other com-
the faculty resources site. Please consult with your instructor. patible immunizations. DTaP is part of the recommended
routine immunization schedule for infants older than
Active Immunity: Bacterial 6 months.
Immunizations
Pertussis (Whooping Cough)
43.5 Active immunity can be induced to prevent
bacterial infections. Pathophysiology: Pertussis is a highly contagious infec-
tion by the gram-negative bacterium Bordetella pertussis
Vaccinations are performed to provide protection against that is transmitted via aerosolized droplets from an
both viral and bacterial pathogens. However, the role of infected individual. Once inhaled, the bacteria attach to
vaccines is very different for each type of infectious agent. the ciliated respiratory epithelial cells and release a toxin.
Chapter 43 Immunizing Agents 767
Table 43.2 Disease Epidemiology and Immunizations
Disease Worldwide Incidence U.S. Incidence Immunization (Age) Remarks
(Annually) (Annually)
Diphtheria About 7000 cases, usually in Under 10 reported cases 2, 4, 6, and 15–18 months; Mucous membrane bacterial
Hepatitis A developing countries 4–6 years toxin infection
Hepatitis B Estimated 1.4 million cases, About 2500 new cases; has Two-dose series: 12 months
Human papilloma virus usually in developing declined by 90% since 1995 and 6–12 months later Route: oral–fecal from carriers;
(HPV) countries Adults at risk for infection immune globulin available
Influenza (Haemophilus About 240 million chronic Fewer than 19,000 new Three-dose series: 0, 1, and
influenzae type b [Hib]) carriers worldwide cases; has declined by over 6–18 months Vaccine recommended for all
Measles (rubeola) 80% since 1988 healthcare providers; immune
Meningococcus Associated with about 70% of About 42% of population First dose at ages 11–12; globulin available
Mumps all cases of cervical and ages 18–59 (genital HPV) second 6–12 months after
oropharyngeal cancers and 7% (oral HPV) are the first 4 years after vaccine approval,
Pertussis infected the incidence of HPV among
Estimated 250,000–500,000 About 36,000 deaths (high Annual vaccine based on females ages 14–19 dropped
Pneumococcal disease deaths; endemic during risk to those over 65 years of estimated exposure over 60%
Poliomyelitis winter months age and in general ill health)
MMR: 12–15 months; Vaccine recommended for
Rabies About 134,000 deaths, Fewer than 100 cases booster: 4–6 years children, immunocompromised
usually in developing patients, older adults, and
Rubella countries (mostly children) About 1000 cases; rates are 11–12 years; booster: age healthcare workers
Tetanus About 12,000 cases, with highest for children under 16
Varicella (chickenpox) about half in central Africa age 1 Highly contagious; airborne and
About 2300 cases, mostly MMR: 12–15 months; droplet exposure
Endemic in many countries; due to outbreaks in booster: 4–6 years
rarely fatal unvaccinated college Airborne droplet exposure;
students 2, 4, 6, and 15–18 months; antibiotics if known exposure
Endemic worldwide; 16 About 32,000 cases 4–6 years
million cases with about Viral parotitis; respiratory
200,000 deaths About 1 million cases with All children younger than 2 droplet infection
about 5000 deaths years (PCV13) and all people
Over 14 million cases with over age 65 (PPSV23) Gram-negative bacterial
over 820,000 deaths Very rare Inactivated virus: 2, 4, and infection, cough; increased
12 months; booster: 4–6 incidence in adolescent age
About 74 cases: almost Found in all continents years group
eradicated
Very rare Preexposure vaccine for Most deaths occur in
Canine rabies epidemic in veterinarians; postexposure individuals ages 65 and older
Africa, Asia, and Central Very rare; about 30 cases immune globulin
America; fewer than 200 20% of children in Nigeria
deaths About 3.5 million cases and MMR: 12–15 months; younger than 5 years are not
About 100,000 cases 100 deaths booster: 4–6 years vaccinated because of fear of
acquired congenitally AIDS and female infertility
2, 4, 6, and 15–18 months;
About 59,000 deaths 4–6 years Viral infection; transmitted via
contaminated saliva; from
Endemic worldwide; rarely Two-dose series: 12–15 peripheral nervous system to
fatal months and 4–6 years central nervous system
Mild disease but fetal cataracts,
deafness, and cardiac
malformations
Spores in soil; illness follows
inadequate or missed
immunizations
Highly contagious; airborne
spread; latent in nerve ganglia;
reoccurs as herpes zoster
(shingles)
Pertussis begins with a low-grade fever and irritated The cough will usually resolve at the termination of the
cough and progresses to spasmodic coughing episodes infection in approximately 2 to 6 weeks. Exhaustion is
characterized by an inspiratory “whoop,” leading to the common in patients experiencing pertussis, as are second-
common name “whooping cough.” The coughing episodes ary respiratory infections. Active pertussis infection is
are productive and may be induced by laughing, talking, treated with the antibiotic erythromycin, with the best
or activity in children, and lead to gagging or vomiting. results seen when treatment is early and aggressive.
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