668 Unit 5 Pharmacology of the Cardiovascular System
deoxyribonucleic acid (DNA) technology to secrete human heparin or the LMWHs. There is no specific antidote for
antithrombin in their milk. The drug is then purified and overdose; administration of protamine is ineffective. This
powdered for reconstitution as an IV infusion. drug is pregnancy category B.
Levels of antithrombin activity in the blood must be 38.5 Warfarin is a widely used drug for oral
monitored before, during, and immediately following ther- anticoagulant therapy.
apy. The initial and subsequent drug doses are based on the
level of antithrombin activity. The most common adverse Although parenteral anticoagulants have the advantage of
effects are hemorrhage and infusion site reaction. ATryn an almost immediate onset of action, drugs given by this
enhances the anticoagulant effect of heparin and LMWHs. route require close medical supervision because adverse
This drug is pregnancy category C. effects such as bleeding can rapidly ensue. When the
patient’s condition allows, oral anticoagulants are used
Dalteparin (Fragmin): As an LMWH, dalteparin has due to their convenience and greater safety.
smaller glycosaminoglycan chains than unfractionated
heparin. Approved in 1994, dalteparin is given by the sub- Warfarin (Coumadin) has been available as an antico-
cutaneous route for the treatment and prophylaxis of DVT agulant for over 50 years and is the historical prototype for
or pulmonary embolism. Other approved indications oral anticoagulants. In acute situations, patients begin anti-
include thrombosis prophylaxis in patients at increased coagulation therapy with heparin and are switched to war-
risk due to unstable angina, an acute MI, or cancer. It has a farin when their condition stabilizes. When transitioning,
longer half-life than heparin, which allows for less fre- the two drugs must be administered concurrently for 2 to
quent dosing. Like other LMWHs, bleeding is the most 3 days. This is because heparin has a brief half-life
serious adverse effect and the drug should not be adminis- (90 minutes), and aPTT returns to normal within 2 to
tered to patients with active bleeding. This drug is preg- 3 hours following discontinuation of heparin. Warfarin, on
nancy category B. the other hand, takes 1 to 3 days of therapy to achieve opti-
mal anticoagulation. Thus, concomitant pharmacotherapy
Enoxaparin (Lovenox): Enoxaparin was the first LMWH is necessary to ensure continuous anticoagulation. During
approved by the U.S. Food and Drug Administration this transition, risk of bleeding increases, due to the addi-
(FDA) in 1993. Indications include treatment and prophy- tive anticoagulant action of the two drugs.
laxis of DVT and pulmonary embolism. Following hip or
lower extremity surgery, enoxaparin may be administered CONNECTIONS: Lifespan
once daily for 7 to 10 days. Some orthopedic procedures Considerations
such as repair of hip fractures require more prolonged
therapy. Enoxaparin may also be administered for the pro- Miscarriage Prevention with Anticoagulants
phylaxis of coronary artery thrombosis and the prevention
of ischemic complications in patients with acute coronary Miscarriage in pregnancy is devastating, and recurrent miscar-
syndrome, for patients with unstable angina, and patients riage even more so. Autoimmune diseases are related to
having percutaneous coronary intervention (PCI). Bleed- poorer obstetric outcomes than that of the general population,
ing is the most serious adverse effect and the drug should especially in mothers with undiagnosed thrombophilias
not be administered to patients with active bleeding. This (genetic hypercoagulability disorders) such as antiphospho-
drug is pregnancy category B. lipid syndrome (APS). Antiphospholipid antibodies are present
in 15% of women with recurrent miscarriage, and there is a
Fondaparinux (Arixtra): Approved in 2001, fondaparinux potential 90% risk of future fetal loss in those women if left
is an anticoagulant used for many of the same indications untreated (Chetty & Duncan, 2015). Other obstetric and neo-
as heparin and the LMWHs, but it has certain differences natal complications related to APS include preeclampsia;
that make it unique. Fondaparinux is a synthetic drug that eclampsia; hemolysis, elevated liver enzymes, and low platelet
consists of only five saccharide units (a pentasaccharide) count (HELLP) syndrome; early delivery and subsequent pre-
that is structurally identical to the region of the heparin maturity; intrauterine growth restriction (IUGR); and placental
molecule that binds AT-III. The pentasaccharide unit is insufficiency (Begum, Ganguly, & Islam, 2015; de Jesús,
able to selectively inhibit Factor Xa without directly affect- Rodrigues, de Jesús, & Levy, 2014).
ing thrombin. Fondaparinux is only given by the subcuta-
neous route and is approved for the prophylaxis of VTE Due to discrepancies in the research on treatment rec-
following orthopedic surgery and the treatment of DVT or ommendations for the use of heparin, LMWH, or aspirin for
pulmonary embolism. Like the LMWHs, fondaparinux is recurrent spontaneous abortion before 10 weeks of preg-
administered as fixed doses based on the patient’s weight, nancy, it is recommended that a woman experiencing such
and routine laboratory monitoring is not required because loss discuss the situation with her provider and whether
aPTT and PT are not accurate measures of drug activity. genetic testing should be conducted. If genetic coagulation
Doses of fondaparinux are not interchangeable with abnormalities are found, heparin or LMWH may be considered
as an option (Andreoli et al., 2013).
Chapter 38 Pharmacotherapy of Coagulation Disorders 669
Whereas heparin is monitored with aPTT values, the warfarin should not switch brands of the drug unless rec-
standard laboratory test used to monitor the effectiveness ommended by the healthcare provider, due to differences
of warfarin is the PT value. The normal PT range is 12 to in bioavailability. For most indications, the therapeutic
15 seconds. During therapeutic anticoagulation, PT should range of serum warfarin levels varies from 1 to 10 mcg/mL
increase to 1.5 to 2 times the patient’s baseline. Because to achieve a target INR value of 2 to 3.
laboratory testing methods for PT vary, however, PT time is
also reported as an international normalized ratio (INR) Mechanism of Action: Warfarin inhibits two enzymes
value; INR values averaging 2.5 are considered therapeutic involved in the formation of activated vitamin K, which is
for most indications. PT is measured daily until the desired required for the synthesis of clotting Factors II, VII, IX, and
level of therapeutic anticoagulation is achieved. Then, the X. Warfarin inhibits the synthesis of new clotting factors
frequency of laboratory testing is decreased to weekly or but does not affect clotting factors that are already circulat-
monthly as the patient’s condition stabilizes. Home moni- ing in the blood. It takes 3 to 4 days for the plasma levels
toring devices are available to provide convenient and reli- of existing clotting factors to fall and for the anticoagulant
able INR values, which can guide the patients to adjust effect of warfarin to appear. After discontinuing the drug,
their own medication amounts. Self-monitoring has its 3 to 4 days are needed for the body to make new clotting
limitations, however. The devices are expensive and the factors and return coagulation to baseline levels.
patient or their caregiver must be capable of understanding
how to properly adjust the dosage. Pharmacokinetics:
Several newer drugs have emerged as significant alter- Route(s) PO
natives to warfarin for stroke prevention. While warfarin
affects coagulation indirectly by inhibiting vitamin K, these Absorption Well absorbed
newer drugs directly inhibit an aspect of the coagulation
cascade. Thus, these drugs are referred to as direct oral Distribution Widely distributed; crosses the
anticoagulants (DOACs). The DOACs include three drugs
that directly inhibit Factor Xa and one that directly inhibits placenta but is not secreted
thrombin. The Factor Xa inhibitors include rivaroxaban
(Xarelto), apixaban (Eliquis), and edoxaban (Savaysa). The in breast milk; 99% bound to
fourth DOAC is dabigatran (Pradaxa), which is a prototype
thrombin inhibitor discussed in Section 38.6. plasma protein
PROTOTYPE DRUG Warfarin (Coumadin) Primary metabolism Hepatic
Classification Therapeutic: Anticoagulant Primary excretion Renal; small amounts in bile
Pharmacologic: Vitamin K antagonist
Onset of action 2–7 days
Therapeutic Effects and Uses: Indications for war-
farin therapy include the long-term prophylaxis of arterial Duration of action 3–5 days; half-life: 0.5–3 days
thromboembolism, including prevention of stroke and MI.
Other uses include the prophylaxis and treatment of DVT Adverse Effects: Like all anticoagulants, the most
or pulmonary embolism in patients undergoing hip or serious adverse effect of warfarin is abnormal bleed-
knee surgery, or in those with long-term indwelling central ing, which may occur in any body system. Warfarin may
venous catheters or prosthetic heart valves. The drug may release pieces of atheromatous plaque from vessel walls,
be given to prevent thromboembolic events in high-risk resulting in systemic cholesterol microembolization that
patients following an MI or an atrial fibrillation episode. may occlude small vessels. For example, “purple-toe syn-
drome” is caused by cholesterol microembolization and
Warfarin is well absorbed after PO administration but severe cases may lead to gangrene or amputation. Long-
takes several days to produce an optimal therapeutic effect. term use of warfarin may increase the risk of osteoporo-
Ninety-nine percent of absorbed warfarin is bound to sis and bone fractures. Black Box Warning: Warfarin can
plasma proteins and is not immediately available to pro- cause major or fatal bleeding, and regular monitoring of
duce its effect. This high level of protein binding is also INR is required. Patients should be instructed about pre-
responsible for some of the many drug–drug interactions vention measures to minimize bleeding risk and to imme-
that occur with warfarin. diately notify healthcare providers of signs and symptoms
of bleeding.
Patient responses to warfarin therapy vary widely.
Dosage levels must be determined individually for each Contraindications/Precautions: Patients with
patient and carefully monitored. Patients stabilized on recent trauma, active internal bleeding, serious bleeding
disorders, intracranial hemorrhage, severe HTN, bacterial
endocarditis, severe CKD, or hepatic impairment should
not take warfarin. When possible, warfarin should be dis-
continued or the dosage lowered before dental or elective
surgical procedures. Patients with heart failure may exhibit
excessive anticoagulation with warfarin, which requires
lower doses. Whenever possible, IM injections of other
medications should be avoided because they may cause
670 Unit 5 Pharmacology of the Cardiovascular System
Table 38.4 Drug–Drug Interactions with Warfarin Practice Application for Patients Receiving Pharmacother-
apy with Anticoagulants.
Interaction Drug or Drug Class
Drugs Similar to Warfarin (Coumadin)
Increased acetaminophen, amiodarone, anabolic steroids,
anticoagulant effect aspirin, azole antifungals, cephalosporins, Apixaban, edoxaban, and rivaroxaban are DOACs that
cimetidine, clopidogrel, danazol, disulfiram, serve as alternatives to warfarin for providing anticoagula-
Decreased heparin, isoniazid, macrolides, metronidazole, tion. These drugs will be considered as a group because
anticoagulant effect nalidixic acid, NSAIDs, omeprazole, paroxetine, they have identical mechanisms and very similar actions.
Mixed effect penicillin, propafenone, quinidine, statins,
Supplements and food tamoxifen, tetracyclines, thyroid hormone, All three drugs in this class are oral medications that
trimethoprim-sulfisoxazole act by inhibiting Factor Xa, resulting in prolonged clotting
time. Initial approvals were granted for rivaroxaban
barbiturates, bile-acid sequestrants, (Xarelto) in 2011, apixaban (Eliquis) in 2012, and edoxaban
carbamazepine, cyclosporine, dicloxacillin, oral (Savaysa) in 2015. Indications for the Factor Xa inhibitors
contraceptives, rifampin include the following.
allopurinol, corticosteroids, ethanol, phenytoin • Reduction in the risk of stroke and systemic embolism
in patients with nonvalvular atrial fibrillation (all
American ginseng, cranberry, feverfew, ginkgo, three drugs)
green tea, vitamin E, vitamin K
• Treatment of DVT and pulmonary embolism (all three
bruising, bleeding, or hematomas. Warfarin should not be drugs)
taken during pregnancy because the drug has been shown
to produce numerous fetal abnormalities, induce fatal • Prophylaxis of DVT in patients who have undergone
bleeding, and can cause fetal death. Warfarin is believed knee or hip replacement surgery (apixaban and
to be safe for lactating women who are at risk for postpar- rivaroxaban).
tum DVT because very little of the drug enters breast milk.
Studies have shown no change in the INR values of lactat- The most serious adverse reaction is excessive bleed-
ing infants whose mothers are receiving warfarin. ing. Unlike warfarin, there is no antidote for Factor Xa
inhibitor overdose. The three drugs carry a black box warn-
Drug Interactions: Drug–drug interactions with ing that abrupt discontinuation can increase the risk of
warfarin are numerous. Because the therapeutic index of thromboembolism. Unless discontinued for a pathologic
warfarin is very low, drugs that interact with warfarin reason (excessive bleeding), another drug should be imme-
have the potential to affect coagulation time and cause diately substituted so that continuous anticoagulation is
harm. Concurrent use with other drugs with anticoagu- obtained. A second black box warning is that spinal or epi-
lant activity, including aspirin, heparin, and antiplatelet dural hematomas may occur in anticoagulated patients
drugs, may produce additive effects and excessive bleed- receiving epidural or spinal anesthesia or who are under-
ing. Extensive protein binding is responsible for numer- going spinal puncture.
ous drug–drug interactions, some of which include
nonsteroidal anti-inflammatory drugs (NSAIDs), diuret- The Factor Xa inhibitors offer significant advantages
ics, selective serotonin reuptake inhibitors (SSRIs) and over warfarin. The Factor Xa inhibitors require no monitor-
other antidepressants, steroids, antibiotics, vaccines, and ing to determine their anticoagulant effect—the same dose
vitamins (e.g., vitamin K). NSAIDs increase bleeding risk. is used for most patients. They exhibit fewer drug–drug
During warfarin therapy, the patient should not take any and drug–food interactions than warfarin. Their anticoagu-
other prescription or over-the-counter (OTC) drugs or lant effect clears in 1–2 days after discontinuation, versus
herbal products unless approved by the healthcare pro- 5–7 days for warfarin.
vider. A listing of selected drugs and supplements affect-
ing warfarin therapy is given in Table 38.4. Herbal/Food: 38.6 The direct thrombin inhibitors and Factor
Herbal supplements such as green tea, ginkgo, feverfew, Xa inhibitors have become important drugs
garlic, cranberry, chamomile, and ginger may increase the in the prevention and treatment of venous
risk of bleeding. thromboembolism.
Pregnancy: Category X. The direct thrombin inhibitors and Factor Xa inhibitors,
listed in Table 38.3, are relatively new drugs in the preven-
Treatment of Overdose: The specific treatment for tion and treatment of venous thromboembolism and pul-
warfarin overdose is PO or parenteral administration of monary emboli. They offer several advantages over
vitamin K1. When administered IV, vitamin K1 can reverse warfarin and heparin.
the anticoagulant effects of warfarin within 6 hours.
The direct thrombin inhibitors have an interesting his-
Nursing Responsibilities: Key nursing implications tory; they were originally derived from chemicals found in
for patients receiving warfarin are included in the Nursing
Chapter 38 Pharmacotherapy of Coagulation Disorders 671
leeches. Leeches are wormlike animals that survive by Mechanism of Action: Dabigatran directly inhibits
sucking and digesting blood from mammals. Medical the action of thrombin without requiring the intermediate
leeches are an ancient treatment that dates back to early step of AT-III inhibition.
Egyptian and Greek civilizations. They were applied to the
skin as a type of bloodletting, which was thought to remove Pharmacokinetics:
harmful substances from the body. Known as hirudother-
apy, the use of leeches was largely discontinued with the Route(s) PO
advent of modern medicine in the early 1900s. However,
leeches are still an approved therapy for relieving venous Absorption 3–7% absorbed
congestion in transplanted or reattached fingers or limbs.
While studying leeches, scientists isolated a potent chemi- Distribution 35% bound to plasma proteins;
cal called hirudin, which prevented blood from coagulat-
ing in the leech. unknown if it crosses the placenta
The direct thrombin inhibitors bind reversibly to or is secreted in breast milk
thrombin, preventing the formation of fibrin. They are
highly specific for thrombin and do not require AT-III as an Primary metabolism Hepatic to active metabolites
intermediate in promoting anticoagulation as does hepa-
rin. They bind to circulating thrombin as well as thrombin Primary excretion Renal 80%
attached to fibrin clots. These drugs exhibit typical antico-
agulant actions and are used for the same types of indica- Onset of action 30–90 min
tions as heparin and the LMWHs. The only drug in this
class given by the PO route is dabigatran. Duration of action Half-life: 12–17 h
The Factor Xa inhibitors bind to activated Factor Xa, Adverse Effects: Like other anticoagulants, the most
which blocks the formation of thrombin from both the serious adverse effect of dabigatran is bleeding. Symp-
intrinsic and extrinsic pathways of the coagulation cascade. toms may include bleeding from puncture or wound sites,
They block Factor Xa in both plasma and in clots, and have epistaxis, hematuria, vaginal bleeding, or GI bleeding.
no effects on platelets. They are well absorbed by the PO Hypersensitivity reactions, including anaphylaxis, have
route and do not require routine monitoring. The number been reported. Dyspepsia and gastritis are common during
of adverse bleeding events is the same, or less, than that of therapy. Black Box Warnings: Premature discontinuation
warfarin. Peak concentrations can be reached in 3 hours. of dabigatran increases the risk of thrombotic events. Epi-
The American College of Chest Physicians (ACCP) now dural or spinal hematomas may occur when administering
recommends 3 months of therapy with dabigatran this drug to patients who are receiving neuraxial anesthe-
(Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), or sia or spinal puncture.
edoxaban (Savaysa) as initial choices for DVT or pulmo-
nary embolus prevention (Kearon et al., 2016). Contraindications/Precautions: Dabigatran
should not be administered to patients with active bleed-
PROTOTYPE DRUG Dabigatran (Pradaxa) ing or those with impaired hemostasis. Patients with
mechanical heart valves should not receive this drug due
Classification Therapeutic: Anticoagulant to an increased risk of thrombotic events. Patients with
Pharmacologic: Direct thrombin severe CKD or on hemodialysis should not receive dabi-
gatran. The drug should be used with caution in patients
inhibitor with recent hemorrhage, recent surgery, intracranial
hemorrhage, ulcerative GI disease, or symptoms of
Therapeutic Effects and Uses: Dabigatran is a direct gastritis.
thrombin inhibitor that was approved in 2010 for stroke
prophylaxis in patients with nonvalvular atrial fibrillation. Drug Interactions: Additive risk for bleeding may
Indications have been extended to include treatment of occur if dabigatran is administered concurrently with
DVT and pulmonary embolus in patients who have been other coagulation modifiers, including warfarin, hepa-
treated with a parenteral anticoagulant for 5 to 10 days, and rin, aspirin, and fibrinolytic drugs. Herbal/Food: Herbal
prophylaxis of DVT and PE in patients who have under- supplements that affect coagulation such as ginger, garlic,
gone hip replacement surgery. Because it is administered green tea, feverfew, St. John’s wort, or ginkgo should be
PO, dabigatran is an alternative to both heparin and war- avoided because they may increase the risk of bleeding.
farin. Although more expensive, dabigatran has equal effi-
cacy to warfarin and does not require the same high degree Pregnancy: Category C.
of laboratory monitoring as does warfarin or heparin.
Treatment of Overdose: Administration of prot-
amine and vitamin K are not effective. In 2015, idaruci-
zumab (Praxbind) was approved for emergency use to
reverse the anticoagulant action of dabigatran. When
given IV, idarucizumab binds to free dabigatran and fully
reverses anticoagulation after 4 hours in most patients.
Nursing Responsibilities: Key nursing implica-
tions for patients receiving dabigatran are included in the
672 Unit 5 Pharmacology of the Cardiovascular System
CONNECTIONS: NURSING PRACTICE APPLICATION
Patients Receiving Pharmacotherapy with Anticoagulants
Assessment
Baseline assessment prior to administration:
• Obtain a complete health history: cardiovascular (including HTN, MI, heart failure) and peripheral vascular disease (including thrombophlebitis), respira-
tory (including previous pulmonary embolism), neurologic (including recent head injury or stroke), hepatic disease, CKD, diabetes, peptic ulcer disease,
hypercholesterolemia, and the possibility of alcoholism or pregnancy. Lifespan: Ask women of menstrual age about length and heaviness of usual
menstrual flow. Obtain a drug history including allergies, current prescription and OTC drugs, herbal preparations, and alcohol use. Be alert to possible
drug interactions.
• Obtain baseline weight; vital signs; electrocardiogram (ECG), if appropriate; and breath sounds. Assess for presence, quality, location of angina,
and for presence of dyspnea or chest pain. Assess extremities for symptoms of thrombophlebitis (e.g., warmth, swelling, tenderness in calf, positive
Homans’ sign), and for location, character, and amount of edema, if present.
• Evaluate appropriate laboratory findings (e.g., aPTT, PT/INR), complete blood count (CBC), renal and liver function studies, arterial blood gases (ABGs)
as appropriate, and lipid profiles.
• 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., existing area of phlebitis exhibits signs of improvement with no symptoms of thrombosis formation; signs
and symptoms of existing thrombosis show gradual improvement: e.g., previous anginal or peripheral extremity pain has diminished or is eliminated;
peripheral pulses are improving in quality and volume).
• Continue periodic monitoring of appropriate laboratory values (e.g., aPTT, PT/INR).
• Assess for adverse effects: bleeding at IV sites, wounds, excessive ecchymosis, petechiae, hematuria, black or tarry stools, rectal bleeding,
coffee-ground emesis, epistaxis, bleeding from gums, hemoptysis, prolonged or heavy menstrual flow; and assess for occult bleeding: pallor,
dizziness, hypotension, tachycardia, abdominal pain, areas of abdominal wall swelling or firmness, lumbar pain, or decreased level of
consciousness (LOC).
Interventions and (Rationales) Implementation
Patient-Centered Care
Ensuring therapeutic effects: • To allay possible anxiety, teach the patient, family, or caregiver
• Continue frequent assessments as above for therapeutic effects, e.g., the rationale for all equipment used (e.g., antiembolic stockings,
intermittent pneumatic sequential compression devices) and
existing area of phlebitis exhibits signs of improvement with no symp- the need for frequent monitoring.
toms of thrombosis formation; signs and symptoms of existing throm-
bosis show gradual improvement: e.g., previous anginal or peripheral
extremity pain has diminished or is eliminated; peripheral pulses are
improving in quality and volume. (Anticoagulants help prevent the
formation of thrombi or prevent existing thrombi from increasing in size.
As the body’s own thrombolysis factors activate, existing thrombi will
gradually reduce in size.)
• Encourage early ambulation postoperatively in the hospitalized • Assist the patient with ambulation postoperatively, and teach active
patient and active range of motion (ROM) if the patient is on bed rest ROM. Teach the patient, family, or caregiver how to perform passive
or has limited mobility. Perform passive ROM for patients unable to ROM exercises for patients unable to perform active ROM.
perform active ROM. (Early ambulation and ROM prevent venous
stasis and thrombosis formation, lessening the need for anticoagu-
lant therapy.)
• Assess the patient’s lifestyle and occasions of travel over extended • Educate patients and consumers about thrombosis prevention during
lengths of time (e.g., air travel, lengthy driving trips) and the fre- travel: stretch periodically, ambulate for short periods, avoid sitting for
quency of such trips. (Prolonged sitting during air or car travel may prolonged periods, and increase fluid intake.
limit blood flow to lower extremities and venous return, promoting
the formation of thrombi. Frequent stretching, ambulating when
possible, and increasing fluids to maintain normal osmolarity and
viscosity may decrease thrombosis formation and lessen the need
for anticoagulant therapy.)
• Encourage appropriate lifestyle changes: lowered fat intake, increased • Encourage the patient to adopt a healthy lifestyle of low-fat food
exercise, limited alcohol intake, limited caffeine intake, and smok- choices, increased exercise, decreased alcohol consumption, and
ing cessation. Provide for dietitian consultation as needed. (Smoking smoking cessation. Provide for appropriate consultation (e.g., dietitian)
increases platelet aggregation and promotes the formation of thrombi. as needed.
Healthy lifestyle changes will support and minimize the need for drug
therapy.)
Minimizing adverse effects: • Anticoagulant use is a high-risk safety concern and is included in The
• Monitor for signs and symptoms of excessive visible bleeding and Joint Commission’s National Patient Safety Goals.
for occult bleeding. (Bleeding is the most common adverse effect • Teach the patient, family, or caregiver the signs and symptoms
of anticoagulant therapy. Frequent assessment for both visible and of excessive bleeding, including occult. If external bleeding
occult bleeding is necessary to prevent hemorrhage and to start early occurs, pressure over the site should be held up to 15 min. If
corrective treatment as appropriate. Diverse Patients: Because some bleeding continues, is severe, or is accompanied by dizziness
drugs such as clopidogrel [Plavix] metabolize through the CYP450 or syncope, immediate medical attention (e.g., 911) should be
system pathways, monitor ethnically diverse patients to ensure optimal obtained.
therapeutic effects and to minimize adverse effects.)
• Lifespan: Women of menstrual age should report excessively heavy or
prolonged menstrual bleeding and should keep a pad count and report
to the healthcare provider.
Chapter 38 Pharmacotherapy of Coagulation Disorders 673
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
• Continue to monitor frequent laboratory tests (aPTT, PT/INR), CBC, and • Instruct the patient on the need to return periodically for laboratory
platelets. (Therapeutic aPTT levels are usually 1.5–2.5 times the normal work and to alert laboratory personnel that anticoagulant therapy is
control value. INR is usually 2–3.5 or 4. Learn own laboratory provider’s being used.
values. Values below the norm indicate less than optimal therapeutic levels
of the drug; values above the norm indicate a high potential for bleeding • Instruct the patient to carry a wallet identification card or wear medical
and hemorrhage. CBC, especially red blood cell [RBC], hemoglobin [Hgb], identification jewelry indicating anticoagulant therapy.
hematocrit [Hct], and platelet levels should remain within normal limits.
Decreasing values on CBC may indicate excessive bleeding and the need
to assess for location. Lifespan: Be especially cautious with the older
adult as age-related hepatic changes may increase the risk of bleeding.)
• Continue to monitor peripheral pulses for quality and volume, complaints of • Teach the patient, family, or caregiver to report immediately any sud-
angina or chest pain, especially if new or of sudden onset or accompanied den pain in the chest, legs or calves, dyspnea, or new-onset anginal
by dyspnea. (Anticoagulants prevent thrombus formation or extension; they pain.
do not prevent emboli from occurring. Monitoring for new or sudden onset
of pain is necessary to ensure prompt treatment of possible emboli.)
• Minimize opportunities for injury or bleeding where possible: Avoid IM Instruct the patient on ways to minimize opportunities for injury or bleeding:
injections, provide a soft toothbrush, and be cautious when providing • Switch to a soft toothbrush and inspect gums after brushing.
care, especially with older adults who have more fragile skin. (Antico- • Use an electric razor, or be extra cautious with a safety razor, holding
agulants raise the risk of bleeding, and causes of even minor bleeding
should be avoided when possible. If minor bleeding occurs, prolonged prolonged pressure over small nicks.
pressure, longer than expected, will be necessary to stop it, and the • Be cautious with food preparation, especially when cutting food.
site should be assessed frequently for oozing. Warfarin and antiplatelet • Avoid contact sports, amusement park rides, or other physical activi-
drugs may continue to have effects after the drug is stopped.)
ties that may cause intense or violent bumping, jostling, or injury.
• Lifespan: Frequently assess older adult family members on anticoagu-
lant therapy who have more fragile skin and may experience skin tears
or ecchymosis more frequently.
• Closely evaluate all new prescriptions or use of OTC medications for • Instruct the patient to consult the healthcare provider before taking any
drug interactions. (Many drugs interact with anticoagulants, enhancing new prescription or OTC medication, including herbal preparations.
the action and increasing the chance for bleeding. All OTC medications
containing salicylates, e.g., aspirin, and NSAIDs are contraindicated.)
• Maintain a normal diet, avoiding increases or decreases in vitamin K– • Teach the patient to maintain a normal diet, avoiding increases or
rich foods (e.g., asparagus, broccoli, cabbage, cauliflower, kale), and decreases in vitamin K–rich foods and limit or eliminate alcohol intake.
limit or eliminate alcohol intake. (Vitamin K is necessary for synthesis Vitamin K supplements and protein supplement drinks (e.g., Ensure or
of clotting agents in the liver. Sudden increases or decreases in dietary Boost), which often have vitamin K added, should also be avoided.
intake of vitamin K–rich foods may increase or decrease the effective-
ness of anticoagulants, particularly oral anticoagulant therapy. Exces- • Advise patients to avoid excessive intake of alcohol while on oral anti-
sive intake of alcohol, more than two drinks in men or one in women coagulants.
per day, may alter the effectiveness of oral anticoagulants.)
• Assess for any symptoms of hepatitis (e.g., darkening urine, light or • Instruct the patient, family, or caregiver to report any signs of possible
clay-colored stools, itchy skin, jaundice of sclera or skin, abdominal hepatitis immediately, especially abdominal discomfort that localizes in
pain, especially in the right upper quadrant [RUQ]) in patients receiv- the RUQ.
ing oral anticoagulant therapy. (Drug-induced hepatitis is a possible
adverse effect of oral anticoagulant therapy.)
• Lifespan: Assess for the possibility of pregnancy before beginning the • Instruct female patients who may be considering pregnancy, or are
drug. (Women on anticoagulant therapy will be monitored closely for pregnant, to notify their provider before starting the drug. Women tak-
labor and the possibility of excessive bleeding. Warfarin is a pregnancy ing warfarin should use extra precautions during sex, such as barrier
category X drug.) contraceptive measures, to prevent pregnancy.
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, equipment needed as appropri-
assessments to discuss the rationale for drug therapy, desired thera- ate and how to use that equipment, and the required length of medica-
peutic outcomes, commonly observed adverse effects, parameters tion therapy needed, with any special instructions regarding renewing
for when to call the healthcare provider, and any necessary monitoring or continuing the prescription as appropriate.
or precautions. (Using time during nursing care helps to optimize and
reinforce key teaching areas.)
Patient self-administration of drug therapy: Teach the patient, family, or caregiver proper self-administration techniques:
• When administering medications, instruct the patient, family, or • Injections of heparin or LMWHs should be administered in the fatty
caregiver in proper self-administration techniques followed by return layers of the abdomen or just above the iliac crest, avoiding the peri-
demonstration. (Utilizing time during nurse administration of these umbilical area by 5 cm (2 in.).
drugs helps to reinforce teaching.) • Skin is drawn up (pinched), and the needle is inserted at a 90-degree angle.
• Injection is given without aspirating for blood return.
• Release the skin and hold slight pressure to the site, but do not mas-
sage the area.
• Have the patient, family, or caregiver return demonstrate until the
proper technique is used and they are comfortable giving the injection.
• Teach the patient on oral anticoagulants to take the medication at the
same time each day.
674 Unit 5 Pharmacology of the Cardiovascular System
Nursing Practice Application for Patients Receiving Phar- effects. They are approved to treat DVT and pulmonary
macotherapy with Anticoagulants. emboli, as well as to reduce the risk of stroke or embolism
in patients with nonvalvular atrial fibrillation. The drugs
Drugs Similar to Dabigatran (Pradaxa) are well tolerated, with the most common adverse effects
being diarrhea, dizziness, and peripheral edema. As with
Other direct thrombin inhibitors include argatroban, all anticoagulants, abnormal bleeding is a potentially seri-
bivalirudin, and desirudin. Lepirudin (Refludan) was ous adverse effect.
withdrawn from the market in 2012.
The Factor Xa inhibitors contain a black box warning
Argatroban (Acova, Novastan): Approved in 2000, arg- that epidermal or spinal hematomas may occur in anticoag-
atroban is a synthetic thrombin inhibitor that is given by ulated patients receiving neuroaxial anesthesia or spinal
the IV route for prophylaxis of thrombosis in patients puncture. The black box warning also cautions against pre-
with HIT and to treat or prevent thrombotic events asso- mature discontinuation of anticoagulants because this places
ciated with PCI. Unlike dabigatran, which is excreted by the patient at risk for adverse events. Apixaban is pregnancy
the kidneys, argatroban is metabolized and eliminated category B. Rivaroxaban and edoxaban are category C.
by the liver and therefore may be used in patients with
CKD. Caution must be observed, however, when admin- Antiplatelet Drugs
istering the drug to patients with hepatic impairment.
Allergic reactions occur in up to 10% of patients receiv- 38.7 Antiplatelet drugs provide anticoagulation
ing argatroban. Bleeding is the most serious adverse by reducing the aggregation properties of
effect and the drug should not be administered to platelets.
patients with active bleeding. This drug is pregnancy
category C. Antiplatelet drugs modify coagulation primarily by inter-
fering with platelet aggregation. Unlike the anticoagulants,
Bivalirudin (Angiomax): Approved in 2000, bivalirudin which are used primarily to prevent thrombosis in veins,
is a direct thrombin inhibitor that is available only by the the primary indications for antiplatelet drugs are to pre-
IV route. Bivalirudin is given concurrently with aspirin to vent clot formation in arteries. The antiplatelet medica-
reduce the incidence of thromboembolic events associated tions are listed in Table 38.5.
with HIT and to provide anticoagulation in patients
undergoing PCI. Back pain is a common adverse effect of Because platelets are a central component of blood
the drug, occurring in about 40% of patients. Nausea, hemostasis, reducing the number of platelets or their func-
vomiting, hypotension, and headache also occur in a sig- tion can profoundly increase bleeding time. Three groups
nificant number of patients. Bleeding is the most serious of drugs are classified as antiplatelet drugs:
adverse effect and the drug should not be administered to
patients with active bleeding. Bivalirudin is as effective as • Aspirin
heparin and produces a lower incidence of serious bleed- • Adenosine diphosphate (ADP) receptor blockers
ing, although it is very expensive. This drug is pregnancy • Glycoprotein IIb/IIIa receptor blockers.
category B.
Aspirin deserves special mention as an antiplatelet
Desirudin (Iprivask): Made through recombinant DNA drug. Because it is available OTC, patients may not con-
technology, desirudin is nearly identical to hirudin and is sider aspirin a potent medication; however, its anticoag-
the only direct thrombin inhibitor administered by the ulant activity is well documented. Aspirin acts by
subcutaneous route. It acts by the same mechanism and binding irreversibly to the enzyme cyclooxygenase
has the same adverse effects and contraindications as (COX) in platelets. This binding inhibits the formation of
bivalirudin. The drug was approved in 2003 for DVT pro- thromboxane A2, a powerful inducer of platelet aggrega-
phylaxis in patients undergoing hip replacement surgery. tion. The anticoagulant effect of a single dose of aspirin
Off-label uses include prevention of thromboembolic may persist for as long as 1 week. Concurrent use of
events in patients with unstable angina and those under- aspirin with other coagulation modifiers should be
going PCI. Allergic reactions, including anaphylaxis, are avoided, unless medically approved. Nursing responsi-
rare. Bleeding is the most serious adverse effect and the bilities and a prototype feature for aspirin are given in
drug should not be administered to patients with active Chapter 41.
bleeding. This drug is pregnancy category C.
38.8 The adenosine diphosphate receptor
Factor Xa inhibitors: Factor Xa inhibitors include betrixa- blockers are antiplatelet drugs prescribed for the
ban (Bevyxxa), rivaroxaban (Xarelto), apixaban (Eliquis), prevention and treatment of arterial thrombosis.
and edoxaban (Savaysa). The four differ somewhat in their
pharmacokinetics, but have similar actions and adverse Although platelets are simply fragments of cells that have
no nucleus, they contain many receptors on their plasma
Chapter 38 Pharmacotherapy of Coagulation Disorders 675
Table 38.5 Antiplatelet Drugs
Drug Route and Adult Dose (Maximum Dose Where Indicated) Adverse Effects
anagrelide (Agrylin) PO: 0.5 mg qid or 1 mg bid (max: 10 mg/day) Nausea, vomiting, diarrhea, abdominal pain,
aspirin (ASA, acetylsalicylic acid) PO: 80 mg daily to 650 mg bid dizziness, headache
dipyridamole (Persantine) PO: 75–100 mg qid as adjunct to warfarin therapy Increased bleeding, central nervous system
vorapaxar (Zontivity) PO: 2.08 mg/day (CNS) effects (dipyridamole), anaphylaxis
(aspirin), interstitial lung disease (anagrelide)
ADP Receptor Blockers PO: 75 mg/day (max: 300 mg/day for life-threatening cases)
clopidogrel (Plavix) PO: 60-mg loading dose followed by 10 mg/day Minor bleeding, dyspepsia, abdominal pain,
prasugrel (Effient) PO: 180-mg loading dose followed by 90 mg bid headache, rash, diarrhea
ticagrelor (Brilinta) Increased clotting time, GI bleeding, blood
dyscrasias, angina
Glycoprotein IIb/IIIa Receptor Antagonists
Dyspepsia, dizziness, pain at injection site,
abciximab (ReoPro) IV: 0.25 mg/kg initial bolus over 5 min, then 0.125 mcg/kg/min for hypotension, bradycardia, minor bleeding
12 h (max: 10 mcg/min) Major hemorrhage, thrombocytopenia
eptifibatide (Integrilin) IV: 180 mcg/kg initial bolus over 1–2 min, then 2 mcg/kg/min for Dyspepsia, nausea, vomiting, dizziness,
24–72 h (max: 180 mcg/kg bolus, 2 mcg/kg/min infusion) myalgia, headache
Tachycardia and palpitations (cilostazol), CNS
tirofiban (Aggrastat) IV: 0.4 mcg/kg/min for 30 min, then 0.1 mcg/kg/min for 12–24 h effects (pentoxifylline), heart failure, MI
Drugs for Intermittent Claudication
cilostazol (Pletal) PO: 100 mg bid
pentoxifylline (Trental) PO: 400 mg tid (max: 1200 mg/day)
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
membranes and their functions are complex. Chemicals require special medical or nursing interventions, such as
such as epinephrine, thromboxane A2, thrombin, sero- suturing or applying a sandbag to a venipuncture site that
tonin, and fibrinogen can bind to these receptors and mod- does not stop bleeding.
ify coagulation through their interaction with the platelets.
PROTOTYPE DRUG Clopidogrel (Plavix)
Following vessel injury, platelets become “sticky,”
bind to exposed collagen, and release substances that Classification Therapeutic: Antiplatelet drug
recruit additional platelets to the site. One of these chemi- Pharmacologic: ADP receptor blocker
cals is ADP, whose function is to promote platelet aggrega-
tion. The ADP receptor blockers comprise a small group of Therapeutic Effects and Uses: Approved in 1997,
drugs that irreversibly alter the plasma membrane of plate- clopidogrel is used for the prophylaxis of arterial throm-
lets. For the remainder of their lifespan, the affected plate- boembolism to reduce the risk of stroke, MI, and death in
lets are unable to recognize the chemical signals required patients with acute coronary syndrome. For patients with
for them to aggregate. ST-elevation MI, this drug has been shown to reduce the
risk of death, reinfarction, or stroke. Clopidogrel has simi-
Ticagrelor (Brilinta), clopidogrel (Plavix), and prasug- lar anticoagulant activity to aspirin but is more expensive.
rel (Effient) are ADP receptor blockers given PO to prevent
thrombi formation in patients who have experienced a Clopidogrel is given PO and has the advantage of
recent thromboembolic event such as stroke or MI. The once-daily dosing. Inhibition of platelet function may per-
newer drugs in this class, ticagrelor and prasugrel, act more sist for 7 to 10 days after the drug is discontinued. When
rapidly than clopidogrel and achieve a more consistent and possible, clopidogrel should be discontinued at least 5 days
effective antithrombotic effect. Adverse effects among the prior to surgery to avoid excessive bleeding.
three drugs are similar.
Mechanism of Action: Clopidogrel inhibits ADP
Drugs affecting platelet aggregation increase the risk receptors on platelets and prolongs bleeding time by
of bleeding should the patient sustain trauma or undergo irreversibly inhibiting platelet aggregation. Clopidogrel
dental or surgical procedures. These drugs are sometimes itself has little activity; however, it is changed to a highly
given concurrently with anticoagulants, which can further active metabolite in the liver through extensive first-pass
increase bleeding risk. Prolonged direct pressure over metabolism.
injection or venipuncture sites may be required to control
bleeding. Bleeding lasting more than 10 minutes may
676 Unit 5 Pharmacology of the Cardiovascular System
CONNECTIONS: Complementary and Alternative Therapies
Garlic
Description: Evidence:
Garlic (Allium sativum) is a perennial plant in the onion family that Garlic is one of the best-studied herbs. Like most other herbal
can be grown and cultivated worldwide. products, garlic likely has some health benefits, but controlled,
scientific studies are lacking and the results are mixed. One of
History and Claims: the more rigorous studies, a meta-analysis of 11 randomized
controlled trials, found that on the whole, taking garlic daily
Garlic has been used for centuries by most cultures as a flavor- reduced blood pressure and decreases the aggregation or
ing and as a medicine. Historical uses have included curing deaf- “stickiness” of platelets, thus producing an anticoagulant effect
ness and earaches, and treating leprosy and scurvy. Modern (Ried, Frank, Stocks, Fakler, & Sullivan, 2008). Subsequent
claims have focused on cardiovascular uses: treatment of high research has found associations between garlic consumption
blood lipid levels, atherosclerosis, and HTN. Other modern and a reduced incidence of cancer, but that correlation has not
claims are that garlic reduces blood glucose levels and has anti- been proven in controlled studies (National Center for Comple-
bacterial and antineoplastic activity. mentary and Integrative Health, 2016; University of Maryland
Medical Center, 2015).
Standardization:
Garlic is safe for consumption in small and moderate
Substances called alliaceous oils have been isolated from garlic amounts. Patients taking anticoagulant medications should limit
and shown to have pharmacologic activity. Dosage forms include their intake of garlic to avoid bleeding complications. Patients
eating prepared garlic oil or the fresh bulbs (cloves) from the with diabetes should monitor their blood glucose levels closely if
plant. In tablet or capsule form, doses range from 1 to 4 g/day. taking high doses of garlic.
Extracts may be standardized by percent allicin.
Pharmacokinetics: be used with caution in patients at high risk for bleeding,
including those with peptic ulcer disease. Severe hepatic
Route(s) PO disease may impair the ability of the liver to convert the
drug to its active metabolite. The drug should be discon-
Absorption Rapidly absorbed tinued at least 5 days prior to elective surgery
Distribution Unknown; unknown if it crosses Drug Interactions: Use with anticoagulants, other
antiplatelet drugs, thrombolytics, or NSAIDs, includ-
the placenta or is secreted in ing aspirin, will increase the risk of bleeding. Drugs that
inhibit hepatic metabolic enzymes—such as the azole
breast milk; 94–98% bound to antifungals, protease inhibitors, erythromycin, verapamil,
or zafirlukast—may diminish the antiplatelet actions of
plasma protein clopidogrel. Drugs that increase hepatic metabolic enzyme
activity, such as barbiturates, rifampin, or carbamazepine,
Primary metabolism Hepatic; metabolized to active may increase the anticoagulant activity of clopidogrel.
Herbal/Food: Herbal supplements that affect coagulation
metabolite such as feverfew, green tea, ginkgo, fish oil, ginger, or gar-
lic may increase the risk of bleeding.
Primary excretion Renal 50%; feces 50%
Treatment of Overdose: There is no specific therapy
Onset of action 1–2 h for clopidogrel overdose. Platelet transfusions may be ben-
eficial in preventing hemorrhage.
Duration of action 5 days
Pregnancy: Category B.
Adverse Effects: Clopidogrel has approximately
the same tolerability as aspirin and adverse effects are Nursing Responsibilities: Key nursing implica-
rarely severe enough to cause discontinuation of therapy. tions for patients receiving clopidogrel are included in
Although excessive bleeding is a potential adverse effect, the Nursing Practice Application for Patients Receiv-
it occurs in only about 1% of patients. Older adults are ing Pharmacotherapy with Anticoagulants. Although
more susceptible to bleeding during therapy and should nursing responsibilities are similar to those for the anti-
be carefully monitored. The incidence of GI bleeding is less coagulant drugs, bleeding risk is lessened with the anti-
than that of aspirin. Common adverse effects are flulike platelet drugs.
syndrome, headache, diarrhea, dizziness, bruising, upper
respiratory tract infection, and rash or pruritus. Black Box
Warning: Because the effectiveness of clopidogrel is depen-
dent on its metabolic activation by CYP450 enzymes, poor
metabolizers will exhibit less therapeutic effect and more
adverse cardiovascular events.
Contraindications/Precautions: Clopidogrel is con-
traindicated in patients with active bleeding and should
Chapter 38 Pharmacotherapy of Coagulation Disorders 677
Drugs Similar to Clopidogrel (Plavix) contraindicated in patients with a history of intracranial
hemorrhage or pathologic bleeding, and that it should be
Other antiplatelet drugs include anagrelide, dipyridamole, discontinued at least 5 days prior to surgery. The black
prasugrel, ticagrelor, and vorapaxar. Aspirin also provides box warning also states that maintenance doses of aspi-
anticoagulation by this mechanism and is discussed in Sec- rin should not exceed 100 mg/day because aspirin
tion 38.7. The first ADP receptor blocker approved, ticlopi- decreases the effectiveness of ticagrelor. This drug is
dine (Ticlid), is no longer available in the United States. pregnancy category C.
Anagrelide (Agrylin): Approved in 1977, anagrelide is an Vorapaxar (Zontivity): In 2014 the FDA approved vora-
antiplatelet medication used for a very specific indication: paxar, a new type of antiplatelet drug, to reduce the risk
to control elevated platelet counts in patients with myelo- for blood clots in patients with a history of MI or other
proliferative neoplasms. Elevated platelet levels in patients thromboembolic disorders. Given PO, it is the first drug to
with these disorders can increase the risk of thrombosis. cause anticoagulation by blocking the protease-activated
Unlike other antiplatelet drugs that reduce platelet aggre- receptor (PAR-1) on platelets. Like other anticoagulants, its
gation, anagrelide reduces the production of platelets. Use primary adverse effect is increased bleeding risk. Vora-
with other antiplatelet drugs such as aspirin increases the paxar carries a black box warning that it should not be
risk of bleeding. This drug is pregnancy category C. administered to patients with a history of stroke, transient
ischemic attack, or intracranial hemorrhage. This drug is
Dipyridamole (Persantine): Approved in 1961, the only pregnancy category B.
approved use of dipyridamole is in combination with
warfarin for postoperative prophylaxis of thromboembo- 38.9 The glycoprotein IIb/IIIa receptor
lism in patients following cardiac valve replacement. By inhibitors are effective antiplatelet drugs
itself, dipyridamole provides little antithrombotic protec- for preventing coagulation.
tion, but it may be combined with aspirin or warfarin to
produce an anticoagulant effect. Dipyridamole acts by a Glycoprotein IIb/IIIa is a receptor found on the surface of
different mechanism than clopidogrel. Rather than block- platelets. The receptor contains two distinct protein chains,
ing ADP receptors, dipyridamole elevates levels of cyclic designated IIb and IIIa. Platelets contain a huge number of
AMP (cAMP), which is a potent inhibitor of platelet glycoprotein IIb/IIIa receptors: approximately 50,000 to
aggregation. Dizziness, abdominal pain, and headache 80,000 per cell. These receptors serve as docking stations,
are the most common adverse effects. This drug is preg- waiting for signals from chemical messengers that indicate
nancy category B. injury may have occurred.
Prasugrel (Effient): Prasugrel is an ADP receptor blocker Substances that normally bind to and activate glyco-
that was approved in 2009 to reduce the risk for throm- protein IIb/IIIa receptors include thrombin, von Wille-
botic events in patients with acute coronary syndrome brand’s factor (vWF), ADP, and thromboxane A2. Following
who undergo PCI. Prasugrel is a prodrug that is rapidly activation of the surface glycoprotein, the platelets change
metabolized to its active form as it crosses the intestinal shape, bind fibrinogen, and become sticky. Essentially, the
mucosa. Antiplatelet effects begin to occur within 30 min- platelets develop an enhanced ability to bind to each other,
utes. Compared to clopidogrel, prasugrel is associated to fibrinogen, and to the exposed collagen of damaged ves-
with a reduced risk of adverse cardiovascular events, such sels. This process is illustrated in Figure 38.2.
as stroke and MI, and it is less prone to interact with other
medications. Prasugrel carries a black box warning that it Inhibition of the glycoprotein IIb/IIIa receptor pre-
can cause serious and life-threatening bleeding. It should vents platelet activation and thrombus formation in
not be used in patients with active bleeding or a history of patients with a recent MI, stroke, and PCI, with or without
transient ischemic attack or stroke. Prasugrel should be stent placement. Although these medications are effective
discontinued at least 7 days prior to expected surgery. This antiplatelet drugs, they are very expensive. Another major
drug is pregnancy category B. disadvantage is that they are given only by the IV route. PO
forms of these drugs recently entered clinical trials but
Ticagrelor (Brilinta): Approved in 2011, ticagrelor is a proved less effective than aspirin in reducing thromboem-
newer coagulation modifier indicated to reduce the risk bolic events.
of thromboembolic events in patients with acute coro-
nary syndrome. In patients with PCI, the drug reduces PROTOTYPE DRUG Abciximab (ReoPro)
the risk of stent thrombosis. Like clopidogrel and prasu-
grel, ticagrelor acts by blocking the ADP receptor on Classification Therapeutic: Antiplatelet drug
platelets. The most frequent adverse effects are dyspnea Pharmacologic: Glycoprotein IIb/IIIa
and bleeding. Ticagrelor carries a black box warning that
the drug can cause serious or fatal bleeding, that it is inhibitor
678 Unit 5 Pharmacology of the Cardiovascular System
Binding Glycoprotein
of platelet IIb/IIIa receptor
activators
Binding of
Thrombin glycoprotein IIb/IIIa
inhibitors
Fibrinogen
No platelet
Thromboxane ADP aggregation
Platelet
aggregation
Figure 38.2 Glycoprotein IIb/IIIa receptor activation of platelet function.
Therapeutic Effects and Uses: Abciximab was the Primary metabolism Rapidly destroyed by proteases
first glycoprotein IIb/IIIa inhibitor approved by the FDA in plasma
in 1994. It is of value in decreasing the incidence of throm- Primary excretion Unknown
boembolic events in patients with acute coronary syn- Onset of action 10 min
drome, and in conjunction with PCI, both before and after Duration of action 72 h; half-life: 10–30 min
the procedure. Abciximab is only available by IV bolus
injection and infusion. It is often given concurrently with Adverse Effects: The most common adverse effect
aspirin, clopidogrel, or heparin to achieve optimal thera- of abciximab is abnormal bleeding, which may occur in
peutic results. any body system. Major bleeding occurs in about 10% of
patients, with the most common bleeding occurring at
Glycoprotein IIb/IIIa receptor inhibitors act very rap- the arterial access site. Hypotension may occur secondary
idly: Platelet function is reduced by as much as 90% in just to loss of blood. Thrombocytopenia occurs in more than
2 hours. Effects may persist for more than 10 days follow- 5% of the patients; thus, blood counts must be periodi-
ing discontinuation of the drug. cally monitored during therapy. Anaphylaxis is rare. Back
pain and chest pain occur in 11% to 18% of patients tak-
Mechanism of Action: Abciximab is an antibody ing the drug.
fragment that binds to glycoprotein IIb/IIIa receptors on
platelets, thus preventing fibrinogen, vWF, and other pro- Contraindications/Precautions: Abciximab is con-
coagulants from activating platelets. traindicated in patients with active bleeding, recent trauma
or surgery, or serious bleeding disorders, or in patients who
Pharmacokinetics: have conditions that place them at high risk for bleeding.
Patients with thrombocytopenia (less than 100,000 cells/mL)
Route(s) IV should not receive this drug. Patients who have received
previous abciximab therapy have a higher risk of anaphy-
Absorption NA laxis and thrombocytopenia upon reexposure to the drug.
Distribution Mostly bound to platelets,
with very little circulating free;
unknown if the drug crosses the
placenta or is secreted in breast Drug Interactions: Concurrent administration of abcix-
imab with heparin, other anticoagulants, or thrombolytics
milk
Chapter 38 Pharmacotherapy of Coagulation Disorders 679
increases the risk of bleeding. Abciximab is contraindicated drug; thus, caution should be used in patients with CKD.
when IV dextran has been used before or during PCI Tirofiban is contraindicated in patients with platelet counts
because bleeding risk is increased. Oral anticoagulants less than 100,000/mm3. Bleeding secondary to the drug’s
should be discontinued at least 7 days prior to abciximab antiplatelet effect is the most common adverse effect. This
use, unless the PT is less than 1.2 times control. Herbal/ drug is pregnancy category B.
Food: Herbal supplements, such as white willow, that con-
tain salicylates may create an additive effect with antiplate- Drugs for Intermittent
let drugs. Ginkgo and feverfew should also be avoided. Claudication
Pregnancy: Category C. 38.10 Coagulation modifiers can be used to treat
symptoms of intermittent claudication.
Treatment of Overdose: There is no specific therapy
for abciximab overdose. Platelet transfusions may be ben- Intermittent claudication (IC) is pain or cramping in the
eficial in preventing hemorrhage. lower legs that worsens with walking or exercise. IC is the
primary symptom of peripheral vascular disease (PVD), in
Nursing Responsibilities: Key nursing implica- which progressive atherosclerosis of vessels causes a lack
tions for patients receiving abciximab are included in of oxygen to major muscles of the leg. Factors that cause
the Nursing Practice Application for Patients Receiving angina pectoris are those that also worsen PVD: diabetes,
Pharmacotherapy with Anticoagulants. Although nurs- smoking, and HTN. Exercise, smoking cessation, reduction
ing responsibilities are similar to those for the anticoagu- of blood pressure, and blood glucose management are
lant drugs, bleeding risk is lessened with the antiplatelet important nonpharmacologic therapies for IC. Medica-
medications. tions are used to reduce symptoms and increase pain-free
walking time, although none are able to reverse the under-
Drugs Similar to Abciximab (ReoPro) lying cause of PVD.
The two other glycoprotein IIb/IIIa inhibitors are eptifiba- Pentoxifylline (Trental) and cilostazol (Pletal) are
tide and tirofiban. specifically approved for IC, although statins, aspirin,
and clopidogrel may also be used in managing the condi-
Eptifibatide (Integrilin): Approved in 1998, eptifibatide tion. Pentoxifylline is a unique drug with anticoagulation
is a synthetic drug administered by the IV route that is properties that acts on red blood cells to reduce their vis-
highly specific to binding the glycoprotein IIa/IIIb recep- cosity and increase their flexibility, allowing them to
tor. Unlike abciximab, the binding of eptifibatide is rap- enter vessels that are partially occluded and prevent
idly reversible and a large amount of unbound drug may thrombi formation. It also inhibits platelet aggregation. It
circulate in the plasma. In overdose situations, platelet is given PO to increase the microcirculation in patients
infusions may be of little benefit because the unbound with IC. Two to three months of therapy with pentoxifyl-
drug will quickly occupy glycoprotein IIb/IIIa receptors line may be necessary before improvement in IC symp-
on the new platelets to prevent their activation by proco- toms is noted.
agulants. The drug is indicated for the prevention of
thromboembolic events in patients with acute coronary Cilostazol is indicated to improve walking distance
syndrome and those undergoing PCI. Aspirin or heparin before the onset of IC pain. Given PO, the drug has anti-
is usually administered concurrently with eptifibatide. platelet and antithrombotic activity. Cilostazol should be
Should platelet count decrease to less than 100,000/mm3, used with care in patients with cardiac disease because it
the aspirin or heparin is discontinued. The kidneys pri- may cause palpitations and tachycardia.
marily excrete the drug; thus, caution should be used in
patients with CKD. Bleeding at the arterial access site is 38.11 Fibrinolysis is a process that removes
the most common adverse effect. This drug is pregnancy thrombi.
category B.
The goal of hemostasis has been achieved once a blood clot
Tirofiban (Aggrastat): Like eptifibatide, tirofiban is an IV is formed and the body is protected from excessive hemor-
synthetic drug highly selective for binding the glycopro- rhage. The process of hemostasis, however, is a positive
tein IIb/IIIa receptor in a rapid, reversible manner. The feedback mechanism in which small amounts of clotting
drug is indicated for the prevention of thromboembolic lead to additional clotting. Without an effective means of
events in patients with acute coronary syndrome and those controlling the process, clotting would spread far beyond
undergoing PCI. Aspirin or heparin is usually adminis- the zone of injury and, indeed, occur throughout the vas-
tered concurrently. Its duration of action (4–8 hours) is lon- cular system until existing clotting factors were used up.
ger than that of eptifibatide but still considerably less than Furthermore, fibrin clots can prevent blood flow to the
abciximab’s duration. The kidneys primarily excrete the
680 Unit 5 Pharmacology of the Cardiovascular System prothrombin, and clotting Factors V and
XII are also inactivated by plasmin. The
(a) body normally regulates fibrinolysis
Plasminogen such that unwanted fibrin clots are
activators removed, while fibrin present in wounds
is left to maintain hemostasis. The steps
of fibrinolysis are shown in Figure 38.3.
Clot in vessel containing ThrombolyticsPlasminogen converted to
inactive plasminogen
plasmin, which digests the clot
38.12 Thrombolytics are used
to dissolve existing intravascular
(b) Enhanced by clots in patients with myocardial
thrombolytics
• Alteplase infarction and stroke.
Plasminogen Plasmin It is often mistakenly believed that the
Inhibited by purpose of anticoagulants such as heparin
hemostatics or warfarin is to digest clots. This is not
• Aminocaproic the case. A totally different type of drug is
acid needed for this goal. The thrombolytics,
listed in Table 38.6, are administered very
Figure 38.3 Steps in fibrinolysis: (a) Clot dissolves when plasminogen is converted differently from the anticoagulants and
to plasmin. (b) Thrombolytics enhance fibrinolysis; hemostatics inhibit fibrinolysis.
antiplatelet drugs, and they produce their
surrounding area. Circulation must eventually be restored effects by different mechanisms. Thrombolytics are pre-
so that the tissue can resume normal activities. scribed for disorders in which an intravascular clot has
Fibrinolysis is the physiologic process that limits clot already formed, such as acute MI, pulmonary embolism,
formation and removes existing clots. During the time a acute ischemic stroke, and DVT.
fibrin clot is forming, the surrounding damaged tissue Thrombolytics promote fibrinolysis by converting
secretes anticoagulant chemicals that limit the spread of the plasminogen to plasmin. The enzyme plasmin then digests
clot to the area of injury. Removal of the clot begins about fibrin, breaking it into small soluble fragments. In essence,
24 to 48 hours following clot formation and continues until the thrombolytics simply accelerate the normal process of
it is dissolved. clot removal in the body. The thrombolytics are also called
Like hemostasis, fibrinolysis involves several cas- fibrinolytics, owing to their destructive effects on fibrin.
cading steps. The process is initiated by plasminogen The therapeutic outcomes of thrombolytic therapy are
activators. The two best studied plasminogen activators strongly dependent on the time frame in which they are
are tissue-plasminogen activator (tPA), which is secreted administered. They are considerably more effective when
by the endothelium of blood vessels, and urokinase- given as soon as possible after the clot has formed—
plasminogen activator (uPA), secreted by the kidney. preferably within 4 hours. The mechanism of action of the
The function of tPA and uPA is to convert the inactive thrombolytics is shown in a Pharmacotherapy Illustrated
protein plasminogen, which is present in the fibrin clot, feature in Chapter 35.
to its active form called plasmin. Plasmin is an enzyme Thrombolytics are nonspecific and have a very narrow
that attacks the fibrin strands, breaking them into small margin of safety between dissolving “normal” and “abnor-
fragments that are soluble and no longer able to hold the mal” clots. Vital signs must be monitored continuously and
clot together. The procoagulation factors fibrinogen, any signs of bleeding may call for discontinuation of
Table 38.6 Thrombolytics
Drug Route and Adult Dose (Maximum Dose Where Indicated) Adverse Effects
alteplase (Activase) IV: Begin with 60 mg and then infuse 20 mg/h over next 2 h Superficial bleeding at injection sites, allergic
reactions
reteplase (Retavase) IV: 10 units over 2 min; repeat dose in 30 min
Serious internal bleeding, intracranial
streptokinase (Streptase) IV: 250,000–1.5 million units over 60 min hemorrhage, HTN
tenecteplase (TNKase) IV: 30–50 mg infused over 5 sec
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
Chapter 38 Pharmacotherapy of Coagulation Disorders 681
therapy. Patients with recent trauma, active bleeding, or dissolves fibrin clots. Alteplase is more fibrin specific than
surgery may have “fresh” clots that could be disrupted by streptokinase but less so than some of the other thrombo-
the action of these drugs. Thus, they may not be candidates lytics. The drug also degrades the procoagulant Factors V
for thrombolytic therapy due to the risk of bleeding. and VIII and lowers the circulating amounts of fibrinogen
and plasminogen.
The use of thrombolytics in older patients is controver-
sial. Research has shown that thrombolytic therapy in Pharmacokinetics:
patients older than age 75 does not decrease mortality from
the MI or stroke the patient has experienced. The risks of Route(s) IV
serious bleeding following drug administration may out-
weigh the therapeutic benefits. Patients older than age 75 Absorption NA
must be carefully screened for contraindicated conditions,
such as uncontrolled HTN, recent ischemic stroke, or cur- Distribution Unknown; unknown if the drug
rent use of anticoagulants.
crosses the placenta or is secreted
Because these medications are rapidly destroyed in the
bloodstream, discontinuing the infusion quickly termi- in breast milk
nates their thrombolytic activity. After the clot is success-
fully dissolved with the thrombolytic, anticoagulant Primary metabolism Hepatic
therapy is initiated to prevent the reformation of clots.
Since the discovery of streptokinase, the first drug in this Primary excretion Renal
class, there have been several subsequent generations of
thrombolytics. The newer drugs such as tenecteplase Onset of action Immediate
(TNKase) are more fibrin specific and are reported to have
fewer adverse effects than streptokinase. Duration of action 3 h; half-life: less than 10 min
The FDA recommends that TNK and tPA not be Adverse Effects: The most common adverse effect
used as abbreviations for thrombolytics because this has of alteplase is bleeding, which may occur superficially at
led to numerous medication errors. Instead, the full catheter access or needle puncture sites, or internally. Signs
generic or trade name should be used on all prescriptions of bleeding such as spontaneous ecchymoses, hematomas,
(FDA, 2015). or epistaxis should be reported to the healthcare provider
immediately. Fibrinolysis of clots in the coronary arteries
PROTOTYPE DRUG Alteplase (Activase) may cause transient dysrhythmias. Angioedema and intra-
cranial bleeding are rare, though serious, adverse effects.
Classification Therapeutic: None
Pharmacologic: Thrombolytic, Contraindications/Precautions: History of stroke
within the past 3 months, recent trauma or surgery,
fibrinolytic active bleeding, severe uncontrolled HTN, intracranial
neoplasm, and arteriovenous malformation are contrain-
Therapeutic Effects and Uses: Produced through dications to the use of alteplase. Whenever possible, par-
recombinant DNA technology, alteplase is identical to enteral injections of other drugs should be avoided during
human tPA. Approved in 1987, alteplase is a preferred alteplase therapy to avoid an increased risk of bleeding at
drug for the treatment of thrombotic stroke, acute MI, and the injection site. Alteplase should not be administered if
acute massive pulmonary embolism. Activase (Cathflo the patient is on warfarin and INR is greater than 1.7 or
Activase) is approved to restore function to central venous PT is greater than 15 seconds.
access devices. Although not routinely indicated for treat-
ing venous clots, the drug may be used in cases where a Drug Interactions: Concurrent use with anticoagu-
limb is at risk of gangrene and possible amputation due to lants, antiplatelet drugs, or NSAIDs, including aspirin,
vessel occlusion. Like other drugs in this class, it is admin- will increase the risk of bleeding. Intravenous nitroglycerin
istered by the IV route. enhances the hepatic degradation of alteplase, reducing
its ability to dissolve clots. Herbal/Food: Use with sup-
To achieve maximum effect, alteplase therapy should plements that affect coagulation such as feverfew, green
begin within 6 hours of onset of MI symptoms and tea, ginkgo, fish oil, ginger, or garlic should be avoided,
within 3 hours of thrombotic stroke. Therapy should be because they may increase the risk of bleeding.
initiated only after intracranial hemorrhage has been
ruled out. Alteplase elicits fewer allergic reactions than Pregnancy: Category C.
streptokinase.
Treatment of Overdose: There is no specific treat-
Mechanism of Action: The primary action of ment for overdose. Excessive bleeding may require the
alteplase is to convert plasminogen to plasmin, which then administration of blood, blood products, or hemostatics.
Nursing Responsibilities: Key nursing implications
for patients receiving alteplase are included in the Nursing
Practice Application for Patients Receiving Pharmacother-
apy with Thrombolytics.
682 Unit 5 Pharmacology of the Cardiovascular System
Drugs Similar to Alteplase (Activase) Although it is much less expensive than other
thrombolytics, streptokinase is considered a second-line
Other thrombolytics include reteplase, streptokinase, and drug because it is less effective at opening arteries.
tenecteplase. Allergic reactions such as urticaria, flushing, and head-
ache occur in 1% to 4% of patients, although anaphy-
Reteplase (Retavase): Approved in 1996, reteplase is used laxis is rare. The body develops antistreptokinase
to treat acute MI with ST elevation due to coronary artery antibodies, which can cause resistance to the effects of
thrombosis and also acute peripheral arterial thromboem- the drug. Streptokinase shares the same contraindica-
bolism. The drug is a modified form of human tPA pro- tions and adverse effects with the other thrombolytics.
duced through recombinant DNA technology. Reteplase The most common adverse effect is abnormal bleeding.
has the same adverse effects and contraindications as Fever occurs in many patients and is managed by
alteplase. It has a more rapid onset of action than alteplase, administering acetaminophen. This drug is pregnancy
perhaps because reteplase is better able to reach the inside category C.
of clots. Like alteplase, it is selective for lysing fibrin and
the most serious adverse effect is bleeding. This drug is Tenecteplase (TNKase): Approved in 2000 for the treat-
pregnancy category C. ment of acute MI with ST elevation with coronary artery
thrombosis, tenecteplase is a modified form of human
Streptokinase (Streptase): Streptokinase, the first tPA. The drug has similar indications, contraindica-
approved thrombolytic, is indicated for the treatment of tions, and adverse effects to alteplase but has greater
acute MI with ST elevation due to coronary artery throm- fibrin specificity and a longer half-life. This may be
bosis, acute pulmonary embolism, DVT, or arterial throm- responsible for a slightly lower incidence of noncere-
boembolism. Streptokinase is obtained from beta-hemolytic bral bleeding with tenecteplase. Another advantage is
streptococci and is less fibrin specific than the other drugs that it can be administered using a single, 5-second
in this class; the drug also breaks down fibrinogen and bolus injection. Allergic reactions are rare. This drug is
other clotting factors. The drug may be administered by IV pregnancy category C.
infusion into the general circulation or introduced via
catheter directly at a site of occlusion.
CONNECTIONS: NURSING PRACTICE APPLICATION
Patients Receiving Pharmacotherapy with Thrombolytics
Assessment
Baseline assessment prior to administration:
• Obtain a complete health history: cardiovascular, peripheral vascular disease, respiratory, neurologic (including recent head injury), recent surgeries or
injuries, hepatic disease, CKD, diabetes, peptic ulcer disease, recent childbirth (within 10 days), or the possibility of pregnancy. Obtain a drug history
including allergies, current prescription and OTC drugs, herbal preparations, and alcohol use. Be alert to possible drug interactions.
• Obtain baseline weight, vital signs, ECG, and breath sounds. Assess presence, quality, location of angina, and for presence of dyspnea or chest pain.
Assess neurologic status.
• Evaluate laboratory findings (aPTT, PT/INR, bleeding time), CBC and platelets, renal and liver function studies, ABGs as appropriate, and lipid profiles.
Support the patient during other required tests (e.g., CT or MRI prior to thrombolytic therapy for stroke).
• Establish all monitoring equipment and necessary lines, or arrange for their insertion (e.g., ECG monitoring, IV, Foley catheter, arterial line).
• Assess the patient’s ability to receive and understand instructions. Include family and caregivers as needed.
Assessment throughout administration:
• Continue frequent assessments for therapeutic effects (e.g., angina has diminished significantly or is eliminated, ECG findings within normal limits,
respiratory effort and ABGs significantly improved).
• Continue frequent monitoring of appropriate laboratory values (e.g., Hgb, Hct, platelets, RBC, urinalysis, ABGs).
• Monitor vital signs and ECG every 15 min during the first hour of infusion, and then every 30 min during the remainder of the infusion. Continue to
monitor vital signs every 30 min to 1 h for the first 8 h following the infusion.
• Assess for adverse effects: bleeding at IV sites, wounds, excessive ecchymosis, petechiae, hematuria, black or tarry stools, rectal bleeding, coffee-
ground emesis, epistaxis, bleeding from gums, hemoptysis, dysrhythmias, and signs of occult bleeding: pallor, dizziness, hypotension, tachycardia,
abdominal pain, areas of abdominal wall swelling or firmness, lumbar pain, or decreased LOC.
• Monitor neurologic status frequently, especially if thrombolytics are used for stroke.
Implementation
Interventions and (Rationales) Patient-Centered Care
Ensuring therapeutic effects: • Teach the patient, family, or caregiver about all procedures and their
• Continue frequent assessments as above for therapeutic effects, e.g., necessity prior to beginning thrombolytic therapy.
previous angina has diminished significantly or is eliminated and ECG • To allay anxiety, teach the patient, family, or caregiver the rationale for
findings show decrease in ischemia. (Thrombolytics rapidly dissolve all equipment used.
existing clots to allow reperfusion of the affected area.)
Chapter 38 Pharmacotherapy of Coagulation Disorders 683
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
• Post-therapy, encourage appropriate lifestyle changes: lowered fat • Encourage the patient to adopt a healthy lifestyle of low-fat food
intake, increased exercise, limited alcohol and caffeine intake, and choices, increased exercise, decreased alcohol consumption, and
smoking cessation. Provide for dietitian consultation as needed. smoking cessation. Provide for appropriate consultation (e.g., dietitian)
(Smoking increases platelet aggregation and promotes the formation as needed.
of thrombi. Healthy lifestyle changes will support and minimize
the need for future drug therapy.)
Minimizing adverse effects: • Allay anxiety by reassuring the patient and explaining the rationale for
• Monitor frequently for signs and symptoms of excessive visible frequent monitoring. Provide adequate pain relief as appropriate.
bleeding: bleeding at IV sites, wounds, hematuria, rectal bleeding,
coffee-ground emesis, bleeding from gums, hemoptysis, bleeding at
previous recent incisional sites; and assess for occult bleeding: pal-
lor, hypotension, tachycardia, dizziness, sudden severe headache,
lumbar pain, and decreased LOC. (Bleeding is the most common
adverse effect of thrombolytic therapy. Frequent assessment for
both visible and occult bleeding is necessary to prevent extensive
hemorrhage and to start early corrective treatment as appropri-
ate. Bleeding risk is elevated up to 2–4 days post-treatment and
if the patient is maintained on anticoagulant or antiplatelet therapy
post-thrombolytics.)
• Monitor vital signs and ECG every 15 min during first hour of infusion, • To allay possible anxiety, teach the patient, family, or caregiver the
and then every 30 min during remainder of the infusion. Continue to rationale for all equipment used and the need for frequent monitoring.
monitor vital signs every 30 min to 1 h for the first 8 h following the
infusion. Report any dysrhythmias immediately. (Frequent monitoring • Teach the patient to report any palpitations, dyspnea, or angina
of vital signs assesses for adverse effects of the drug, including hypo- postinfusion.
tension and tachycardia associated with bleeding, and for dysrhyth-
mias. Dysrhythmias may occur postperfusion of the coronary arteries
or may be associated with adverse effects. Further treatment may be
necessary.)
• Maintain the patient on bed rest and with limited activity during the • Provide explanation and rationale that activity will be limited during the
infusion. (Limited physical activity and bed rest decrease the chance infusion and for up to 8 h post-treatment.
for bruising, injury, and bleeding.)
• Monitor neurologic status frequently, especially if thrombolytics are • To allay possible anxiety, teach the patient, family, or caregiver the
used for stroke. (A sudden change in neurologic status or sudden se- rationale for the frequent assessments and provide reassurance.
vere headache is a possible sign of an intracranial bleed with increased
intracranial pressure.) • Instruct the family to report immediately any change in the patient’s
mental status or LOC during the postinfusion period.
• Avoid invasive procedures during infusion and up to 8 h postinfusion • Teach the patient that after any required procedures, pressure will be
when possible. (Any puncture site or site of invasive procedure will maintained on the site for a prolonged period of time.
create an additional site for bleeding. Whenever an invasive procedure
must be used, e.g., ABGs, the site must be maintained under pressure
for 30 min or longer to prevent hemorrhage.)
• Continue to monitor laboratory work (Hgb, Hct, platelet counts, and • Provide explanation for the need for activity restriction and frequent
bleeding time) frequently post-treatment. Periodic CBC and ABGs monitoring during this time.
may also be monitored. Risk of bleeding remains high for 2–4 days
postinfusion.
Patient understanding of drug therapy: • The patient, family, or caregiver should have an understanding of the
• Use opportunities during administration of thrombolytic therapy to rationale behind thrombolytic therapy, equipment, and monitoring that
will be used, and the care required in the postinfusion period.
explain the rationale for drug therapy, desired therapeutic outcomes,
required monitoring for adverse effects, and precautions that will be • Allow family members time to discuss fears and concerns, and provide
taken during the infusion and during the immediate postinfusion time referral to support and ancillary providers as appropriate.
period. (Using time during nursing care helps to reassure the patient
and allay anxiety.)
• Provide support and reassurance to family and caregivers during the
time of treatment. (Thrombolytics are used to treat potentially life-
threatening conditions. Providing support, reassurance, and appropri-
ate referrals, e.g., pastoral care or social service support, assists family
members in a stressful situation.)
Patient self-administration of drug therapy: • Teach the patient, family, or caregiver in the proper self-administration
• Provide education during the postinfusion period about required medi- techniques of anticoagulants or antiplatelet drugs as appropriate.
cal care follow-up, postinfusion drug therapy (e.g., anticoagulants or
antiplatelet drugs), and lifestyle changes. (Using time during nursing
care helps to reinforce teaching and assess for any questions or con-
cerns the patient or family may have.)
684 Unit 5 Pharmacology of the Cardiovascular System
Hemostatics control bleeding. The combination of aminocaproic acid
with desmopressin (DDAVP) has been used to reduce
38.13 Hemostatics are used to promote the postoperative bleeding in patients undergoing cardiopul-
formation of clots. monary bypass.
The hemostatics, or antifibrinolytics, have an action oppo- During acute hemorrhage, aminocaproic acid can be
site to that of anticoagulants: to shorten bleeding time. given IV to reduce bleeding in 1 to 2 hours. It is also avail-
Although their mechanisms differ, all drugs in this class able in tablet form. The therapeutic serum level is 100 to
prevent fibrin from dissolving, thus enhancing the stability 400 mcg/mL.
of the clot and preventing excessive bleeding. The hemo-
statics, listed in Table 38.7, have very specific indications, Mechanism of Action: Aminocaproic acid occupies
and none are commonly prescribed. binding sites on plasminogen and plasmin. This effectively
prevents digestion of the fibrin clot by plasmin.
Aminocaproic acid (Amicar) and tranexamic acid (Cyk-
lokapron, Lysteda) are hemostatics that are administered IV. Pharmacokinetics:
Injection sites should be monitored frequently for thrombo-
phlebitis and extravasation. These drugs may affect muscles, Route(s) PO, IV
causing wasting and weakness. High doses can promote the
formation of abnormal clots. Chest pain and shortness of Absorption Rapidly absorbed from GI tract
breath may indicate pulmonary thrombus or embolus. Use
is contraindicated in patients with DIC or severe CKD. Distribution Widely distributed; unknown
PROTOTYPE DRUG Aminocaproic Acid (Amicar) if it crosses the placenta or is
Classification Therapeutic: Drug for shortening bleed- secreted in breast milk
ing time
Primary metabolism Unknown
Pharmacologic: Hemostatic,
antifibrinolytic Primary excretion Renal
Therapeutic Effects and Uses: Approved in 1982, Onset of action 1–2 h
aminocaproic acid is prescribed for conditions where
there is excessive hemorrhage due to clots being dis- Duration of action 3–4 h
solved rapidly or prematurely. Excessive fibrinolysis
is associated with conditions such as aplastic anemia, Adverse Effects: Aminocaproic acid is well tolerated
hepatic cirrhosis, postoperative cardiac surgery, and in and adverse effects are generally mild. By inhibiting fibri-
certain carcinomas. It is most commonly prescribed fol- nolysis, the incidence of thrombosis may increase. Myopa-
lowing surgery to reduce postoperative bleeding. Patients thy is an uncommon adverse effect that requires monitoring
with hemophilia A (see Section 38.14) may receive amino- because the drug may lead to rhabdomyolysis. Rapid IV
caproic acid immediately following dental procedures to administration may cause hypotension or bradycardia.
Contraindications/Precautions: Since aminoca-
proic acid tends to stabilize clots, it should be used cau-
tiously in patients with a recent history of thromboembolic
disease, including those with DIC. Aminocaproic acid is
contraindicated in patients with urinary tract bleeding
because the drug promotes the formation of clots in the
renal pelvis or ureters that may cause obstruction. Caution
Table 38.7 Hemostatics
Drug Route and Adult Dose Adverse Effects
aminocaproic acid (Amicar) (Maximum Dose Where Indicated) Allergic skin reactions, nausea, sinus and nasal symptoms,
headache
IV: 4–5 g for 1 h, then 1–1.25 g/h until bleeding is
controlled Anaphylaxis, thrombosis, bronchospasm, nephrotoxicity
Headache, dizziness, flushing, nosebleed, mild abdominal
desmopressin (DDAVP, Stimate) IV: 0.3 mcg/kg infused over 15–30 min pain
Intranasal: 300 mg (1 spray per nostril)
Hyponatremia, thrombosis
thrombin (Evithrom, Recothrom, Topical: Amount varies based on the size of the Incision-site complications, pruritus, nausea
Thrombinar) treated area
Antibody development, anaphylaxis, atrial fibrillation
tranexamic acid (Cyklokapron, PO: Two 650-mg tablets tid for a maximum of 5 days Headache, nasal and sinus symptoms, back and abdominal
Lysteda) IV: 10 mg/kg, tid or qid, for 2–8 days pain
Anaphylaxis, thromboembolic events
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
Chapter 38 Pharmacotherapy of Coagulation Disorders 685
must be used when administering the drug to patients Drugs Similar to Aminocaproic
with serious CKD because the drug may accumulate to
toxic serum levels. Acid (Amicar)
Drug Interactions: Aminocaproic acid antagonizes Other hemostatics include desmopressin, thrombin
the action of thrombolytic drugs. Hypercoagulation (recombinant), and tranexamic acid.
may occur with concurrent use of estrogens and oral
contraceptives. In individuals with hemophilia, concur- Desmopressin (DDAVP, Stimate): Approved in 1978,
rent administration of aminocaproic acid with Factor IX DDAVP differs from other hemostatics in being a hormone
increases the risk of thrombosis and acute MI. Herbal/ similar to vasopressin (antidiuretic hormone [ADH]), a
Food: Unknown. drug that promotes the renal conservation of water. As a
hemostatic, it is approved for the treatment of spontaneous
Pregnancy: Category C. bleeding, trauma-induced hemorrhage or bleeding pro-
phylaxis in patients with hemophilia A, or von Wille-
Treatment of Overdose: Overdose may lead to brand’s disease type 1 with Factor VIII activity. The drug
hypotension and renal failure. No treatment for overdose may be given parenterally in acute care scenarios, or by the
is known, although hemodialysis or peritoneal dialysis nasal route (Stimate) for prophylaxis. Because desmopres-
may be used to remove the drug. sin inhibits diuresis, caution must be used to prevent water
intoxication. Headache and facial flushing are common
Nursing Responsibilities: adverse effects of the intranasal formulation. Tolerance
rapidly develops to the actions of desmopressin, although
• Check IV site frequently for extravasation or thrombo- this is usually not a problem when the drug is used to treat
phlebitis and immediately change the site if this hemorrhage because only one to two doses are needed.
occurs. Desmopressin has uses beyond hemostasis that include
the control of excessive or nocturnal urination (enuresis)
• Monitor laboratory tests for creatine phosphokinase and polydipsia in patients with diabetes insipidus. This
(CPK) activity, and obtain urinalyses for early detec- drug is pregnancy category B.
tion of myopathy. Report fever, myalgia, reddish-
brown urine, or decrease in urine output to the Thrombin, topical (Evithrom, Recothrom, Thrombinar):
healthcare provider. Topical thrombin is applied with a spray or gelatin sponge
to areas that are oozing blood and for minor bleeding from
• Observe for signs of thrombophlebitis or embolism. If capillaries. The drug is not to be used for serious arterial
signs develop, immediately discontinue the drug and bleeding or bleeding over large areas. Care must be taken
notify the provider. not to inject this drug or to allow systemic absorption due
to the risk of thrombi formation.
• Monitor vital signs and urine output throughout ther-
apy and for up to 24 hours post-therapy. Thrombin-JMI is an older form of thrombin prepared
from cow blood. Allergic reactions may occur in patients
Lifespan and Diversity Considerations: hypersensitive to cow products. Approved by the FDA in
2007, human thrombin (Evithrom) is prepared from human
• Monitor renal function laboratory tests more fre- plasma. Although screened and treated to inactivate
quently with the older adult because normal changes viruses, products obtained from human plasma carry a
related to aging or the development of myopathy or small risk for transmission of infectious agents, such as
rhabdomyolysis may increase the risk of renal failure. viruses and the Creutzfeldt–Jakob disease agent. In 2008
the FDA approved thrombin (recombinant) (Recothrom),
Patient and Family Education: the first recombinant formulation of thrombin. The topical
thrombins are pregnancy category C drugs.
• Immediately report any of the following to the health-
care provider: difficulty urinating, reddish-brown Tranexamic acid (Cyklokapron, Lysteda): Like aminoca-
urine, arm or leg pain, chest pain, difficulty breathing, proic acid, tranexamic acid produces an antifibrinolytic
bleeding, clotting, dizziness, drowsiness, confusion, or effect by inhibiting plasminogen and plasmin activity. The
convulsions. drug was first approved in 1986 as an IV medication to
reduce or prevent bleeding in patients with hemophilia
• Make position changes slowly when moving from a who are undergoing dental procedures. In 2009, the PO
lying to a standing position to prevent dizziness and form of the drug (Lysteda) was approved for the treatment
possible fainting. of excessive menstrual bleeding. Because the drug inhibits
clot removal, patients must be monitored carefully for
• Observe for increased toxicity with oral contraceptives signs and symptoms of thromboembolism. Taking Lysteda
and estrogen.
• Immediately notify the healthcare provider of any
known or suspected pregnancy.
• Do not breastfeed while taking this drug without
approval of the healthcare provider.
686 Unit 5 Pharmacology of the Cardiovascular System
concurrently with hormonal contraceptives increases the donors contains all the necessary components to replace
risk of thromboembolic adverse effects. The drug is 8 to the missing clotting factor(s). Unfortunately, contamina-
10 times more potent and has a longer half-life than amino- tion of blood products with the human immunodeficiency
caproic acid. Adverse effects are similar to those of amino- virus (HIV), hepatitis B, and hepatitis C in the early 1980s
caproic acid. Tranexamic acid is pregnancy category B. infected most patients with hemophilia and resulted in a
significant percentage of deaths in transfusion recipients.
Drugs for Hemophilia Although all donated blood is screened for viral pathogens,
fresh frozen plasma is now rarely used to treat hemophilia
38.14 Hemophilia is treated by replacing due to a small risk of viral contamination.
the missing clotting factor(s) or by inhibiting
coagulation. Hemophilia A is now treated with the administration
of a concentrated solution of Factor VIII. A large number
Hereditary disorders of coagulation are relatively rare and of products are available, and trade names include
may be caused by deficiency in any blood factor in the Advate, Alphanate, Bioclate, Helixate, Humate, Hyate,
coagulation cascade. Symptoms of congenital coagulation Koate, Kogenate, Kovaltry, Monarc, Monoclate, NovoEight,
disorders manifest as bleeding in muscles or weight- Nuwiq, Recombinate, ReFacto, Xuriden, and Xyntha. Fac-
bearing joints, ecchymoses, epistaxis, gingival bleeding, tor VIII products differ in purity and whether they are
and abnormally long bleeding times following trauma or derived from plasma or through recombinant DNA tech-
surgery. Joint bleeding causes chronic inflammation and nology. Factor concentrates were once obtained by pooling
may result in permanent deformity and loss of mobility. the plasma from human donors, but this has been replaced
by creating ultra-high-purity factors through recombinant
Some patients have mild forms of hemophilia, exhibit- DNA technology to lower the risk of viral contamination.
ing no symptoms of excessive bleeding until they experi- There is still a very small risk of viral contamination and
ence major trauma or surgery. The most severe forms of allergic reaction because human cells and albumin are used
these disorders, however, are diagnosed shortly after birth to prepare some of the recombinant DNA products. Most
and require a lifetime of lifestyle adjustment and pharma- factor concentrates are subjected to dry heat, vapor heat,
cotherapy. Because symptoms associated with the different solvent detergent, or a monoclonal antibody to remove any
clotting disorders are nonspecific, diagnosis requires labo- viruses that may remain.
ratory assays for each of the clotting factors to determine
which deficiency is causing the disorder. Factor VIII therapy in people with hemophilia is indi-
cated for acute bleeding due to trauma and to prevent peri-
The pharmacotherapy of hereditary coagulation disor- operative bleeding associated with medical and surgical
ders has resulted in a remarkable change in the lifespans of procedures. Prompt and early therapy is required for acute
afflicted patients. Prior to 1960, the average lifespan of a bleeding events. A typical regimen for a bleeding episode
male with severe hemophilia A was 11 years; the lifespan is includes an initial bolus dose followed 8 hours later by a
now 50 to 60 years. second dose. Subsequent doses are administered every
12 hours until a target blood level of Factor VIII is reached:
PharmFACT 30% to 50% of normal level for minor bleeding episodes
and 100% for major bleeding. Some regimens substitute a
Hemophilia A is the most common X-linked genetic disease. continuous infusion of the drug, rather than bolus doses.
Of the 20,000 people with hemophilia A in the United States,
about 50% to 60% have the most severe form of the disease Patients with severe hemophilia A may receive pro-
(Zaiden, 2016). phylactic therapy with Factor VIII with the goal of prevent-
ing chronic joint damage and disability. For prophylaxis, a
Hemophilia A: Lack of clotting Factor VIII results in typical regimen is 10 to 20 international units/kg of Factor
hemophilia A, which accounts for approximately 80% of VIII given 3 times per week. The target level for Factor VIII
all hemophilia. Adequate amounts of Factor VIII are neces- prophylaxis ranges from 1% to 5% of normal. To be most
sary to activate Factor X in the intrinsic coagulation path- effective, therapy should begin before joint damage has
way. Because the gene for Factor VIII is carried on the X occurred, usually prior to age 2. Prophylactic therapy is
chromosome, hemophilia A is a sex-linked disease with very expensive and must be continued throughout the
nearly all cases occurring in males. Females are asymp- patient’s lifespan. A central venous access device may be
tomatic carriers. Remarkably, patients may have a 75% installed to allow more convenient dosing.
reduction in the amount of Factor VIII in the blood and yet
have no major symptoms. Those with 1% or less of Factor Adverse reactions to Factor VIII administration are
VIII have severe forms of the disease. uncommon. Flushing, headache, dyspnea, and urticaria
may signal an allergic reaction. Anaphylaxis is possible,
The traditional treatment for hemophilia A is adminis- though rare. About 30% of patients will develop antibodies
tration of fresh frozen plasma. Plasma obtained from blood (called inhibitors) to Factor VIII that can significantly
Chapter 38 Pharmacotherapy of Coagulation Disorders 687
decrease the therapeutic effect of the drug. Patients who of choice for this disorder. The drug is administered for
experience this inhibition may receive higher doses of Fac- treating and preventing excessive bleeding events such as
tor VIII or they may receive activated Factor VIIIa. Factor acute trauma or surgery. Products containing recombinant
VIIIa is very expensive and is used only when medically Factor IX include Alprolix, BeneFIX, Idelvion, Rebinyn, and
necessary. Rixubis. A typical regimen for acute bleeding includes an
initial dose of 20 to 80 international units/kg, followed by
Desmopressin is an alternative therapy for treating repeat doses every 24 hours until the target level of Factor
minor bleeding episodes in patients with mild hemophilia IX is obtained. Target levels can sometimes be achieved
A. Available by infusion or intranasal spray, desmopressin after a single dose and maintained with lower doses. Factor
causes the release of Factor VIII and vWF from storage sites IX is also administered prophylactically to reduce the inci-
within the body. The drug can cause a two- to fourfold dence of spontaneous bleeding. Hemostatic drugs such as
increase in Factor VIII levels. Desmopressin therapy is usu- aminocaproic acid and tranexamic acid may be used for
ally limited to 2 to 3 days because repeated administration short-term therapy to reduce bleeding related to dental pro-
results in a diminished response. If desmopressin is used cedures in patients with hemophilia B.
for a minor surgical procedure, a test dose is usually admin-
istered 1 week prior to surgery to determine if the patient is Hemophilia C: Factor XI deficiency, or hemophilia C,
responsive to the drug. In adults with hemophilia, 10% to occurs in equal numbers of males and females and is a
20% of patients will not respond to desmopressin therapy. mild form of hemophilia. In the general population, hemo-
Those with severe forms of the disease have no internal philia C occurs at a rate of 1 per million births, but it affects
storage depots of Factor VIII or vWF; thus, the drug will be up to 13% of those with Ashkenazi Jewish heritage. No
ineffective in these patients. therapy is generally indicated unless the patient is under-
going a medical, surgical, or dental procedure. Adminis-
Other therapies for hemophilia A include the hemo- tration of fresh frozen plasma supplies adequate amounts
static drugs aminocaproic acid and tranexamic acid. These of Factor XI to prevent or slow bleeding during these
drugs are primarily used for short-term therapy to reduce procedures.
bleeding related to dental procedures.
von Willebrand’s Disease The most common inherited
Hemophilia B: Hemophilia B, or Christmas disease, is coagulation disorder, von Willebrand’s disease (vWD),
caused by a deficiency of Factor IX, and comprises about affects 1 in every 100 to 500 people. This disorder results in
20% of those with hemophilia. Factor IX, in conjunction a decrease in quantity or quality of vWF, which is required
with activated Factor VIII, is required for the activation of for platelet adhesion to injured blood vessel endothelium.
Factor X in the coagulation cascade. Like Factor VIII, the vWF is also a carrier molecule for Factor VIII, protecting it
gene for Factor IX is on the X chromosome. Thus symp- from destruction as it circulates through the blood. Thus, a
tomatic disease occurs predominantly in males. The dis- deficiency in vWF will decrease levels of Factor VIII and
ease is much less common than hemophilia A, but affect coagulation. Like hemophilia, the disease has mild
symptoms of excessive bleeding are the same. Laboratory and severe forms, both characterized by abnormal bleed-
testing is necessary to distinguish between the two ing. The disease affects males and females equally, and life
diagnoses. expectancy is usually normal.
Treatment of hemophilia B is through replacement ther- This type of bleeding disorder is treated with Factor
apy with Factor IX. Like Factor VIII, fresh frozen plasma VIII concentrate as well as desmopressin, which promotes
and pooled factor concentrates were historically used to the release of stored vWF. For the most severely affected
supply the missing clotting factor. The development of a patients, plasma products containing vWF may be required.
recombinant form of Factor IX in 1996, however, removed
the risk of viral contamination and has become the therapy
Understanding Chapter 38
Key Concepts Summary 38.2 Coagulation disorders are caused by decreased
numbers of platelets or by deficiencies in specific
38.1 Thromboembolic disorders are abnormalities of clotting factors.
hemostasis that include deep vein thrombosis and
pulmonary embolism.
688 Unit 5 Pharmacology of the Cardiovascular System 38.9 The glycoprotein IIb/IIIa receptor inhibitors
are effective antiplatelet drugs for preventing
38.3 The normal coagulation process can be modified coagulation.
by a number of different mechanisms.
38.10 Coagulation modifiers can be used to treat
38.4 Heparin is the traditional drug for rapid symptoms of intermittent claudication.
anticoagulation.
38.11 Fibrinolysis is a process that removes thrombi.
38.5 Warfarin is a widely used drug for oral
anticoagulant therapy. 38.12 Thrombolytics are used to dissolve existing
intravascular clots in patients with myocardial
38.6 The direct thrombin inhibitors and Factor infarction and stroke.
Xa inhibitors have become important drugs
in the prevention and treatment of venous 38.13 Hemostatics are used to promote the formation
thromboembolism. of clots.
38.7 Antiplatelet drugs provide anticoagulation by 38.14 Hemophilia is treated by replacing the missing
reducing the aggregation properties of platelets. clotting factor(s) or by inhibiting coagulation.
38.8 The adenosine diphosphate receptor blockers are
antiplatelet drugs prescribed for the prevention
and treatment of arterial thrombosis.
CASE STUDY: Making the Patient Connection
Remember the patient “Jihyo Yun” at the of swelling, painful right lower extremity × 3 days. Car-
beginning of the chapter? Now read the dio: Heart rate regular without murmurs; blood pressure,
remainder of the case study. Based on the 118/74 mmHg; all pulses present equal and strong in all
information presented within this chap- extremities; no respiratory distress—regular, clear, breath
ter, respond to the critical thinking ques- sounds; audible bowel sounds in all four quadrants. Her
tions that follow. right mid-calf area has 3–4+ pitting edema, and is hot and
painful to touch and she has a moderate amount of vari-
Jihyo Yun had looked forward to the trip and was anxious cosities in lower extremities bilaterally.
to see her grandchildren. When her son accepted an execu-
tive position with his company, she had no idea that he Jihyo had a hysterectomy 15 years ago, and does not
would be relocated to Bangkok. The trip would be long but drink alcohol or use tobacco. She takes occasional aspirin
certainly worth the effort. She never dreamed in her for muscle aches, and has no known allergies. Her family
74 years that she would be flying out of the United States, history indicates that her father died from a stroke and
much less to Thailand. When the opportunity came to see her mother died of “old age.” She has one sister who has
her son and his family, she jumped at the chance. After all, diabetes.
it had been 5 years since he had left their home in
Chicago. Jihyo was diagnosed with DVT in her right leg. The
treatment plan was to admit her into the hospital for anti-
When she returned from her trip, she noticed some coagulant therapy and pain control. In the hospital setting,
pain in her right leg. Although she sees herself as a healthy Jihyo will receive heparin therapy. You are the nurse caring
older woman, she does experience occasional arthritis pain. for this patient.
Considering that she was on a commercial airliner for more
than 20 hours, she did not think much about the leg dis- Critical Thinking Questions
comfort. However, after a few days, her leg became increas-
ingly more painful and swollen. She could not imagine 1. Jihyo asks, “How soon will the heparin dissolve my
what was causing this problem. Finally, after 3 days, Jihyo blood clot?” How would you respond to this question?
became worried about what seemed to be increasing leg
swelling and pain. 2. What patient education should you provide Jihyo
about anticoagulation therapy?
She is seen in her healthcare provider’s office. The fol-
lowing health information is documented in her medical 3. What is an aPTT? How will this test be used to
record: direct heparin therapy?
Jihyo Yun, 74-year-old Asian American woman. Her 4. What factors predisposed this patient to DVT?
physical examination revealed the following findings:
alert, oriented 74-year-old woman with chief complaint 5. What should Jihyo be taught about taking aspirin
for arthritis pain?
Answers to Critical Thinking Questions are available on the
faculty resources site. Please consult with your instructor.
Chapter 38 Pharmacotherapy of Coagulation Disorders 689
Additional Case Study 2. What special precautions should Lewis take while on
this drug?
You are attending your annual family reunion and begin
talking to your favorite uncle, Lewis, about his recent hos- 3. Are there any foods that he should avoid or limit in
pitalization. Lewis Kinard, a 55-year-old man, was recently his diet?
discharged from the hospital following an episode of atrial
fibrillation. He returned home with instructions to take 4. What laboratory testing will be done to determine
warfarin (Coumadin) 10 mg daily. He has many questions this drug’s effectiveness?
for you, his favorite relative.
Answers to Additional Case Study questions are available on
1. Why would someone with atrial fibrillation be the faculty resources site. Please consult with your instructor.
prescribed Coumadin?
Chapter Review 1. The drug will be given IV, and the patient should
be able to go home later today.
1. A patient with deep vein thrombosis is being treated
with a heparin infusion. The nurse would monitor 2. The patient should remain quiet and lying down
for therapeutic effectiveness by noting which of during drug administration and for up to 8 hours
the following? after infusion.
1. Activated partial thromboplastin time (aPTT) 3. The risk of bleeding returns to normal within
2. Prothrombin time (PT) 24 hours after the drug has been infused.
3. Platelet counts
4. International normalized ratio (INR) 4. An increase in vitamin K–rich foods or a
supplement will be needed for the week following
2. Which of the following should the nurse include in the treatment.
the teaching plan for a patient receiving subcutaneous
heparin? (Select all that apply.) 5. A patient who is taking clopidogrel (Plavix) to pre-
vent another stroke asks the nurse how the medica-
1. Inject medication in the deep fatty layer of the tion works. The nurse’s response should be based on
abdomen. an understanding that Plavix:
2. When brushing your teeth, use a soft toothbrush. 1. Inhibits platelet aggregation to prevent clot
3. Hold direct pressure on any puncture sites for formation.
15 minutes. 2. Activates antithrombin III and subsequently
4. Use dental floss daily after brushing. inhibits thrombin.
5. Take a daily aspirin tablet, 325 mg, to prevent
3. Inhibits enzymes involved in the formation of
inflammation at the injection site. vitamin K.
3. A patient who is taking warfarin (Coumadin) states, “I 4. Converts plasminogen to plasmin to dissolve fibrin
wake up every morning with arthritis pain and I always clots.
take aspirin or ibuprofen.” The nurse’s response would
be based on which physiologic concepts? 6. A patient will be receiving dabigatran (Pradaxa).
Which of the following is true concerning this drug
1. Aspirin and ibuprofen (Motrin) will counteract the therapy? (Select all that apply.)
therapeutic effects of many anticoagulants.
1. Ginger, garlic, and green tea may increase the risk
2. Anticoagulants will reduce the half-life of drugs of bleeding.
such as aspirin and ibuprofen.
2. Vitamin B12 is used to augment this drug’s
3. Many substances such as aspirin and ibuprofen response.
will increase the risk of bleeding.
3. Pradaxa is used for deep vein thrombosis.
4. The combination of aspirin products with
anticoagulants will worsen arthritis pain. 4. Activated partial thromboplastin time may be
monitored to determine effectiveness.
4. What should the nurse teach the patient who is to
receive alteplase (Activase) as part of the treatment 5. This drug is contraindicated for patients with
for myocardial infarction? gastritis.
See Answers to Chapter Review in Appendix A.
690 Unit 5 Pharmacology of the Cardiovascular System
References Kearon, C., Akl, E. A., Ornelas, J., Blaivas, A., Jimenez, D.,
Bounameaux, H., … Moores, L. (2016). Antithrombotic
American Stroke Association. (2014). Anti-clotting therapy for VTE disease: CHEST guideline and expert
agents explained. Retrieved from http://www. panel report. CHEST Journal, 149(2), 315–352.
strokeassociation.org/STROKEORG/LifeAfterStroke/ doi:10.1016/j.chest.2015.11.026
HealthyLivingAfterStroke/ManagingMedicines/Anti-
Clotting-Agents-Explained_UCM_310452_Article. National Center for Complementary and Integrative
jsp#.V_VoKyjt4RY Health. (2016). Garlic. Retrieved from https://nccih.nih.
gov/health/garlic/ataglance.htm
Andreoli, L., Chighizola, C., Banzato, A., Pons-Estel, G., de
Jesus, G., & Erkan, D. (2013). Estimated frequency of Patel, K. (2016). Deep venous thrombosis. Retrieved from http://
antiphospholipid antibodies in patients with pregnancy emedicine.medscape.com/article/1911303-overview
morbidity, stroke, myocardial infarction, and deep vein
thrombosis: A critical review of the literature. Arthritis Ried, K., Frank, O. R., Stocks, N. P., Fakler, P., & Sullivan, T.
Care & Research, 65, 1869–1873. doi:10.1002/acr.22066 (2008). Effect of garlic on blood pressure: A systematic
review and meta-analysis. BMC Cardiovascular Disorders, 8,
Begum, N., Ganguly, S., & Islam, F. (2015). 13. doi:10.1186/1471-2261-8-13
Antiphospholipid syndrome in pregnancy. Journal of
Bangladesh College of Physicians & Surgeons, 33(2), 86–90. University of Maryland Medical Center. (2015). Garlic.
doi:10.3329/jbcps.v33i2.28041 Retrieved from http://umm.edu/health/medical/
altmed/herb/garlic
Chetty, M., & Duncan, W. C. (2015). Investigation and
management of recurrent miscarriage. Obstetrics, U.S. Food and Drug Administration. (2015). FDA
Gynaecology & Reproductive Medicine, 25, 31–36. information in medication errors involving activase and
doi:10.1016/j.ogrm.2014.11.004 TNKase. Retrieved from https://www.fda.gov/
downloads/ForHealthProfessionals/
de Jesús, G. R., Rodrigues, G., de Jesús, N. R., & Levy, R. A. LearningActivities/UCM464193.pdf
(2014). Pregnancy morbidity in antiphospholipid syndrome:
What is the impact of treatment? Current Rheumatology Zaiden, R. A. (2016). Hemophilia A. Retrieved from http://
Reports, 16, 403. doi:10.1007/s11926-013-0403-6 emedicine.medscape.com/article/779322-overview#a2
Selected Bibliography Gulseth, M. P. (2016). Overview of direct oral anticoagulant
therapy reversal. American Journal of Health-System
Bauer, K. A. (2015). Current challenges in the management Pharmacy, 73(10, Suppl. 2), S5–S13. doi:10.2146/ajhp150966
of hemophilia. The American Journal of Managed Care,
21(Suppl. 6), s112–s122. Harter, K., Levine, M., & Henderson, S. O. (2015).
Anticoagulation drug therapy: A review. Western
Cabral, K. P., & Ansell, J. E. (2015). The role of Factor Xa Journal of Emergency Medicine, 16(1), 11–17. doi:10.5811%
inhibitors in venous thromboembolism treatment. 2Fwestjem.2014.12.22933
Vascular Health and Risk Management, 11, 117.
doi:10.2147/VHRM.S39726 Khoshmohabat, H., Paydar, S., Kazemi, H. M., & Dalfardi,
B. (2016). Overview of agents used for emergency
Comerota, A. J., & Ramacciotti, E. (2016). A comprehensive hemostasis. Trauma Monthly, 21(1), e26023. doi:10.5812/
overview of direct oral anticoagulants for the traumamon.26023
management of venous thromboembolism. The
American Journal of the Medical Sciences, 352(1), 92–106. Lincoff, A. M. (2015). What role for glycoprotein IIb/IIIa
doi:10.1016/j.amjms.2016.03.018 inhibition in contemporary coronary intervention?
JACC: Cardiovascular Interventions, 8(12), 1583–1585.
Depta, J. P., & Bhatt, D. L. (2015). New approaches to doi:10.1016/j.jcin.2015.06.020
inhibiting platelets and coagulation. Annual Review of
Pharmacology and Toxicology, 55, 373–397. doi:10.1146/ Robertson, L., Kesteven, P., & McCaslin, J. E. (2015). Oral
annurev-pharmtox-010814-124438 direct thrombin inhibitors or oral factor Xa inhibitors
for the treatment of deep vein thrombosis. Cochrane
Dominguez, J. A. (2016). Peripheral arterial occlusive disease Database of Systematic Reviews, 6, Art. No. CD010956.
treatment & management. Retrieved from emedicine. doi:10.1002/14651858.CD010956.pub2
medscape.com/article/460178-treatment
Schweickert, P. A., Gaughen, J. R., Kreitel, E. M., Shephard, T.
Giordano, A., Musumeci, G., D’Angelillo, A., Rossini, R., J., Solenski, N. J., & Jensen, M. E. (2016). An overview of
Biondi Zoccai, G., Messina, S., … Fiammetta Romano, M. antithrombotics in ischemic stroke. The Nurse Practitioner,
(2016). Effects of glycoprotein IIb/IIIa antagonists: Anti 41(6), 48–55. doi:10.1097/01.NPR.0000483077.47966.6e
platelet aggregation and beyond. Current Drug Metabolism,
17, 194–203. doi:10.2174/1389200217666151211121112
“For me, the worst part is the
isolation from people. It’s almost
unbearable. I feel so lonely.
If I could just be with people,
I know I would feel better.”
Patient “Carl Guenther”
Chapter 39
Pharmacotherapy
of Hematopoietic Disorders
Chapter Outline Learning Outcomes
cc Physiology of Hematopoiesis After reading this chapter, the student should be able to:
cc Hematopoietic Growth Factors
1. Describe the physiology of hematopoiesis.
Erythropoietin
PROTOTYPE Epoetin Alfa (Epogen, Procrit), p. 693 2. Describe how aspects of hematopoiesis can be
Colony-Stimulating Factors modified by the administration of pharmacologic
PROTOTYPE Filgrastim drugs.
(Granix, Neupogen, Zarxio), p. 697
Platelet Enhancers 3. Explain the functions of erythropoietin.
PROTOTYPE Oprelvekin
(Neumega), p. 700 4. Explain the functions of colony-stimulating factors.
cc Classification of Anemias
cc Antianemic Drugs 5. Classify types of anemia based on their causes.
Iron Deficiency Anemia
PROTOTYPE Ferrous Sulfate 6. Illustrate the metabolism, storage, and transfer of
(Feosol, Feostat, Others), p. 705 iron in the body.
Pernicious Anemia
PROTOTYPE Cyanocobalamin (Nascobal), p. 708 7. Identify the role of intrinsic factor in the absorption
of vitamin B12.
8. Compare and contrast anemias caused by vitamin
B12 and folate deficiency.
9. Describe the nurse’s role in the pharmacologic
management of hematopoietic disorders.
10. 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.
11. Apply the nursing process to care for patients
receiving pharmacotherapy for hematopoietic
disorders.
691
692 Unit 5 Pharmacology of the Cardiovascular System
Key Terms folic acid, 708 pernicious anemia, 707
hematopoiesis, 692
anemia, 702 hemosiderin, 703 pluripotent stem cells
colony-stimulating factors intrinsic factor, 707 (hemocytoblasts), 692
(CSFs), 695 transferrin, 703
ferritin, 703
folate, 708
The blood serves all other cells in the body and is the only these regulatory agents, shown in Figure 39.1, are now
fluid tissue. Because of its diverse functions, diseases affect- available in sufficient quantities to be used as medications.
ing blood constituents have widespread effects on the
body. This chapter examines medications used to enhance PharmFACT
the functions of erythrocytes, leukocytes, and platelets.
Pharmacology of the hematopoietic system is a small, The recommended dietary allowance of iron for a woman is
though emerging, branch of medicine. 10 to 15 mg. However, during pregnancy, a woman’s body
needs 1 g of iron daily: 300 mg for the fetus, 500 mg for
Physiology of Hematopoiesis expansion of the maternal RBCs, and 200 mg due to
excretion (National Institutes of Health, 2016a).
39.1 Hematopoiesis is a dynamic process that is
responsive to the changing demands of the body. The pharmacologic management of hematopoietic dis-
orders often involves simply replacing a deficient sub-
Blood is a highly dynamic tissue; over 200 billion new stance that is essential to hematopoiesis. In some cases, the
blood cells are formed every day. The process of blood cell drug is identical, or very closely resembles, the deficient
formation is called hematopoiesis, or hemopoiesis. In endogenous factor. For example, the drug epoetin alfa
adults, hematopoiesis occurs primarily in red bone mar- (Epogen, Procrit) is identical to the natural hormone eryth-
row and requires B vitamins, vitamin C, copper, iron, and ropoietin and stimulates the production of RBCs in the
other nutrients. Before proceeding, the student should same manner. Administration of antianemic medications
read the brief review of blood found in Chapter 28. such as ferrous sulfate or vitamin B12 supplies the patient
with essential factors that may be deficient.
Hematopoiesis responds to internal and external chal-
lenges faced by the body. For example, the production of Some of the hematopoietic drugs have become impor-
white blood cells (WBCs) can increase tenfold in response tant adjunct medications in the pharmacotherapy of malig-
to infection. The number of red blood cells (RBCs) can nancies. Antineoplastic drugs often are toxic to bone
increase as much as fivefold in response to anemia or marrow and cause neutropenia, a reduced number of
hypoxia. Homeostatic control of hematopoiesis is influ- WBCs. Neutropenia is a primary cause of patient morbidity
enced by a number of hormones and growth factors, which and mortality in the treatment of cancer. Hematopoietic
allow for points for pharmacologic intervention. The pro- drugs can be used to boost the WBC counts in these patients.
cess of hematopoiesis is illustrated in Figure 39.1.
Natural hormones that regulate some aspect of blood
The process of hematopoiesis begins in bone marrow formation are called hematopoietic growth factors. These
with pluripotent stem cells (hemocytoblasts), which are drugs and their doses are listed in Table 39.1.
capable of maturing (differentiating) into any blood cell
type. What determines whether the stem cell produces CONNECTION Checkpoint 39.1
RBCs, macrophages, lymphocytes, or perhaps platelets?
The specific path taken by the pluripotent stem cell depends From what you learned in Chapter 28, name the three formed elements
on the internal needs of the body. These needs are transmit- of blood. What percentage of whole blood do the formed elements
ted to pluripotent stem cells by regulatory substances that comprise? Answers to Connection Checkpoint questions are avail-
include various hormones and proteins. For example, high able on the faculty resources site. Please consult with your instructor.
amounts of the hormone erythropoietin circulating through
the blood signal the stem cells to differentiate into erythro- Hematopoietic Growth Factors
cytes. Many types of cells secrete cytokines (interferons
and interleukins) that signal the stem cells to increase or 39.2 Erythropoietin stimulates production
decrease the production of specific WBCs. Through recom- of red blood cells and is used to treat anemia.
binant deoxyribonucleic acid (DNA) technology some of
The process of RBC formation, or erythropoiesis, is regu-
lated by the hormone erythropoietin. In adults, 90% of
Chapter 39 Pharmacotherapy of Hematopoietic Disorders 693
Pluripotent stem cell
(hemocytoblast)
Myeloid stem cell Lymphoid stem cell
Interleukins
Erythro- Colony-
poietin stimulating
factors
Megakaryocyte Reticulocyte Myeloblast
Thrombopoietin
Platelets Erythrocytes Granular leukocytes B lymphocytes T lymphocytes
and macrophages
Figure 39.1 Hematopoiesis: Blood cells are formed from stem cells under the influence of hormones such as
thrombopoietin, colony-stimulating factors, and erythropoietin.
erythropoietin is secreted by the kidneys and 10% is to epoetin alfa but has a duration of action that is 2 to 3
secreted by the liver. times longer. These drugs are sometimes called erythropoi-
etic growth factors.
The primary signal to increase the renal secretion of
erythropoietin is hypoxia, a reduction in oxygen reaching PROTOTYPE DRUG Epoetin Alfa (Epogen, Procrit)
the proximal tubule cells in the kidney. Once secreted,
erythropoietin travels to the bone marrow where it inter- Classification Therapeutic: Hematopoietic growth
acts with receptors on stem cells and delivers the message factor, drug for anemia
to increase erythrocyte production. Just as important,
erythropoietin also stimulates the production of hemoglo- Pharmacologic: Erythropoietin
bin (Hgb), which is required for a functional erythrocyte.
Hemorrhage, chronic obstructive pulmonary disease, ane- Therapeutic Effects and Uses: Approved in 1989
mia, or high altitudes may increase serum levels of erythro- by the U. S. Food and Drug Administration, epoetin alfa
poietin as much as 1000-fold in response to severe hypoxia. is made through recombinant DNA technology and is
Erythropoietin is marketed as the drug epoetin alfa (Epo- functionally identical to human erythropoietin. Although
gen, Procrit). Darbepoetin alfa (Aranesp) is closely related the drug may be administered intravenously (IV), the
694 Unit 5 Pharmacology of the Cardiovascular System
Table 39.1 Hematopoietic Growth Factors
Drug Route and Adult Dose Adverse Effects
(Maximum Dose Where Indicated)
Erythropoietic Growth Factors
Subcutaneous/IV: 0.45 mcg/kg once per wk (max: 74 mg/kg) Headache, fever, nausea, vomiting, diarrhea,
darbepoetin alfa (Aranesp) insomnia, cough, upper respiratory infection, edema,
Subcutaneous/IV: Start with 50–100 units/kg/dose and adjust pyrexia, rash
epoetin alfa (Epogen, Procrit): to target Hct range of 30–33% (max: 36%); Hct should not
erythropoietin increase by more than 4 points in any 2-wk period HTN, seizures, HF, MI, stroke
Colony-Stimulating Factors IV: 5–10 mcg/kg by 30-min infusion or as a subcutaneous Flulike syndrome, fever, dyspnea, nausea, vomiting,
filgrastim (Granix, Neupogen, single bolus dose weakness, alopecia, peripheral edema, arthralgia,
Zarxio): granulocyte-CSF bone pain
pegfilgrastim (Neulasta) Subcutaneous: 6 mg once per chemotherapy cycle
sargramostim (Leukine): GM-CSF Thrombocytopenia, cutaneous vasculitis, pericardial
IV: 250 mcg/m2/day infused over 2 h for 14 days, begin 2–4 h effusion (sargramostim), tachycardia (sargramostim),
Platelet Enhancers after bone marrow transfusion and not less than 24 h after acute respiratory distress syndrome
eltrombopag (Promacta) last dose of chemotherapy or 12 h after last radiation therapy
PO: 50 mg once daily (max: 75 mg/day) Arthralgia, myalgia, paresthesia, insomnia
Bone marrow fibrosis, thromboembolism,
hematologic malignancy, hepatotoxicity
oprelvekin (Neumega) Subcutaneous: 50 mcg/kg once daily starting 6–24 h after Edema, fever, headache, dizziness, dyspnea, fatigue,
completing chemotherapy for 14–21 days or until platelet rash, nausea, vomiting
count is at least 50,000/mcL
Tachycardia, febrile neutropenia, pleural effusion,
anaphylaxis, dysrhythmias, candidiasis
romiplostim (Nplate) Subcutaneous: 1 mcg/kg/wk initial dose; may increase by Arthralgia, dizziness, insomnia, myalgia, abdominal
increments of 1 mg/kg weekly until platelet count is at least pain, dyspepsia, paresthesia
50,000/mcL
Thromboembolism, bone marrow fibrosis
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
subcutaneous route is generally preferred because lower Epoetin alfa is given to patients undergoing chemo-
doses are needed, absorption is slower, and a more sus- therapy for nonmyeloid malignancies to counteract the
tained response can be achieved. Epoetin is not used for anemia commonly caused by antineoplastic drugs. It
the emergency correction of severe anemia or as a substi- should be carefully noted that the anemia must be second-
tute for transfusion because it has a gradual onset of action. ary to the chemotherapy, not to the cancer itself. Research
The hematocrit (Hct) increases 2% per week during the has shown that the administration of epoetin alfa does not
initial weeks of epoetin therapy and some patients require benefit patients when the anemia is caused by the malig-
2 to 6 weeks for a change in Hct to occur. Most patients nancy; in fact, mortality is increased in these patients by the
on epoetin therapy also receive iron supplements to meet administration of the drug. Care must be taken not to
the increased demands caused by the elevated erythrocyte administer epoetin alfa to patients with myeloid malignan-
production. Although epoetin alfa does not cure any pri- cies such as myelogenous leukemia, because the drug may
mary disease, it reduces anemia symptoms and dramati- increase tumor growth.
cally improves the patient’s ability to perform activities of
daily living (ADLs). A typical initial regimen for epoetin Mechanism of Action: Epoetin alfa stimulates the
alfa requires 50 to 100 units/kg 3 times per week until a division and differentiation of stem cells in the bone mar-
target Hgb level of 10 to 12 g/dL is achieved. row to become erythrocytes. Erythropoietin also promotes
the synthesis of Hgb and causes a shift of marrow reticulo-
Epoetin is indicated for the treatment of anemia associ- cytes into the circulation.
ated with chronic kidney disease (CKD). Patients with
CKD often experience anemia because they are unable to Pharmacokinetics:
secrete sufficient endogenous erythropoietin. The drug is
occasionally prescribed to reduce the need for transfusions Route(s) IV, subcutaneous
in patients with anemia prior to elective surgery, if a signifi-
cant blood loss is expected. Patients with HIV infection Absorption Readily absorbed (subcutaneous)
who are receiving zidovudine may receive epoetin alfa to
treat anemia caused by antiretroviral drugs. Distribution Unknown if the drug crosses the
placenta or is secreted in breast
milk
Chapter 39 Pharmacotherapy of Hematopoietic Disorders 695
Primary metabolism Plasma Drugs Similar to Epoetin Alfa
Primary excretion Mostly feces; 10% renal
Onset of action 7–14 days (Epogen, Procrit)
Duration of action 2 weeks; half-life: 4–13 h
The only other erythropoietic growth factor is darbepoetin
Adverse Effects: The most serious adverse effect alfa. A similar drug, peginesatide (Omontys), was
of epoetin alfa is hypertension (HTN), which occurs in approved in 2012 but recalled in 2013 due to serious safety
30% of patients receiving the drug. An antihyperten- concerns.
sive drug may be indicated. Some patients with CKD
develop neutralizing antibodies to subcutaneous epo- Darbepoetin alfa (Aranesp): Approved in 2001, darbepo-
etin alfa, which can lead to a rapidly developing severe etin alfa has a chemical structure that closely resembles
anemia known as pure red cell aplasia. Seizures may that of epoetin alfa, differing only by two carbohydrate
occur during the first 90 days of therapy, especially if chains. It has the same mechanism of action, efficacy, and
blood pressure and Hct rise rapidly. Common adverse safety profile as epoetin alfa. It is administered by the sub-
effects include headache, fever, nausea, diarrhea, and cutaneous or IV route and has an extended duration of
edema. Black Box Warning: The risk of serious cardio- action that allows it to be administered once weekly. Maxi-
vascular and thromboembolic events is increased with mum response occurs in 2 to 4 weeks. Darbepoetin alfa is
epoetin alfa therapy. Transient ischemic attacks (TIAs), approved for the treatment of anemia associated with can-
myocardial infarctions (MIs), and strokes have occurred cer chemotherapy or CKD. Like epoetin alfa, darbepoetin
in patients with CKD who are on dialysis and being should be administered only to patients with anemia sec-
treated with epoetin alfa. Epoetin increased the rate of ondary to the chemotherapy and not caused by the malig-
deep vein thrombosis (DVT) in patients not receiving nancy itself. In addition, Hgb levels should be maintained
concurrent anticoagulation. The lowest dose possible below 12 g/dL to reduce the risks of serious cardiovascu-
should be used in patients with cancer because the drug lar adverse events. Darbepoetin has similar adverse effects
can promote tumor progression and shorten overall and the same black box warning as epoetin alfa. This drug
survival in some patients. is pregnancy category C.
Contraindications/Precautions: The drug should 39.3 Colony-stimulating factors increase
not be given to patients with uncontrolled HTN because the production of leukocytes.
epoetin alfa may increase blood pressure. The risk of
thromboembolic events, stroke, and MI greatly increases Regulation of WBC production, or leukopoiesis, is more
when Hgb level rises above 12 g/dL. Patients with known complicated than erythropoiesis because the blood has
hypersensitivity to products derived from mammal cells, different types of leukocytes. Adding to the complica-
such as albumin, should not receive this drug. tion is that a large number of substances modify the syn-
thesis and activation of leukocytes and the processes of
Drug Interactions: Androgens can increase blood vis- leukopoiesis regulation are incompletely understood.
cosity, resulting in an increased response from epoetin alfa. Pharmacologically, the most important substances are
The effectiveness of epoetin alfa will be greatly reduced colony-stimulating factors (CSFs). CSFs are hormones
in patients with iron deficiency or other vitamin-depleted that stimulate the growth and differentiation of one or
states. Whenever possible, such deficiencies should be cor- more types of leukocytes.
rected prior to initiating epoetin alfa therapy. Hemodialy-
sis patients with preexisting heart disease who are taking CSFs are produced by a diverse group of cells includ-
epoetin may require increased doses of heparin. Herbal/ ing endothelial cells, fibroblasts, macrophages, and T lym-
Food: Unknown. phocytes. Normally present at minute levels in the blood,
the production of CSFs rapidly increases when the body
Pregnancy: Category C. receives a bacterial challenge. The leukopoietic growth fac-
tors are active at very low concentrations; each stem cell
Treatment of Overdose: Overdose may lead to poly- stimulated by these growth factors is capable of producing
cythemia (too many erythrocytes), which can be corrected as many as 1000 mature leukocytes. The CSFs not only
by phlebotomy. increase the production of new leukocytes, but they also
activate existing WBCs. Examples of enhanced functions
Nursing Responsibilities: Key nursing implica- include increased migration of leukocytes to antigens,
tions for patients receiving epoetin alfa are included in the increased antibody toxicity, and increased phagocytosis.
Nursing Practice Application for Patients Receiving Phar-
macotherapy with Erythropoietin. CSFs are named according to the types of blood cells
that they stimulate. For example, granulocyte colony-
stimulating factor (G-CSF) increases the production of
neutrophils, the most common type of granulocyte. Granu-
locyte-macrophage colony-stimulating factor (GM-CSF)
696 Unit 5 Pharmacology of the Cardiovascular System
CONNECTIONS: NURSING PRACTICE APPLICATION
Patients Receiving Pharmacotherapy with Erythropoietin
Assessment
Baseline assessment prior to administration:
• Obtain a complete health history: cardiovascular (including HTN, MI) and peripheral vascular disease, respiratory (including previous pulmonary embo-
lism), neurologic (including stroke), hepatic disease, or CKD. Obtain a drug history including allergies, current prescription and over-the-counter (OTC)
drugs, herbal preparations, and alcohol use. Be alert to possible drug interactions.
• Obtain baseline weight and vital signs, especially blood pressure.
• Evaluate appropriate laboratory findings (e.g., complete blood count [CBC], activated partial thromboplastin time [aPTT], international normalized ratio
[INR], transferrin and serum ferritin levels, renal and liver function studies).
• Assess the patient’s ability to receive and understand instructions. Include family and caregivers as needed.
Assessment throughout administration:
• Continue assessment for therapeutic effects (e.g., Hct, RBC count significantly improved), patient’s activity level and ability to carry out ADLs has
improved.
• Continue frequent monitoring of appropriate laboratory values (e.g., CBC, aPTT, INR).
• Monitor vital signs frequently, especially blood pressure, during the first 2 wk of therapy.
• Assess for adverse effects: HTN, headache, neurologic changes in level of consciousness (LOC), or premonitory signs and symptoms of
seizure activity (e.g., aura), angina, signs of thrombosis development in peripheral extremities (e.g., leg pain, pale extremity, diminished
peripheral pulses).
Implementation
Interventions and (Rationales) Patient-Centered Care
Ensuring therapeutic effects: • Instruct the patient on the need to return frequently for follow-up
• Continue frequent assessments as above for therapeutic effects. (RBC laboratory work.
count increases rapidly in the first 2 wk of therapy. CBC and platelet
count should show continued improvement. Blood pressure and pulse
should remain within normal limits or within the parameters set by the
healthcare provider.)
• Encourage adequate rest periods and fluid intake. (The patient • Encourage the patient to rest when fatigued, and to space activities
may be significantly fatigued due to low Hgb and Hct levels. throughout the day to allow for adequate rest periods.
Adequate fluid intake helps maintain adequate fluid balance as
Hct levels rise.) • Encourage intake of water and nonhyperosmolar beverages.
Minimizing adverse effects: • Teach the patient, family, or caregiver how to monitor the pulse and
• Continue to monitor for adverse effects, especially HTN, peripheral blood pressure as appropriate. Ensure proper use and functioning of
any home equipment obtained.
thrombosis, or seizure activity. (Because Hct rapidly increases during
the first 2 wk of therapy, HTN or seizures may occur and should be • Instruct the patient, family, or caregiver to report headache
reported immediately. Peripheral thrombosis, including coronary or (especially if sudden onset or severe), changes in LOC,
cerebral, may also occur. Lifespan: Be especially cautious with the weakness or numbness in extremities, or premonitory signs
older adult who may be at greater risk for thromboembolic events due and symptoms of seizure activity (e.g., aura), angina, or symptoms
to age-related vascular changes.) of peripheral thrombosis (e.g., leg pain, pale extremity, diminished
peripheral pulses).
• Assess transportation needs of the patient and refer to appropriate • Advise the patient, family, or caregiver to consult with the healthcare
resources as needed. (Driving may be restricted up to 90 days after provider about driving or other hazardous activities during the first
initiation of drug therapy.) several months of drug therapy.
• Continue to monitor aPTT prior to dialysis in patients with CKD. • Explain any changes in the medication routine to the patient and
(Heparin dose during dialysis may need to be increased as Hct provide rationale.
increases.)
• Lifespan: Assess for the possibility of pregnancy or breastfeeding • Instruct female patients who may be considering pregnancy, or are
before beginning the drug. (Epoetin is a pregnancy category C drug pregnant or breastfeeding, to notify their provider before starting the
and the effects during breastfeeding are not fully known.) drug.
• Lifespan: When administering epoetin alpha to premature infants, use • To allay anxiety, offer parents rationales for all treatments provided for
preservative-free formulations. (Epoetin alfa may contain preserva- the infant.
tives such as benzyl alcohol. Benzyl alcohol may cause fetal gasping
syndrome.)
• Encourage adequate dietary intake of iron, folic acid, and vitamin B12. • Teach the patient to maintain a healthy diet with adequate amounts
Provide dietary consult as needed. Consider nutritional supplements of iron, folic acid, and vitamin B12 (found in meats, dairy, eggs,
of these nutrients if the diet is inadequate. (Response to epoetin alfa fortified cereals and breads, leafy green vegetables, citrus fruits,
may be decreased if blood levels of iron, folic acid, and vitamin B12 are beans and peas).
deficient.)
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.)
Chapter 39 Pharmacotherapy of Hematopoietic Disorders 697
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
Patient self-administration of drug therapy: • Teach the patient, family, or caregiver proper self-administration
• When administering medications, instruct the patient, family, or care- techniques. If an indwelling subcutaneous soft catheter (e.g., Insuflon
soft catheter) is left in place for injections, teach the patient, family, or
giver in proper self-administration techniques followed by teach-back. caregiver proper care of the site and catheter, and any schedule for
(Utilizing time during nurse administration of these drugs helps to rotating sites.
reinforce teaching.) Proper technique includes:
• The vial should be gently rotated to mix the content, never shaken. • Have the patient, family, or caregiver return demonstrate until the
Vials are kept under refrigeration and should be gently warmed in proper technique is used and the individual is comfortable giving
the hand. injections.
• All vials are for one-time use only and any remaining amount should be
discarded.
• If an indwelling subcutaneous soft catheter (e.g., Insuflon soft catheter)
is left in place, the patient, family, or caregiver should be taught appro-
priate site care, insertion technique as appropriate, and the schedule
for rotating sites.
stimulates both neutrophil and macrophage production. PROTOTYPE DRUG Filgrastim (Granix, Neupogen,
The process of identifying the many endogenous CSFs, Zarxio)
determining their normal functions, and discovering their
potential value as therapeutic agents is an emerging area of Classification T herapeutic: Drug for increasing neutro-
pharmacology. phil production
Through recombinant DNA technology, several CSFs are Pharmacologic: Colony-stimulating
now available as medications (see Table 39.1). The goal of factor
CSF therapy is to produce a rapid increase in the number of
neutrophils in patients who have suppressed immune sys- Therapeutic Effects and Uses: Produced through
tems (neutropenia). CSF therapy shortens the length of time recombinant DNA technology, filgrastim is nearly iden-
patients are neutropenic and susceptible to life-threatening tical in structure to human G-CSF and has the same bio-
bacterial and fungal infections. Neutropenia may also cause logic activity. Approved in 1991, its primary actions are to
chemotherapy schedules to be delayed or abandoned. By increase neutrophil production in the bone marrow and to
raising neutrophil counts, CSFs can assist in keeping antineo- enhance the phagocytic and cytotoxic functions of existing
plastic dosing regimens on schedule (and more effective). neutrophils. The subcutaneous route is preferred, although
The degree of increase in circulating neutrophils is dose filgrastim may also be administered by slow IV infusion.
related. Indications for CSF therapy include the following: A typical regimen is 5 to 10 mcg/kg given once or twice
daily. Continued therapy is based on absolute neutrophil
• Patients with cancer whose bone marrow has been counts (ANCs): Therapy is usually discontinued once lab-
suppressed by antineoplastic drugs oratory results indicate 10,000 cells/mm3 or greater.
• Patients with cancer who are receiving bone marrow TBO-filgrastim (Granix) was approved in 2012 as a
transplants self-administration kit so the drug may be injected at home.
Although not chemically identical to Neupogen, it has
• Patients with severe, chronic neutropenia (such as identical actions and adverse effects. In 2015, filgrastim-
those with AIDS) sndz (Zarxio) was the first biosimilar product approved in
the United States. It has the same indications, effectiveness,
• Patients undergoing peripheral mobilization of hema- and adverse effects as Neupogen.
topoietic progenitor cells for collection by leukaphere-
sis (collection of WBCs from a blood sample). Mechanism of Action: Filgrastim acts by the same
mechanism as endogenous G-CSF. The drug causes an
It is often difficult to assess the adverse effects of CSF increase in neutrophil production in the bone marrow,
medications because the same types of patient symptoms resulting in higher levels of circulating neutrophils.
may be caused by the condition or disease being treated.
Nonspecific adverse effects include nausea, vomiting, Pharmacokinetics:
fatigue, fever, and flushing. Therapy requires careful labora-
tory monitoring to avoid producing too many neutrophils. Route(s) IV, subcutaneous
Several recent research studies have suggested that the risk
of developing acute myeloid leukemia or myelodysplastic Absorption Rapidly absorbed (subcutaneous)
syndrome may be doubled when CSFs are administered to
patients undergoing chemotherapy for breast cancer. Distribution Unknown if it crosses the placenta
or is secreted in breast milk
698 Unit 5 Pharmacology of the Cardiovascular System
Primary metabolism Unknown Pegfilgrastim (Neulasta): Approved in 2002, pegfilgras-
Primary excretion Renal tim is a form of filgrastim bonded to a molecule of polyeth-
Onset of action 4h ylene glycol (PEG). This delays the renal excretion of the
Duration of action 4 days molecule, allowing the drug to remain in the body with a
sustained duration of action. Its only approved indication
Adverse Effects: Although filgrastim is well tolerated, is prophylaxis of chemotherapy-induced neutropenia. The
the drug is associated with potentially serious adverse drug is given by the subcutaneous route, once per chemo-
effects and close monitoring is required. Nausea and vom- therapy cycle. It should not be administered 14 days before
iting occur in the majority of patients. Bone pain may occur or 24 hours after the administration of cytotoxic chemo-
in up to 33% of patients receiving filgrastim. The pain may therapy. Adverse effects, interactions, and contraindica-
be diffuse or localized to bones with the greatest amount tions are the same as those of filgrastim. This drug is
of bone marrow: long bones, sternum, ribs, and pelvis. The pregnancy category C.
degree of pain is dose dependent and can usually be man-
aged with nonopioid analgesics. Frequent laboratory tests Sargramostim (Leukine): Sargramostim is structurally
are conducted to ensure that excessive numbers of neutro- very similar to natural GM-CSF and has the same biologic
phils (leukocytosis) do not occur. Leukocyte counts higher activity. It may be administered IV, but subcutaneous is the
than 100,000 cells/mm3 increase the risk of serious adverse preferred route. The drug has multiple effects that include
effects such as respiratory failure, intracranial hemorrhage increasing the number of circulating neutrophils, eosino-
or infarction, retinal hemorrhage, and MI. Hyperuricemia phils, and monocytes; activating macrophages; increasing
and elevated lactate dehydrogenase and alkaline phos- the cytotoxic activity of monocytes; and enhancing the bac-
phatase levels occur in a significant number of patients. tericidal activity of other cells of the immune system. Indi-
Splenomegaly may occur in 30% of patients receiving cations include decreasing the period of neutropenia in
long-term therapy with filgrastim. Other common adverse patients treated for acute lymphocytic leukemia or Hodg-
effects include fatigue, rash, epistaxis, decreased platelet kin’s disease and those having autologous bone marrow
counts, neutropenic fever, alopecia, and diarrhea. Allergic transplantation. Typically, therapy with sargramostim is
reactions, including anaphylaxis, are rare. initiated when ANC is less than 500 cells/mm3 and contin-
ues until an ANC of 1500 cells/mm3 for 3 consecutive days
Contraindications/Precautions: Patients with is achieved. To prevent leukocytosis, sargramostim should
hypersensitivity to Escherichia coli (E. coli) proteins should be discontinued if the ANC rises above 10,000 cells/mm3.
not receive filgrastim because this microbe is used to pro-
duce the recombinant drug. Patients with sickle cell dis- Like filgrastim, bone pain is a common adverse effect.
ease should be treated with caution because filgrastim may A serious adverse effect of sargramostim is respiratory dis-
worsen this condition. Filgrastim should not be adminis- tress that occurs during the IV infusion the first time the
tered to patients with myeloid cancers. drug is administered, which appears to be related to the
trapping of granulocytes in the pulmonary circulation.
Drug Interactions: Because antineoplastic drugs and The patient develops difficulty breathing, tachycardia, low
CSFs produce opposite effects, filgrastim is not administered blood pressure, and lightheadedness. These symptoms
until at least 24 hours after a chemotherapy session. Lithium usually call for discontinuing sargramostim therapy. This
causes the release of neutrophils and may contribute to fil- drug is pregnancy category C.
grastim-induced leukocytosis. Herbal/Food: Unknown.
CONNECTION Checkpoint 39.2
Pregnancy: Category C.
Zarxio is a biosimilar drug to filgrastim (Neupogen). From Chapter 1,
Treatment of Overdose: Overdose can lead to leuko- define the term biosimilar and describe how a biosimilar drug com-
cytosis and should be prevented by discontinuing the drug pares to its reference product. Answers to Connection Checkpoint
when ANC rises above 10,000 cells/mm3. There is no spe- questions are available on the faculty resources site. Please consult with
cific therapy for overdose. your instructor.
Nursing Responsibilities: Key nursing implications 39.4 Platelet enhancers may be used to treat
for patients receiving filgrastim are included in the Nurs- thrombocytopenia.
ing Practice Application for Patients Receiving Pharmaco-
therapy with Colony-Stimulating Factors. The production of platelets, or thrombocytopoiesis, begins
when megakaryocytes in the bone marrow start shedding
Drugs Similar to Filgrastim membrane-bound packets. These packets enter the blood-
stream and become platelets. A single megakaryocyte can
(Granix, Neupogen, Zarxio) produce thousands of platelets.
The two other CSFs are pegfilgrastim and sargramostim.
Chapter 39 Pharmacotherapy of Hematopoietic Disorders 699
CONNECTIONS: NURSING PRACTICE APPLICATION
Patients Receiving Pharmacotherapy with Colony-Stimulating Factors
Assessment
Baseline assessment prior to administration:
• Obtain a complete health history including recent or current infections; recent surgeries, injuries, or wounds; yeast infections (e.g., thrush); vaccination
history; cardiac conditions (e.g., dysrhythmias, heart failure [HF]); respiratory, renal, and hepatic conditions. Obtain a drug history including allergies,
current prescription and OTC drugs, herbal preparations, and alcohol use. Be alert to possible drug interactions.
• Obtain baseline weight and vital signs. Assess level of fatigue.
• Evaluate appropriate laboratory findings (e.g., CBC, WBC, or ANC, renal and liver function studies, uric acid levels, and electrocardiogram [ECG]).
ANC 5 total WBC count multiplied by the total percentage of neutrophils (segmented plus bands); e.g., WBC 5,000 3 (0.45 segs 1 0.05 banded
neutrophils) 5 5000 3 0.5 5 ANC of 2500.
• Assess the patient’s ability to receive and understand instructions. Include family and caregivers as needed.
Assessment throughout administration:
• Continue assessment for therapeutic effects (e.g., CBC, WBC, or ANC has increased, no signs or symptoms of infection).
• Continue frequent monitoring of appropriate laboratory values (e.g., CBC, WBC, or ANC, Hct, platelet count, renal and hepatic laboratory results,
uric acid levels).
• Monitor vital signs and level of fatigue.
• Assess for adverse effects: bone pain (especially lower back, posterior iliac crests, and sternum), fever, nausea, anorexia, hyperuricemia, anemia,
ST-segment depression on ECG, angina, respiratory distress, and allergic reaction. Continue to assess for infection and fatigue related to the drug
treatment (e.g., chemotherapy).
Implementation
Interventions and (Rationales) Patient-Centered Care
Ensuring therapeutic effects: • Instruct the patient on the need to return frequently for follow-up
• Continue frequent assessments as above for therapeutic effects. (Rise laboratory work.
in WBC or ANC counts will depend on the condition treated, e.g., depth
and length of nadir from cytotoxic chemotherapy. Counts are usually
monitored twice per week or as ordered by the healthcare provider.)
• Encourage adequate rest periods and adequate fluid intake. (The • Encourage the patient to rest when fatigued and to space activities
patient may be significantly fatigued due to the drug therapy. Adequate throughout the day to allow for adequate rest periods.
fluid intake helps maintain adequate urinary output and prevent urinary
tract infections.) • Encourage intake of water and nonhyperosmolar beverages, and drink-
ing whenever thirsty.
Minimizing adverse effects:
• Continue to monitor for adverse effects: bone pain (especially lower • Instruct the patient to report any severe bone pain not relieved by
nonnarcotic analgesics.
back, posterior iliac crests, and sternum), fever, nausea, anorexia,
hyperuricemia, anemia, ST-segment depression on ECG, angina, respi- • Teach the patient to report any palpitations, dizziness, angina, or
ratory distress, and allergic reaction. Continue to assess for infection dyspnea immediately.
and fatigue related to drug treatment, e.g., chemotherapy. (Bone pain
tends to occur 2–3 days prior to rise in circulating WBCs due to the • Gout-prone patients should report signs and symptoms of gout and
production of WBCs in bone marrow. ST-segment depression on ECG increase fluid intake to enhance renal elimination of uric acid.
may occur with potential for serious dysrhythmias. Respiratory distress
may develop after administration of sargramostim and should be Instruct the patient in hygiene and infection control measures such as:
reported immediately. Hyperuricemia may cause gout-like conditions.) • Wash hands frequently.
• Avoid crowded indoor places.
• Maintain meticulous infection control measures. Immediately report any • Avoid people with known infections or young children, because they
signs and symptoms of fever or infections, especially viral or fungal.
(The patient will continue to be at risk for infections until WBC or ANC have a higher risk of having an infection.
levels rise. Opportunistic infections, such as yeast, and viruses, such • Cook food thoroughly and do not consume raw fruits or vegetables.
as herpes simplex, may occur. Parameters will be set by the healthcare
provider for reporting fever, e.g., any temperature over 38°C [100.5°F], Allow the family or caregiver to prepare raw meats or fish and to
dependent on the underlying disease condition and drug therapy.) clean up.
• Instruct the patient to report any fever per the parameters set by the
healthcare provider, and symptoms of infection such as wounds with
redness or drainage, increasing cough, increasing fatigue, white patch-
es on oral mucous membranes, white and itchy vaginal discharge, or
itchy blister-like vesicles on the skin.
• Monitor ECG periodically for ST-segment depression or dysrhythmias, • Instruct the patient to report any palpitations, dizziness, or angina
and report immediately. (Sargramostim may cause significant ST- immediately.
segment depression with potential for serious dysrhythmias, especially
in patients with previous cardiac conditions.)
• Monitor for signs of dyspnea or respiratory distress, especially when • Instruct the patient to immediately report any dyspnea, respiratory
accompanied by tachycardia and hypotension, and report immediately. distress, palpitations, or dizziness.
(Sargramostim may cause respiratory distress as granulocyte counts
rise, especially in patients with preexisting respiratory disorders.)
• Monitor for signs and symptoms of allergic-type reactions. (The patient • Instruct the patient to immediately report symptoms of allergic reaction
may be hypersensitive to proteins used in the drug development process.) such as rash, urticaria, wheezing, and dyspnea.
(continued )
700 Unit 5 Pharmacology of the Cardiovascular System
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
• Monitor hepatic status during drug administration period. (Filgrastim • Instruct the patient to report any significant itching, yellowing of the
may cause an elevation in liver enzymes.) sclera or skin, darkened urine, or light or clay-colored stools.
• Stop administration when WBC counts reach a level determined by • Instruct the patient on the importance of returning regularly for
the healthcare provider. (Filgrastim may be stopped when neutrophil laboratory work.
counts reach 10,000/mm3, sargramostim when neutrophil counts
reach 20,000/mm3, or as ordered by the provider.)
• Assess for spleen enlargement periodically and report. (Filgrastim has • Instruct the patient, family, or caregiver to report any symptoms of left
been associated with rare but potentially fatal cases of splenomegaly upper abdominal pain or left shoulder pain, which may indicate spleen
and rupture.) enlargement or rupture.
• Lifespan: Monitor laboratory results for pediatric patients with forms • Teach the patient, family, or caregiver that frequent laboratory studies
of congenital neutropenia (e.g., congenital agranulocytosis) more fre- may be needed.
quently. (Patients with these disorders are at greater risk for developing
acute myelogenous leukemia [AML] and myelodysplastic neutropenia
[MDS] related to drug therapy.)
• Lifespan: Assess for the possibility of pregnancy or breastfeeding • Instruct women who may be considering pregnancy, or are pregnant
before beginning the drug. (Colony-stimulating factors are pregnancy or breastfeeding, to notify their provider before starting the drug.
category C drugs and the effects during breastfeeding are not fully
known.)
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 assess- the drug, appropriate dose and scheduling, what adverse effects to
observe for and when to report them, and the anticipated length of
ments to discuss the rationale for drug therapy, desired therapeutic medication therapy.
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.)
Patient self-administration of drug therapy: • Teach the patient, family, or caregiver in proper self-administration
• When administering medications, instruct the patient, family, or care- techniques. If indwelling subcutaneous soft catheter (e.g., Insuflon soft
catheter) is left in place for injections, teach the patient, family, or care-
giver in proper self-administration techniques followed by teach-back. giver proper care of the site, catheter, and any schedule for rotating
(Utilizing time during nurse administration of these drugs helps to sites.
reinforce teaching.) Proper technique includes:
• The vial should be gently rotated to mix the contents, never shaken. • Have the patient, family, or caregiver return demonstrate until the
Vials are kept under refrigeration and should be gently warmed in the proper technique is used and the individual is comfortable giving the
hand. injection.
• All vials are for one-time use only and any remaining amount should be
discarded.
• If an indwelling subcutaneous soft catheter (e.g., Insuflon soft catheter)
is left in place, the patient, family, or caregiver should be taught
appropriate site care, insertion technique as appropriate, and schedule
for rotating sites.
Megakaryocyte activity is controlled by the hormone chronic immune (idiopathic) thrombocytopenia purpura
thrombopoietin, which is produced by the liver and bone (ITP). Chronic ITP is a disorder characterized by inade-
marrow. Thrombopoietin is not available as a medication, quate platelet production or increased platelet destruction.
although it has undergone clinical trials. Oprelvekin (Neu- Patients with ITP experience a high risk for bruising and
mega) is a hematopoietic growth factor available to enhance bleeding, which may occur anywhere in the body.
platelet production. This drug is functionally equivalent to
endogenous interleukin-11 (IL-11). Interleukins are cyto- PROTOTYPE DRUG Oprelvekin (Neumega)
kines secreted by monocytes, lymphocytes, and other cell
types that signal cells in the immune system to respond to Classification Therapeutic: Platelet enhancer
an infection. Over 30 interleukins have been identified but Pharmacologic: Interleukin
only a few have been isolated and approved as drugs.
Therapeutic Effects and Uses: Produced through
Romiplostim (Nplate) and eltrombopag (Promacta) are recombinant DNA technology, oprelvekin is used to stimu-
classified as thrombopoietin receptor agonists. These drugs late the production of platelets in patients who are at risk
activate the natural thrombopoietin receptor, thus inducing for severe thrombocytopenia caused by the chemotherapy
megakaryocyte division and differentiation. Both drugs of nonmyeloid cancers. Approved in 2002, the drug short-
take 10 to 15 days to produce their effects. They are ens the time that the patient is thrombocytopenic and most
approved to improve platelet function in patients with
Chapter 39 Pharmacotherapy of Hematopoietic Disorders 701
susceptible to adverse bleeding events. Dosing is initiated Drug Interactions: Oprelvekin should not be admin-
6 to 24 hours after chemotherapy and continues daily until istered within 24 hours of chemotherapy because the
the platelet count is greater than 50,000/mm3. Dosing cytotoxic effects of the antineoplastic drugs decrease the
beyond 21 days is not recommended. Platelet counts will effectiveness of the drug. Concurrent use with thiazide or
remain elevated for about 7 days after the last dose. Ther- loop diuretics may cause serious hypokalemia. Herbal/
apy with oprelvekin decreases the need for platelet infu- Food: Unknown.
sion. Oprelvekin is only given by the subcutaneous route.
Pregnancy: Category C.
Mechanism of Action: Oprelvekin is equivalent to
endogenous IL-11 and directly stimulates the synthesis Treatment of Overdose: Overdose may result in seri-
and maturation of megakaryocytes into platelets. ous adverse effects, and close monitoring of cardiovascu-
lar and renal function is necessary. No specific therapy is
Pharmacokinetics: available.
Route(s) Subcutaneous Nursing Responsibilities:
Absorption 80% absorbed • Notify the prescriber prior to administration if the
patient has a history of leukemia, multiple myeloma,
Distribution Well distributed to highly or other myeloid malignancies.
perfused organs; unknown if it • Monitor for and immediately report signs and symp-
toms of fluid overload, hypokalemia, and cardiac
crosses the placenta or is secreted dysrhythmias.
in breast milk • Monitor patients with preexisting fluid retention con-
ditions carefully, such as HF, pleural effusion, or asci-
Primary metabolism Not metabolized tes, for worsening of symptoms.
Primary excretion Renal • This drug has a black box warning for possible anaphy-
laxis. Promptly report any signs and symptoms of aller-
Onset of action 5–9 days gic reaction to the provider and discontinue the drug.
Duration of action 7 days; half-life: 6.9 h Lifespan and Diversity Considerations:
Adverse Effects: Oprelvekin causes many adverse • Tachycardia, cardiomegaly, papilledema, conjunctival
effects, although most are reversible upon discontinu- redness, and bone changes may occur more frequently
ation of therapy. The most common adverse effects in children taking oprelvekin than in adults. Carefully
include nausea, vomiting, edema, neutropenic fever, dys- monitor heart rate and heart sounds, changes in visual
pnea, mucositis, and diarrhea. Fluid retention is a seri- acuity or eye pain, and for complaints of bone pain or
ous adverse effect that occurs in about 60% of patients changes in gait. Further cardiac testing (e.g., echocar-
and can be a concern for patients with preexisting car- diography) and frequent eye exams may be warranted.
diovascular disease or CKD. Adverse effects related to
fluid retention may be severe and include pulmonary Patient and Family Education:
edema, pericardial effusion, and ascites. Cardiovascu-
lar adverse effects include transient atrial dysrhythmias, • Do not take any other prescription or nonprescription
sinus tachycardia, vasodilation, and peripheral edema. drugs, dietary supplements, or herbal products with-
Papilledema (swelling of the optic nerve) can occur dur- out the approval of the healthcare provider.
ing therapy and result in blurred vision, loss of visual
acuity, and blindness, in rare cases. Black Box Warning: • Immediately report shortness of breath, swelling of
Although not common, allergic reactions, including ana- feet or ankles, rapid weight gain, chest pain, unusual
phylaxis, have been reported with oprelvekin. The drug fatigue or weakness, irregular heartbeat, fever of 38°C
should be permanently discontinued if a patient experi- (100.5°F) or higher, unusual bruising or bleeding, or
ences a hypersensitivity reaction. blurred vision.
Contraindications/Precautions: Oprelvekin is con- • For self-administration, follow the procedure demon-
traindicated in patients who have shown hypersensitiv- strated to prevent contamination of the vial, syringe,
ity to the drug on a previous exposure. It should be used or medicine. Never touch the rubber stopper of the
with caution in patients with cardiac disease, especially vial or the needle of the syringe with your fingers. Dis-
HF, dysrhythmias, and left ventricular dysfunction, since pose of needles and syringes as directed by a health-
fluid retention is a common adverse effect that can worsen care provider.
these conditions. Oprelvekin should not be used following
myeloablative therapy because the drug exhibits increased • Do not drive or perform other hazardous activities
toxicity. The drug should be used with caution in patients until the effects of the drug are known because this
with preexisting visual impairment; papilledema is a dose- drug may cause drowsiness or dizziness.
limiting adverse effect in children receiving this drug.
702 Unit 5 Pharmacology of the Cardiovascular System
• Notify the healthcare provider of any difficulty walk- CONNECTION Checkpoint 39.3
ing or bone pain, changes in visual acuity or eye pain,
or rapid heart rate. Abciximab, eptifibatide, and tirofiban are drugs that can cause
severe ITP. From what you learned in Chapter 38, to what class
• Immediately notify the healthcare provider of any do these drugs belong and what is the primary indication for their
known or suspected pregnancy. use? Answers to Connection Checkpoint questions are available on
the faculty resources site. Please consult with your instructor.
• Do not breastfeed while using this drug without
approval of the healthcare provider. Classification of Anemias
Drugs Similar to Oprelvekin (Neumega) 39.5 Anemias may be caused by hemorrhage
or a change in red blood cell production or
The two other platelet enhancers are eltrombopag and destruction.
romiplostim.
Anemia is a condition in which RBCs have a reduced
Eltrombopag (Promacta): Approved in 2008, eltrombopag capacity to deliver oxygen to tissues. Anemia is a serious
is an oral medication that increases the number of platelets health problem that can have a major impact on the quality
in the blood by activating thrombopoietin receptors. Its of life. It is estimated that over 3.4 million Americans have
only indication is for the treatment of thrombocytopenia in the disorder. Although there are dozens of possible causes
patients with chronic ITP who have not responded to corti- of anemia, most fall into one of the following categories:
costeroids, immunoglobulins, or splenectomy. The drug
carries a black box warning that it may cause hepatotoxic- • Blood loss due to hemorrhage
ity. Liver laboratory values (alanine aminotransferase • Increased erythrocyte destruction
[ALT], aspartate aminotransferase [AST], and bilirubin) • Decreased erythrocyte production.
must be closely monitored and the drug discontinued if
abnormal values persist. The most common adverse effects Anemia is considered a sign of an underlying disorder,
include nausea, diarrhea, upper respiratory tract infection, rather than a distinct disease. For example, anemia is com-
vomiting, increased ALT, myalgia, urinary tract infection, monly associated with peptic ulcer, various malignancies,
oropharyngeal pain, increased AST, pharyngitis, back and CKD. For therapy to be successful, the underlying
pain, influenza, paresthesia, and rash. Because of the pathology must be identified and treated. Despite the fact it
potential for serious adverse effects, the drug is available is often considered secondary to other diseases, proper
through a restricted distribution program. This drug is treatment of anemia is necessary to improve the patient’s
pregnancy category C. ability to adequately perform ADLs.
Romiplostim (Nplate): Like eltrombopag, romiplostim Classification of anemia is generally based on a
was approved in 2008 and increases platelet count by acti- description of the erythrocyte’s size and color. Sizes are
vating the thrombopoietin receptor. Also like eltrombopag, described as normal (normocytic), small (microcytic), or
the only indication is for the treatment of thrombocytope- large (macrocytic). Color is based on the amount of Hgb
nia in patients with chronic ITP who have not responded present and is described as normal red (normochromic) or
to corticosteroids, immunoglobulins, or splenectomy. light red (hypochromic). This classification is shown in
Romiplostim, however, does not exhibit hepatotoxicity. Table 39.2. It is not unusual for patients to have more than
The most common adverse effects are arthralgia, dizziness, one type of anemia concurrently.
insomnia, myalgia, pain in extremity, abdominal pain,
shoulder pain, dyspepsia, and paresthesia. It is only Depending on the type of anemia, several vitamins
administered by subcutaneous injection and the drug has a and minerals may be given to enhance the oxygen-carrying
restricted distribution program. This drug is pregnancy capacity of blood. The most common antianemic drugs are
category C. iron salts, cyanocobalamin (Nascobal), and folic acid. Doses
of these drugs are listed in Table 39.3.
Table 39.2 Classification of Anemia
Morphology Description Examples
Pernicious anemia, folate deficiency anemia
Macrocytic-normochromic Large, abnormally shaped erythrocytes with normal Hgb
Microcytic-hypochromic concentration Iron deficiency anemia, thalassemia
Normocytic-normochromic
Small, abnormally shaped erythrocytes with decreased Hgb Aplastic anemia, hemorrhagic anemia, sickle cell
concentration disease, hemolytic anemia
Destruction or depletion of normal erythroblasts or mature
erythrocytes
Chapter 39 Pharmacotherapy of Hematopoietic Disorders 703
Table 39.3 Antianemic Drugs
Drug Route and Adult Dose (Maximum Dose Where Indicated) Adverse Effects
cyanocobalamin (Nascobal) Diarrhea, hypokalemia, rash
IM/deep subcutaneous: 30 mcg/day for 5–10 days, then Anaphylaxis
folic acid 100–200 mcg/month
Intranasal: 1 spray (500 mcg) in one nostril once weekly Flushing, rash
PO/IM/subcutaneous/IV: less than 1 mg/day
Iron Salts Hypersensitivity
ferrous fumarate (Feostat, others) PO: 200 mg tid or qid Nausea, heartburn, constipation, dark
stools
ferrous gluconate (Fergon, Ferralet) PO: 325–600 mg qid; may be gradually increased to 650 mg
qid as needed Cardiovascular collapse, aggravation of
peptic ulcers or ulcerative colitis, hepatic
ferrous sulfate (Feosol, Feostat, others) PO: 100–200 mg elemental iron q12h necrosis, hypotension (ferumoxytol),
anaphylaxis (iron dextran), respiratory arrest
ferumoxytol (Feraheme) IV: Single dose of 510 mg followed by a second 510-mg dose (iron dextran), seizures (iron dextran)
3–8 days later
iron dextran (Dexferrum) IM/IV: Dose is individualized and determined from a table supplied
by the drug manufacturer that correlates body weight to Hgb values
(max: 100 mg within 24 h)
iron sucrose (Venofer) IV: 100–200 mg by slow IV injection or infusion
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
CONNECTIONS: Community- production in cells. It is also a component of certain anti-
Oriented Practice oxidant enzymes that assist in clearing the body of free
radicals. Most iron in the body, 60% to 80%, is associated
Epoetin Alfa for Blood Doping with Hgb inside erythrocytes. Knowledge of iron balance
and homeostasis is necessary to understand the pharmaco-
Blood doping, withdrawing blood from an athlete and then therapy of iron deficiency anemia. Factors affecting iron
re-transfusing it before a competitive sporting event, has been balance are illustrated in Figure 39.2.
used by some athletes in an attempt to gain a competitive edge.
With increased RBCs and higher Hgb levels, oxygen-carrying The two basic forms of iron in biological systems are fer-
capacity is thought to increase, boosting endurance. With the rous (Fe21) and ferric (Fe31). Most food contains iron in the
advent of epoetin alfa, blood doping took on new meaning. Some ferric state, which is not absorbed in the gastrointestinal (GI)
athletes found that the use of epoetin well before an athletic meet tract. In the presence of stomach acid, however, the ferric form
achieved the same effects without the ability to detect the drug is converted to the ferrous form, which is readily absorbed in
through testing. Charges of blood doping with epoetin were ini- the duodenum. Iron absorption is dynamic; if the body senses
tially difficult to prove, but as more sophisticated tests became a shortage of iron in the blood, GI absorption increases. When
available, detection of the presence of the drug was possible, and iron stores are plentiful, less iron is absorbed from food. Since
athletes were ejected from events or had their winnings disquali- adults only need about 8 mg of iron per day, a normal diet
fied. Newer drugs, without new tests to detect them initially, are supplies sufficient amounts of the mineral for most people.
on the horizon, and the race against cheating in sports continues.
Other factors affect the absorption of iron. Iron in
Blood doping is not without a price, however. Increased heme, which is found in meat, fish, and poultry, is 3 times
blood volume and viscosity have led to hypertension, throm- more absorbable than the nonheme iron found in vegeta-
bosis, and death. Undeterred, some athletes, desperate for a bles and grains. Thus meats are considered the best natural
competitive edge, continue to use it. Adolescents involved in source of absorbable iron. Calcium inhibits the absorption
competitive sports activities may have heard about epoetin of iron; thus, those who drink milk with meals are at greater
and may question its advantages. The nurse plays a key role in risk for iron deficiency. Vitamin C increases iron absorption
providing accurate information about epoetin and related about 30%, while black tea diminishes absorption.
drugs and counseling athletes about the risks and adverse
effects of performance-enhancing drugs. Because free iron is toxic, the body binds the mineral to
the protein complexes ferritin, hemosiderin, and transfer-
Antianemic Drugs rin. Ferritin and hemosiderin maintain iron stores inside
cells, whereas transferrin transports iron to sites through-
39.6 Administration of iron salts can rapidly out the body where it is needed, such as to the bone mar-
reverse symptoms of iron deficiency anemia. row for incorporation into Hgb. Serum ferritin levels are a
reliable indicator of how much iron is being stored by the
Iron is a mineral essential to the function of several mito- body. Low serum ferritin levels (less than 12 ng/mL) are
chondrial enzymes involved in metabolism and energy characteristic of iron deficiency anemia. In addition to Hgb,
704 Unit 5 Pharmacology of the Cardiovascular System
Dietary iron
Absorption
Muscle Plasma Bone
Myoglobin Fe-transferrin marrow
Liver Storage Red blood
cells
Iron loss
in feces RBC
Figure 39.2 Iron metabolism. destruction
Bilirubin
Spleen
major storage depots for iron are the liver and myoglobin Iron therapy is initiated to alleviate symptoms of ane-
in skeletal muscle. mia caused by blood loss or dietary deficiency. Once diag-
nosed, a primary goal is to identify the etiology of the
After erythrocytes die, nearly all of the iron in their disorder and treat the underlying pathology. Choice of
Hgb is incorporated into transferrin and recycled for later therapy depends on the etiology and severity of the
use. Because of this efficient recycling, only about 1 mg of deficiency:
iron is excreted from the body per day, making daily dietary
iron requirements in most individuals quite small. Vegetar- • Mild anemia may be prevented or corrected in most
ians are at higher risk of iron deficiency anemia because of patients by increasing the intake of iron-rich foods,
a lack of heme intake from meat and must take care to such as fish, red meat, fortified cereal, and whole-
select foods rich in iron. Iron requirements may double grain breads.
during growth, pregnancy, and menses; thus, intake of iron
must be increased to maintain proper iron balance. • Moderate anemia is corrected by oral iron supple-
mentation.
Iron deficiency is the most common cause of anemia
worldwide. More than 50% of patients diagnosed with iron • Severe anemia, and that caused by iron malabsorption
deficiency anemia have GI bleeding, such as may occur disorders, is corrected by parenteral iron therapy.
from GI malignancies or chronic peptic ulcer disease (PUD).
In the United States and Canada, iron deficiency most com- CONNECTIONS: Patient Safety
monly occurs in women of childbearing age due to preg-
nancy and as a result of blood losses during menses. Iron Poisoning in Children
Low-dose iron supplements are recommended during
pregnancy to prevent this condition. Certain individuals While talking with a group of young mothers, the nurse
have an increased demand for iron, including those who are becomes concerned about the remarks made by one of the
on meat-free diets or undergoing intensive athletic training. members. The mother states, “I insist that my children take
These conditions may require more than the recommended iron-fortified vitamins every day. My children really enjoy taking
dietary allowance (RDA) of iron (see Chapter 61). In unde- the cute little cartoon vitamins. They call the vitamins their
veloped countries, the primary cause of iron deficiency ane- ‘morning candy.’” How should the nurse respond? Is this
mia is the lack of meat or fresh fruits and vegetables in the statement made by the mother concerning to the nurse?
diet. The most significant effect of iron deficiency is a reduc-
tion in erythropoiesis, resulting in symptoms of anemia. Answers to Patient Safety questions are available on the faculty
resources site. Please consult with your instructor.
Chapter 39 Pharmacotherapy of Hematopoietic Disorders 705
PROTOTYPE DRUG Ferrous Sulfate (Feosol, Feostat, Primary excretion Feces, urine, and skin
Others) Onset of action 3 days to 4 weeks
Duration of action Unknown
Classification Therapeutic: Drug for anemia
Pharmacologic: Iron supplement Adverse Effects: The most common adverse effects of
ferrous sulfate are nausea and vomiting, which will occur
Therapeutic Effects and Uses: Ferrous sulfate is to some degree in most patients. Taking the drug with food
an iron supplement containing about 20% elemental iron. will diminish GI upset but can decrease the absorption of
Desiccated (dried) ferrous sulfate contains 30% elemen- iron by 50% to 70%. The degree of nausea and vomiting
tal iron. It is inexpensive and available in a wide variety is dose related and serious symptoms may require a dos-
of dosage forms to prevent or rapidly reverse symptoms age adjustment. Contact of liquid iron with teeth should
of iron deficiency anemia. Enteric-coated and extended be avoided because the drug can cause brown stains.
release forms are available. If tolerated, the drug should Iron preparations will darken stools but this is a harmless
be taken on an empty stomach, at least 1 hour before or adverse effect. Because constipation is common, especially
2 hours after a meal. in older adults, an increase in dietary fiber intake is indi-
cated. Black Box Warning: Unintentional overdoses of
In general, patients with iron deficiency respond rap- iron-containing products are a leading cause of fatal poi-
idly to the administration of ferrous sulfate. Although a soning of children.
positive therapeutic response may be achieved in 48 hours,
therapy may continue for several months to replenish the Contraindications/Precautions: Iron salts should not
storage depots for iron. As the deficiency is corrected, the be administered for anemia other than that caused by iron
body will absorb a smaller percentage of elemental iron in deficiency, because iron will not correct these conditions and
each dose until iron intake balances iron loss. This is assum- may build to toxic levels. The drug should not be adminis-
ing, of course, that the source of the iron imbalance, such as tered to patients with hemochromatosis, a disease in which
bleeding or dietary insufficiency, has been corrected. Labo- the patient has excess iron stores. Ferrous sulfate may irri-
ratory evaluation of Hgb, transferrin, and Hct levels is con- tate the stomach mucosa and increase bleeding in patients
ducted regularly to assess the progress of pharmacotherapy. with PUD. The drug may cause diarrhea if administered to
Dosage is decreased as therapy progresses and the defi- patients with regional enteritis or ulcerative colitis.
ciency is corrected.
Drug Interactions: Absorption is reduced when oral
If rapid, symptomatic improvement is not experienced, iron salts are given concurrently with antacids, proton
the reasons for the treatment failure must be carefully pump inhibitors, or calcium supplements. Iron decreases
explored. The patient may be experiencing continued the absorption of tetracyclines, fluoroquinolones,
bleeding or may have a malabsorption disorder that pre- levodopa, and etidronate. To prevent possible interactions,
vents the iron from being absorbed. A common reason for it is advisable to take iron supplements 1 to 2 hours before
treatment failure is lack of adherence to pharmacotherapy. or after other medications. Herbal/Food: Food (especially
Patients may stop taking the drug due to severe nausea and dairy products), coffee, and tea will inhibit iron absorp-
vomiting, or they may take the drug with food or other tion. Vitamin C will increase absorption.
drugs that inhibit iron absorption. Excellent assessment
and teaching skills on the part of the nurse are key to Pregnancy: Category A.
achieving successful pharmacotherapeutic outcomes in
these patients. Treatment of Overdose: Iron is very toxic and most
overdoses are unintentional, occurring in children under
Mechanism of Action: After absorption, most iron is the age of 6 years. The antidote for acute iron intoxication
used by the body to make Hgb. Laboratory values of Hgb is the parenteral drug deferoxamine (Desferal). This che-
should increase 2 to 4 g/dL every 3 weeks until normal lating drug binds iron, which is removed by the kidneys,
values are achieved. In addition, therapy is continued until turning the urine a reddish-brown color.
serum ferritin levels return to normal, indicating that the
iron storage depots are filled. Nursing Responsibilities:
Pharmacokinetics: • Give on an empty stomach if possible because oral
iron preparations are best absorbed between meals. If
Route(s) PO GI adverse effects are prominent, give with or imme-
diately after meals with adequate liquid.
Absorption 5–30% absorbed
• If the patient experiences difficulty swallowing tablets
Distribution Well distributed; crosses or capsules, recommend a liquid formulation or a less
corrosive form, such as ferrous gluconate.
the placenta
Primary metabolism Undergoes extensive
enterohepatic recirculation
706 Unit 5 Pharmacology of the Cardiovascular System
• Dilute liquid preparations well and give them through Table 39.4 Iron Content of Oral Iron Formulations
a straw or place them on the back of the tongue with a
dropper to prevent staining of teeth and to mask the Preparation Elemental Dose Needed to
unpleasant taste. Iron Provide 200 mg of
Elemental Iron per Day
• Mix Feosol elixir with water because it is not compati-
ble with milk or fruit juice. Fer-In-Sol (drops) may be carbonyl iron 100% 200 mg
given in water or in fruit or vegetable juice, according 33% 600 mg
to the manufacturer. ferrous fumarate 12% 720 mg
30% 660 mg
• Iron therapy may be continued for 2 to 3 months after ferrous gluconate
the Hgb level has returned to normal (roughly twice 20% 1000 mg
the period required to normalize Hgb concentration). ferrous sulfate: 100% 200 mg
desiccated
• Monitor bowel movements because constipation is a
common adverse effect. Increase the amount of fluids ferrous sulfate: regular
and soluble fiber in the diet.
polysaccharide-iron
Lifespan and Diversity Considerations: complex
• Due to age-related changes in peristalsis and bowel on iron content and degree of GI tolerability. Table 39.4
function, monitor the older adult for constipation. lists the amount of elemental iron in these drugs.
Increase the amount of fluids and soluble fiber in the
diet. A stool softener or laxative may be needed. A large number of brand-name iron products and for-
mulations are available, including tablets, drops, elixirs,
• Keep iron preparations in a secured location if there and suspensions. Nausea, vomiting, constipation, and diar-
are young children in the household to prevent unin- rhea are common adverse effects with all oral iron prepara-
tentional poisoning. tions. Slow-release products, called carbonyl iron
(Feosol-caps, Ferronyl), are more expensive but are less
Patient and Family Education: dangerous in children following unintentional ingestion
because there is a longer period for intervention before toxic
• Do not take tablets or capsules within 1 hour of effects materialize. Some products have an enteric coating
bedtime. so that the capsule or tablet dissolves in the intestine, thus
causing less gastric irritation. Recall, however, that stomach
• Do not crush tablets or empty the contents of capsules acid is necessary to convert iron to its more absorbable
because this may cause GI distress. form. In addition, enteric coatings are less reliable because
they may dissolve after the drug has passed the duodenum,
• Take ferrous sulfate with a full glass of water. Rinse which is the primary site for iron absorption. Vitamin C is
mouth with clear water immediately after ingestion. added to many oral iron supplements because it enhances
iron absorption. Some products are formulated as multivi-
• Consume citrus fruit or tomato juice with iron prepa- tamins. For example, Niferex PN Forte, which is formulated
rations (except the elixir form) because ascorbic acid specifically for pregnant or lactating women, contains a
(vitamin C) increases iron absorption. polysaccharide-iron complex and vitamins A, D, C, folic
acid, B complex, calcium, iodine, magnesium, copper, and
• Avoid taking iron salts with milk, eggs, antacids, or zinc. Adding extra enhancers such as additional vitamins,
caffeine beverages, because these inhibit drug extended release properties, or an enteric coating increases
absorption. the cost of the drug but not necessarily its effectiveness. The
amount of elemental iron in the product and adverse effects
• Iron preparations cause dark green or black stools. should be the primary factors guiding therapy.
This is a harmless side effect.
Parenteral iron salts: Ferumoxytol (Feraheme), iron
• Report constipation or diarrhea to the healthcare pro- dextran (Dexferrum), iron sucrose (Venofer), and ferric
vider. Symptoms may be relieved by adjustments in gluconate (Ferrlecit) are parenteral preparations reserved
dosage or diet, or by changing to another iron for patients who cannot tolerate oral iron preparations or
preparation. who have a malabsorption disorder preventing iron
absorption from the GI tract. Giving parenteral iron does
Drugs Similar to Ferrous Sulfate not lead to a faster recovery for patients with iron defi-
(Feosol, Feostat, Others) ciency anemia because the body is limited as to how
quickly it can make Hgb and new RBCs. These drugs are
At least eight iron salts are available for administration to clearly more toxic than the oral iron products and require
patients with iron deficiency anemia. Iron salts are often careful monitoring during pharmacotherapy.
classified by their route of administration, either oral (PO)
or parenteral.
Oral iron salts: Oral iron salts include ferrous fumarate,
ferrous gluconate, polysaccharide-iron complex, and car-
bonyl iron. The choice of specific drug and dose are based
Chapter 39 Pharmacotherapy of Hematopoietic Disorders 707
Ferumoxytol (Feraheme) is a newer iron salt approved Dietary vitamin B12 (from meat)
to treat iron deficiency associated with chronic kidney dis-
ease (with or without dialysis). The drug consists of iron Free B12 IF = Intrinsic factor
oxide protected by a carbohydrate shell. The shell remains IF Parietal cells
intact until the drug enters macrophages, whereby the iron
is released to its storage depots. The advantage of ferumoxy- B12 - IF
tol over other iron salts is that it can be administered safely
by the IV route and can raise iron levels more rapidly. Ileum B12 can be absorbed
only in last 60 cm of
All parenteral drugs are equally effective at raising B12 - IF the small intestine
iron levels. All are given IV. Iron dextran is also available
by the IM route although this is rarely used due to pain at B12 To Liver
the injection site and unreliable absorption from the mus- storage B12 storage
cle. Iron sucrose and iron gluconate have more limited Blood (3–5 yr supply)
application. They are approved only for patients with iron vessel Excretion
deficiency anemia undergoing chronic hemodialysis who
are also receiving erythropoietin. To growing cells B12 to bile
(recycled)
Anaphylaxis has been reported with all parenteral iron
salts, and several contain a black box warning to this effect. Figure 39.3 Metabolism of vitamin B12.
Patients should be observed for at least 30 minutes following
the completion of the infusion to assess for possible allergic only bacteria can make this vitamin. Because the body
reactions, which may cause respiratory arrest and circula- requires only miniscule amounts of vitamin B12 (3 mcg/
tory collapse. Some healthcare providers order test doses day), deficiency of this vitamin is usually not due to insuf-
prior to every administration of IV iron salts, because ana- ficient dietary intake. Instead, the most common cause of
phylaxis may occur on second and subsequent doses. Ferric vitamin B12 deficiency is absence of intrinsic factor, a pro-
gluconate produces a lower incidence of anaphylactic shock. tein secreted by stomach cells. Intrinsic factor forms a com-
plex with vitamin B12, which is then absorbed into the
Common adverse reactions of iron dextran are hypo- circulation. Without the formation of this complex, vitamin
tension, headache, muscle pain, and joint pain; these are B12 is not absorbed from the intestine. Figure 39.3 illustrates
more severe when given IV. Iron dextran appears to the metabolism of vitamin B12.
increase bone density in the joints, which is the probable
cause of the muscle and joint pain. Frequent adverse effects Deficiency of intrinsic factor is caused by inflamma-
with ferric gluconate include cramping, nausea, vomiting, tory diseases of the stomach or by gastric resection. Inflam-
hypotension, and rash. Iron sucrose is well tolerated, with matory diseases of the small intestine that affect food and
some patients experiencing leg cramps and hypotension. nutrient absorption may also cause vitamin B12 deficiency.
Because vitamin B12 is found primarily in foods of animal
CONNECTION Checkpoint 39.4 origin, strict vegetarians may require a vitamin supple-
ment to avoid deficiency. The center portion of the vitamin
From what you learned in Chapter 8, explain why a patient who is B12 molecule contains the metal ion cobalt, which is a
pregnant has a substantially higher iron requirement compared to micromineral essential to human nutrition.
a nonpregnant woman. Answers to Connection Checkpoint ques-
tions are available on the faculty resources site. Please consult with The most profound consequence of vitamin B12 defi-
your instructor. ciency is a megaloblastic anemia called pernicious anemia,
which affects both the hematologic and nervous systems.
39.7 Pernicious anemia may be successfully
treated with the administration of vitamin B12.
Vitamin B12 and folic acid are dietary nutrients essential for
rapidly dividing cells. The continuous, high rate of erythro-
poiesis occurring throughout the lifespan demands a contin-
uous supply of these vitamins. Without them, the normal
production of RBCs is interrupted and large, immature eryth-
rocytes that are unable to carry the same amount of oxygen as
normal RBCs are released into the blood, and anemia results.
Vitamin B12 is an essential component of two coen-
zymes required for normal cell growth and DNA replica-
tion. Neither plants nor animals synthesize vitamin B12;
708 Unit 5 Pharmacology of the Cardiovascular System
In pernicious anemia, the hematopoietic stem cells produce Therapeutic Effects and Uses: Cyanocobalamin is a
abnormally large erythrocytes that do not fully mature. purified form of vitamin B12 that is indicated for patients
Although RBCs are most affected, lack of maturation of all with vitamin B12 deficiency anemia. Treatment of vita-
blood cell types may occur in severe disease. Symptoms of min B12 deficiency is most often by weekly, biweekly, or
pernicious anemia are often nonspecific and develop monthly intramuscular (IM) or subcutaneous injections. A
slowly, sometimes over several years. Profound nervous typical regimen for pernicious anemia would be 100 mcg
system symptoms distinguish this disease from most other IM or subcutaneous once daily for 1 week, followed by
anemias and include memory loss, confusion, unsteadi- 100 mcg on alternate days for 7 doses. Dose reduction con-
ness, tingling or numbness in the limbs, delusions, mood tinues, with administration every 3 to 4 days for another
disturbances, and even hallucinations in severe deficien- 2 to 3 weeks, then 100 mcg IM monthly for life. Oral
cies. Permanent nervous system impairment may result if vitamin B12 formulations are available primarily as vita-
the disease remains untreated for 6 to 12 months. Pharma- min supplementation, although they are only effective in
cotherapy includes the administration of cyanocobalamin, patients who have sufficient amounts of intrinsic factor
a form of vitamin B12. Prior to administration of vitamin and normal absorption in the small intestine.
B12, the nurse should assess for other causes of anemia
including GI bleeding, GI surgery, tapeworm infestation, An intranasal spray formulation (Nascobal) is avail-
and gluten enteropathy. able that provides for once-weekly dosage. Nascobal is
generally used for maintenance therapy after normal
Folic acid, or folate, is a B-complex vitamin that is vitamin B12 levels have been restored by parenteral
essential for normal DNA and ribonucleic acid (RNA) syn- preparations. The intranasal form is also indicated to
thesis. Like B12 deficiency, insufficient folic acid levels can prevent vitamin B12 deficiency in people who are strict
manifest as anemia. In fact, the metabolisms of vitamin B12 vegetarians.
and folic acid are intricately linked; a B12 deficiency will
create a lack of activated folic acid. Folate deficiency is one Parenteral administration of cyanocobalamin rapidly
of the most common types of anemias in the United States. reverses most signs and symptoms of B12 deficiency, usu-
ally within a few days or weeks. If the disease has been
Folic acid does not require intrinsic factor for intestinal prolonged, symptoms may take longer to resolve, and
absorption, and the most common cause of deficiency is some neurologic damage may be permanent. In most cases,
insufficient dietary intake. This is often observed in patients treatment must often be maintained for the remainder of
with chronic alcoholism because their diets are often defi- the patient’s life. Periodic laboratory blood testing and Hgb
cient in this nutrient, and ethanol interferes with folate values are used to gauge the success of pharmacotherapy.
metabolism in the liver. Fad diets and absorption diseases
of the small intestine can also lead to folate-deficiency ane- Mechanism of Action: Administration of cyano-
mia. Hematopoietic symptoms of folate deficiency are the cobalamin reverses vitamin B12 deficiency and results in
same as those for B12 deficiency; however, no neurologic rapid improvement of anemia symptoms. Normal RBC
signs are present. Folate deficiency during pregnancy has production resumes, with laboratory evaluation of blood
been linked to neural birth defects such as spina bifida. and bone marrow showing continuous improvement over
Mild deficiency or prophylaxis of folate deficiency is accom- about 7 days. Therapy may extend to several months to
plished by increasing the dietary intake of folic acid through restore hepatic stores of the vitamin.
fresh green vegetables, beans, and wheat products. In cases
when adequate dietary intake cannot be achieved, therapy Pharmacokinetics:
with folic acid is warranted. Folic acid is presented as a
drug prototype for water-soluble vitamins in Chapter 61. Route(s) PO, IM, deep subcutaneous,
intranasal
PharmFACT
Absorption Well absorbed; PO absorption
A deficiency of vitamin B12, folate, or vitamin B6 may increase requires intrinsic factor
the blood level of homocysteine, an amino acid normally
found in the blood. An elevated blood level of homocysteine Distribution Widely distributed; crosses the
is a risk factor for heart disease and stroke (National placenta; secreted in breast milk
Institutes of Health, 2016b).
Primary metabolism Primarily converted in tissues
PROTOTYPE DRUG Cyanocobalamin (Nascobal) to coenzyme B12 and stored in
liver; extensive enterohepatic
Classification Therapeutic: Agent for anemia recirculation
Pharmacologic: Vitamin supplement
Primary excretion Renal
Onset of action Peak serum level: 8–12 h (PO),
1–2 h (intranasal), and 1 h (IM/
subcutaneous)
Duration of action Half-life: 6 days
Chapter 39 Pharmacotherapy of Hematopoietic Disorders 709
Adverse Effects: Adverse effects from cyanoco- • Monitor vital signs in patients with cardiac disease
balamin are uncommon. Because hypokalemia may and in those receiving parenteral cyanocobalamin. Be
occur, serum potassium levels are monitored periodi- alert to symptoms of pulmonary edema, which may
cally. A small percentage of patients receiving B12 exhibit occur early in therapy.
rashes, itching, or other signs of allergy. Anaphylaxis is
possible, though rare, with parenteral administration. • Obtain a complete diet and drug history and inquire
Sodium retention occurs in some patients, with possible into alcohol drinking patterns for all patients receiving
worsening of HF. cyanocobalamin to identify and correct poor dietary
habits.
Contraindications/Precautions: Patients with sus-
pected sensitivity to cobalt should receive an intradermal Lifespan and Diversity Considerations:
test dose because they may experience allergic reactions
or anaphylaxis to the drug. Monotherapy with folic acid • Evaluate the older adult’s nutritional status and
will not improve symptoms of vitamin B12 deficiency ane- weight during each monthly visit for their injection
mia. Cyanocobalamin is contraindicated in patients with and laboratory work.
severe pulmonary disease and should be used cautiously
in patients with heart disease because of the potential for • Due to undetected heart disease, monitor the older
sodium retention caused by the drug. adult for edema or signs and symptoms of HF.
Drug Interactions: Drug interactions with cyanoco- Patient and Family Education:
balamin are minor and are normally not clinically signifi-
cant. Herbal/Food: Unknown. • Do not discontinue taking this drug without approval
of the healthcare provider. The drug will be required
Pregnancy: Category A (C when used parenterally). lifelong.
Maternal requirements for vitamin B12 increase during
pregnancy and lactation, although the drug should not be • If using the spray form, prime the pump before the
taken in higher than recommended amounts. first use by pumping the spray a few times until a fine
mist appears. If it has been longer than 5 days between
Treatment of Overdose: Overdosage has not been uses, prime the pump again. Sniff gently while
reported with this drug. spraying.
Nursing Responsibilities: • Eat foods that are rich sources of B12 (nonpernicious
anemia) such as nutrient-fortified breakfast cereals,
• Monitor serum potassium levels during the first vitamin B12-fortified soy milk, organ meats, clams,
48 hours. Conversion to normal erythropoiesis oysters, egg yolk, crab, salmon, sardines, muscle
increases the erythrocyte potassium requirement and meat, milk, and dairy products.
can result in severe hypokalemia and sudden death.
Drugs Similar to Cyanocobalamin
(Nascobal)
There are no drugs similar to cyanocobalamin.
Understanding Chapter 39
Key Concepts Summary 39.5 Anemias may be caused by hemorrhage or a
change in red blood cell production or destruction.
39.1 Hematopoiesis is a dynamic process that is
responsive to the changing demands of the body. 39.6 Administration of iron salts can rapidly reverse
symptoms of iron deficiency anemia.
39.2 Erythropoietin stimulates production of red blood
cells and is used to treat anemia. 39.7 Pernicious anemia may be successfully treated with
the administration of vitamin B12.
39.3 Colony-stimulating factors increase the production
of leukocytes.
39.4 Platelet enhancers may be used to treat
thrombocytopenia.
710 Unit 5 Pharmacology of the Cardiovascular System
CASE STUDY: Making the Patient Connection
Remember the patient children’s hospital. He had even considered working as a
“Carl Guenther” at the greeter at his neighborhood department store.
beginning of the chapter?
Now read the remainder As he went through chemotherapy, the associated
of the case study. Based on nausea and vomiting were well managed with antiemetic
the information presented drugs. His physical appearance did not change much
within this chapter, because Carl had minimal hair loss due to the chemother-
respond to the critical thinking questions that follow. apy. Now he faces an exceedingly low WBC count and has
been advised to avoid potential sources of infection,
“A real people-person who never met a stranger.” That is including people. By far this is the worst adverse effect of
how family and friends have always described Carl Guen- the chemotherapy for Carl. He feels socially isolated and
ther. His positive and outgoing personality is well known depressed. Is this the end?, he wonders. Am I to die lonely?
in the community. When Carl was informed about his pros-
tate cancer, he handled the diagnosis well and with his Critical Thinking Questions
usual optimism. He was confident that the chemotherapy
would be successful. His mantra for years had been to 1. The healthcare provider orders filgrastim (Neupogen)
“Live every day as if it were your last.” However, the treat- 10 mcg/kg daily for 4 days. Carl asks you, his nurse,
ment for the cancer had adverse effects that he did not “How does this drug work?” What is your response?
expect and his enthusiasm diminished.
2. List interventions that should be followed during
Carl is a 72-year-old retired sales representative for a this period of chemotherapy-induced neutropenia to
chain of department stores. His entire career was centered protect Carl from infection.
on interacting with all kinds of people. When he retired, his
outgoing nature was an asset for the many community 3. What adverse effects would you monitor in
agencies at which he volunteered. He was active in the patients receiving Neupogen?
local Lions Club, his church’s outreach ministry, and at the
Answers to Critical Thinking Questions are available on the
faculty resources site. Please consult with your instructor.
Additional Case Study 2. What adverse effects should Betty watch for while
taking Feosol?
When the blood test returned from Betty Arnold’s preem-
ployment physical, the results indicated anemia. “No won- 3. Is there a best time of the day to take this medication?
der I feel so exhausted all the time,” she said. “I thought my Why?
fatigue was from taking care of my five children, my home,
and my aging parents.” When she saw her primary health- Answers to Additional Case Study questions are available on the
care provider, she was diagnosed with iron deficiency ane- faculty resources site. Please consult with your instructor.
mia and prescribed ferrous sulfate (Feosol) 160-mg
sustained release tablets daily.
1. As the nurse, you will provide teaching for this patient
about dietary sources of iron. Create a list of foods
high in iron.
Chapter Review 2. Darbepoetin (Aranesp) is prescribed for each of the
following patients. A nurse should question the order
1. Which statement would the nurse include in the care for which condition?
plan for a patient receiving epoetin alfa?
1. A patient with HIV who is receiving zidovudine
1. Avoid fresh fruit and vegetables and partially 2. A patient with uncontrolled hypertension
cooked meats. 3. A patient with chronic kidney disease
4. A patient with chemotherapy-induced anemia
2. Encourage frequent rest periods to minimize fatigue.
3. Limit exposure to direct sunlight and use
sunscreen when outdoors.
4. Protect tissues and mucous membranes from
traumatic injury.
Chapter 39 Pharmacotherapy of Hematopoietic Disorders 711
3. The patient is being treated with filgrastim (Neupo- 1. Patients who regularly consume large amounts of
gen). Which of the following would the nurse monitor alcohol are often deficient in this nutrient.
to determine the effectiveness of this drug?
2. Alcohol facilitates folate metabolism in the liver,
1. Red blood cell counts which destroys vitamin B12.
2. Platelet counts
3. White blood cell counts 3. Patients who regularly consume large amounts of
4. Reticulocyte count and mean cell volume (MCV) alcohol are at high risk for neutropenia, a condition
that develops from vitamin B12 loss.
4. The nurse is teaching the patient about oprelvekin
(Neumega). Which statement, if made by the patient, 4. Liver cirrhosis caused by large amounts of alcohol
indicates that additional health teaching is needed? ingestion diminishes natural physiologic deposits
of B12.
1. “This drug stimulates the production of platelets.”
2. “I should weigh myself and watch for fluid 6. The nurse is teaching a patient about ferrous sulfate
(Feosol). What instructions should be included in the
retention.” teaching plan for this patient? (Select all that apply.)
3. “I will report vision changes to my healthcare
1. This drug should be taken on an empty stomach at
provider.” least 1 hour before or 2 hours after a meal.
4. “I will add more iron-rich foods to my diet.”
2. Getting liquid iron on teeth should be avoided
5. A patient who regularly consumes significant because the drug can cause brown stains.
amounts of alcohol is prescribed cyanocobalamin
(Nascobal) and states, “I don’t understand why my 3. Iron preparation may darken stools and cause
healthcare provider has prescribed B12 injections.” The constipation.
nurse’s response would be based on which physio-
logic concept? 4. Vitamin E is added to many oral iron supplements
because it enhances iron absorption.
5. This drug can be taken with caffeinated beverages.
See Answers to Chapter Review in Appendix A.
References National Institutes of Health, Office of Dietary
Supplements. (2016b). Vitamin B12: Dietary supplement
National Institutes of Health, Office of Dietary fact sheet. Retrieved from http://ods.od.nih.gov/
Supplements. (2016a). Iron: Dietary supplement fact sheet. factsheets/VitaminB12-HealthProfessional
Retrieved from http://ods.od.nih.gov/factsheets/
Iron-HealthProfessional/#h2
Selected Bibliography Gallagher, T., Darby, S., Vodanovich, M., Campbell, L., &
Tovey, J. (2015). Patient blood management nurse vs
Betcher, J., Van Ryan, V., & Mikhael, J. (2015). Chronic transfusion nurse: Is it time to merge? British Journal of
anemia and the role of the infusion therapy nurse. Nursing, 24, 492–495. doi:10.12968/bjon.2015.24.9.492
Journal of Infusion Nursing, 38, 341–348. doi:10.1097/
NAN.0000000000000122 Kaplow, R., & Spinks, R. (2015). Neutropenia: A nursing
perspective. Current Problems in Cancer, 39, 297–308.
Boxer, L. A., Bolyard, A. A., Kelley, M. L., Marrero, T. M., doi:10.1016/j.currproblcancer.2015.07.009
Phan, L., Bond, J. M., … Dale, D. C. (2015). Use of
granulocyte colony–stimulating factor during Rumore, M. M., Cobb, E., Sullivan, M., & Wittman, D.
pregnancy in women with chronic neutropenia. (2016). Biosimilars: Opportunities and challenges for
Obstetrics and Gynecology, 125(1), 197–203. doi:10.1097/ nurse practitioners. The Journal for Nurse Practitioners, 12,
AOG.0000000000000602 181–191. doi:10.1016/j.nurpra.2015.08.027
Camaschella, C. (2015). Iron-deficiency anemia. The New Saeed, A. N., & Al-Atiyyat, N. (2015). Management of
England Journal of Medicine, 372, 1832–1843. chemotherapy-induced febrile neutropenia among adult
doi:10.1056/NEJMra1401038 oncology patients: A review. Canadian Oncology Nursing
Journal, 25, 281–284. doi:10.5737/23688076253281284
Chatterjee, R., Shand, A., Nassar, N., Walls, M., &
Khambalia, A. Z. (2016). Iron supplement use in Thiagarajan, P. (2016). Platelet disorders. Retrieved from
pregnancy–Are the right women taking the right http://emedicine.medscape.com/article/
amount? Clinical Nutrition, 35, 741–747. doi.10.1016/j. 201722-overview#a1
clnu.2015.05.014
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Unit 6
Pharmacology
of Body Defenses
CHAPTER 40 Review of Body Defenses and the Immune System / 714
CHAPTER 41 Pharmacotherapy of Inflammation and Fever / 723
CHAPTER 42 Immunostimulants and Immunosuppressants / 741
CHAPTER 43 Immunizing Agents / 762
713
Chapter 40
Review of Body Defenses
and the Immune System
Chapter Outline Learning Outcomes
cc Organization of the Lymphatic System After reading this chapter, the student should be able to:
cc Innate (Nonspecific) Body Defenses
1. Identify the major components of the lymphatic
Inflammation system.
cc Specific (Adaptive) Body Defenses
2. Describe the components of the nonspecific body
Humoral Immune Response defense system and their functions.
Cell-Mediated Immune Response
3. Compare and contrast specific and nonspecific body
defenses.
4. Identify the signs and symptoms of inflammation.
5. Outline the basic steps in the acute inflammatory
response.
6. Explain the role of histamine and other chemical
mediators in the inflammatory response.
7. Compare and contrast the humoral and cell-
mediated immune responses.
714
Chapter 40 Review of Body Defenses and the Immune System 715
Key Terms histamine, 718 lymphatic system, 715
immunity, 715 phagocytes, 717
adaptive defenses, 719 inflammation, 718 plasma cells, 720
antibodies, 720 innate body defenses, 715 T cells, 720
antigens, 719 interferons (IFNs), 718
B cell, 720 lymph nodes, 715
complement system, 717
cytokines, 720
The human body is under continuous attack from a host of principal lymphoid organs in the body. Lymph nodes are
foreign invaders, including viruses, bacteria, fungi, and even solid, spherical bodies that are packed with macrophages
single-celled animals. Some of these pathogens intentionally and lymphocytes, which are cells specialized to recognize
seek out humans because it is an essential part of their life- anything that is “non-self” or foreign to the body. Recogni-
cycle, whereas others happen to be “at the right place and tion of these foreign agents activates the immune response,
time” when a cut or scrape allows entrance into the body. which neutralizes or removes the pathogens before they
Fortunately, the body’s extensive defenses are capable of can reach the general circulation. Each lymph node serves
mounting a rapid and effective response against most of as a minifilter, removing up to 99% of the foreign agents
these pathogens. Drugs used to modify body defenses, which entering the node. Should a pathogen be clever enough to
include anti-inflammatory drugs, immunostimulants, immu- escape surveillance in a particular lymph node, it is then
nosuppressants, and vaccines, are presented in Chapters 41 faced with passing through dozens, and sometimes hun-
through 43. The purpose of this chapter is to review the fun- dreds, more lymph nodes in the lymphatic system.
damental concepts of body defenses that apply to the phar-
macotherapy of the immune system and infectious disease. In addition to lymph vessels and nodes, lymphoid tis-
For a more thorough review of this topic, the student should sues line connective tissue at every potential portal of
consult an anatomy and physiology textbook. entrance into the body, including the gastrointestinal (GI)
tract, respiratory tract, and genitourinary tract. Lymphoid
Organization of the tissue contains lymphocytes, which “patrol” the region for
Lymphatic System potential injury or exposure to microbes. Other large collec-
tions of lymphoid tissue include the tonsils, spleen, and thy-
40.1 The lymphatic system is the primary organ mus. These are considered organs of the lymphatic system.
system that protects the body from invasion by
foreign agents. Although the lymphatic system can be divided into
individual structures and components for ease of study, it
The components of the lymphatic system provide the body is best to think of it as an integrated whole. The various
with immunity, which is the ability to resist injury and components of this system are in continuous communica-
infections. The lymphatic system comprises a network of tion and work together as a single unit to accomplish effec-
cells, vessels, and tissues that provide immune surveillance. tive immune surveillance. A malfunction in a single
This monitoring function begins when fluid leaves the cap- component may affect the effectiveness of the entire lym-
illaries due to the osmotic forces and high pressure in the phatic system. An overview of the primary divisions of
capillaries. This fluid, known as lymph, enters blind-ended immunity is shown in Figure 40.1.
lymphatic vessels and slowly travels on its journey through
the lymphatic system. As much as 3 L of fluid per day travel PharmFACT
through the highly branched lymphatic vessel network to
eventually return to the cardiovascular circulation. Tumors are able to create new lymphatic vessels, a process
called lymphangiogenesis. The new lymphatic vessels
Lymphatic vessels carry more than escaped fluid. induced by the cancer closely correlate to metastasis and
Viruses, bacteria, cellular debris, and even cancer cells can clinical outcome (Dieterich & Detmar, 2016).
enter these vessels. Should these pathogens or cancer cells
be permitted to return to the bloodstream, an infection (or Innate (Nonspecific) Body Defenses
cancer) could quickly spread throughout the body with
potentially disastrous consequences. Fortunately, before 40.2 Innate body defenses are the body’s first
these pathogens can return to the general circulation, they line of defense against pathogens.
must pass through dozens of lymph nodes, which are the
Innate body defenses are those that are present even
before an infection has occurred and that provide the
716 Unit 6 Pharmacology of Body Defenses Invader
stimulates
stimulates
Innate defenses Adaptive defenses
Phagocytes Complement Antigen-presenting cells
(cell eaters), proteins, dendritic cells
histamine most important
natural
killer cells
CD4 T cell CD8 T cell
Activated
helper T cells
Antibody-mediated immunity Cell-mediated immunity
Activation of B-cell clones: Activation of e ector and
memory T-cell clones:
Memory B cells
(ready to respond Helper T cells
to future infection (facilitate adaptive
by same invader) response)
Plasma cells Cytotoxic T cells
(secrete (kill infected cells)
antibodies)
Antibodies Regulatory T cells
(work with (limit response)
phagocytes
and complement
proteins to
eliminate
pathogens)
Figure 40.1 Overview of body defenses.
From Biology: A Guide to the Natural World, Technology Update (5th ed., p. 563), by D. Krogh, 2014. San
Francisco, CA: Benjamin Cummings.
first line of protection from pathogens. These are categorizing the innate defenses is to consider them as
sometimes referred to as nonspecific defenses because types of barriers:
they are unable to distinguish one type of threat from
another; the body’s response is the same regardless of • Physical barriers: skin and mucous membranes
the particular pathogen. A summary of nonspecific • Cellular barriers: phagocytes and natural killer cells
body defenses is given in Table 40.1. A useful way of • Process barriers and antimicrobial proteins: comple-
ment, fever, inflammation, and interferons.
Chapter 40 Review of Body Defenses and the Immune System 717
Table 40.1 Summary of Nonspecific Body Defenses
Component Functions
Physical Barriers
Skin Forms a mechanical barrier to prevent pathogens and other harmful substances from entering the body. Surface contains
keratin, which is resistant to water and acid.
Mucous membranes Line the portals of entry to inhibit the entry of pathogens. Mucus inhibits microbial growth. Cilia in the respiratory tract and
saliva in the mouth discourage pathogen entry.
Cellular Barriers
Phagocytes Ingest antigens. Specific types include neutrophils, eosinophils, and monocytes, which differentiate into macrophages. Also
include dendritic cells that reside deep in the skin, in lymph nodes, and in the inner lining of the respiratory and digestive
tracts.
Natural killer (NK) cells Directly attack virus-infected and cancer cells by releasing substances that are toxic to the antigen.
Process Barriers and Antimicrobial Proteins
Complement Promotes inflammation and phagocytosis; lyses microbes.
Fever Systemic response that increases body temperature to activate body defenses; inhibits the growth of some microbes.
Inflammation Limits the spread of infection and releases substances that attract phagocytes; initiates repair of the injured area.
Interferons Proteins secreted by cells infected by viruses. They protect uninfected cells and also stimulate the activity of phagocytes and
NK cells; used as medications to treat certain types of cancer.
Physical barriers: The skin and mucous membranes are blood, in lymphatic tissues, and in locations where patho-
considered the first line of defense against pathogen inva- gens have the highest likelihood of entering. For example,
sion. The intact skin is a formidable physical barrier to the deeper layers of the epidermis contain specialized
pathogens. The cells of the epidermis are packed tightly phagocytes called dendritic cells, which are able to remove
together, which discourages penetration by microbes. The pathogens that penetrate the superficial layers. Phagocytes
outer layer of skin cells is continually shed, along with any have the ability to migrate to distant sites when an infec-
microbes that may be clinging to them. The accessory struc- tion is detected, a process called chemotaxis.
tures of the skin secrete sebum (oil), sweat, and antimicro-
bial peptides that discourage microbial growth on the Phagocytes have proteins on their surface that allow
surface. The skin is also colonized with a variety of bacteria them to recognize cells and cellular components that are
and fungi that are normally harmless to the host. This “non-self.” When recognized as “non-self,” the pathogen is
microbiota (flora) competes with pathogens for space and internalized and destroyed within the phagocyte. Pieces of
nutrients, thus creating an unfavorable growth environ- the microbe are sometimes displayed on the plasma mem-
ment for harmful organisms. However, should the skin brane of the phagocyte, which serves to activate other com-
become broken or compromised by needlesticks or cathe- ponents of the immune response. Not all pathogens can be
ters, some species of normal flora may become pathogenic. engulfed by phagocytosis. Some, such as Mycobacterium
tuberculosis, are not only resistant to phagocytosis, but they
The body cavities that open to the outside environ- can also multiply while residing inside macrophages.
ment are lined with a mucosal epithelium that not only
provides a physical barrier, but also contains proteins, lyso- Cancer cells or virus-infected cells attract a different
zymes, and other substances that discourage pathogen type of innate cellular response: natural killer (NK) cells.
growth. The respiratory tract secretes a sticky mucus that Found in most lymphoid organs, NK cells are not phago-
traps microbes. The stomach and genitourinary tracts pro- cytic, but they do release toxins that kill cancer cells or virus-
vide an acidic environment that kills many microbes. Like infected cells. NK cells also secrete chemicals that enhance
the skin, the mucosa of the mouth, colon, and vagina have inflammation and modulate the adaptive immune response.
a normal population of flora, which discourages pathogen
growth by competing for space and nutrients. Process barriers and antimicrobial proteins: Processes
and proteins associated with innate defenses are comple-
Cellular barriers: Once physical barriers are breached, ment activation, fever, inflammation, and interferons. The
phagocytes are the primary cells of innate immunity. The complement system is a cluster of 20 plasma proteins that
primary job of phagocytes is to engulf pathogens and other combine in a specific sequence and order when an infection
foreign substances that enter the body. Once engulfed, the occurs. Activation of complement attracts phagocytes to
phagocytes destroy the microbe in vesicles called lyso- the infection site, attacks and breaks down the cell walls of
somes, which contain powerful destructive enzymes. As pathogens, and stimulates the inflammatory process.
expected, phagocytes are found in large numbers in the
Fever and inflammation are also key processes of the
nonspecific defense system. Fever accelerates body defenses
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