1318 Unit 10 Pharmacology of the Endocrine System
Mechanism of Action: Sildenafil inhibits PDE-5 and Nursing Responsibilities:
increases and preserves cGMP levels in the penis. This relaxes
smooth muscle in the corpus cavernosa, allowing increased • Obtain a complete physical examination, including a
blood flow into the penis and allowing a harder and longer history of sexual dysfunction; cardiovascular or
lasting erection in about 70% of men taking the drug. peripheral vascular disease; thyroid, hepatic, or kid-
ney disease; diabetes; or prostatic hyperplasia.
Pharmacokinetics: PO
Route(s) Rapid; bioavailability: 40% • Obtain a complete drug history including prescrip-
Absorption 96% protein bound tion, OTC, and recreational or illicit drug use.
Distribution Hepatic (CYP3A4 and 2C9)
Primary metabolism 80% feces, 12% renal • Obtain baseline vital signs and notify the healthcare
Primary excretion 20–60 min provider of blood pressure below 90/60 mmHg.
Onset of action 24 h; half-life: 4 h
Duration of action • Notify the prescriber if the patient takes a drug for
angina or HTN such as nitroglycerin because these
Adverse Effects: Sildenafil is well tolerated and adverse drugs may cause a sudden, unsafe drop in blood
effects are usually transient and mild. Common adverse pressure.
effects include headache, dizziness, flushing, rash, and
nasal congestion. The most serious adverse effect, hypoten- • Monitor liver function tests. Patients with cirrhosis or
sion, occurs in patients who are concurrently taking organic severe decreased liver function may start with lower
nitrates for angina and can result in MI and sudden cardiac doses to prevent hepatotoxicity.
death. Sildenafil can produce blurred vision, increased sen-
sitivity to light, or changes in color perception in 10% of • Monitor for visual adverse effects such as blurred
patients using it. Priapism, a sustained erection lasting lon- vision, the inability to differentiate between green and
ger than 6 hours, has been reported with sildenafil use and blue, perception of a blue tinge to objects, or photo-
may lead to permanent damage of penile tissue. phobia. Observe safety precautions until it is known
whether sensory-perceptual alterations occur to pre-
Contraindications/Precautions: Sildenafil is contra- vent falls and other injuries.
indicated in patients who are taking nitrates and in those
with hypersensitivity to this drug. It is contraindicated • Monitor for presence of headache, dizziness, flushing,
in patients with severe cardiovascular disease, recent MI, rash, and nasal congestion.
stroke, heart failure, or dysrhythmias, and in the presence
of anatomic deformities of the penis. This drug should be Lifespan and Diversity Considerations:
used with caution in patients with CKD or hepatic impair-
ment. Patients with preexisting visual disturbances should • Monitor hepatic and renal function laboratory values
not use sildenafil. and cardiac status more frequently in the older adult
because normal physiologic changes related to aging
Drug Interactions: Cimetidine, erythromycin, and may increase the risk of adverse effects.
ketoconazole will increase serum levels of sildenafil and
necessitate lower drug doses. Concurrent use with nitrates Patient and Family Education:
is contraindicated and will result in hypotension and pos-
sibly death. Protease inhibitors (ritonavir, amprenavir, oth- • Keep all laboratory visits to evaluate liver function.
ers) will cause increased sildenafil levels, which may lead • Take this drug 30 to 60 minutes before anticipated sex-
to toxicity. Rifampin may decrease sildenafil levels, leading
to decreased effectiveness. Concurrent use of sildenafil with ual activity. Do not take more than one dose in a
drugs that lower blood pressure, including alpha1-adrenergic 24-hour period.
antagonists, should be avoided due to the potential for addi- • Alert all healthcare providers to the use of sildenafil
tive hypotension. Herbal/Food: Administration of sildenafil before starting any new medication.
with high-fat meals should be avoided because absorption is • Avoid high-fat meals before taking this drug because
decreased. Grapefruit juice increases the plasma concentra- it may cause a delay in drug action.
tions of sildenafil and may cause adverse effects. • Immediately report any chest pain, unrelieved visual
changes, eye pain, lights or flashes in the eyes, or an
Pregnancy: Category B (not approved for women). erection that lasts longer than 4 hours or is painful to
the healthcare provider.
Treatment of Overdose: There is no specific treat-
ment for overdose. Drugs Similar to Sildenafil (Viagra)
The other PDE-5 inhibitors are avanafil, tadalafil, and
vardenafil.
Avanafil (Stendra): The newest ED drug, avanafil, was
approved in 2012 and acts by the same mechanism as the
other three PDE-5 inhibitors. It acts in 15 to 30 minutes,
which is the fastest of the drugs in this class. It has a
Chapter 71 Drugs for Disorders and Conditions of the Male Reproductive System 1319
duration of about 6 hours, which is short compared to disintegrating tablet (ODT) form of this drug (Staxyn)
36 hours for tadalafil. Avanafil may be taken twice daily. was approved. Headache, flushing, rhinitis, and dyspep-
This drug’s absorption is not affected by food. The adverse sia are the common adverse effects. Vardenafil may pro-
effects and contraindications are the same as those of other long the QT interval and is to be used with caution in
drugs in this class. This drug is pregnancy category C (not patients who are taking nitrates. Administration with
approved for women). high-fat meals should be avoided because absorption
is decreased. This drug is pregnancy category B (not
Tadalafil (Cialis): Initially approved in 2003, tadalafil acts approved for women).
by the same mechanism as sildenafil, which is relaxation of
penile arterial and trabecular smooth muscle. This drug’s Pathophysiology of Benign
absorption is not affected by food. It acts within about Prostatic Hyperplasia
60 minutes and has a longer duration of action than silde-
nafil: up to 36 hours. The longer duration allows for more 71.7 Benign prostatic hyperplasia is an
spontaneity of sexual activity. Contraindications include enlargement of the prostate that occurs in older
patients who take nitrates, and dosing can be prescribed men.
every 72 hours. Tadalafil produces less blood pressure
decrease than the other drugs in this class, making it safer The prostate is a gland the size of a walnut that surrounds
for patients with heart failure or a history of MI. It also the male urethra. Its primary function is to contribute flu-
results in a lower incidence of visual disturbances. Other ids to the ejaculate. The prostate contains two major types
adverse effects are similar to those of sildenafil. A daily of tissues:
dosing of 2.5-mg tadalafil for erectile dysfunction was
approved in 2008. This drug is pregnancy category B (not • Epithelial tissue. This is the glandular portion of the
approved for women). prostate that secretes fluids for the ejaculate. The
growth of prostatic epithelial tissue is controlled by
Like sildenafil, tadalafil (Adcirca) is also approved to the presence of androgens. Testosterone is converted
treat pulmonary arterial HTN. The dose for this indication to its active metabolite, dihydrotestosterone (DHT), in
is higher, at 40 mg/day. In 2011, tadalafil (Cialis) was the epithelial cells of the prostate by the enzyme
approved for the symptomatic treatment of BPH. Although 5-alpha reductase.
its exact mechanism is still being investigated, tadalafil is
believed to reduce BPH symptoms by relaxing urinary • Stomal tissue. This is smooth muscle tissue, which is
smooth muscles and increasing blood perfusion and oxy- controlled by alpha1-adrenergic receptors. When acti-
genation of the bladder and prostatic tissue. vated, these receptors cause the smooth muscle to con-
tract around the urethra.
Vardenafil (Levitra, Staxyn ODT): Like other drugs in
this class, vardenafil allows for relaxation of arterial and Benign prostatic hyperplasia (BPH), an abnormal
trabecular smooth muscle in the penis. Approved in enlargement of the prostate, is the most common benign
2003, vardenafil acts within 30 to 60 minutes and its neoplasm in older men. The exact cause of BPH is unknown.
effects continue for 4 to 5 hours. In 2010, an orally It is present in 70% of men by age 60 and 90% by age 80.
Other than age, the risk factors for BPH include a family
CONNECTIONS: Patient Safety history of the disorder, smoking, heavy alcohol consump-
tion, HTN, diabetes, a diet high in meats and fats, and Afri-
Increased Plasma Drug Concentrations can American ancestry. BPH is not considered to be a
precursor to prostate carcinoma, though it is well known
A 53-year-old man is prescribed sildenafil (Viagra) for treat- that many men with BPH eventually experience prostate
ment of erectile dysfunction. His medical history reveals no cancer.
cardiovascular disease and no other medication use, and his
blood pressure is within normal range. Later that evening, he is The characteristic feature of BPH is an enlargement of
admitted to the emergency department with reports of chest the prostate gland that decreases the outflow of urine by
pain and dizziness and has a blood pressure of 80/48 mmHg. obstructing the urethra, causing difficult urination. The
The triage nurse notes in the electronic health record that the pathogenesis of BPH involves two components: static and
patient took two acetaminophen (Tylenol) tablets 4 hours dynamic. The static factors are caused by the physical
before taking the sildenafil. A dietary history reveals that he fol- enlargement of the prostate gland due to the overgrowth of
lows a gluten-free diet and drinks three glasses of grapefruit the epithelial cells. The gland can double or triple in size
juice daily. What is a potential cause of this patient’s symp- with aging, creating a blockage of urine outflow at the neck
toms, and what should the nurse teach this patient? of the bladder. The dynamic factors are due to excessive
numbers of alpha1-adrenergic receptors located in stromal
Answers to Patient Safety questions are available on the faculty tissue in the neck of the urinary bladder and in the prostate
resources site. Please consult with your instructor.
1320 Unit 10 Pharmacology of the Endocrine System
Pharmacotherapy Illustrated 71.1
Mechanism of Action of Antiprostatic Drugs
Bladder Urethra
Prostate gland Dynamic factors:
• Alpha1-adrenergic receptors are
Static factors:
• Gland enlarges under the activated in smooth muscle in
urethra and neck of bladder
influence of testosterone • Smooth muscle contracts to
• Enlarged gland creates narrow the lumen of the urethra
physical obstruction of
urethra
Relaxed
smooth
muscle
Shrunken Open lumen
gland
Open lumen
Alpha-reductase inhibitors Alpha1-adrenergic blockers
interfere with testosterone prevent the activation of alpha
metabolism. receptors.
gland. When activated, these receptors compress the ure- Some men may have minimal enlargement and experi-
thra and provide resistance to urine outflow from the blad- ence moderate symptoms, whereas others may have
der. The two mechanisms of disease, static and dynamic, extremely enlarged glands and be asymptomatic. This is
have led to two different classes of drugs for treating the because the smooth muscle in the urinary bladder has
symptoms of BPH. These mechanisms are shown in Phar- the ability to compensate for the obstruction by contract-
macotherapy Illustrated 71.1. ing with greater force to eject the urine stream. Over
time, the bladder is no longer able to compensate and
Certain frequently used medications may worsen symp- symptoms of BPH manifest, such as increased urinary
toms of BPH. Alpha1-adrenergic drugs, which include decon- frequency (usually with small amounts of urine),
gestants such as pseudoephedrine and phenylephrine, increased urgency to urinate, postvoid leakage, exces-
activate alpha1-adrenergic receptors in the bladder neck, sive nighttime urination (nocturia), decreased force of
restricting urine flow. Drugs with anticholinergic effects such the urine stream, and a sensation that the bladder did
as antihistamines, TCAs, or phenothiazines may worsen the not completely empty.
associated urinary retention. Testosterone and other anabolic
steroids may increase prostate enlargement, which contrib- Some patients do not seek medical attention until com-
utes to the physical obstruction of the urethra. Drugs that plications caused by the long-standing obstruction at the
worsen symptoms of BPH should be avoided in older men. neck of the urinary bladder arise. Serious complications
include recurrent urinary infections, incontinence, gross
There is no clear correlation between the symptoms hematuria, bladder stones, and CKD.
experienced by patients and the size of the prostate.
Chapter 71 Drugs for Disorders and Conditions of the Male Reproductive System 1321
Pharmacotherapy of Benign inhibitors. Research has shown that combination ther-
Prostatic Hyperplasia apy with an alpha1 antagonist and a 5-alpha reductase
inhibitor is more effective than therapy with either drug
71.8 In its early stages, benign prostatic alone. This is the preferred treatment for patients with
hyperplasia may be treated successfully with moderate symptoms of BPH. More recently, tadalafil
drug therapy. (Cialis), a PDE-5 inhibitor, joined the list of approved
drugs for BPH.
The goal of treatment for patients with BPH focuses on
minimizing the urinary obstruction and preventing com- The alpha1-adrenergic antagonists act on the stromal
plications. Drug therapy can only treat symptoms; it can- tissue of the prostate to relax smooth muscle in the pros-
not reverse or cure BPH. Patients who are asymptomatic or tate gland, bladder neck, and urethra, thus easing the
who present with mild symptoms generally do not receive urinary obstruction. Doxazosin (Cardura) and terazosin
pharmacotherapy. Not all BPH is progressive, and many (Hytrin) are of particular value to patients who have
patients never experience moderate or advanced symp- both HTN and BPH; these two disorders occur concur-
toms. Patient education such as avoiding caffeine or alco- rently in about 25% of men older than 60. Three alpha1
hol intake, eliminating drugs that worsen BPH, and antagonists, silodosin (Rapaflo), tamsulosin (Flomax),
restricting fluids close to bedtime may be sufficient to and alfuzosin (Uroxatral), are selective for the prostate
achieve symptomatic improvement. Morning diuretic and have no effect on blood pressure at normal doses.
therapy may be used to reduce nighttime diuresis. The Drugs in this class improve urine flow and reduce other
patient is reevaluated at 6- to 12-month intervals to assess symptoms of BPH after 1 to 2 weeks of therapy. Common
for worsening symptoms. adverse effects include headache, fatigue, and dizziness.
Doxazosin and terazosin are not associated with an
When symptoms of BPH worsen, pharmacotherapy is increased risk of sexual dysfunction, but ejaculatory dis-
indicated. Only a few drugs are available for the pharma- orders have been reported with silodosin, tamsulosin,
cotherapy of BPH, and these are listed in Table 71.4. Drugs and alfuzosin. Reflex tachycardia due to stimulation of
that are used to treat BPH have limited effectiveness and baroreceptors is common with alpha1 antagonists.
have value only in treating mild to moderate disease as an Additional information on the alpha1 antagonists is pre-
alternative to surgery. Because pharmacotherapy does not sented in Chapter 16.
cure the disease, these medications must be taken for the
remainder of the patient’s life or until surgery is indicated. Some patients are unable to tolerate the cardiovascu-
If the drugs are discontinued, the prostate returns back to lar adverse effects of the alpha1-adrenergic antagonists.
its enlarged state and symptoms of BPH return. In advanced For these patients, the 5-alpha reductase inhibitors are
cases, transurethral resection of the prostate or a laser pros- used as monotherapy. These drugs act by blocking 5-alpha
tatectomy is needed to restore the patency of the urethra. reductase, the enzyme responsible for converting testos-
terone to DHT, which is its active metabolite. Without
The major drug classes for treating BPH are the DHT the hormonal signal for prostatic epithelial tissue
alpha1-adrenergic antagonists and the 5-alpha reductase
Table 71.4 Drugs for Benign Prostatic Hyperplasia
Drug Route and Adult Dose (Maximum Dose Where Indicated) Adverse Effects
Alpha1-Adrenergic Antagonists
alfuzosin (Uroxatral) PO: 10 mg/day (max: 10 mg/day) Orthostatic hypotension, headache,
doxazosin (Cardura) PO: 1–8 mg/day (max: 8 mg/day) dizziness, decreased libido, decreased
doxazosin XL (Cardura XL) Extended release: 4–8 mg/day (max: 8 mg/day) ejaculate volume
silodosin (Rapaflo) PO: 8 mg once daily with a meal First-dose phenomenon (severe hypotension
tamsulosin (Flomax) PO: 0.4 mg 30 min after a meal (max: 0.8 mg/day) and syncope), tachycardia
terazosin (Hytrin) PO: Start with 1 mg at bedtime, then 1–5 mg/day (max: 20 mg/day)
5-Alpha Reductase Inhibitors Sexual dysfunction, decreased libido,
dutasteride (Avodart) PO: 0.5 mg/day decreased ejaculate volume, gynecomastia
finasteride (Proscar) PO: 5 mg/day (max: 5 mg/day) Possible increased risk for prostate cancer
Phosphodiesterase-5 Inhibitors See Table 71.3
tadalafil (Cialis) PO: 5 mg once daily
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
1322 Unit 10 Pharmacology of the Endocrine System
CONNECTIONS: Complementary and Alternative Therapies
Saw Palmetto
Description Standardization
Saw palmetto (Serenoa repens) is a dwarf palm tree that Saw palmetto is available in capsule, tablet, and liquid dosage
grows in the coastal regions of the southern United States. forms. PO saw palmetto products should be standardized to con-
The berries of the saw palmetto are used in supplements. tain 80% or more of the active ingredients, which are fatty acids.
More than 2 million men in the United States use saw pal-
metto each year in the hopes that it will treat their symptoms Evidence
of BPH.
Although several clinical studies have suggested that saw pal-
History and Claims metto may be beneficial in treating BPH symptoms, there has
been no conclusive evidence to demonstrate that it is as effec-
Like finasteride, saw palmetto is thought to help stop a cascade tive as finasteride in treating mild to moderate BPH (National
of prostate-damaging enzymes that may create BPH. In theory, Center for Complementary and Integrative Health, 2016).
it occupies binding sites on the prostate that are typically occu- Although considered a safe supplement, saw palmetto may
pied by DHT, an enzyme that may trigger BPH, inhibiting growth cause damage to the liver and pancreas, and it is vital that the
of the prostate gland. nurse obtain a thorough health and supplement use history and
advise the patient of its potential adverse effects.
growth is eliminated, thus causing the enlarged prostate is prescribed to promote hair regrowth in patients with
to shrink in size. The most commonly prescribed drug in male-pattern baldness. Doses of finasteride are five times
this class is finasteride (Proscar), which is featured below higher when prescribed for BPH than when prescribed for
as a prototype for BPH. These drugs may take several baldness.
months to shrink the size of the prostate; thus, they are
not appropriate for severe disease. The 5-alpha reductase Off-label indications for finasteride take advantage of
inhibitors produce few adverse effects, although they can its antiandrogen effects. It may be used to treat mild to
cause sexual dysfunction and gynecomastia in some moderate hirsutism in females. Although some clinical tri-
patients. Because they are pregnancy category X, patients als suggested the drug exerted a protective effect against
who are taking these drugs should not donate blood prostate cancer, the drug insert from the manufacturer
because of the possibility that the donated blood would clearly states it is not to be prescribed for this purpose.
be given to a pregnant woman.
Mechanism of Action: Finasteride acts by inhibiting
CONNECTION Checkpoint 71.3 5-alpha reductase, which is the enzyme responsible for con-
verting testosterone to one of its metabolites, 5-alpha dihy-
Alpha1-adrenergic antagonists are very susceptible to causing the drotestosterone. This active metabolite causes proliferation
first-dose phenomenon. From what you learned in Chapter 16, de- of prostate cells and promotes enlargement of the gland.
fine this phenomenon and describe what should be done to minimize Finasteride promotes regression of prostate epithelial tissue
its effects. Answers to Connection Checkpoint questions are available and decreases mechanical obstruction of the urethra.
on the faculty resources site. Please consult with your instructor.
Pharmacokinetics:
PROTOTYPE DRUG Finasteride (Proscar)
Route(s) PO
Classification Therapeutic: Drug for BPH
Pharmacologic: Antiandrogen, 5-alpha Absorption Well absorbed
reductase inhibitor Distribution Crosses the blood–brain barrier;
Therapeutic Effects and Uses: Approved in 1992, found in semen; 90% bound to
finasteride is a PO drug that inhibits the metabolism of tes-
tosterone. The drug is sometimes called an antiandrogen. plasma protein
Finasteride shrinks enlarged prostates, helping to restore
urinary function. It is most effective in patients with larger Primary metabolism Hepatic (CYP3A4)
prostates. It is sometimes prescribed in combination with
doxazosin to reduce the risk of symptomatic progression Primary excretion 39% renal, 57% feces
of BPH. This drug is also marketed as Propecia, which
Onset of action Maximum effects take
3–6 months
Duration of action 2 weeks
Adverse Effects: Finasteride is well tolerated and
adverse effects are generally mild and transient. Finas-
teride causes various types of sexual dysfunction in up
to 16% of patients, including gynecomastia, impotence,
Chapter 71 Drugs for Disorders and Conditions of the Male Reproductive System 1323
diminished libido, and ejaculatory disorders such as Pregnancy: Category X.
decreased volume of ejaculate. The drug reduces sperm
production and may impair fertility. The actual incidence Treatment of Overdose: There is no specific treat-
of drug-induced sexual dysfunction is difficult to estimate ment for overdose.
because a large percentage of older men develop these
symptoms as a consequence of aging or comorbid condi- Nursing Responsibilities: Key nursing implications
tions. Other minor adverse effects include headache, nau- for patients receiving finasteride are included in the Nurs-
sea, rash, dizziness, and asthenia. Men over age 55 may ing Practice Application for Patients Receiving Pharmaco-
have a slightly increased risk of developing high-grade therapy for Benign Prostatic Hyperplasia.
prostate cancer.
Drugs Similar to Finasteride (Proscar)
Contraindications/Precautions: Contraindica-
tions to finasteride include hypersensitivity to the drug, The only other 5-alpha reductase inhibitor is dutasteride.
pregnancy (category X), lactation, or use in women and
children. The pregnant nurse or pharmacist should avoid Dutasteride (Avodart): Approved in 2001, dutasteride is
handling crushed medication because it may be absorbed a PO drug approved only for the treatment of BPH. Com-
through the skin and cause harm to a male fetus. Caution pared to finasteride, dutasteride causes a greater inhibi-
must be used when administering the drug to patients tion of 5-alpha reductase and thus is able to more
with CKD or hepatic impairment. effectively lower DHT levels. Dutasteride has a half-life of
5 weeks and it remains in the body for several months
Drug Interactions: Use with anticholinergics may after the drug is stopped. Like finasteride, sexual adverse
decrease the effects of finasteride. Use of finasteride with effects such as reduced ejaculate volume, diminished
testosterone will result in a reduction in the effects of both libido, and ED occur in some patients. Other warnings,
drugs. Herbal/Food: Saw palmetto may potentiate the contraindications, and actions are the same as those of fin-
effects of finasteride. asteride. Jalyn is a fixed-dose combination drug that con-
tains dutasteride with tamsulosin. Dutasteride is
pregnancy category X.
CONNECTIONS: NURSING PRACTICE APPLICATION
Patients Receiving Pharmacotherapy for Benign Prostatic Hyperplasia
Assessment
Baseline assessment prior to administration:
• Obtain a complete health history including cardiovascular, peripheral vascular, thyroid, hepatic, or kidney disease; diabetes; prostatic hyperplasia
(PSA); or prostatic cancer.
• Obtain a drug history including allergies, current prescription and OTC drugs, herbal preparations, alcohol use, and smoking. Be alert to possible drug
interactions.
• Evaluate appropriate laboratory findings (e.g., CBC, hepatic and renal function tests).
• Obtain baseline vital signs.
• 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., urinary stream increases, lessened urinary retention).
• Continue periodic monitoring of CBC, hepatic and renal function laboratory values, and PSA levels.
• Monitor vital signs at each healthcare visit.
• Assess for adverse effects: nausea, headache, rash, dizziness, or sexual dysfunction.
Implementation
Interventions and (Rationales) Patient-Centered Care
Ensuring therapeutic effects: • Teach the patient to continue taking the medication consistently during
• Monitor appropriate medication administration for optimal results. the early months of therapy and that the drug may take several months
to achieve its full effects.
(Full therapeutic effects from 5-alpha reductase inhibitors may take
3–6 months to be achieved.)
Minimizing adverse effects: • Teach the patient to immediately report any increasing symptoms of
• Continue to monitor hepatic function laboratory values periodically. urinary retention or slowing of the urinary stream. A prostate examina-
tion may be indicated.
(Hepatotoxicity is a potential adverse effect. Lifespan: Age-related
physiologic differences may place the older adult at greater risk for • Teach the patient to immediately report any symptoms of abdominal or
hepatotoxicity. Diverse Patients: Because finasteride metabolizes right upper quadrant discomfort or pain, yellowing of the skin or sclera,
through the CYP450 system pathways, monitor ethnically diverse fatigue, anorexia, darkened urine, clay-colored stools, weakness,
patients to ensure optimal therapeutic effects and to minimize adverse lethargy, nausea, or vomiting.
effects.)
(continued )
1324 Unit 10 Pharmacology of the Endocrine System
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
• Monitor BP at each clinical visit. Check weight and for presence of • Teach the patient taking alpha1-adrenergic antagonists to monitor BP
edema. (Alpha1-adrenergic antagonists may trigger sodium and water on a weekly basis. Report any BP over 140/90 mmHg, or as directed,
retention with resulting increases in weight, BP, and possible edema. to the healthcare provider. Report any weight gain of 1 kg (2 lb) in 24 h
Immediately report any BP over 140/90 mmHg, peripheral edema, or or 2 kg (5 lb) in 1 wk to the healthcare provider. Report any peripheral
weight gain.) edema. Ensure proper functioning of any equipment used at home.
• Monitor urine output and symptoms of dysuria such as hesitancy or • Have the patient promptly report urinary hesitancy, frequency, or an
nocturia. (5-alpha reductase inhibitors may cause urinary frequency, increase in nocturia.
nocturia, or hesitancy.)
• Give the first dose of any alpha1-adrenergic antagonist at bedtime. (A • Instruct the patient to take the first dose of medication at bedtime,
first-dose response may result in a greater initial drop in BP than sub- immediately before going to bed, and to avoid driving for 12–24 h after
sequent doses. This may also occur if the dose is increased. Lifespan: the first dose, or when the dosage is increased, until the effects are
Be cautious with the older adult who has a greater risk for falls.) known. If dizziness occurs, the patient should sit or lie down and not
attempt to stand or walk until the sensation passes.
• Do not abruptly stop alpha1-adrenergic antagonists used for BPH. • Teach the patient not to stop the medication abruptly and to call the
(Rebound HTN and tachycardia may occur.) healthcare provider for instructions if unable to take the medication for
more than 2 days due to illness.
• Protect against unintentional exposure to 5-alpha reductase inhibitors • Teach the patient to keep the drug in a secure location to guard against
by women of childbearing age and children, including through handling unintentional exposure to women of childbearing age or children.
of crushed or broken drugs. (The drug has teratogenic effects and han-
dling by women of childbearing age should be avoided. Men should • Teach the patient to use condoms consistently for sexual activity to
wear condoms during sexual activity and should not donate blood avoid exposing women of childbearing age to semen, which may also
while taking the drug and up to 1 month after stopping the drug.) contain the drug.
• Instruct the patient not to donate blood during the time the drug is
taken and up to 1 month after the drug is stopped.
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, the appropriate dose and scheduling, what adverse effects to
observe for, and when to report them.
assessments to discuss the rationale for drug therapy, desired thera-
peutic outcomes, commonly observed adverse effects, parameters
for when to call the healthcare provider, and any necessary monitoring
or precautions. (Using time during nursing care helps to optimize and
reinforce key teaching areas.)
Patient self-administration of drug therapy: • The patient, family, or caregiver is able to discuss the appropriate dos-
• When administering the medication, instruct the patient or caregiver in ing and administration needs.
proper self-administration of the drug, e.g., consistently over several
months of therapy, followed by teach-back. (Utilizing time during nurse
administration of these drugs helps to reinforce teaching.)
Understanding Chapter 71
Key Concepts Summary 71.5 Male infertility is treated with endocrine drugs that
boost sperm production.
71.1 Male reproductive function is controlled through
the secretion of androgens. 71.6 Erectile dysfunction is a common disorder that
may be successfully treated with inhibitors of the
71.2 Androgens are used to treat hypogonadism and enzyme phosphodiesterase-5.
delayed puberty in males, and breast cancer in
females. 71.7 Benign prostatic hyperplasia is an enlargement of
the prostate that occurs in older men.
71.3 Often abused by athletes, anabolic steroids can
cause serious adverse effects. 71.8 In its early stages, benign prostatic hyperplasia may
be treated successfully with drug therapy.
71.4 Male sexual dysfunction may have both medical
and psychologic etiologies.
Chapter 71 Drugs for Disorders and Conditions of the Male Reproductive System 1325
CASE STUDY: Making the Patient Connection
Remember the patient “Mike recently prescribed tadalafil (Cialis) for a diagnosis of ED.
Mayhew” at the beginning of Mike also has a past history of HTN and is taking nifedip-
the chapter? Now read the ine (Procardia).
remainder of the case study.
Based on the information pre- Critical Thinking Questions
sented within this chapter,
respond to the critical think- 1. What factors in Mike’s life and health history do you
ing questions that follow. think are contributing to the diagnosis of ED?
One year after his divorce, Mike, a 34-year-old man, began 2. If you were the nurse, what patient education instruc-
dating and soon met Dana. The couple found that they had tions would you provide to Mike regarding adminis-
a lot in common and enjoyed each other’s company. As the tration of tadalafil (Cialis) along with nifedipine
relationship grew, the couple became more intimate and (Procardia)?
sexually involved. However, the emotional scars from his
previous marriage were painful and deeply affected him. 3. After considering both options, Mike would rather be
prescribed sildenafil (Viagra) instead of tadalafil
After the divorce, Mike was depressed and had low (Cialis). What should the healthcare provider discuss
self-esteem. The condition required short-term hospitaliza- with Mike about this request?
tion, and he now follows up on an outpatient basis with a
psychiatrist. He has been taking antidepressants and was Answers to Critical Thinking Questions are available on the
faculty resources site. Please consult with your instructor.
Additional Case Study 2. What education would you provide Mr. Jones that he
may find helpful in dealing with BPH?
Morrie Jones, a 72-year-old man, has been having difficulty
with urinary frequency and excessive nighttime urination. 3. What additional health history and physical assess-
He scheduled an appointment with his healthcare provider ment findings would be considered in diagnosing this
and is diagnosed with BPH. He is prescribed finasteride condition?
(Proscar) and needs to see his healthcare provider again in
6 months. Answers to Additional Case Study questions are available on
the faculty resources site. Please consult with your instructor.
1. How would you explain the purpose of finasteride
(Proscar) in treating BPH?
Chapter Review 3. “Have you ever had an allergic reaction to
penicillin products?”
1. An adult patient has been receiving testosterone
(Testoderm) for the treatment of primary hypogo- 4. “Have you ever been treated for gastric ulcers?”
nadism. Which laboratory test would the nurse
monitor to determine that this drug therapy is 3. The nurse is teaching a patient who has received a
effective? prescription testosterone gel (AndroGel) for treatment
of symptoms related to low androgen levels. What
1. Red blood cell count instructions should the nurse give the patient? (Select
2. Sperm count all that apply.)
3. FSH
4. LH 1. “Apply the gel to the scrotal and perineal area daily.”
2. The patient with erectile dysfunction is being evalu- 2. “Avoid exposing women to the gel or to areas of
ated for pharmacotherapy. Which question should the skin where gel has been applied.”
nurse ask prior to initiating therapy with sildenafil
(Viagra)? 3. “Report any weight gain over 2 kilograms
(5 pounds) in 1 week’s time.”
1. “Are you currently taking medications for
angina?” 4. “Avoid showering or swimming for at least 12 to
14 hours after applying the gel.”
2. “Do you have a history of diabetes?”
5. “Maintain a low-fat diet and return periodically for
blood lipid laboratory studies.”
1326 Unit 10 Pharmacology of the Endocrine System
4. The nurse is counseling a patient about the goal of 3. Finasteride affects both near and far vision in older
therapy with sildenafil (Viagra). What will the nurse adult men.
teach the patient about the drug’s effects?
4. Six to 12 months may be required before the
1. It should always result in a penile erection within benefits of finasteride are achieved.
10 minutes.
5. The drug may cause significant dizziness, which
2. It is not effective if sexual dysfunction is can be avoided by making position changes slowly.
psychologic in nature.
6. A patient who has taken finasteride (Proscar) for the
3. It will result in less intense feelings with past 8 months reports a sudden increase in urinary hes-
prolonged use. itancy, urinary retention, and slowing of the urinary
stream. What will the nurse teach this patient to do?
4. It may heighten sexual response in female partners.
1. Continue to take the drug to achieve full effects.
5. The nurse is teaching the patient about the use of fin- 2. Decrease the intake of coffee, tea, and alcohol.
asteride (Proscar). What patient teaching related to 3. Discuss the use of a low-dose diuretic with the
this medication is needed? (Select all that apply.)
healthcare provider.
1. Finasteride promotes shrinkage of an enlarged 4. Return to the healthcare provider for a prostate
prostate and helps restore urinary function.
exam.
2. The drug should not be handled by women who
may be pregnant. See Answers to Chapter Review in Appendix A.
References National Center for Complementary and Integrative
Health (2016). Saw palmetto. Retrieved from https://
LaBotz, M., & Griesemer, B. A. (2016). Use of performance- nccih.nih.gov/health/palmetto/ataglance.htm
enhancing substances. Pediatrics, 138, e20161300.
doi:10.1542/peds.2016-1300
Selected Bibliography Matsui, H., Sopko, N. A., Hannan, J. L., & Bivalacqua, T. J.
(2015). Pathophysiology of erectile dysfunction. Current
Bruzziches, R., Francomano, D., Gareri, P., Lenzi, A., & Drug Targets, 16(5), 411–419. doi:10.2174/1389450116051
Aversa, A. (2013). An update on pharmacological 50504114041
treatment of erectile dysfunction with phosphodiesterase
type 5 inhibitors. Expert Opinion on Pharmacotherapy, 14, Moore, G., & Rogers, J. A. (2016). Flibanserin: Novel
1333–1344. doi:10.1517/14656566.2013.799665 treatment for hypoactive sexual desire disorder in
women. The Journal for Nurse Practitioners, 12(3),
Centers for Disease Control and Prevention. (2017). 210–211. doi:10.1016/j.nurpra.2015.10.016
Prostate cancer. Retrieved from http://www.cdc.gov/
cancer/prostate Samplaski, M. K., Loai, Y., Wong, K., Lo, K. C., Grober, E.
D., & Jarvi, K. A. (2014). Testosterone use in the male
Chehab, M., Madala, A., & Trussell, J. C. (2015). On-label infertility population: Prescribing patterns and effects
and off-label drugs used in the treatment of male on semen and hormonal parameters. Fertility and
infertility. Fertility and Sterility, 103, 595–604. Sterility, 101, 64–69. doi:10.1016/j.fertnstert.2013.09.003
doi:10.1016/j.fertnstert.2014.12.122
Seftel, A. D., Kathrins, M., & Niederberger, C. (2015).
Deters, L.A. (2016). Benign prostatic hypertrophy. Retrieved Critical update of the 2010 Endocrine Society clinical
from http://emedicine.medscape.com/article/437359- practice guidelines for male hypogonadism: A
overview#a1 systematic analysis. Mayo Clinic Proceedings, 90,
1104–1115. doi:10.1016/j.mayocp.2015.06.002
Garg, H., & Kumar, R. (2015). Empirical drug therapy for
idiopathic male infertility: What is the new evidence? Winters, B. R., & Walsh, T. J. (2014). The epidemiology of
Urology, 86, 1065–1075. doi:10.1016/j.urology.2015. male infertility. Urologic Clinics of North America, 41,
07.030 195–204. doi:10.1016/j.ucl.2013.08.006
Kim, E. D. (2016). Erectile dysfunction. Retrieved from http://
emedicine.medscape.com/article/444220-overview
Unit 11
Additional Drug Classes
CHAPTER 72 Pharmacotherapy of Bone and Joint Disorders / 1328
CHAPTER 73 Pharmacotherapy of Dermatologic Disorders / 1364
CHAPTER 74 Pharmacotherapy of Eye and Ear Disorders / 1389
CHAPTER 75 Emergency Preparedness: Bioterrorism and
Management of Poisoning / 1409
1327
“My clothes just don’t seem to
fit right anymore. My pant legs
are dragging on the ground.
Is it possible that I’m getting
shorter?”
Patient “Charlene Coleman”
Chapter 72
Pharmacotherapy of Bone
and Joint Disorders
Chapter Outline Learning Outcomes
cc Role of Calcium in Body Homeostasis After reading this chapter, the student should be able to:
cc Regulation of Calcium Balance
cc Pharmacotherapy of Calcium Imbalances 1. Describe the role of calcium in maintaining
homeostasis in the nervous, muscular, skeletal, and
Calcium Supplements cardiovascular systems.
PROTOTYPE Calcium Salts, p. 1333
cc Pathophysiology of Metabolic Bone Disease 2. Identify the recommended dietary allowance and
cc Pharmacotherapy of Metabolic Bone Disease the normal serum levels of calcium.
Vitamin D Therapy
PROTOTYPE Calcitriol (Calcijex, Rocaltrol), p. 1338 3. Explain the roles of parathyroid hormone, calcitonin,
Bisphosphonates and vitamin D in maintaining calcium balance.
PROTOTYPE Alendronate (Fosamax), p. 1340
Selective Estrogen Receptor Modulators 4. Explain the etiology, pathogenesis, and
PROTOTYPE Raloxifene (Evista), p. 1343 pharmacotherapy for hypocalcemia, hypercalcemia,
Calcitonin and Miscellaneous Drugs osteomalacia, osteoporosis, rickets, osteoarthritis,
cc Pathophysiology and Pharmacotherapy of Joint rheumatoid arthritis, and gout.
Disorders
Osteoarthritis 5. Describe the nurse’s role in the pharmacologic
Rheumatoid Arthritis management of bone and joint disorders.
PROTOTYPE Adalimumab (Humira), p. 1350
cc Pharmacotherapy of Gout and Hyperuricemia 6. For each of the classes shown in the chapter outline,
PROTOTYPE Colchicine (Colcrys), p. 1356 identify the prototype and representative drugs and
PROTOTYPE Allopurinol explain the mechanism(s) of drug action, primary
(Lopurin, Zyloprim), p. 1357 indications, contraindications, significant drug
interactions, pregnancy category, and important
adverse effects.
7. Apply the nursing process to the care of patients
receiving pharmacotherapy for bone and joint
disorders.
1328
Chapter 72 Pharmacotherapy of Bone and Joint Disorders 1329
Key Terms disease-modifying antirheumatic osteoporosis, 1336
drugs (DMARDs), 1349 Paget’s disease, 1337
acute gouty arthritis, 1355 rheumatoid arthritis (RA), 1348
bisphosphonates, 1339 gout, 1355 selective estrogen receptor
bone deposition, 1330
bone resorption, 1330 hyperuricemia, 1355 modulators (SERMs), 1343
calcitonin, 1330 uricosurics, 1357
calcitriol, 1331 metabolic bone disease (MBD), xanthine oxidase, 1357
cholecalciferol, 1331 1336
osteoarthritis (OA), 1346
osteomalacia, 1337
Disorders associated with bones and joints can lead to calcium is in an active, ionized form that participates in
immobility and affect a patient’s ability to fulfill activities intracellular functions, including neuromuscular activity
of daily living (ADLs). In addition, the skeletal system and blood coagulation. This is the only physiologically and
serves as the primary repository for calcium, which is one clinically significant form of calcium. An adequate amount
of the body’s most important minerals. of free or ionized calcium is required for normal body func-
tions. Most of the remaining 50% of calcium in plasma is
This chapter focuses on the pharmacotherapy of bound to plasma proteins, primarily albumin, and other
important skeletal and joint disorders such as osteomala- substances and is unavailable for general use by the body.
cia, osteoporosis, arthritis, and gout. The importance of cal-
cium balance and the action of vitamin D are stressed To maintain homeostasis, the body must obtain suffi-
because they are critical to the proper structure and func- cient amounts of calcium through proper nutrition and
tion of bones. dietary supplements. Unfortunately, only 30% to 50% of
dietary calcium is absorbed from the small intestine. The
Role of Calcium in Body amount absorbed, however, is dynamic and changes with
Homeostasis body conditions. Absorption is increased by moderate
amounts of fat or high protein intake, high gastric acidity,
72.1 Adequate levels of calcium in the body are and when certain hormones are secreted in response to low
necessary to transmit nerve impulses, to prevent blood calcium. Decreased absorption occurs with vitamin D
muscle spasms, and for proper bone health. deficiency, high-fat diet, decreased gastric acidity, certain
hormones secreted in response to high blood calcium, and
Calcium balance is critical to the proper functioning of the conditions that increase gastrointestinal (GI) motility such
nervous, muscular, skeletal, and cardiovascular systems. as diarrhea. Dietary calcium that remains unabsorbed is
In the nervous system calcium ions influence the release of excreted in feces. Calcium can also be lost through the nails,
neurotransmitters and the excitability of all neurons. Con- hair, sweat, and other body fluids. In lactating women,
traction is dependent on calcium ion movement in skeletal, large amounts are lost through breast milk.
smooth, and cardiac muscle cells. Calcium is important for
the normal functioning of other body processes such as The recommended dietary allowance (RDA) of cal-
blood coagulation by converting prothrombin into throm- cium for healthy adults is 1000 to 1200 mg/day. Higher
bin and in activating enzymes that catalyze many essential amounts are needed by pregnant and lactating women,
chemical reactions. growing children, and postmenopausal women, as given in
Table 72.1. The best dietary sources of calcium are dairy
Calcium is the major cation for the structure of the products. The calcium found in milk is the most readily
bones and teeth. Total body content of calcium is about available form because milk contains sufficient amounts of
1200 g or approximately 2% of the total body weight. More vitamin D, which is necessary for calcium absorption.
than 99% of that calcium is in the skeletal system and is Other rich sources of calcium include seafood, such as
bound as a hard matrix known as hydroxyapatite crystals. salmon, oysters, and clams, and green leafy vegetables,
Only about 1% of the calcium in bone is rapidly exchange- such as kale, broccoli, spinach, and mustard greens. If the
able with blood calcium; the remaining calcium is more body does not obtain enough dietary calcium, it will
stable and slowly exchanged. remove calcium from the bones, resulting in bones that
become soft and weakened and that eventually develop
Much of the calcium found outside of bone circulates osteoporosis. The importance of meeting the daily RDA for
in the blood. Calcium exists in plasma in three forms: ion- calcium is vital to both women and men. Although not as
ized, bound, and complexed. About 50% of the serum
1330 Unit 11 Additional Drug Classes
Table 72.1 Recommended Dietary Allowances ionized calcium decrease, the parathyroid glands secrete
PTH. PTH directly increases calcium reabsorption in the
for Calcium renal tubule and releases calcium from bone (resorption).
PTH indirectly increases serum calcium by promoting
Age/Condition U.S. RDA (mg) the formation of activated vitamin D, which then
0–6 months increases calcium absorption from the GI tract. The over-
7–12 months 200 all effect of these physiologic changes is to rapidly
1–3 years 260 (within minutes) increase serum calcium, returning it to
4–8 years 700 normal levels.
9–18 years 1000
19–50 years 1300 The parathyroid glands are regulated by a typical neg-
51–70 years 1000 ative feedback loop. An increase in the ionized serum cal-
1000 (men) cium is recognized by calcium receptors in the parathyroid
71+ 1200 (women) gland, which suppress PTH secretion. A second piece of the
Pregnant and lactating women (14–18 years) 1200 negative feedback loop is that activated vitamin D also
Pregnant and lactating women (19–50 years) 1300 shuts down PTH secretion. Without PTH present, the
1000 absorption of calcium from the GI tract is diminished, the
reabsorption in the kidney tubule decreases, and calcium
prevalent, men may develop bone conditions such as osteo- remains deposited in bone.
porosis, and adequate calcium intake should be added to
their list of preventive healthcare interventions. The exchange of calcium between the serum and bones
is influenced by PTH and calcitonin. PTH stimulates bone
The normal serum calcium range varies widely and is cells called osteoclasts. These cells accelerate the process of
dependent on gender, age, and season. A normal reference bone resorption, or demineralization, which breaks down
range may be considered 8.5 to 10.5 mg/dL. Serum cal- bone into its mineral components. Once bone is broken
cium concentrations that exceed 11.5 mg/dL result in down (resorbed), calcium becomes available to be trans-
symptoms of hypercalcemia, which causes a decrease in ported and used elsewhere in the body. The opposite of this
sodium permeability across cell membranes. This is a dan- process is bone deposition, or bone building, which is
gerous state because nerve conduction depends on the accomplished by cells called osteoblasts. This process,
proper influx of sodium into cells. When calcium levels in which removes calcium from the blood to be placed in
the bloodstream are below 8.0 mg/dL, a state of hypocal- bone, is stimulated by the hormone calcitonin. It is impor-
cemia develops and the cell membranes become hyperex- tant to note that maintaining normal serum calcium levels
citable. If this situation becomes severe, convulsions or takes precedence over the calcium requirements of the
muscle spasms may result. bone. If serum calcium levels are low, bone resorption will
occur even if it compromises the structural integrity of the
PharmFACT bone matrix.
In the United States, 2 million osteoporotic fractures occur Calcitonin: When serum calcium levels become
each year. It is estimated that almost 10 million individuals elevated, the hormone calcitonin is released by the
have osteoporosis. (Bethel, 2017). thyroid gland. Calcitonin acts in opposition to PTH and
vitamin D to decrease the plasma levels of calcium by
Regulation of Calcium Balance inhibiting the resorption of calcium from bone and
increasing the excretion of calcium by the kidney, thus
72.2 Calcium balance is regulated by decreasing the concentration of serum calcium. It is
parathyroid hormone, calcitonin, and vitamin D. important to note that calcitonin does not affect the
rates of calcium absorption from the small intestine.
Calcium balance is controlled by parathyroid hormone, Calcitonin is available as a medication for the treatment
calcitonin, and vitamin D. Acting together, these three sub- of osteoporosis.
stances regulate the rate of absorption of calcium from the
small intestine, the excretion of calcium from the kidney, Vitamin D: Vitamin D and calcium metabolism are inti-
and the movement of calcium into and out of bone. Cal- mately related: Absorption of calcium is increased in the
cium balance is illustrated in Figure 72.1. presence of vitamin D, and absorption is inhibited by vita-
min D deficiency. Thus, calcium disorders are often associ-
Parathyroid hormone: Parathyroid hormone (PTH) is ated with vitamin D disorders.
secreted from the parathyroid gland, as illustrated in
Figure 72.1. The parathyroid glands contain calcium Vitamin D is unique among vitamins because it is the
receptors that are able to sense very small changes in only vitamin that the body is able to synthesize from pre-
serum calcium concentration. When the serum levels of cursor molecules. Several steps, however, are required
Chapter 72 Pharmacotherapy of Bone and Joint Disorders 1331
Hypocalcemia
Parathyroid glands
Parathyroid hormone (PTH)
Conversion of calcifediol to with PTH
calcitriol (activated vitamin D)
Small Bone Kidneys
intestine Calcium reabsorption
Calcium reabsorption
Calcium absorption Normal serum
calcium level
Figure 72.1 Calcium balance.
before vitamin D can act on target tissues, as illustrated in abnormalities. The primary function of calcitriol is to
Figure 72.2. In the skin, cholecalciferol, the inactive form of increase calcium absorption from the GI tract. Dietary cal-
vitamin D, is synthesized from cholesterol. Exposure of the cium is absorbed more efficiently in the presence of active
skin to sunlight or ultraviolet light increases the level of vitamin D and PTH, resulting in higher serum levels of
cholecalciferol in the blood. Cholecalciferol can also be calcium, which is then transported to bone, muscle, and
obtained from dietary products such as milk or other foods other tissues.
fortified with vitamin D.
CONNECTION Checkpoint 72.1
Following its absorption from dietary sources or for-
mation in the skin, cholecalciferol is converted to an inter- Inhibition of calcium transport into cells can have important
mediate vitamin form called calcifediol. Kidney enzymes physiologic effects. From what you learned in Chapter 30, what
metabolize calcifediol to calcitriol, the active form of vita- are the primary indications for pharmacotherapy with calcium
min D. PTH stimulates the formation of calcitriol at the channel blockers? Answers to Connection Checkpoint questions
level of the kidneys. Patients with extensive kidney dis- are available on the faculty resources site. Please consult with your
ease are unable to adequately synthesize calcitriol and instructor.
thus frequently experience calcium and vitamin D
1332 Unit 11 Additional Drug Classes
Cholecalciferol calcium in the urine. Most patients with chronic
(inactive vitamin D) kidney disease (CKD) will require calcium and
Skin Diet vitamin D therapy to prevent hypocalcemia.
Liver Another etiology for hypocalcemia is hypo-
parathyroidism leading to decreased secretion of
Calcifediol PTH, as occurs when the thyroid and parathy-
(intermediate form) roid glands are diseased or surgically removed.
A rare cause of hypocalcemia is pseudohypo-
PTH Kidney parathyroidism, which is an uncommon group
Parathyroid glands of genetic disorders where the target organs for
PTH (bone and kidneys) become resistant to the
Calcitriol hormone. Recombinant PTH (Natpara) is avail-
(active vitamin D) able as an adjunct to calcium and vitamin D ther-
apy in controlling hypoglycemia in patients with
Increased absorption hypoparathyroidism.
of calcium in
Drug therapy is occasionally a cause of
the small intestine hypocalcemia. Blood transfusions and certain
anticonvulsants such as phenytoin and pheno-
Figure 72.2 Pathway for vitamin D activation. barbital can lower serum calcium levels. In addi-
tion, overtreatment with drugs that are used to
Pharmacotherapy of Calcium lower serum calcium can result in overshooting
Imbalances normal levels. Some of these include furose-
mide, phosphate therapy, or bisphosphonates.
72.3 Hypocalcemia and hypercalcemia are Of special concern is long-term therapy with
treated with nutritional adjustments or with corticosteroids, which is a very common cause
pharmacotherapy. of hypocalcemia and osteoporosis. To help pre-
vent corticosteroid-induced osteoporosis,
Calcium imbalances occur frequently. When minor, dietary patients should receive daily supplements of
means may be used to correct the imbalance; however, calcium and vitamin D.
serious imbalances require pharmacotherapy.
Hypocalcemia is frequently asymptomatic.
Treatment of Hypocalcemia Signs and symptoms of hypocalcemia are those
of nerve and muscle excitability. The symptoms include
Hypocalcemia is not a disease but is a sign of underlying confusion, paresthesias around the mouth and in the dig-
pathology; thus, diagnosis of the cause of hypocalcemia is its, carpopedal spasms, and hyperreflexia. Muscle twitch-
essential. Many factors can cause hypocalcemia. Lack of ing, tremors, or cramping may be evident. Two clinical
sufficient dietary calcium or vitamin D intake is a common signs are Chvostek’s sign and Trousseau’s sign.
cause and one that can be easily reversed by nutritional Chvostek’s sign is elicited by tapping on the facial nerve
adjustments. If hypocalcemia occurs despite normal just below the temple. A positive sign is a twitch of the
dietary intake, GI causes must be examined, such as exces- nose or lip. Trousseau’s sign is the contraction of the hand
sive vomiting or the presence of malabsorption disorders. and fingers when the arterial blood flow in the arm is
Damage to renal tubular cells may cause excessive loss of occluded for 5 minutes.
Intestinal cramping and hyperactive bowel sounds
may be present because the low calcium levels affect the
smooth muscle of the GI tract. Severe symptoms include
convulsions, laryngeal spasms, and tetany. Tetany is a con-
tinuous muscle spasm that can interfere with breathing
and even cause death. The characteristic electrocardiogram
(ECG) change is a prolonged QT interval, indicating pro-
longed ventricular depolarization with characteristically
weak cardiac muscle contractions.
Unless the hypocalcemia is especially severe or life
threatening, adjustments in diet may be attempted prior to
initiating therapy with calcium supplements. Increasing
the consumption of calcium-rich foods, especially dairy
Chapter 72 Pharmacotherapy of Bone and Joint Disorders 1333
products, fortified orange juice, cereals, and green leafy IV calcium gluconate can protect the heart against the
vegetables, is often sufficient to restore calcium balance. hyperexcitability of excessive potassium (hyperkalemia)
and help to maintain cardiorespiratory function during
PROTOTYPE DRUG Calcium Salts magnesium sulfate toxicity (hypermagnesemia) situations.
IV calcium salts have been administered during cardiac
Classification Therapeutic: Calcium supplement arrest due to their ability to increase cardiac muscle tone
Pharmacologic: Drugs for hypocalcemia and the force of systolic contraction (positive inotropic
effect). However, the use of calcium salts in cardiac resusci-
Therapeutic Effects and Uses: Calcium salts are tation has declined and is limited to patients with cardiac
available in a wide variety of products and formulations. disease who have hypocalcemia because calcium salts may
Calcium has two major forms: complexed and elemental. cause dysrhythmias at high doses.
Most calcium supplements are in the form of complexed
calcium. These products are often compared on the basis Mechanism of Action: Calcium salts restore the nor-
of their ability to release elemental calcium into the blood- mal serum levels of calcium, which promotes deposition
stream. The greater the ability of complexed calcium to of the mineral in bone. This helps to restore bone strength
release elemental calcium, the more potent the supplement. and prevent fractures. Calcium also restores normal neuro-
Table 72.2 lists the doses for selected calcium supplements. muscular function and muscular contraction.
For mild, chronic hypocalcemia, effective and inexpen- Pharmacokinetics: The pharmacokinetics of calcium
sive calcium supplements are readily available over the salts varies by the route of administration and the specific
counter (OTC) in a variety of formulations. Calcium car- formulation. They are widely distributed and excreted pri-
bonate and calcium citrate are two common salts for rou- marily in the feces, with about 20% in the urine. The dura-
tine supplementation. Many calcium supplements also tion of action of calcium salts is generally only a few hours.
contain vitamin D.
Adverse Effects: Oral (PO) calcium products are safe
The administration of intravenous (IV) calcium salts and produce few adverse effects when used as directed.
may be necessary for severe cases of hypocalcemia or if the The most common adverse effect of calcium supplements
patient is in tetany. Repeated infusions are sometimes is hypercalcemia, which is caused by taking too much of
required to return the serum calcium level to normal. Con- this supplement. This can be especially serious in the IV
stant monitoring of serum calcium is required during IV formulations. Symptoms of hypercalcemia include drowsi-
administration to prevent hypercalcemia. ness, lethargy, weakness, headache, anorexia, constipation,
increased gastric acid secretion, nausea, vomiting, a tin-
In addition to preventing or treating hypocalcemia, gling sensation, increased urination, and thirst. IV admin-
calcium salts are administered for many other conditions, istration of calcium may cause pain and burning at the IV
including osteoporosis, Paget’s disease, osteomalacia, site, severe venous thrombosis, necrosis, sloughing of the
chronic hypoparathyroidism, rickets, pregnancy, lacta skin (with extravasation), hypotension, sensations of heat
tion, and rapid childhood growth. Calcium carbonate is a waves (peripheral vasodilation), fainting, bradycardia,
common antacid used to treat heartburn. It may also be cardiac dysrhythmias, and cardiac arrest. Large doses of
used to bind excessive dietary phosphate in patients with
hyperphosphatemia caused by end-stage renal failure.
Table 72.2 Selected Calcium Salts
Drug Route and Adult Dose Adverse Effects
Calcium Content (Maximum Dose Where Indicated)
Constipation, nausea, vomiting,
Calcium Supplements (All doses are in terms of elemental calcium.) metallic taste
calcium acetate (PhosLo) 25% PO: 2–4 tablets with each meal (each tablet contains Hypercalcemia (drowsiness, lethargy,
169 mg elemental calcium) headache, anorexia, nausea,
vomiting, increased urination, and
calcium carbonate (Rolaids, Os-Cal, 40% PO: 1–2 g bid–tid thirst), dysrhythmias, cardiac arrest,
Tums, others) confusion, delirium, stupor, coma
calcium chloride 27 mg Ca/mL IV: 0.5–4 g by slow infusion (1 mL/min)
calcium citrate (Citracal) 21% PO: 1–2 g bid–tid
calcium gluconate (Kalcinate) 9% (PO); 9 mg PO: 0.5–2 g bid–tid
Ca/mL (IV) IV: 0.5–4 g by slow infusion (1 g/h)
calcium lactate (Cal-Lac) 13% PO: 325–650 mg bid–tid before meals
calcium phosphate tribasic (Posture) 39% PO: 1–2 g bid–tid
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
1334 Unit 11 Additional Drug Classes
supplemental calcium may lead to the formation of symp- Treatment of Overdose: Measures may be taken to
tomatic kidney stones. treat cardiac abnormalities caused by the hypercalcemia
that results from overdose.
Contraindications/Precautions: Calcium salts are
contraindicated in patients with ventricular fibrillation, Nursing Responsibilities: Key nursing implica-
metastatic bone disease, renal calculi, hypercalcemia, pre- tions for patients receiving calcium supplementation are
disposition to hypercalcemia, hyperparathyroidism, certain included in the Nursing Practice Application for Patients
malignancies, and digoxin toxicity. Calcium salts should Receiving Pharmacotherapy for Osteoporosis.
not be injected into the myocardium or administered by
the subcutaneous or intramuscular (IM) route. Caution Drugs Similar to Calcium Salts
must be used with patients who have renal or cardiac
insufficiency, dysrhythmias, dehydration, diarrhea, hyper- A large number of calcium salts are available. A summary
phosphatemia, sarcoidosis, or history of kidney stones. of their indications is shown in Table 72.3.
Immobilized patients are at high risk for the development
of hypercalcemia. Treatment of Hypercalcemia
Drug Interactions: Concurrent use with digoxin In patients with CKD, the kidneys are unable to control
increases the risk of dysrhythmias and enhances the ino- mineral metabolism. As a consequence, the parathyroid
tropic effects of digoxin. Magnesium may compete for GI glands secrete large amounts of parathyroid hormone,
absorption. Calcium decreases the absorption of tetracy- which can cause serious hypercalcemia. This disorder is
clines and fluoroquinolones, such as ciprofloxacin. Their called secondary hyperparathyroidism (secondary HPT)
use may antagonize the effects of verapamil and possibly because the condition is not a disease of the parathyroid
other calcium channel blockers. Herbal/Food: Zinc-rich gland itself but is a consequence of CKD.
foods such as shellfish, dried beans, sesame seeds, pump-
kin seeds, and many meats may decrease the absorption of The two drugs for treating secondary HPT, cinacalcet
calcium. Alcohol, caffeine, and carbonated beverages affect (Sensipar) and etelcalcetide (Parsabiv), are called calcimi-
the absorption of calcium. Oxalic acid in spinach, rhubarb, metics because they mimic the effects of calcium in tissues.
Swiss chard, and beets can suppress calcium absorption. The drugs act on the calcium sensors in the parathyroid, in
Phytic acid, which is present in bran and whole-grain cere- effect tricking the gland into thinking the body has plenty
als, depresses calcium absorption. of calcium. The gland thus reduces its secretion of parathy-
roid hormone.
Pregnancy: Category B or C.
Cinacalcet was approved by the U.S. Food and Drug
Administration (FDA) in 2004. Given PO, the dose is slowly
Table 72.3 Indications for Selected Calcium Salts
Management of Management of Management of Prevention and Mineral Electrolyte
Hyperkalemia Treatment of Supplement Replenishment
Salt Antacid Hypermagnesemia Hyperphosphatemia Hypocalcemia Cardiotonic
X
calcium X
acetate X
X X XX
calcium X
carbonate X XX X
calcium X XX
chloride
XX
calcium
citrate X XX X
calcium XX
glubionate XX
calcium
gluconate
injection
calcium
lactate
calcium
phosphate,
dibasic
Chapter 72 Pharmacotherapy of Bone and Joint Disorders 1335
CONNECTIONS: NURSING PRACTICE APPLICATION
Patients Receiving Pharmacotherapy for Osteoporosis
Assessment
Baseline assessment prior to administration:
• Obtain a complete health history including musculoskeletal, GI, cardiovascular, neurologic, endocrine, hepatic, or kidney disease. Obtain a drug history
including allergies, current prescription and OTC drugs, and herbal preparations, alcohol use, or smoking. Be alert to possible drug interactions.
• Obtain a history of any current symptoms and their effect on ADLs. Assess muscle strength and gait and note any pain or discomfort on movement or
at rest. Obtain bone density studies if ordered.
• Obtain a dietary history, noting adequacy of essential vitamins, minerals, and nutrients obtained through food sources, particularly calcium, vitamin D,
and magnesium. Note amount of soda or other nondairy fluid intake daily.
• Note sunscreen use and amount of sun exposure.
• Obtain baseline height, weight, and vital signs.
• Evaluate appropriate laboratory findings (e.g., complete blood count [CBC], electrolytes, calcium, phosphorus, and magnesium levels, hepatic and
renal function studies).
• Assess the patient’s ability to receive and understand instructions. Include family and caregivers as needed.
Assessment throughout administration:
• Assess for desired therapeutic effects (e.g., calcium, phosphate, and magnesium levels are within normal limits, bone density studies show
improvement).
• Continue monitoring laboratory values as appropriate, especially calcium, phosphorus, and magnesium.
• Assess for and promptly report adverse effects: nausea, vomiting, abdominal pain, esophageal irritation, constipation, diarrhea, or symptoms of elec-
trolyte imbalances. Severe GI irritation or pain should be reported immediately.
Implementation
Interventions and (Rationales) Patient-Centered Care
Ensuring therapeutic effects: • Encourage adequate amounts of calcium, vitamin D, and magnesium
• Review the dietary history with the patient and discuss food source from food sources. Provide educational pamphlets or web-based
references to reputable sources as needed (e.g., NIH Office of Dietary
options for correcting any deficiencies, particularly calcium and vitamin D. Supplements). Provide dietitian referral as needed.
Encourage the patient to adopt a healthy lifestyle of increased activity
or exercise, adequate sun exposure, limited or eliminated caffeine, • Encourage limited amounts of sun exposure daily without sunscreen,
soda, and alcohol consumption. (Adequate amounts of calcium, approximately 15–20 min. Discourage prolonged sun exposure beyond
vitamin D, and magnesium are needed for bone health. Any deficiencies that time.
should be corrected before bisphosphonates are started. Adequate
sun exposure, approximately 15–20 min/day without sunscreen, • Teach the patient that excessive soda, caffeine, and other nondairy
may assist in vitamin D formation. Excessive soda, caffeine, or other consumption may diminish absorption of dietary calcium.
nondairy intake may increase the risk of osteoporosis due to lessened
calcium consumption and decreased calcium absorption from caffeine • Encourage adequate activity and exercise, especially weight-bearing
effects.) exercise, 3–5 times per week.
• Follow administration guidelines for optimal results. (Calcium supple- • Teach the patient the appropriate administration guidelines for best
ments and vitamin D should be taken with meals or within 1 h after results. Ensure that the patient is able to remain upright if bisphospho-
meals for best absorption. Bisphosphonates should be taken on an nates are used.
empty stomach with a full glass of water and the patient should remain
upright for 30 min to 1 h. Bisphosphonates and calcium preparations
should be taken 2 h apart.)
Minimizing adverse effects: • Instruct the patient to immediately report any new onset of nausea or
• Monitor for GI irritation or abdominal pain. (Bisphosphonates may any increasing or severe chest or abdominal discomfort or pain.
cause esophageal irritation and erosion. Increasing nausea, gastric, or
abdominal pain should be reported immediately.)
• Continue to monitor periodic laboratory work, especially calcium, mag- • Instruct the patient on the need to return periodically for laboratory
nesium, phosphorus, vitamin D, and creatinine as needed. Assess for work.
signs or symptoms of hypo- or hypercalcemia. (Calcium, magnesium,
phosphorus, and vitamin D levels should return to, and remain within, • Instruct the patient to immediately report symptoms of hypocalcemia
normal limits. Increased creatinine levels may indicate renal effects and (muscle spasms, facial grimacing, irritability, hyperreflexes) or hypercal-
may require discontinuation of medications.) cemia (increased bone pain, anorexia, nausea, vomiting, constipation,
thirst, lethargy, or fatigue).
• Monitor the use of vitamin D. Excessive intake may lead to toxic • Instruct the patient not to take additional or large amounts of vitamin D
effects. (Fat-soluble vitamins are stored in the body and may ac- unless instructed by the provider.
cumulate and result in toxic levels. Monitor liver function studies and
for symptoms such as nausea, vomiting, headache, fatigue, dry and • Encourage the patient to obtain fat-soluble vitamins from natural
itchy skin, blurred vision, or palpitations. Report any symptoms im- sources through a balanced diet whenever possible.
mediately.)
• Increase fluid intake, avoiding caffeine or soda. (Increased fluid intake • Encourage the patient to increase fluid intake to 2 L/day, divided
decreases the risk of renal calculi formation.) throughout the day, but avoid highly caffeinated beverages and exces-
sive soda intake.
• Monitor adherence to the recommended regimen. (Bone remodeling • Teach the patient to continue taking the drug therapy regularly to
occurs over several months and effects may not be noted immediately. ensure full effects. Therapeutic response may take 1–3 months and
The patient may discontinue drug therapy because of a perceived lack effects continue after the drug has been discontinued.
of response.)
(continued )
1336 Unit 11 Additional Drug Classes
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
• Note and promptly report any new-onset thigh or groin pain, unilaterally • Teach the patient to promptly report any new onset of groin or thigh
or bilaterally. (An increased incidence of atypical fractures has been pain, either unilaterally or bilaterally.
noted in some patients taking bisphosphonates, particularly with long-
term use or with concurrent corticosteroid use. Thigh or groin pain has • Advise the patient to review the need for continued bisphosphonate
been noted to occur prior to fracture and should be reported to the use with the healthcare provider based on bone density studies on a
provider for assessment.) regular basis.
Patient understanding of drug therapy: • The patient should be able to state the reason for the drug, appropriate
• Use opportunities during administration of medications and during dose and scheduling, what adverse effects to observe for and when to
report them, and the anticipated length of the medication therapy.
assessments to discuss the rationale for drug therapy, desired thera-
peutic outcomes, commonly observed adverse effects, parameters
for when to call the healthcare provider, and any necessary monitoring
or precautions. (Using time during nursing care helps to optimize and
reinforce key teaching areas.)
Patient self-administration of drug therapy: • The patient, family, or caregiver is able to discuss appropriate dosing
• When administering the medication, instruct the patient, family, or and administration needs including:
• Calcium supplements: Take with meals or immediately after meals.
caregiver in proper self-administration of the drug, e.g., taken with • Bisphosphonates: Take with a full glass of plain water and remain in
additional fluids, followed by teach-back. (Utilizing time during nurse an upright position for 30 min to 1 h after taking.
administration of these drugs helps to reinforce teaching.)
escalated until serum PTH and calcium levels return to nor- by defective osteoblasts that have an abnormally short lifes-
mal values. Overtreatment may cause hypocalcemia. Nau- pan or work less efficiently, resulting in slow bone deposi-
sea, vomiting, and diarrhea are common during therapy. tion. The second and more popular theory suggests that the
This drug is a strong inhibitor of CYP450 enzymes and osteoclasts have increased activity, resorbing bone at an
should be used with caution in patients who are receiving increased rate. The common factor between the two theories
other drugs that are CYP450 substrates or inhibitors. Etelcal- is that normal bone turnover is altered, with the rate of
cetide, approved in 2017, is administered by the IV route, resorption greater than bone formation, resulting in a
usually at the end of a hemodialysis session. The most com- decrease in total bone density and an altered bone structure.
mon adverse effects are hypocalcemia, muscle spasms, diar-
rhea, nausea, vomiting, headache, and paresthesia. Numerous risk factors have been identified for osteo-
porosis. Women are 4 times more likely than men to
Pathophysiology of Metabolic develop this condition, and the most common risk factor
Bone Disease associated with the development of osteoporosis is the
onset of menopause. When women reach menopause,
72.4 Metabolic bone disease is characterized estrogen secretion declines, and bones become weak and
by abnormal bone structure. fragile. In women with osteoporosis, fractures often occur
in the hips, wrists, forearms, or spine. In some cases, a lack
Metabolic bone disease (MBD) is a general term that of dietary calcium and vitamin D contributes to bone dete-
refers to a cluster of disorders that have in common defects rioration. The metabolism of calcium in osteoporosis is
in the structure of bone. MBDs are caused by abnormal illustrated in Figure 72.3.
amounts of the minerals or hormones responsible for bone
homeostasis, such as calcium, phosphate, vitamin D, or Major risk factors for osteoporosis include the
PTH. Some MBDs have a genetic etiology, whereas others following:
are iatrogenic and caused by certain drugs and therapies.
• Excessive alcohol intake (more than 4 drinks per day
Osteoporosis: Osteoporosis is an MBD characterized for men or 2 for women)
by bone demineralization, decreased bone density, and
subsequent fractures. Osteoporosis is the most prevalent • Gonadal hormone deficiency (estrogen or androgen)
MBD in the United States. This disorder is usually asymp- • Increasing age
tomatic until the bones become brittle enough to fracture • Low body weight (less than 58 kg or 128 lb)
or for vertebrae to collapse. • Low calcium or vitamin D intake
• Low level of physical activity or immobilization
Normal bone remodeling requires a balance between • Menopause
bone deposition (gain) and bone resorption (loss). The exact • Personal history of fracture or family history of osteo-
pathophysiology of osteoporosis is unknown, but there are
two major theories. In the first, osteoporosis may be caused porotic fracture
• Tobacco use
• Caucasian or Asian.
Chapter 72 Pharmacotherapy of Bone and Joint Disorders 1337
(a) Normal calcium intake Bone Many factors contribute to the development of osteomala-
Deposition cia and rickets, but the most important is a deficiency of
vitamin D and calcium. This risk factor for the disease is
Intestine Normal bone extremely rare in the United States, being most prevalent
homeostasis: in older adults, premature infants, and individuals on
Deposition = strict vegetarian diets. Other factors that may result in the
resorption development of osteomalacia include malabsorption dis-
orders of the small bowel, damage to the renal tubules,
Blood Resorption adverse effects of anticonvulsant therapy, hepatic impair-
ment, or a limited exposure to sunlight.
To body Bone
(b) Low calcium intake The promotion of breastfeeding over vitamin D–
Osteoporotic bone: fortified formulas is thought to be responsible for some
No deposition Resorption exceeds cases of osteomalacia, particularly in mothers who are
deposition. Bone vitamin D deficient. In addition, the increased use of sun-
Intestine becomes fragile. screens to prevent skin cancer inhibits the formation of
adequate vitamin D by sunlight. The replacement of
Blood Excess vitamin D–fortified milk with carbonated beverages
resorption by children and teens also contributes to the possibility
of rickets. Nurses need to emphasize the importance of
To body getting enough extra dietary vitamin D to children and
pregnant women. Drug therapy for children and adults
Figure 72.3 Calcium metabolism in osteoporosis. consists of calcium salts and vitamin D.
Several methods are available for measuring bone Symptoms of osteomalacia include hypocalcemia,
mineral density (BMD) but the “gold standard” for the muscle weakness, muscle spasms, and diffuse bone pain,
diagnosis of osteoporosis is dual-energy x-ray absorptiom- especially in the hip area. Patients may also experience
etry (DEXA). BMD at the spine and hip is measured and pain in the arms, legs, and spine. Classic signs of rickets
data are reported as T-scores. Positive T-scores represent in children include bowlegs and a pigeon breast. Chil-
the BMD values of a young adult between the ages of 30 dren may also develop a slight fever and become restless
and 35, which is the period of peak bone strength. Negative at night.
T-scores indicate some loss in BMD. Osteopenia, or a low
bone mass, is present when the T-score is between –1 and The standard test for diagnosing osteomalacia is to
–2.5. Osteoporosis is defined as a T-score of –2.5 or less. determine vitamin D status by measuring the serum levels
Nutritional adjustments and drug therapy are initiated of 25-hydroxyvitamin D. Additional tests may include
when T-scores fall into the osteopenic or osteoporosis bone radiographs and computed tomography (CT) scans of
ranges. the vertebral column.
Drug therapies for osteoporosis include calcium and Paget’s disease: Paget’s disease, or osteitis deformans,
vitamin D therapy, bisphosphonates, estrogen receptor is a chronic, progressive condition characterized by accel-
modulators, parathyroid hormone analogs (abaloparatide erated remodeling of the bone, producing enlarged and
[Tymlos] and teriparatide [Forteo]), denosumab, and softened bones. With this disorder, the processes of bone
calcitonin. resorption and bone formation occur simultaneously but
at a very high rate. The rapid turnover causes new bone to
Osteomalacia: Osteomalacia, referred to as rickets in be weak and brittle, resulting in deformities and fractures.
children, is a disorder characterized by softening of bones Paget’s disease can occur in any bone, but it most often
without alteration of basic bone structure. Weight-bearing affects the vertebrae, skull, sternum, pelvis, femur, and
stress on the softened bones causes skeletal deformities. tibia. Paget’s disease occurs with equal frequency in men
and women over 40 years of age. The cause of Paget’s dis-
ease is unknown.
Although many patients with Paget’s disease are
asymptomatic, approximately 10% experience vague, non-
specific complaints for many years. Symptoms include
pain of the hips and femurs, joint inflammation, headaches,
facial pain, and hearing loss if bones around the ear are
affected. Nerves along the spinal column may be pinched
because of the abnormal vertebral bone growth.
1338 Unit 11 Additional Drug Classes
The evaluation of Paget’s disease is based on radio- PROTOTYPE DRUG Calcitriol (Calcijex, Rocaltrol)
graphic and laboratory findings. The enzyme alkaline
phosphatase (ALP) is elevated in the blood because of the Classification Therapeutic: Vitamin D
extensive bone turnover. The disease is usually confirmed Pharmacologic: Bone resorption
by early detection of this enzyme in the blood. Calcium is
also liberated because of its close association with phos- inhibitor
phate. If diagnosed early enough, symptoms can be treated
successfully. If the diagnosis is made late in the progression Therapeutic Effects and Uses: Calcitriol is the
of the disease, permanent skeletal abnormalities develop active form of vitamin D. This medication is used in cases
and other disorders may appear, including arthritis, kidney of hypocalcemia and for patients who have hypoparathy-
stones, and heart disease. roidism. Calcitriol reduces bone resorption and is useful in
treating rickets. Patients with CKD are unable to synthe-
Bisphosphonates are the primary pharmacotherapy size sufficient calcitriol and thus will receive this drug as
for Paget’s disease. Calcitonin may be used as a second-line replacement therapy.
drug. Patients with Paget’s disease should consume ade-
quate amounts of calcium and vitamin D on a daily basis. The effectiveness of calcitriol depends on having an
adequate amount of calcium; therefore, it is usually pre-
Pharmacotherapy of Metabolic scribed in combination with calcium supplements. It is
Bone Disease available for administration via the oral (PO) route in the
form of tablets and solutions. An IV solution for injection is
72.5 Vitamin D therapy is indicated for available to treat dialysis-associated hypocalcemia.
treating osteomalacia, hypoparathyroidism,
and osteoporosis. Mechanism of Action: Calcitriol elevates serum cal-
cium levels, decreases elevated blood levels of phosphate,
Inactive, intermediate, and active forms of vitamin D are and decreases bone resorption and demineralization by
available as medications. Patients’ vitamin D needs vary promoting the intestinal absorption and renal reabsorp-
depending on how much sunlight they receive. After age tion of calcium. The rising calcium levels provide negative
70, the RDA of vitamin D increases from 400 units/day to feedback to the parathyroid glands, reducing the secretion
600 units/day. In severe cases of malabsorption disorders, of PTH. Calcitriol itself also provides negative feedback to
patients may receive 50,000 to 100,000 units/day. Because the parathyroid glands.
vitamin D is needed to absorb calcium from the GI tract,
many supplements combine vitamin D and calcium into a Pharmacokinetics:
single tablet.
Route(s) PO (tablets, capsules, or
Several forms of vitamin D are available for therapy.
Three of those products—ergocalciferol, cholecalciferol, solution), IV
and calcitriol—are identical to the forms of vitamin D that
occur in nature. Each vitamin D product has a slightly dif- Absorption Readily absorbed from the GI
ferent potency and pharmacokinetics. Indications for vita-
min D products include the following: tract
• Hypocalcemia Distribution Widely distributed; crosses the
• Hypophosphatemia
• Osteomalacia (rickets) placenta; small amounts are
• Osteoporosis prophylaxis
• Parathyroid dysfunction secreted in breast milk; 99% bound
• Vitamin D deficiency.
to vitamin D–binding protein
Vitamin D is a fat-soluble vitamin that is stored by the
body. It is possible to consume too much of this vitamin or Primary metabolism Hepatic
to show signs of overdose from prescription medications.
Excess vitamin D will cause calcium to leave bones and Primary excretion Mostly feces with small amounts
enter the blood. The signs and symptoms of hypercalcemia,
such as anorexia, vomiting, excessive thirst, fatigue, and in urine
confusion, may become evident. Kidney stones may occur,
and bones may fracture easily. Onset of action 2–6 h
Duration of action 3–5 days
Adverse Effects: The adverse effects of vitamin D
therapy include symptoms of hypercalcemia, such as pal-
pitations, anorexia, nausea, vomiting, blurred vision, pho-
tophobia, constipation, abdominal cramps, metallic taste,
headache, weakness, dry mouth, thirst, increased urina-
tion, and muscle or bone pain.
Contraindications/Precautions: This drug should
not be given to patients with hypercalcemia or those who
have evidence of vitamin D toxicity. Caution must be used
in patients with CKD who are at increased risk for vitamin D–
induced hypercalcemia.
Chapter 72 Pharmacotherapy of Bone and Joint Disorders 1339
Drug Interactions: Thiazide diuretics may enhance Cholecalciferol (Delta-D): Cholecalciferol (vitamin D3) is
the effects of vitamin D, causing hypercalcemia. Too much the form of vitamin D that is produced in the skin after expo-
vitamin D may cause dysrhythmias in patients who are sure to ultraviolet (UV) light. It is activated by the liver and
receiving digoxin. Magnesium antacids or supplements kidneys to form calcitriol. Once activated, cholecalciferol
should not be given concurrently owing to an increased produces the same actions and adverse effects as calcitriol. It
risk of hypermagnesemia. Orlistat (Xenical) may prevent is an oral dietary supplement for the prophylaxis and treat-
the absorption of fat-soluble nutrients such as vitamin D. ment of vitamin D deficiency. Fosamax plus D is a combina-
Corticosteroids inhibit the absorption of calcium, which is tion drug containing alendronate and cholecalciferol.
a major effect of vitamin D. Herbal/Food: Unknown.
Doxercalciferol (Hectorol): Doxercalciferol is an analog of
Pregnancy: Category C. vitamin D that is given by either the PO or IV route. This
drug is activated by the liver alone: No kidney metabolism is
Treatment of Overdose: Vitamin D overdose results necessary. Adverse effects are the same as those of calcitriol.
in hypercalcemia, hypercalciuria, and hyperphosphatemia. However, caution must be taken to avoid the rapid develop-
If the overdosage was recent, emesis should be induced to ment of hypercalcemia when this drug is administered by the
remove any remaining drug from the stomach. All vita- IV route. Its only approved indication is for the treatment of
min D and calcium supplements are discontinued and the secondary hyperparathyroidism and resultant bone disease.
patient is placed on a low-calcium diet until the hypercal-
cemia resolves. Ergocalciferol (Calciferol, Drisdol): Ergocalciferol (vita-
min D2) is a natural vitamin D analog found in plants, for-
Nursing Responsibilities: Key nursing implications tified milk, eggs, and cereals. Once activated, ergocalciferol
for patients receiving calcitriol are included in the Nursing produces actions and adverse effects identical to those of
Practice Application for Patients Receiving Pharmacother- calcitriol. Bile is required for its absorption, and the drug
apy for Osteoporosis. requires adequate kidney function to be metabolized to its
active form. Indications for therapy with ergocalciferol are
Drugs Similar to Calcitriol the same as those for calcitriol.
(Calcijex, Rocaltrol)
Paricalcitol (Zemplar): Paricalcitol is an analog of vitamin D
Other forms of vitamin D for therapy include calcifediol, that is given by either the PO or IV route. Adverse effects
cholecalciferol, doxercalciferol, ergocalciferol, and parical- are the same as those of calcitriol; however, caution must
citol. Doses for the vitamin D preparations are given in be taken to avoid the rapid development of hypercalcemia
Table 72.4. when this drug is administered by the IV route. The only
indication for paricalcitol is for the treatment of secondary
Calcifediol (Rayaldee): Calcifediol is an analog of vitamin hyperparathyroidism and resultant bone disease.
D3 that is converted to the active hormone, calcitriol, in the
kidneys. Calcifediol was approved in 2016 for the treat- 72.6 Bisphosphonates increase bone density and
ment of secondary hyperparathyroidism in adult patients are used to treat osteoporosis and Paget’s disease.
with CKD. It has the same adverse effects as calcitriol.
Caution must be used to avoid overtreatment, because this The most frequently prescribed drug class for osteoporosis
may cause severe hypercalcemia. This drug is pregnancy is the bisphosphonates. These drugs are structural
category C.
Table 72.4 Vitamin D Preparations
Drug Route and Adult Dose (Maximum Dose Where Indicated) Adverse Effects
calcifediol (Rayaldee) PO: 30–60 mcg once daily Diarrhea, infection, hypertension, dizziness
calcitriol (Calcijex, Rocaltrol) PO: 0.25–0.50 mcg/day Hypercalcemia, bone pain, lethargy, anorexia,
IV: Begin with 1–4 mcg 3 times/wk nausea, vomiting, increased urination,
hallucinations, dysrhythmias, anemia
cholecalciferol (Delta-D) PO: 400–1000 international units/day
doxercalciferol (Hectorol) PO: 10 mcg, 3 times/wk
IV: 4 mcg, 3 times/wk
(max: 60 mcg/wk [PO]; 18 mcg/wk [IV])
ergocalciferol (Calciferol, Drisdol) PO: 15–25 mcg once daily
IV: 4 mcg 3 times/wk
paricalcitol (Zemplar) IV: 0.04–0.1 mcg/kg, every other day (max: 24 mcg/kg)
PO: 1–4 mcg every other day or 3 times/wk
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
1340 Unit 11 Additional Drug Classes
analogs of pyrophosphate, which is a natural substance “punched-out,” osteolytic lesions that release large
that inhibits bone resorption. Bisphosphonates bind to amounts of calcium into the blood. Bisphosphonates sup-
hydroxyapatite in bone and suppress osteoclast activity, press osteoclast activity, thus slowing the rate of bone
thus increasing bone mass density and reducing the inci- resorption and the rate of calcium release. Thus some of
dence of fractures by about 50%. Examples include etidro- these drugs are approved for treating hypercalcemia due to
nate (Didronel), alendronate (Fosamax), zoledronate malignancy. It is important to note that bisphosphonates
(Reclast, Zometa), risedronate (Actonel, Atelvia), and are not antineoplastics; they have no effect on tumor cells
pamidronate (Aredia), which is available as an injectable and are given only as a palliative measure.
drug. Etidronate also inhibits bone demineralization that
could lead to osteomalacia; the other bisphosphonates do The most frequent adverse effects of bisphosphonates
not have this effect. In addition to treating postmenopausal include GI symptoms such as nausea, vomiting, abdominal
osteoporosis, some of the bisphosphonates are approved pain, dyspepsia, and esophageal irritation. Because these drugs
to treat corticosteroid-induced osteoporosis. A summary of are poorly absorbed from the intestinal tract, they must be
the indications for bisphosphonates is given in Table 72.5 taken on an empty stomach with plain water, at least 30 minutes
and their doses are listed in Table 72.6. before any other fluid, food, or medications. To avoid esopha-
geal irritation, the patient should stay in an upright position for
The beneficial effects of bisphosphonates on bone mass at least 30 minutes following the dose. Bisphosphonates are not
density increase rapidly during the first year of therapy and metabolized and are excreted in the urine.
plateau after 2 to 3 years. Even after discontinuation of ther-
apy, bone density will remain increased for up to 1 year. For Patients taking the bisphosphonates are evaluated on a
optimal effects, the patient must have adequate dietary con- regular basis to determine if the drug is still necessary. To
sumption of calcium and vitamin D; any deficiencies should avoid the possibility of long-term adverse effects, these
be corrected prior to initiating bisphosphonate therapy. drugs are usually discontinued after several years of ther-
Studies suggest that once-weekly dosing with bisphospho- apy in patients who have a low risk for fracture.
nates may give the same bone density benefits as daily dos-
ing because of their extended duration of drug action. One unusual adverse effect that may occur during
bisphosphonate therapy is osteonecrosis of the jaw. Symp-
Bisphosphonates are also preferred drugs for the phar- toms include local pain and swelling, loosening of teeth,
macotherapy of Paget’s disease. For this disorder, therapy and infection at the site of the lesion. It is not clear what
is usually cyclic, with bisphosphonates administered until causes the necrosis. Discontinuing the bisphosphonate
serum ALP levels return to normal followed by several does not resolve the lesion because the drugs are incorpo-
months without drugs. When the serum ALP level becomes rated in bone for many months and perhaps years.
elevated, therapy is begun again. The pharmacologic goals
are to slow the rate of bone reabsorption and encourage the PROTOTYPE DRUG Alendronate (Fosamax)
deposition of strong bone.
Classification Therapeutic: Drug for osteoporosis
Several bisphosphonates are used to treat bone metas- and Paget’s disease
tases and malignant hypercalcemia. Bone metastases are
characterized by osteoclast hyperactivity, which creates Pharmacologic: Bisphosphonate, bone
resorption inhibitor
Table 72.5 Indications for Bisphosphonates
Osteoporosis in Glucocorticoid- Breast Multiple
Cancer Myeloma/Bone
Postmenopausal Osteoporosis Induced Paget’s Hypercalcemia Metastases Metastases
Disease of Malignancy
Drug Women in Men Osteoporosis X
alendronate X X XX
(Fosamax)
etidronate X
(Didronel)
ibandronate X
(Boniva)
pamidronate X XX
(Aredia) X
risedronate X X XX
(Actonel, Atelvia)
zoledronate X X X
(Reclast,
Zometa)
Chapter 72 Pharmacotherapy of Bone and Joint Disorders 1341
Table 72.6 Selected Drugs for Osteoporosis and Other Bone Disorders
Drug Route and Adult Dose Adverse Effects
Bisphosphonates (Maximum Dose Where Indicated)
alendronate (Fosamax) Nausea, dyspepsia, diarrhea, bone pain, back pain
etidronate (Didronel) Osteoporosis: PO: 10 mg/day or 70 mg once weekly Bone fractures, nephrotoxicity, hypocalcemia,
ibandronate (Boniva) Paget’s disease: PO: 40 mg/day for 6 months hypophosphatemia, gastric ulcer, esophageal perforation,
PO: 5–10 mg/kg/day for 6 months or 11–20 mg/kg/day for dysrhythmias, anemia, osteonecrosis of the jaw, atrial
pamidronate (Aredia) 3 months fibrillation
risedronate (Actonel, Atelvia) PO: 2.5 mg/day or one 150-mg tablet per month, taken on
zoledronate (Reclast, Zometa) the same date each month Orthostatic hypotension, dizziness, nausea, headache,
IV: 3 mg every 3 months fatigue
Miscellaneous Drugs IV: 15–90 mg in 1000 mL normal saline or D5W over 4–24 h Hypercalcemia, hypercalciuria, urolithiasis, risk for
abaloparatide (Tymlos) PO: 5 mg/day or 35 mg once weekly at least 30 min before osteosarcoma
the first drink or meal of the day Flushing of the face and hands, pain at the injection site
IV (Zometa): 4-mg single dose infused over at least 15 min; Anaphylaxis
may be repeated q3–4wk for cancer Dizziness, noncardiac chest pain, HTN, nausea, anorexia,
IV (Reclast): one 5-mg single dose per year, infused over at hypocalcemia, myalgia
least 15 min Hypocalcemia, seizures
Fatigue, asthenia, hypophosphatemia, nausea,
Subcutaneous: 80 mcg/day using a prefilled pen hypercholesterolemia, musculoskeletal pain, and cystitis
Hypocalcemia, serious infections, osteonecrosis of jaw
calcitonin-salmon (Miacalcin) Subcutaneous/IM: salmon, 4–8 international units/kg bid for Muscle spasms, diarrhea, headache, nausea, vomiting
cinacalcet (Sensipar) hypercalcemia; 100 international units every 1–3 days for Severe hypocalcemia, worsening heart failure, GI bleeding
denosumab (Prolia, Xgen) osteoporosis or Paget disease Hot flashes, leg cramps, peripheral edema, flu syndrome,
arthralgia, sweating
PO: Start with 30 mg once daily; may increase q2–4wk until Breast pain, vaginal bleeding, pneumonia, chest pain,
target PTH of 150–300 mg/mL (max: 300 mg/day) for venous thromboembolism, stroke
secondary hyperparathyroidism Dizziness, depression, insomnia, vertigo, rhinitis,
increased cough, leg cramps, nausea, arthralgia
Subcutaneous (Prolia): 60 mg every 6 months Syncope, angina, transient hypercalcemia, risk for
Subcutaneous (Xgen): 120 mg q4wk osteosarcoma
etelcalcetide (Parsabiv) IV: 5-mg bolus
raloxifene (Evista) PO: 60 mg/day
teriparatide (Forteo) Subcutaneous: 20 mcg/day using a prefilled pen
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
Therapeutic Actions and Uses: First approved in Alendronate is also used off-label for treating hypercal-
1995, alendronate is the best studied drug in this class. cemia due to malignancy. Several regimens for alendronate
Alendronate is approved for the following indications: are available: once daily (10 mg), twice weekly (35 mg), or
once weekly (70 mg). Although the once weekly is more
• Prevention and treatment of osteoporosis in post- convenient, higher doses can produce more GI-related
menopausal women adverse effects. All doses must be taken on an empty stom-
ach, preferably in a fasting state 2 hours before breakfast.
• Treatment of glucocorticoid-induced osteoporosis in
both women and men Therapeutic effects of alendronate may take 1 to
3 months to appear and may continue for several months
• Treatment to increase bone mass in men with after therapy is discontinued. This drug lowers serum alka-
osteoporosis line phosphatase, which is the enzyme associated with
bone turnover, without major adverse effects.
• Treatment of symptomatic Paget’s disease in both
women and men.
1342 Unit 11 Additional Drug Classes
The safety and effectiveness of long-term therapy with before taking any other supplements or other medica-
alendronate is still being investigated. Patients should be tions. Herbal/Food: The patient’s diet must have adequate
regularly evaluated to determine the need for continued amounts of vitamin D, calcium, and phosphates. Excessive
therapy, and the drug discontinued after 3 to 5 years of use amounts of calcium supplements or dairy products reduce
in those at low risk for fractures. alendronate absorption.
Mechanism of Action: Alendronate inhibits Pregnancy: Category C.
osteoclast-mediated bone resorption to minimize loss of
bone density. Its effects appear to be localized to resorption Treatment of Overdose: Hypocalcemia is an
sites of active bone turnover and it does not interfere with expected effect of overdose and may be treated with PO or
bone mineralization. IV calcium compounds.
Pharmacokinetics: Nursing Responsibilities: Key nursing implica-
tions for patients receiving alendronate are included in the
Route(s) PO Nursing Practice Application for Patients Receiving Phar-
macotherapy for Osteoporosis.
Absorption Less than 1% (significantly
Drugs Similar to Alendronate (Fosamax)
decreased by food or beverages)
Other bisphosphonates include etidronate, ibandronate,
Distribution Rapid skeletal uptake; unknown pamidronate, risedronate, and zoledronate.
if secreted in breast milk; 78% Etidronate (Didronel): Etidronate was the first bisphos-
phonate approved in the United States in 1977. It is less
bound to plasma protein selective for bone than some of the other medications in
this class and is not a first-line drug. It is approved for
Primary metabolism Not metabolized moderate to severe Paget’s disease and for hypertrophic
ossification following total hip replacement or spinal cord
Primary excretion 50% excreted unchanged in injury. It is used off-label as an alternative to other bisphos-
phonates for prevention of postmenopausal and cortico-
the urine steroid-induced osteoporosis. It is available by the PO
route. Like all bisphosphonates, etidronate causes GI
Onset of action 3–6 weeks mucosa irritation and bone and joint pain. This drug is
nephrotoxic and may increase the risk of dysrhythmias.
Duration of action 12 weeks or more after This drug is pregnancy category C.
discontinuation Ibandronate (Boniva): Ibandronate was approved in 2003
for the prevention and treatment of postmenopausal osteo-
Adverse Effects: The most common adverse effect of porosis. In addition to its oral formulation, it is the only IV
alendronate is hypocalcemia, which is usually transient bisphosphonate approved for the prophylaxis of post-
and mild. Other adverse effects include diarrhea, constipa- menopausal osteoporosis. When administered IV, injec-
tion, flatulence, nausea, vomiting, GI irritation, a metallic tions are spaced 3 months apart. Off-label indications
or altered taste perception, hypocalcemia, hypophosphate- include Paget’s disease, bone metastases from prostate
mia, abdominal pain, dyspepsia, myalgia, and headache. cancer, and malignant hypercalcemia. Adverse effects are
Pathologic fractures may occur if the drug is taken longer similar to those of other drugs in this class. This drug is
than 3 months or in cases of chronic overdose. Although pregnancy category C.
rare, this drug may cause serious esophagitis, which is
why patients should remain in an upright position at Pamidronate (Aredia): Approved in 1991, pamidronate is
least 30 minutes after receiving a dose. Osteonecrosis of available by slow IV infusion for hypercalcemia, moderate
the jaw has occurred spontaneously in patients taking to severe Paget’s disease, and bone metastases due to
bisphosphonates. breast cancer or multiple myeloma. It may be used off-
label to treat osteoporosis and osteogenesis imperfecta.
Contraindications/Precautions: Contraindications Caution must be used when treating patients with CKD or
include patients with osteomalacia or who have hyper- those who are receiving nephrotoxic drugs because signifi-
sensitivity to this drug. Caution should be used in patients cant renal function deterioration can occur with pamidro-
with CKD, heart failure, hyperphosphatemia, liver disease, nate, even after a single dose. Other common adverse
fever or infection, active upper GI problems, and preg- effects are nausea, fever, constipation, and dyspnea. Pami-
nancy. This drug is contraindicated in patients with abnor- dronate is pregnancy category D.
malities of the esophagus that delay esophageal emptying,
such as stricture or achalasia, and in those who are unable
to stand or sit upright for at least 30 minutes following
administration of the drug.
Drug Interactions: Calcium, iron, antacids contain-
ing aluminum or magnesium, and certain mineral supple-
ments interfere with the absorption of alendronate and
have the potential to decrease its effectiveness. Patients
should wait at least 30 minutes after taking alendronate
Chapter 72 Pharmacotherapy of Bone and Joint Disorders 1343
Risedronate (Actonel, Atelvia): Approved in 1998, rise- Certain estrogens are produced by plants. These sub-
dronate is considered a first-line drug for the treatment of stances, called phytoestrogens, mimic the effects of natural
glucocorticoid-induced and postmenopausal osteoporosis, estrogen and are thought to exert beneficial effects on the
and it is also approved to treat symptomatic Paget’s dis- cardiovascular system and possibly protection from cancer.
ease. It may be used off-label to treat osteolytic lesions due For example, soybeans, flax seed, and tofu are rich sources
to multiple myeloma. Available by the PO route, it is of phytoestrogens.
reported to cause less GI distress than other bisphospho-
nates. Like other oral bisphosphonates, it is contraindi- SERMs are medications that may activate or inhibit
cated in patients who are unable to sit upright for at least ERs. Thus, SERMs may be estrogen agonists or antagonists,
30 minutes after drug administration or who have disor- depending on the specific drug and the tissue involved. For
ders that cause delayed esophageal emptying. Atelvia is a example, raloxifene (Evista) blocks estrogen receptors in
delayed release form of the drug that can be taken once the uterus and breast; it has no estrogen-like proliferative
weekly. Arthralgia, back pain, diarrhea, abdominal pain, effects on these tissues that might promote cancer. Raloxi-
and dyspepsia are common adverse effects. This drug is fene does, however, have estrogen-like effects that reduce
pregnancy category C. bone resorption, thus increasing bone density and reduc-
ing the likelihood of fractures. It is most effective in pre-
Zoledronate (Reclast, Zometa): Originally approved in venting vertebral fractures. The dose for raloxifene is
2001, zoledronate (also called zoledronic acid) is available shown in Table 72.6.
by the IV route to treat hypercalcemia of malignancy, mul-
tiple myeloma, and bone metastases. One advantage of The other SERMs include tamoxifen, toremifene
Zometa is that it can be infused over 15 to 20 minutes com- (Fareston), and bazedoxifene (Duavee). Tamoxifen and
pared to 2 to 4 hours for pamidronate. Frequent adverse toremifene are used to treat metastatic breast cancer in
effects include nausea, fatigue, anemia, bone pain, consti- postmenopausal women (see Chapter 57). Bazedoxifene is
pation, fever, vomiting, and dyspnea. formulated in a fixed-dose combination with conjugated
estrogens to manage symptoms of menopause as well as to
In 2007, the FDA expanded the indications for zoledro- prevent bone fractures (see Chapter 69).
nate (Reclast) to include prevention or treatment of post-
menopausal osteoporosis, osteoporosis in men, and Paget’s PROTOTYPE DRUG Raloxifene (Evista)
disease. A major advantage of Reclast is that its prolonged
duration of action results in a once-yearly dose for Paget’s Classification Therapeutic: Drug for osteoporosis
disease and osteoporosis prophylaxis. Reclast is available prophylaxis
by IV infusion, administered over at least 15 minutes. Com-
mon adverse effects include bone pain, pyrexia, nausea, Pharmacologic: Selective estrogen
headache, arthralgia, fatigue, and constipation. receptor modifier
Reclast and Zometa are not interchangeable and the Therapeutic Effects and Uses: Approved in 1997,
drugs should not be administered concurrently. Zoledro- raloxifene is primarily used for the prevention or treat-
nate is nephrotoxic and should be used with caution in ment of osteoporosis in postmenopausal women. In 2007,
patients with CKD. Like pamidronate, zoledronate is preg- it was approved for the prophylaxis of invasive breast
nancy category D and should not be used during cancer in postmenopausal women at high risk for breast
pregnancy. cancer. High risk of breast cancer is defined as at least one
breast biopsy showing carcinoma or atypical hyperplasia
72.7 Selective estrogen receptor modulators or having a first-degree relative with breast cancer. Other
increase bone mass density and prevent fractures factors considered are current age, number of breast biop-
in postmenopausal women. sies, age at menarche, nulliparity, or age of first live birth.
It is important for nurses and patients to understand that
Selective estrogen receptor modulators (SERMs) are this drug is for the prevention, not treatment, of breast
drugs that bind to estrogen receptors (ERs). Estrogen exerts carcinoma.
its effects on target tissues by interacting with ERs and
causing either activation or inhibition of specific cellular Raloxifene increases bone mass density, reducing ver-
actions. ERs are found in the reproductive organs of both tebral fractures. It does not appear to reduce the incidence
males and females where they enhance the development of of fractures at nonvertebral sites. Raloxifene also reduces
reproductive tissues. But ERs are found in more than just serum total cholesterol and low-density lipoproteins
reproductive tissues. In the cardiovascular system, ERs are (LDLs) without lowering high-density lipoproteins (HDLs)
responsible for lowering blood cholesterol, and in the or triglycerides. Unlike estrogen, which causes prolifera-
brain, these receptors influence behavior and mood. In tion of uterine and breast tissue, causing adverse effects,
bone, ERs help to maintain bone mineral density. raloxifene is an estrogen antagonist on these tissues. Ral-
oxifene has been used off-label to treat uterine leiomyomas,
1344 Unit 11 Additional Drug Classes
for pubertal gynecomastia, and for the prevention of bone Treatment of Overdose: Overdose with raloxifene is
loss in men with prostate cancer. uncommon and symptoms are given supportive treatment.
Mechanism of Action: As a selective estrogen recep- Nursing Responsibilities: Key nursing implications
tor antagonist or agonist, raloxifene decreases bone resorp- for patients receiving raloxifene are included in the Nurs-
tion while increasing bone mass and density by activating ing Practice Application for Patients Receiving Pharmaco-
estrogen receptors. therapy for Osteoporosis.
Pharmacokinetics: PO Drugs Similar to Raloxifene (Evista)
Route(s)
Absorption 60% absorbed The other SERMs are discussed in previous chapters:
Distribution tamoxifen and toremifene in Chapter 57 and bazedoxifene
Crosses the placenta; unknown with conjugated estrogens in Chapter 69.
Primary metabolism if secreted in breast milk; 95%
bound to plasma protein CONNECTION Checkpoint 72.2
Primary excretion
Onset of action Hepatic; extensive first-pass From what you learned in Chapter 57, what are the indications for
Duration of action metabolism pharmacotherapy with tamoxifen? Answers to Connection Check-
point questions are available on the faculty resources site. Please consult
Primarily in feces with your instructor.
8 weeks 72.8 Calcitonin and several miscellaneous drugs
are used for osteoporosis and other metabolic
Half-life: 28 h bone diseases.
Adverse Effects: The most common adverse effects of Several miscellaneous drugs are used to treat MBDs.
raloxifene therapy are hot flashes, leg cramps, and weight Although they act by different mechanisms, they are pre-
gain. Less common adverse effects include fever, arthral- sented together in this section because each is the only
gia, myalgia, arthritis, depression, insomnia, chest pain, drug in its class.
peripheral edema, decreased serum cholesterol, nausea,
dyspepsia, vomiting, flatulence, GI disorders, gastroenteri- Calcitonin-salmon (Miacalcin): Calcitonin is a hormone
tis, cystitis, migraine, flulike symptoms, endometrial dis- that is produced and secreted by the thyroid gland in
order, breast pain, and vaginal bleeding. Raloxifene may response to elevated serum calcium levels. This hormone
cause fetal harm when administered to a pregnant woman. directly inhibits osteoclasts. The function of calcitonin is to
Black Box Warning: Raloxifene increases the risk of lower serum calcium levels by decreasing bone resorption
venous thromboembolism and death from strokes. Women and increasing the urinary excretion of calcium. It acts in
with a history of venous thromboembolism should not direct opposition to PTH and vitamin D.
take this drug.
As a drug calcitonin is obtained from salmon and is
Contraindications/Precautions: This drug is con- approved for the treatment of osteoporosis in women who
traindicated during lactation and pregnancy and in are more than 5 years postmenopause. Because calcitonin
women who may become pregnant. Patients with a history is less effective for reducing osteoporosis-related fractures
of venous thromboembolism and those who are hypersen- than the bisphosphonates, it is considered a second-line
sitive to raloxifene should not take this drug. Raloxifene treatment. The dose for calcitonin is given in Table 72.6.
should be discontinued 72 hours before prolonged immo-
bilization is anticipated due to risk of thromboembolic In addition to treating osteoporosis, calcitonin is indi-
events. cated for Paget’s disease and hypercalcemia. In Paget’s dis-
ease calcitonin slows the rate of bone turnover and decreases
Drug Interactions: Concurrent use with warfarin the incidence of bone pain. It is most effective in treating
may decrease prothrombin time (PT). Decreased ral- hypercalcemia caused by hyperparathyroidism or prolonged
oxifene absorption will result from concurrent use with immobility or that accompanies certain malignancies.
ampicillin or cholestyramine. Use of raloxifene with other
highly protein-bound drugs (e.g., ibuprofen, indometha- Calcitonin is available by subcutaneous or IM injec-
cin, diazepam) may interfere with binding sites. Patients tion. In 2016, the intranasal forms of calcitonin were
should not take cholesterol-lowering drugs or ERT con- removed from the market. Subcutaneous injections are ini-
currently with this medication. Herbal/Food: Black tially given as a daily dose then decreased to 2 to 3 times
cohosh has estrogenic effects and may interfere with the per week. Adverse effects of calcitonin include nausea,
actions of raloxifene. injection-site inflammation, and generalized flushing of the
face and hands. This drug is pregnancy category C.
Pregnancy: Category X.
Chapter 72 Pharmacotherapy of Bone and Joint Disorders 1345
CONNECTIONS: Using Research in Practice
Predicting Bone Loss
Several studies have investigated the effects of ethnicity on the angle of the femur, may also help predict fracture risk (Broy et
development of bone loss. There has been no clear association al., 2015).
for both men and women between ethnicity and bone loss even
when controlling for other factors such as body mass index DEXA screening remains a definitive measure of bone loss
(BMI), fat versus lean body mass, and socioeconomic status and of estimating fracture risk and can provide information on
(Jackson & Mysiw, 2014). Exceptions have been noted, and both bone density and hip geometry measurements. Other non-
women, especially Asian women who take bisphosphonates for DEXA screening tools have also been found to be effective at
long durations, were found to have a higher rate of femoral shaft estimating risk of fracture. They include the World Health Organi-
fractures (Lo et al., 2014). In a study of men and differences in zation’s fracture risk assessment tool (FRAX), the men’s osteo-
bone loss, Araujo et al. (2014) found that men with higher porosis risk estimation score (MORES), and the osteoporosis
incomes had less BMD loss than those with low or moderate self-assessment screening tool (OST), and these can be used
incomes. This may be due, in part, to increased options for diet with or without DEXA to predict risk (Cass, Shepherd, Asirot,
and exercise related to income. Physical activity, history of or Mahajan, & Nizami, 2016; Kanis et al., 2015, 2016; Pang &
current smoking, and BMI are also risk factors that predict frac- Inderjeeth, 2014). In addition to DEXA and fracture risk assess-
ture risk. Finally, it appears that hip geometry measurements ment tools, Najafi, Dahlberg, and Hansson (2016) recommend
obtained during DEXA imaging, such as the size, shape, and the use of balance measures such as standing on one leg with
eyes closed.
Denosumab (Prolia, Xgen): Approved in 2010, deno- subcutaneous route and are available as prefilled pen injec-
sumab is used to prevent bone fractures in postmeno- tors. Both teriparatide (approved in 2002) and abaloparatide
pausal women and to prevent skeletal-related events in (approved in 2017) carry a black box warning that PTH ana-
patients with bone metastases with solid tumors. It is con- logs cause osteosarcomas in laboratory animals. Because of
sidered a first-line drug for osteoporosis prevention in this, they should not be used in patients with an increased
patients at high risk for fracture. Denosumab is given by risk for osteosarcoma. The black box warning also states
subcutaneous injection, either every 4 weeks (Xgen) or that the PTH analogs should not be used for more than
every 6 months (Prolia). The drug is a monoclonal anti- 2 years during a patient’s lifetime. Teriparatide may be used
body classified as a RANKL inhibitor. RANKL is a protein off-label to treat hypoparathyroidism and corticosteroid-
that binds to the RANK receptor on osteoblasts. Once induced osteoporosis. Teriparatide is well tolerated, with
bound, RANKL promotes the removal of calcium from dizziness and leg cramps being the most frequent adverse
bone. By inhibiting this action, denosumab helps to main- effects. Abaloparatide has no pregnancy rating. Teriparatide
tain bone mineral density and prevent fractures due to is rated as pregnancy category C.
osteoporosis or bone metastases. Common adverse effects
include fatigue, asthenia, hypophosphatemia, nausea, Pathophysiology and
hypercholesterolemia, musculoskeletal pain, and cystitis. Pharmacotherapy of Joint
Because the drug can cause severe hypocalcemia, serum Disorders
calcium levels should be monitored regularly and calcium
supplements and vitamin D administered as necessary. 72.9 Osteoarthritis is treated with a combination
Some patients also experience osteonecrosis of the jaw. of analgesics and nonpharmacologic therapies.
This drug is pregnancy category C and is contraindicated
during pregnancy. A simple classification of joint disorders places them into
two categories: noninflammatory and inflammatory. The
Parathyroid hormone analogs: Abaloparatide (Tymlos) and most common of the noninflammatory disorders is osteo-
teriparatide (Forteo) are forms of human PTH produced by arthritis. Common inflammatory joint disorders such as
recombinant DNA technology. Their only approved indica- rheumatoid arthritis and gout are covered in Sections 72.10
tion is for the treatment of osteoporosis in men and post- and 72.11, respectively. These joint conditions are frequent
menopausal women. These drugs are reserved for patients indications for pharmacotherapy, with joint pain being
with a high risk of bone fractures. The actions of the PTH common to all disorders. Analgesics and anti-inflamma-
analogs are identical to those of endogenous PTH. Unlike tory drugs are important components of pharmacotherapy.
other medications that simply reduce bone resorption, the A few additional drugs are specific to the particular joint
PTH analogs also stimulate the production of new bone. pathology. Pharmacotherapy Illustrated 72.1 shows the
These actions increase bone mass density and reduce the types of joint pathology and their drug therapy.
incidence of fractures. Both drugs are given daily by the
1346 Unit 11 Additional Drug Classes Cortical bone
Pharmacotherapy Illustrated 72.1 Cancellous bone
Synovial membrane
Joint Disorders Articular cartilage
Periosteum
Joint capsule
Meniscus
(a) Normal
Bone cysts Loose fragments Pannus
of cartilage
Osteophytes Masses of uric
(bone spurs) Loss of acid (tophi)
cartilage
Calcified
cartilage Sclerotic Proliferative Uric acid
bone synovitis crystals
Worn
cartilage Erosion of Inflamed Swollen and
cartilage synovium inflamed joint
Periarticular Erosion
fibrosis of bone
(b) Advanced osteoarthritis (c) Rheumatoid arthritis (d) Gout
Acetaminophen NSAIDs Colchicine
NSAIDs Corticosteroids Probenecid
Tramadol Hydroxychloroquine Allopurinol
Topical ointments NSAIDs
Intra-articular (or other DMARD) Sulfinpyrazone
Biologic response
corticosteroids
modifiers
Osteoarthritis (OA) is a progressive, degenerative type, has no known cause but is associated with increasing
joint disease caused by the breakdown of articular carti- age. The causes of secondary OA include trauma, mechani-
lage. It is the most common cause of disability in the United cal stress, inflammation of the joint structures, neurologic
States, affecting over 30 million people. Weight-bearing disorders, use of certain medications, and joint instability.
joints such as the knee, vertebral column, and hip are most Excessive weight contributes to the development of OA,
commonly affected. The hands are also affected because particularly in the knee and hip. Other risk factors associ-
they are frequently used. OA may be classified as idio- ated with OA include decreased estrogen in menopausal
pathic or secondary. Idiopathic OA, the most common women, excessive growth hormone, and increased PTH.
Chapter 72 Pharmacotherapy of Bone and Joint Disorders 1347
As cartilage thins in the affected joints, there is less hip and knee are affected. Weight loss has been associ-
padding and, eventually, the underlying bone is affected. ated with decreased pain and disability. Surgical proce-
The bone thickens in the exposed areas, forming bone spurs dures such as joint replacement and reconstructive
and cysts that narrow the joint space. As these growths surgery may become necessary when other methods are
enlarge, small pieces may break off, leading to inflamma- ineffective.
tion of the synovial membrane and a loss of lubricating
fluid. This leads to further pain, inflammation, and destruc- The goals of pharmacotherapy for OA include reduc-
tion of the synovial membrane lining the joint. The affected ing pain and inflammation and minimizing disability. The
joint becomes unstable and more susceptible to injury, with initial treatment for most patients is acetaminophen. Acet-
partial joint dislocations and other deformities that are aminophen is inexpensive, participates in few drug–drug
common in advanced disease being seen. interactions, and has fewer serious adverse effects than
other analgesics. For patients whose pain is unrelieved by
The onset of OA is usually gradual, with pain and stiff- acetaminophen, nonsteroidal anti-inflammatory drugs
ness in one or more joints being the first manifestations. (NSAIDs), including naproxen and ibuprofen derivatives,
The patient with OA typically describes a deep, aching, are usually given. Because high doses of NSAIDs can result
localized pain, which is usually aggravated by movement in GI bleeding and affect platelet aggregation, patients
and relieved by rest. Pain at night may be accompanied by must be carefully monitored. Aspirin is no longer recom-
paresthesias. As the disease advances, the range of motion mended because the high doses needed to produce pain
(ROM) of the joint decreases; this is often accompanied by relief in patients with OA may cause GI bleeding. Tramadol
complaints of progressive pain. Bone enlargement can (Ultram) has become a popular drug for the treatment of
increase joint size; flexion contractures contribute to joint moderate to severe pain. Opioids such as codeine may be
instability. It is important to note that OA is not accompa- combined with acetaminophen for severe pain. The stu-
nied by the degree of inflammation associated with other dent should refer to Chapter 25 for a complete discussion
forms of arthritis. The joints of a patient with OA are char- of the actions and adverse effects of analgesics.
acteristically hard and cool to palpation. A patient with OA
is shown in Figure 72.4. The diagnosis of OA is typically In acute cases, intra-articular corticosteroid injections
made through a medical history, physical examination, and may be used. With intra-articular injections, a long-acting
routine x-rays. corticosteroid such as triamcinolone is injected directly into
the joint space of the affected joint. Pain relief generally
Nonpharmacologic therapies are an essential compo- lasts 3 months following the injection. Although this proce-
nent of OA management. Walking, nonimpact aerobics, dure relieves pain on a temporary basis, it can speed the
and passive ROM exercises are important to maintain destruction of cartilage if it is performed more frequently
joint flexibility. Improving muscle strength, especially of than every 4 to 6 months.
the quadriceps muscle, will help patients improve their
ability to perform ADLs. Bracing may help keep joints Many patients use topical medications, including salic-
positioned correctly and relieve pain. Knowledge of ylates (Aspercreme and Sportscreme), capsaicin (Capza-
proper body mechanics and posture may offer some ben- sin), and counterirritants (Bengay and Icy Hot), which are
efit. Patients who are obese should consider a weight loss sold OTC as creams, gels, sprays, patches, or ointments, to
program, especially if weight-bearing joints such as the relieve OA pain. These therapies are well tolerated and
produce few adverse effects. These products should not be
Figure 72.4 Patient with osteoarthritis. used more than 4 times daily and should be discontinued if
irritation occurs.
Courtesy of JPC-PROD/Shutterstock.
Another drug therapy option for patients with moder-
ate OA who do not respond adequately to analgesics
includes hyaluronate sodium (Hyalgan), a chemical nor-
mally found in high amounts within the synovial fluid.
Administered by injection directly into the knee joint, this
drug replaces or supplements the body’s natural hyal-
uronic acid, which deteriorates as a result of the inflamma-
tion of OA. Treatment consists of one injection per week for
three to five injections. Hyalgan helps provide a barrier
that prevents friction and further inflammation of the joint
by coating the articulating cartilage surface. Information
that is given to the patient prior to administration should
include adverse effects such as pain or swelling at the injec-
tion site and the avoidance of any strenuous activities for
approximately 48 hours after injection.
1348 Unit 11 Additional Drug Classes
CONNECTIONS: Complementary and Alternative Therapies
Glucosamine and Chondroitin for Osteoarthritis
Description capsules, or in powder form, with a typical dose being 1.5 g/day.
Chondroitin is derived from bovine or shark cartilage and is also
Many patients use OTC herbal medicines to relieve the pain and taken orally, with doses in the range of 800 to 1200 mg/day.
inflammation associated with OA. Two of the most commonly
used agents are glucosamine and chondroitin. Evidence
History and Claims Typical of many other specialty supplements, research regard-
ing the effectiveness of chondroitin and glucosamine has deliv-
Glucosamine is a natural substance that is an important building ered mixed results. In most European countries, these two
block of cartilage. With aging, glucosamine is lost with the natu- supplements are prescribed for the symptomatic treatment of
ral thinning of cartilage. As cartilage wears down, the joints lose knee OA (Henrotin, Marty, & Mobasheri, 2014). In the United
their normal cushioning ability, resulting in the pain and inflam- States, large research trials have not demonstrated significant
mation of OA. Chondroitin is another substance that forms part improvement in pain in patients who took chondroitin for osteo-
of the matrix between cartilage cells. arthritis, and there is insufficient evidence to suggest that glu-
cosamine improves joint structure (Center for Complementary
The use of glucosamine is thought to reduce cartilage and Integrative Health, 2016).
breakdown and improve cartilage production and repair. Chon-
droitin is another dietary supplement purported to repair carti- Glucosamine and chondroitin supplements are known to
lage damaged by inflammation or injury. interact with warfarin (Coumadin), increasing the risk of bleed-
ing, and some studies suggest that large doses may cause renal
Standardization damage. As with all supplements, patients should be encour-
aged to talk with their healthcare provider about using the sup-
Glucosamine is made from the crushed shells of shrimps, lob- plement and at what dosage.
sters, and crabs, although non-shellfish forms are available for
patients allergic to shellfish. It is available as oral tablets,
72.10 Pharmacotherapy for rheumatoid RA because it affects women about 3 times more frequently
arthritis includes analgesics, anti-inflammatory than men. Infectious organisms, such as the Epstein-Barr
drugs, corticosteroids, and disease-modifying virus, may play a role in an individual developing the auto-
antirheumatic drugs. immune processes seen with RA.
Rheumatoid arthritis (RA) is a chronic, progressive auto- The course of RA is variable and the rate at which joint
immune disease that causes inflammation of the joints. It is deformities develop is not consistent. Disease progression is
characterized by disfigurement and inflammation of mul- typically fastest during the first 6 years, slowing thereafter.
tiple joints. RA is less common than OA, with RA affecting The onset is typically insidious, though it may be acute if pre-
over 2 million people in the United States. Typically RA cipitated by a stressor, such as infection. The patient with
occurs at an earlier age than OA, with the incidence of RA early RA typically experiences morning joint stiffness, swell-
increasing up to age 70. It is important to differentiate ing, pain, and generalized fatigue. The joints may be slightly
between the two types of arthritis because the treatments reddened, warm, and tender to palpation. The pattern of
are very different. joints involved is usually symmetric. The upper extremity
joints are often involved, beginning with the hands and
In RA, autoantibodies known as rheumatoid factors wrists, as well as the joints of the toes, ankles, and knees. As
attack the individual’s tissues, activating complement and the disease worsens, the morning stiffness can extend several
drawing leukocytes into the area, where they attack the hours into the day and occur with any periods of prolonged
cells of the synovial membranes and blood. Inflammation rest. The persistent inflammation causes deformities of the
first occurs in the synovial membranes, which line joint joints and the supporting ligaments, tendons, and muscles,
cavities, then progresses to the surrounding articular carti- making activity painful. Muscle weakness and decreased
lage. The damaged synovial membrane swells and the per- ROM may be apparent. Most or all synovial joints are eventu-
sistent inflammation spreads and damages the surrounding ally affected. A patient with RA is shown in Figure 72.5.
blood vessels, ligaments, and tendons. The swelling also
causes hemorrhage, coagulation, and deposits of fibrin PharmFACT
within the joints. This ultimately leads to scar tissue forma-
tion that immobilizes the joint. Genetic factors account for 50% of the risk for developing
rheumatoid arthritis. Disease concordance in identical twins
The exact etiology of RA is not known, but it is likely a is 15% to 20%, which suggests that nongenetic factors also
combination of environmental and genetic factors. Female play an important role (Smith, 2017).
reproductive hormones may influence the development of
Chapter 72 Pharmacotherapy of Bone and Joint Disorders 1349
Figure 72.5 Patient with rheumatoid arthritis. for long-term therapy due to its adverse effects on the GI
system and platelet aggregation. Acetaminophen is effec-
Courtesy of Lee319/Shutterstock. tive at relieving pain and fever but has no anti-inflamma-
tory actions. Although the analgesics relieve symptomatic
Joint manifestations in RA typically precede systemic pain, they have little effect on disease progression.
manifestations, which are associated with advancing dis-
ease. Extreme fatigue, anorexia, weight loss, anemia, and Corticosteroids may be considered for moderate or
low-grade fever are common. Rheumatoid nodules may severe RA. Because of their potent anti-inflammatory
develop in the subcutaneous tissue of the forearm, toes, action, the goal of therapy with corticosteroids is to relieve
and fingers and in the viscera surrounding the heart, lungs, the symptoms associated with RA flare-ups. They are not
dura, and intestinal tract. Inflammation of the blood ves- used for prolonged therapy because of their long-term
sels can result in vasculitis. Respiratory complications, adverse effects, which include a greater susceptibility to
including pleurisy, pneumonitis, and fibrosis, are common infections, poor wound healing, and osteoporosis. Severe
as well as cardiac complications such as pericarditis and rebound symptoms can occur if these medicines are
myocarditis. abruptly discontinued. For these reasons, corticosteroids,
when used, are given at the lowest daily doses possible.
Diagnosis of RA is based on the patient’s history, phys-
ical examination, and diagnostic tests. Laboratory tests that The progression of tissue damage characteristic of RA
are helpful in supporting a diagnosis of RA include eleva- can be slowed or modified with a diverse group of drugs
tions in the serum rheumatoid factor, erythrocyte sedimen- called disease-modifying antirheumatic drugs
tation rate (ESR), antinuclear antibody titers, and serum (DMARDs). These drugs modify immune and inflamma-
immunoglobulin levels. Routine x-rays are used to deter- tory responses. They have been found to reduce mortality
mine the degree of structural joint damage. rates, improve symptoms, and enhance the quality of life in
patients with RA. Doses of DMARDs are listed in Table 72.7.
Like OA, nonpharmacologic therapies are an essential The medications are grouped as follows:
component of RA management. ROM and joint and muscle
strengthening exercises are important if the patient is to • Nonbiologic DMARDs
continue performing normal ADLs. Psychologic counsel- • Biologic DMARDs (anti–tumor necrosis factor [TNF]
ing may be helpful to help the patient deal with a poten-
tially debilitating disease. Braces, splints, canes, and drugs)
walkers can assist in ambulation. Loss of excess weight can • Biologic DMARDS (non–anti-TNF drugs).
help take the stress off inflamed joints. Proper rest helps
reduce pain. The choice of a specific DMARD depends on the
experiences of the healthcare provider and the response of
The primary goals of RA pharmacotherapy are to man- the patient to therapy. Many rheumatologists consider
age inflammation, reduce pain, and maximize physical methotrexate to be the first-line therapy for the initial
abilities. Pharmacotherapy for the relief of pain associated treatment of RA. It acts quickly, has a relatively favorable
with RA includes the same classes of analgesics used for safety profile, is low cost, and slows the progression of the
OA. Therapy is begun with NSAIDs, because these drugs disease. A once-weekly subcutaneous formulation of
relieve both pain and inflammation. NSAIDs that are used methotrexate (Otrexup) was approved in 2013 for severe
to treat RA are usually given in doses that are higher than RA that has not responded to other forms of therapy.
those for the patient with OA. Aspirin is not recommended Other nonbiologic DMARDs considered for initial ther-
apy include hydroxychloroquine (Plaquenil) and sul-
fasalazine (Azulfidine). Risks of toxicity with these drugs
is among the lowest associated with DMARDs. Nonbio-
logic DMARDs such as azathioprine (Azasan, Imuran)
and leflunomide (Arava) have more adverse effects than
other DMARDs, but may be used in combination with
some of the biologic therapies.
Biologic therapies are a newer DMARD therapy for
the treatment of RA. These drugs block steps in the inflam-
matory response, reduce joint inflammation, and slow the
progression of joint damage. Adalimumab (Humira), etan-
ercept (Enbrel), certolizumab pegol (Cimzia), golimumab
(Simponi), and infliximab (Remicade) are tumor necrosis
factor (TNF) antagonists. TNF is a naturally occurring
cytokine produced by macrophages and activated T cells
that mediates inflammation and modulates cellular
1350 Unit 11 Additional Drug Classes
Table 72.7 Selected Disease-Modifying Antirheumatic Drugs
Drug Route and Adult Dose Adverse Effects
(Maximum Dose Where Indicated)
Chills, fever, malaise, myalgia
Nonbiologic DMARDS Myelosuppression, hepatotoxicity, lymphoproliferative disorders
azathioprine PO: 1 mg/kg/day once or in divided doses bid for 6–8 wk Anorexia, nausea, vomiting, headache, and personality changes
(Azasan, Imuran) (max: 2.5 mg/kg/day) Retinopathy, agranulocytosis, aplastic anemia, seizures
Diarrhea, elevated hepatic enzymes, alopecia, rash
Maintenance dose: 1–2.5 mg/kg/day as a single dose or divided Hepatotoxicity, immunosuppression
Headache, glossitis, gingivitis, mild leukopenia, nausea
hydroxychloroquine PO: 400–600 mg/day for 4–12 wk, then 200–400 mg once daily Ulcerative stomatitis, myelosuppression, aplastic anemia,
(Plaquenil) Maintenance dose: 10–20 mg/day hepatic cirrhosis, nephrotoxicity, sudden death, pulmonary
fibrosis, teratogenicity
leflunomide (Arava) PO: 100-mg loading dose for 3 days, then 20 mg/day Headache, anorexia, nausea, vomiting
Anaphylaxis, Stevens–Johnson syndrome (SJS),
methotrexate PO: 7.5 mg once/wk or 2.5 mg q12h for 3 doses once/wk agranulocytosis, leukopenia, reversible oligospermia
(Otrexup, Rheumatrex, (max: 20 mg/wk)
Trexall) Local reactions at the injection site (pain, erythema, myalgia),
Subcutaneous (Otrexup): 10–25 mg once weekly nasopharyngitis
Serious infection, sepsis, and invasive fungal infections, lupus-
sulfasalazine PO: 500–1000 mg/day (max: 3 g/day) like syndrome, positive antinuclear antibodies, tumor lysis
(Azulfidine) syndrome, heart failure exacerbations, SJS, increased
malignancies, neutropenia.
Biologic DMARDs (Anti-TNF Drugs)
Local reactions at the injection site (pain, erythema, myalgia),
adalimumab Subcutaneous: 40 mg every other week nasopharyngitis
(Humira) Serious infection, sepsis, and invasive fungal infections, tumor
lysis syndrome, neutropenia, increased malignancies
certolizumab pegol Subcutaneous: 400 mg initially and at wk 2 and 4, followed by (tofacitinib), anaphylaxis, hypotension (rituximab), bowel
(Cimzia) 200 mg every other week obstruction and perforation (rituximab, tocilizumab, tofacitinib)
etanercept (Enbrel) Subcutaneous: 25 mg twice weekly; or 0.08 mg/kg or 50 mg
once weekly
golimumab (Simponi) Subcutaneous: 50 mg once monthly (for RA) or 100 mg q4wk
(for ulcerative colitis)
infliximab (Remicade) IV: 3 mg/kg at wk 0, 2, and 6, then q8wk
Biologic DMARDs (Non–Anti-TNF Drugs)
abatacept (Orencia) IV: 500–1000 mg given at 0, 2, and 4 wk, then q4wk thereafter
anakinra (Kineret) Subcutaneous: 100 mg/day
rituximab (Rituxan) IV: 1000 mg q2wk for a total of 2 doses (give a corticosteroid
30 min prior to infusion)
sarilumab (Kevzara) Subcutaneous: 150 mg/1.14 mL or 200 mg/1.14 mL using a
prefilled syringe
tocilizumab IV: 4–8 mg/kg every other week
(Actemra) Subcutaneous: 162 mg every week or every other week
tofacitinib (Xeljanz) PO: 5 mg bid
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
immune responses. Elevated levels of TNF are found in PROTOTYPE DRUG Adalimumab (Humira)
the synovial fluid of patients with RA. Certolizumab pegol
(Cimzia) and golimumab (Simponi) are newer generation Classification Therapeutic: Antirheumatic drug,
TNF blockers. Anakinra (Kineret) and abatacept (Orencia) antimalarial
are biologic drugs that block actions of interleukins in Pharmacologic: Disease-modifying
inflammatory pathways. The biologic drugs appear to be antirheumatic drug
effective and relatively nontoxic but they are expensive
(about $20,000 per year); thus they are normally not pre- Therapeutic Effects and Uses: Initially intro-
scribed until conventional therapy has been attempted duced to treat RA in 2002, adalimumab was the first
and failed. Combinations of biologic and nonbiologic fully human monoclonal antibody approved by the FDA.
drugs may be effective for patients unresponsive to Since then it has become one of the best selling drugs
monotherapy. in history. Indications for the drug have expanded to
Chapter 72 Pharmacotherapy of Bone and Joint Disorders 1351
include psoriatic arthritis, ankylosing spondylitis, poly- Nursing Responsibilities: Key nursing implications
articular juvenile idiopathic arthritis, Crohn’s disease, for patients receiving adalimumab are included in the
hidradenitis suppurativa, ulcerative colitis, chronic Nursing Practice Application for Patients Receiving Phar-
plaque psoriasis, and uveitis. Amjevita is a biosimilar macotherapy for Rheumatoid Arthritis and Osteoarthritis.
drug approved in 2016 for seven indications of adalim-
umab. A biosimilar is a biologic drug that is substantially Other DMARDS for Rheumatoid
similar in clinical properties. Arthritis
Adalimumab is administered by the subcutaneous The first- and second-choice DMARDs are described next.
route, usually every other week. Doses differ by indication. Gold salts (Auranofin, Aurothioglucose, gold sodium thio-
The drug is available in a single-use pen injection system malate) and penicillamine (Cuprimine, Depen) are
for home administration. DMARDs that are rarely used and the student should refer
to a drug guide for information. Cyclosporine and azathio-
Mechanism of Action: Adalimumab blocks the prine are immunosuppressants that occasionally are used
inflammatory activity of TNF. High levels of TNF are as DMARDs. They are described in Chapter 42.
often found in patients with inflammatory disorders such
as RA. TNF Blockers: The TNF blockers include the monoclonal
antibodies adalimumab, certolizumab, etanercept, golim-
Pharmacokinetics: umab, and infliximab. Although each of these drugs is
unique, they have similar actions and adverse effects. The
Route(s) Subcutaneous most common adverse effects are injection-site reactions
such as pain, swelling, and bruising. Other adverse effects
Absorption Peak levels occur in about include upper respiratory tract infection, neutropenia, and
rare cases of central nervous system (CNS) demyelinating
5 days disorders such as multiple sclerosis. Also, some of these
medications may worsen or cause heart failure. Because they
Distribution Unknown are potent immunosuppressants, all pose an increased risk
for serious infections and malignancy. These drugs carry a
Primary metabolism Unknown black box warning that reactivation of latent infections such
as tuberculosis may occur. The warning also includes an
Primary excretion Unknown increased risk for lymphoma and other malignancies, espe-
cially when used in children and adolescents treated for
Onset of action 4–5 weeks juvenile RA. All TNF blockers are pregnancy category B.
Duration of action 10–20 days • Adalimumab (Humira): See the prototype feature
above.
Adverse Effects: The most common adverse effects
are injection-site pain, upper respiratory infection, • Certolizumab pegol (Cimzia). Certolizumab was
increased creatine phosphate, headache, and rash. approved in 2008 for the treatment of moderate to
Black Box Warning: Due to its ability to suppress the severe RA, ankylosing spondylitis, psoriatic arthritis,
immune system, patients are at increased risk for the and Crohn’s disease unresponsive to safer medica-
development of serious infections and malignancies. tions. The drug is given as a subcutaneous injection,
Latent infections such as tuberculosis and hepatitis B usually every other week.
virus may become reactivated. Leukemias, lymphomas,
and other malignancies have been reported with TNF • Etanercept (Enbrel). Approved in 1998, etanercept is
blockers. Although rare, fatal cases of hepatosplenic approved for the treatment of moderate to severe RA,
T-cell lymphoma have been documented with TNF psoriatic RA in adults, polyarticular juvenile RA in chil-
blockers. dren ages 2 and older, ankylosing spondylitis, and
plaque psoriasis. Etanercept is administered by the sub-
Contraindications/Precautions: There are no con- cutaneous route twice a week. Concurrent use of etan-
traindications. As a precaution, patients should be moni- ercept with sulfasalazine may result in leukopenia.
tored for the development of infections or malignancies.
• Golimumab (Simponi). Golimumab was approved in
Drug Interactions: Adalimumab should not be 2009 for the management of moderate to severe RA,
administered concurrently with the TNF blockers anakinra active psoriatic RA in adults, and active ankylosing
or abatacept. Administration of live vaccines should be spondylitis in adults. More recently, the drug was
avoided. Concurrent use with other immunosuppressants approved to treat moderate to severe ulcerative colitis
should be avoided or carefully monitored to avoid an
increased risk for serious infections. Herbal/Food: Echi-
nacea should be avoided because it may decrease the
immunosuppressive effects of adalimumab.
Pregnancy: Category B
Treatment of Overdose Treatment is supportive.
1352 Unit 11 Additional Drug Classes
that cannot be managed by first-line medications. with salicylates and glucocorticoids. The primary adverse
Golimumab is usually combined with methotrexate effects of hydroxychloroquine are GI related, such as
and is given as a subcutaneous injection once a month. anorexia, weight loss, nausea, and vomiting. Possible ocu-
• Infliximab (Remicade). Originally approved in 1998, lar effects include blurred vision, photophobia, diminished
infliximab is indicated for moderate to severe RA, pso- ability to read, and blacked-out areas in the visual field.
riatic RA, ankylosing spondylitis, Crohn’s disease, Hydroxychloroquine is pregnancy category C.
ulcerative colitis, and plaque psoriasis. For RA inflix-
imab is usually combined with methotrexate and is Leflunomide (Arava): Approved in 1998, leflunomide is a
given as an IV infusion over several hours, followed DMARD with a unique mechanism of action. It inhibits an
by subsequent injections in weeks 2 and 6 and every enzyme in mitochondria that is responsible for the synthe-
8 weeks thereafter. Acetaminophen and diphenhy sis of pyrimidines, which are building blocks for DNA and
dramine (Benadryl) are given prior to infusion to ribonucleic acid (RNA). The result is an inhibition in B-cell
decrease the symptoms of infusion reaction such as and T-cell function. Reduced cytokine and antibody pro-
chest pain, tachycardia, shortness of breath, and duction by these cells reduces inflammation and joint
lightheadedness. destruction. After a loading dose for 3 days, this drug is
given PO once daily. Leflunomide has an exceptionally
Abatacept (Orencia): Abatacept was approved in 2005 for long half-life, and it can be detected in the blood as long as
the treatment of moderate to severe RA in adults and for 2 years after discontinuation. If toxicity occurs, the admin-
juvenile idiopathic RA in children ages 6 and older. The istration of cholestyramine for 11 days can clear most leflu-
drug acts by inhibiting the actions of T cells, which are nomide from the body. Common adverse effects include
often hyperactive in patients with RA. It is administered as diarrhea, nausea, vomiting, headache, and alopecia. Leflu-
an IV infusion, usually every 2 to 4 weeks. Headache, nomide is hepatotoxic and liver function must be regularly
upper respiratory tract infection, and nausea are common monitored during therapy. The possibility of pregnancy
adverse effects. Like other immunosuppressants, there is should be excluded before therapy is begun because this
an increased risk of serious infections or reactivation of drug is pregnancy category X.
latent infections. The risk for malignancies may also be
increased. Although abatacept is sometimes used in combi- Methotrexate (Otrexup, Rheumatrex, Trexall): Methotrex-
nation with other DMARDs, it should not be administered ate is prescribed for a number of proliferative and inflam-
concurrently with TNF blockers due to a high incidence of matory diseases, including various carcinomas and
serious infections. This drug is pregnancy category C. leukemias, immunosuppression following kidney trans-
plantation, severe psoriasis, and RA. Methotrexate is a
Anakinra (Kineret): Approved in 2001, anakinra inhibits folic acid antagonist, and a potent immunosuppressant.
interleukin-1 (IL-1), an important chemical mediator of Gastric irritation and stomatitis are the most frequent
inflammation. It is approved for RA that has not responded adverse effects; these are minimized by the concurrent use
to one or more DMARDs. A major disadvantage of this of folic acid. Patients, particularly those who are older,
drug is that it must be given daily by the subcutaneous obese, or have diabetes or CKD, need to be monitored for
route. Injection-site reactions such as pain, swelling, hepatotoxicity, bone marrow suppression, and pneumoni-
edema, and bruising occur more often than with the other tis. The possibility of pregnancy should be excluded before
drugs in its class. Ice and hydrocortisone cream are recom- therapy is begun because this drug is pregnancy category X.
mended to diminish the pain, along with site rotation. A prototype feature for methotrexate may be found in
Upper respiratory infections and influenza symptoms Chapter 57.
occur in many patients. The manufacturer recommends
that anakinra not be administered concurrently with TNF Rituximab (Rituxan): Rituximab (Rituxan) is a monoclo-
inhibitors such as etanercept due to an increased risk of nal antibody originally approved in 1997 as an antineo-
infections. Anakinra is pregnancy category B. plastic drug. The drug binds to CD20, a surface protein
present on B lymphocytes involved in certain leukemias
Hydroxychloroquine (Plaquenil) Approved in 1955, and lymphomas. Once bound, rituximab lyses the tumor
hydroxychloroquine is approved for the treatment of RA. cells. Later, it was discovered that B lymphocytes also play
This drug is also used for the prophylaxis and treatment of a major role in producing the severe inflammation associ-
malaria, but chloroquine (Aralen) is the preferred drug for ated with RA. In 2006, rituximab was approved to treat
this parasitic infection (see Chapter 53). It may be used to moderate to severe RA that has not responded to therapy
treat systemic lupus erythematosus in patients who have with TNF blockers. For RA, the drug is administered con-
not responded well to other anti-inflammatory drugs. currently with methotrexate. Common adverse effects
Hydroxychloroquine therapy for 3 to 6 months is required include upper respiratory tract infection, urinary tract
to achieve therapeutic effects. For full effectiveness, infection, and bronchitis. Rituximab can produce adverse
hydroxychloroquine is most often prescribed concurrently
Chapter 72 Pharmacotherapy of Bone and Joint Disorders 1353
effects such as serious infections, life-threatening dys- diminishes the absorption of sulfasalazine. Sulfasalazine
rhythmias, and tumor lysis syndrome. This drug is preg- is pregnancy category B.
nancy category C.
Tocilizumab (Actemra): Tocilizumab was approved in
Sarilumab (Kevzara): Approved in 2017, sarilumab acts 2010 for the treatment of moderate to severe RA in adults
by blocking receptors for interleukin-6 (IL-6), a substance and for juvenile idiopathic arthritis in children ages 2 and
secreted by immune cells that promotes inflammation and older. Like sarilumab, tocilizumab acts by inhibiting IL-6
activates the immune response. It may be used as mono- and may be used as monotherapy or in combination with
therapy or in combination with other DMARDs such as other DMARDs such as methotrexate. It is administered
methotrexate to treat moderate to severe RA in patients by either the IV or subcutaneous route. Headache, upper
who have not responded to one or more DMARDS. This respiratory tract infection, hypertension (HTN), and
drug may cause neutropenia; therefore, it should be increased liver enzymes are common adverse effects. Like
avoided if an active infection is present. The drug is not other immunosuppressants, the risk of serious infections
recommended for patients with active hepatic disease. or reactivation of latent infections is increased. Tocili-
Sarilumab does not have a pregnancy rating. zumab therapy should not be initiated if the absolute
neutrophil count (ANC) is less than 2000/mm3, if the
Sulfasalazine (Azulfidine): Sulfasalazine is a sulfon- platelet count is below 100,000/mm3, or if liver enzymes
amide and, having been approved in 1950, one of the are elevated (1.5 times normal). This drug is pregnancy
oldest drugs for RA. It is also approved for juvenile RA, category C.
Crohn’s disease, and ulcerative colitis. It is available as
an enteric-coated tablet that must be taken 3 to 4 times Tofacitinib (Xeljanz): Tofacitinib is a newer biologic
daily. Its beneficial effects are noted quickly, often after DMARD, approved in 2013 to treat RA that has not
4 weeks of therapy. GI complaints such as nausea, vomit- responded adequately to methotrexate therapy. This drug
ing, anorexia, diarrhea, and abdominal pain occur in a acts by inhibiting Janus kinase (JAK). JAKs are enzymes
significant number of patients taking this drug, and that signal the immune system to release certain cytokines
these may cause discontinuation of therapy. The adverse that cause inflammation. By blocking the signaling path-
GI effects are better tolerated if therapy starts with a low way, JAK inhibitors (sometimes called Jakinibs) reduce the
dose that is gradually increased. Headache; blood dys- progress and clinical symptoms of RA. Like some other
crasias, especially leukopenia; and skin rashes are also biologic therapies, tofacitinib carries a black box warning
frequent. Regular monitoring of CBCs for bone marrow that its use may result in serious infections and that the
suppression should be conducted. Patients with allergies existence of latent tuberculosis should be excluded prior to
to sulfur or other sulfonamides should not receive sul- therapy. The black box warning also notes that lymphoma
fasalazine. Concurrent administration with iron supple- and other malignancies have developed in patients taking
ments or antibiotics should be avoided because doing so this drug. Tofacitinib is pregnancy category C.
CONNECTIONS: NURSING PRACTICE APPLICATION
Patients Receiving Pharmacotherapy for Rheumatoid Arthritis and Osteoarthritis
Assessment
Baseline assessment prior to administration:
• Obtain a complete health history including musculoskeletal, GI, cardiovascular, neurologic, endocrine, hepatic, or kidney disease. Obtain a drug history
including allergies, current prescription and OTC drugs and herbal preparations; alcohol use; or smoking. Be alert to possible drug interactions.
• Obtain a history of any current symptoms or pain and their effect on ADLs. Assess for inflammation, nodules, deformities, as well as location, and note
the presence of pain or discomfort, time of day of occurrence, on movement, or at rest. Assess effects on sleep.
• Obtain a dietary history and the effect of the disease on the ability to obtain food sources, cooking, and eating. Assess adequacy of fluid intake.
• Obtain baseline weight and vital signs.
• Evaluate appropriate laboratory findings (e.g., CBC, sedimentation rate, hepatic and renal function studies, rheumatoid factor, coagulation panels,
bleeding time, electrolytes, glucose, lipid profile).
• 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., symptoms of acute inflammation are diminished or absent, pain is diminished or absent, ability to carry out
ROM and ADLs has increased).
• Continue monitoring vital signs and level of pain.
• Continue to monitor laboratory studies as ordered.
• Assess for and promptly report adverse effects: symptoms of GI bleeding (dark or tarry stools, hematemesis, coffee-ground emesis, or blood in the stool),
abdominal pain, severe tinnitus, dizziness, drowsiness, lightheadedness, palpitations, tachycardia, HTN, increased respiratory rate and depth, pulmonary
congestion, edema, diminished urine output, fever, infections, visual effects (blurred vision, photophobia, blacked-out areas in the vision field).
(continued )
1354 Unit 11 Additional Drug Classes
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
Ensuring therapeutic effects: • Teach the patient to supplement drug therapy with nonpharmacologic
• Continue assessments as above for therapeutic effects. (Diminished in- measures, e.g., a balance between low-impact activity and rest, application
of warm or cool compresses, or warm showers prior to activity.
flammation, pain, stiffness, improved ROM, and ability to carry out ADLs
should continue to improve.) • Teach the patient to promptly report increasing pain, stiffness, and
decreased ability to carry out ADLs. Hospitalization may be required
during acute exacerbations dependent on the severity of symptoms.
• Continue to assess fluid and nutrition intake. (Inflammation, pain, and • Encourage the patient to eat small, nutrient-dense foods with adequate
deformities may make eating and drinking difficult. Dietitian consultation fluids frequently throughout the day to maintain nutrition and hydration
may be required.) as well as to conserve energy. The family or caregiver may need to
prepare meals, and a dietary consult may be useful.
• Continue to monitor CBC, sedimentation rate, RA factor, hepatic and • Instruct the patient on the need to return for periodic laboratory testing.
renal laboratory values, glucose, electrolytes, and lipid levels.
Minimizing adverse effects: • Instruct the patient to promptly report any continued inflammation, pain,
• Instruct the patient to promptly report any worsening inflammation or increased joint involvement, or general worsening of symptoms.
pain, increased joint involvement, or overall worsening of symptoms.
(Drugs for RA treat the symptoms and slow the progression of the dis-
ease but are not a cure. Acute exacerbations may require hospitalization
and a change in the medication regimen.)
• Continue to monitor periodic laboratory work: CBC, coagulation panels, • Instruct the patient on the need to return periodically for laboratory work.
bleeding time, electrolytes, glucose, hepatic and renal function tests, and
lipid levels. (Aspirin, salicylates, and NSAIDs affect platelet aggregation
and should be monitored when used long term or if excessive bleeding
or bruising is noted. Corticosteroids may affect electrolytes, glucose, and
lipid levels. DMARDs may cause hemolysis, agranulocytosis, or aplastic
anemia. Lifespan: Age-related physiologic differences may place the
older adult at greater risk for adverse hepatic, renal, or cardiac effects.)
• Monitor for abdominal pain, black or tarry stools, blood in the stool, • Instruct the patient to immediately report any signs or symptoms of GI
hematemesis, coffee-ground emesis, dizziness, lightheadedness, or bleeding.
hypotension, especially if associated with tachycardia. (NSAIDs and
glucocorticoids may cause GI irritation and bleeding.) • Teach the patient to take the drug with food or milk to decrease GI irrita-
tion. Enteric-coated tablets should be swallowed whole without chew-
ing, crushing, or breaking. Alcohol use should be avoided or eliminated.
• Monitor for tinnitus, difficulty hearing, lightheadedness, or difficulty with • Instruct the patient to immediately report any signs or symptoms of ring-
balance and report promptly. (NSAIDs and salicylates may be ototoxic ing, humming, buzzing in ears, difficulty with balance, dizziness, vertigo,
and cause hearing loss.) or nausea.
• Monitor urine output and renal function studies periodically. Weigh the • Instruct the patient on NSAIDs and salicylates to report any changes in
patient on corticosteroids daily and report weight gain of 1 kg (2 lb) or the quantity of urine output, darkening of urine, or edema promptly.
more in a 24-h period or more than 2 kg (5 lb) per week, or increasing
peripheral edema. (NSAIDs and salicylates may be nephrotoxic. Patients • Teach the patient on NSAIDs and salicylates to increase fluid intake,
on long-term or high-dose therapy should monitor urine output and have especially if fever is present.
periodic renal function studies. Daily weight is an accurate measure of
fluid status and takes into account intake, output, and insensible losses.) • Instruct the patient to weigh self daily, ideally at the same time of day.
The patient should report a weight gain of more than 1 kg (2 lb) in a 24-h
period or more than 2 kg (5 lb) per week, or increasing peripheral edema.
• Observe for skin rashes, fever, stomatitis, flulike symptoms, or general • Teach the patient to immediately report any flulike symptoms, fever,
malaise. (Bone marrow suppression may occur with corticosteroids or mouth irritation or soreness, or skin rashes.
DMARDs and result in an increased risk of infection.)
• Periodically monitor vision in patients on NSAIDs or DMARDs. Immedi- • Teach the patient on NSAIDs or DMARDs to obtain eye examinations
ately report unusual changes in visual acuity, blurred or diminished vision, twice yearly or more frequently as instructed by the provider. Immedi-
reports of spots in vision, difficulty reading, blacked-out areas of the vision ately report any sudden changes in vision.
field, or changes to color sense to the provider. (NSAIDs may cause
blurred or diminished vision, decreased color sense, diplopia, or scoto-
mas. DMARDs may cause significant retinal changes with blurred vision,
difficulty reading, photophobia, or blacked-out areas of the vision field.)
Patient understanding of drug therapy: • The patient should be able to state the reason for the drug, appropriate
• Use opportunities during administration of medications and during dose and scheduling, what adverse effects to observe for and when to
report them, and the anticipated length of medication therapy.
assessments to discuss the rationale for the drug therapy, desired
therapeutic 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: • The patient, family, or caregiver is able to discuss appropriate dosing
• When administering the medication, instruct the patient, family, or and administration needs.
caregiver in proper self-administration of the drug, e.g., taken with food
or meals or with additional fluids, followed by teach-back. (Utilizing time
during nurse administration of these drugs helps to reinforce teaching.)
Chapter 72 Pharmacotherapy of Bone and Joint Disorders 1355
CONNECTION Checkpoint 72.3 ingestion of alcohol, dehydration, stress, injury to the joint,
or fever. Gouty arthritis most often occurs in the big toes,
Chloroquine (Aralen) and hydroxychloroquine (Plaquenil) are very heels, ankles, wrists, fingers, knees, or elbows and may be
similar, and both may be used to treat malaria. From what you accompanied by an elevated temperature. With chronic
learned in Chapter 53, what organism causes malaria? Describe gout, bumps called tophi, or deposits of sodium urate crys-
how these drugs are used for prophylaxis of malaria. Answers to tals in the subcutaneous tissue, may be present, particularly
Connection Checkpoint questions are available on the faculty resources on the outer ear, arms, and fingers. Deposits of urate crys-
site. Please consult with your instructor. tals in the kidneys may lead to the development of urinary
calculi and kidney failure. Nephrolithiasis occurs in 10% to
Pharmacotherapy of Gout 25% of patients with gout and is more likely to occur in
and Hyperuricemia patients with low fluid intake and when the urine is acidic.
72.11 Gout is treated with drugs that decrease Gout may be difficult to diagnose because early symp-
joint pain and inflammation and lower uric toms may be vague. Although most people with gout have
acid levels. hyperuricemia, the serum levels of uric acid may be normal
even during an acute attack. To confirm a diagnosis, a
Gout is a form of acute arthritis caused by an accumula- synovial fluid analysis may be performed to evaluate for
tion of uric acid (urate) crystals in the joints and other the presence of uric acid crystals or to rule out synovial
body tissues, causing inflammation. Between 1% and 3% fluid infection as the cause of the symptoms.
of the U.S. population are affected by gout. Of patients
with gout 90% are men, who first manifest symptoms In its early phases, treatment of gout is very successful.
between the ages of 30 and 60; women are affected after The goals of gout pharmacotherapy are threefold:
menopause.
• Termination of acute episodes
Gout may be classified as primary or secondary. Pri- • Prevention of future gout attacks
mary gout is caused by genetic errors in the metabolism of • Avoidance of the formation of gout complications,
purines. Uric acid is a waste product created by the meta-
bolic breakdown of the nucleic acids DNA and RNA. The such as tophi and kidney stones.
kidneys are responsible for excreting uric acid. High levels
of uric acid crystals may result from an increased metabo- Combination therapy using anti-inflammatory drugs
lism of nucleic acids or the reduced excretion of uric acid and uric acid inhibitors such as probenecid (Probalan),
by the kidneys. Primary gout may therefore be viewed as febuxostat (Uloric), and allopurinol (Lopurin, Zyloprim) is
an imbalance in the handling of uric acid by the body. The the mainstay of gout therapy. Uric acid inhibitors block the
production of uric acid crystals exceeds the excretion capa- accumulation of uric acid in the blood or uric acid crystals
bility of the kidneys. Primary gout is inherited as an within the joints. When uric acid accumulation is blocked,
X-linked trait; males inherit the disorder through female the symptoms associated with gout diminish. These drugs
carriers. are most effective when taken within the first 12 hours of
an acute attack. About 80% of the patients using uric acid
Secondary gout is caused by diseases or drugs that inhibitors experience GI complaints such as abdominal
increase the metabolic turnover of nucleic acids or that cramping, nausea, vomiting, and diarrhea. Drugs for gout
interfere with the excretion of uric acid. Some examples of are listed in Table 72.8.
drugs that may cause gout include thiazide diuretics, aspi-
rin, cyclosporine, and alcohol, when ingested on a chronic NSAIDs are the preferred drugs for treating the pain
basis. Conditions that can cause secondary gout include and inflammation of acute episodes of gout. Commonly
diabetic ketoacidosis, hypothyroidism, multiple myeloma, used NSAIDs include indomethacin (Indocin) and
CKD, and diseases associated with a rapid cell turnover naproxen (Naprosyn), which are taken PO every day. Aspi-
such as leukemia, hemolytic anemia, and polycythemia. rin should be avoided because it can increase uric acid lev-
els and worsen symptoms. Corticosteroids may be used to
The primary diagnostic criterion for gout is the serum treat exacerbations of acute gout, particularly when the
uric acid level. Hyperuricemia is defined as a serum uric symptoms are in a single joint and the medication can be
acid level of 7 mg/dL. Patients with mild hyperuricemia delivered intra-articularly. The most commonly used corti-
are asymptomatic. Once the level of uric acid rises to satu- costeroid is prednisone. Most patients report that symp-
ration levels in body fluids, urate crystals form and symp- toms improve within a few hours of treatment and that an
toms appear, usually with a sudden onset. acute episode terminates within a week.
Acute gouty arthritis occurs when needle-shaped uric Prophylaxis of gout includes dietary management,
acid crystals accumulate in joints, resulting in extremely avoidance of drugs that worsen the condition, and therapy
painful, red, and inflamed tissue. Attacks have a sudden with antigout medications. Patients should avoid high-
onset, often occur at night, and may be triggered by purine foods such as organ meats, legumes, alcoholic bev-
erages, mushrooms, and oatmeal because these foods form
1356 Unit 11 Additional Drug Classes
Table 72.8 Drugs for Gout
Drug Route and Adult Dose Adverse Effects
allopurinol (Lopurin, Zyloprim) (Maximum Dose Where Indicated)
Drowsiness, skin rash, diarrhea
colchicine (Colcrys) PO (primary): 100 mg/day (max: 800 mg/day)
PO (secondary): 200–800 mg/day Severe skin reactions, bone marrow depression,
IV: 200–400 mg/m2/day hepatotoxicity, kidney failure
PO for prophylaxis: 0.5 mg once or twice daily Nausea, vomiting, diarrhea, GI upset
PO for gout flare: 1.2 mg followed by another dose
of 0.6 mg 1 h later Bone marrow depression, aplastic anemia, leukopenia,
thrombocytopenia, agranulocytosis, severe diarrhea,
febuxostat (Uloric) PO: 40–80 mg once daily nephrotoxicity
lesinurad (Zurampic) PO: 200 mg once daily Liver enzyme elevation, nausea, arthralgia, rash
pegloticase (Krystexxa) IV: 8 mg q2wk Thromboembolism, gout flare
probenecid (Probalan) PO: 250 mg bid for 1 wk, then 500 mg bid (max: 3 g/day)
Headache, influenza, increased blood creatinine,
gastroesophageal reflux disease.
Acute kidney failure, major cardiovascular events
Gout flare, nausea, ecchymosis, nasopharyngitis
Anaphylaxis, infusion reaction, worsening heart failure
Nausea, vomiting, headache, anorexia, flushed face
Anaphylaxis, severe skin reactions, hepatotoxicity, anemia,
aplastic anemia, leukopenia
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
nucleic acids when they are metabolized. Patients should serum uric acid levels. Should the patient note the onset of an
avoid aspirin, niacin, and diuretics because their use can acute episode, the dose can be increased until symptoms sub-
precipitate an acute episode of gout. Renal complications side. It is important to understand, however, that colchicine
may be avoided by adequate fluid intake and consumption does not inhibit uric acid synthesis and does not promote
of a low-protein diet. uric acid excretion. Thus, if the patient has escalating serum
uric acid levels, allopurinol and sulfinpyrazone are the pre-
PROTOTYPE DRUG Colchicine (Colcrys) ferred drugs for prophylaxis (see Section 72.12). Patients who
are on colchicine prophylaxis therapy may discontinue the
Classification Therapeutic: Antigout drug drug after they have been symptom free for a year and have
Pharmacologic: Anti-inflammatory drug normal serum uric acid levels. In some patients, discontinua-
tion may precipitate an acute gout episode.
Therapeutic Effects and Uses: Colchicine is a nat-
ural product obtained from the autumn crocus, which is Mechanism of Action: Colchicine inhibits the migra-
grown in gardens and found in meadows throughout the tion of neutrophils into the area of inflammation. This drug
United States and Canada. It has been used for centuries reduces the inflammation associated with acute gouty
as a natural product. Although first available by prescrip- arthritis by inhibiting the synthesis of microtubules, which
tion prior to 1938, colchicine was not officially approved are the subcellular structures responsible for helping white
by the FDA until 2009. The trade-name form, Colcrys, is blood cells infiltrate an area.
approved for the treatment and prophylaxis of acute gout
flares and for familial Mediterranean fever. Pharmacokinetics:
Although NSAIDs have largely replaced colchicine as Route(s) PO
first-line therapy, it is prescribed for some patients with
acute gouty arthritis. It is much more effective if taken Absorption Rapidly absorbed
within 24 hours of the onset of symptoms. Colchicine has
several off-label indications that include amyloidosis, Distribution Widely distributed; concentrated
Paget’s disease, hepatic cirrhosis, and Mediterranean fever.
in leukocytes, kidney, liver,
Although colchicine has no analgesic properties, patients
experience pain relief due to the reduction in inflammation. spleen, and intestinal tract
Low doses of colchicine may be used as prophylactic therapy
for gouty arthritis in patients with normal or slightly elevated Primary metabolism Hepatic
Primary excretion Feces
Onset of action 12 h
Duration of action Half-life: variable (1.7–20.9 h)
Chapter 72 Pharmacotherapy of Bone and Joint Disorders 1357
Adverse Effects: The most significant adverse effects of crystal: calcium pyrophosphate. The patient is treated with
of colchicine are GI related and these may occur in up to analgesics or anti-inflammatory drugs; no therapy is
80% of patients. Adverse effects include nausea, vomiting, available to dissolve these types of crystals (Saadeh, 2016).
abdominal pain, anorexia, and diarrhea. This drug may
cause bone marrow toxicity, and aplastic anemia, leuko- 72.12 Hyperuricemia is treated with drugs that
penia, thrombocytopenia, or agranulocytosis may occur. reduce serum levels of uric acid.
Additional adverse effects include hepatotoxicity, mental
confusion, azotemia, proteinuria, hematuria, and oliguria. Many patients with increased uric acid levels are asymp-
Severe irritation and tissue damage may occur if the IV tomatic. In most cases, pharmacotherapy is not indicated
formulation leaks around the injection site. for asymptomatic patients. For patients with repeated
acute episodes of chronic gout, however, prophylactic
Contraindications/Precautions: This drug is con- pharmacotherapy should be used to lower serum uric acid
traindicated in patients with a known hypersensitivity levels. Prophylaxis may be obtained by blocking the for-
to colchicine, and in those with CKD, pregnancy, or GI, mation of uric acid or by increasing its excretion.
hepatic, or cardiac impairment. Patients with blood dys-
crasias should not receive colchicine. Colchicine should be Allopurinol (Lopurin, Zyloprim) is a preferred drug
used with caution in older adults and debilitated patients, for gout prophylaxis. Allopurinol acts by inhibiting xan-
or in patients with an early manifestation of GI, renal, thine oxidase, which is the enzyme responsible for the for-
hepatic, or cardiac disease. mation of uric acid. Blocking the synthesis of uric acid will
lower serum uric acid levels, thus preventing gout. It is also
Drug Interactions: Concurrent use with NSAIDs may used in patients with CKD or those who have renal obstruc-
increase the risk of serious GI symptoms. Colchicine may tion caused by uric acid stones.
exhibit additive bone marrow toxicity with cyclosporine,
phenylbutazone, and other drugs that adversely affect bone Uricosurics are drugs that increase the rate of excre-
marrow. Erythromycin may increase serum colchicine lev- tion of uric acid by blocking its reabsorption in the kidney.
els. Loop diuretics may decrease colchicine effects. Alcohol These drugs are most effective in preventing hyperurice-
or products that contain alcohol may cause skin rashes and mia associated with chronic gout and should not be used to
result in additive liver damage. Colchicine may increase a treat acute attacks of gouty arthritis. The uricosuric drugs
patient’s sensitivity to CNS depressants. Colchicine may have no analgesic or anti-inflammatory properties. Proben-
also directly interfere with the absorption of vitamin B12. ecid (Probalan) is an older uricosuric drug used for gout
Herbal/Food: Alcohol and foods that are rich in purines, prophylaxis. This drug may precipitate acute gout during
including salmon, sardines, and organ meats, should be the period of initial therapy because it mobilizes uric acid
avoided. Foods that cause the urine to become more alka- that has been stored in the body. Concurrent administra-
line, such as milk, fruits, carbonated drinks, most vegeta- tion of colchicine can help prevent this adverse effect.
bles, molasses, and baking soda, may increase the risk of
kidney stones. Lesinurad is a newer uricosuric that offers fewer
adverse effects and drug interactions than probenecid. It is
Pregnancy: Category C (PO) or D (IV). approved only in combination with a xanthine oxidase
inhibitor such as allopurinol. Drugs for hyperuricemia and
Treatment of Overdose: Overdoses (including unin- gout are listed in Table 72.8.
tentional ingestion of autumn crocus) may cause severe GI
distress, shock, paralysis, delirium, respiratory failure, and Acute hyperuricemia can occur following antineoplastic
death. Treatment is symptomatic and may include gastric therapy as part of a serious condition called tumor lysis syn-
lavage and hemodialysis. drome when cancer cells are broken down. The massive load
of uric acid crystals can result in acute kidney failure and pos-
Nursing Responsibilities: Key nursing implications sibly death. Rasburicase (Elitek) is a recombinant form of the
for patients receiving colchicine are included in the Nurs- enzyme urate oxidase, which can lower serum uric acid levels
ing Practice Application for Patients Receiving Pharmaco- when given IV to patients receiving antineoplastic therapy.
therapy for Gout.
PROTOTYPE DRUG Allopurinol (Lopurin, Zyloprim)
Drugs Similar to Colchicine (Colcrys)
Classification Therapeutic: Antigout drug
Colchicine is the only drug in this class. Pharmacologic: Xanthine oxidase
inhibitor
PharmFACT
Therapeutic Effects and Uses: Allopurinol is an
Pseudogout is a type of arthritis that can cause symptoms older drug that was approved in 1966 for gout and its com-
similar to gout but involves accumulation of a different type plications. It controls the hyperuricemia that causes severe
gout and reduces the possibility of flare-ups of acute gouty
1358 Unit 11 Additional Drug Classes
attacks. It is also approved to prevent recurrent neph- cyclophosphamide, and cyclosporine. An increased hypo-
rolithiasis due to calcium oxalate stones in patients with glycemic effect may be seen with chlorpropamide. The
elevated uric acid levels. It may be used prophylactically risk of ototoxicity is increased when allopurinol is used
to reduce the severity of the hyperuricemia associated with thiazides and angiotensin-converting enzyme (ACE)
with antineoplastic and radiation therapies, both of which inhibitors. Aluminum antacids taken concurrently with
increase plasma uric acid levels by promoting nucleic acid allopurinol may decrease its effects. An increased effect
degradation. This drug takes 1 to 3 weeks to bring serum may be seen with phenytoin, theophylline, and antican-
uric acid levels to within the normal range. cer drugs, necessitating the need for altered doses of these
medications. Herbal/Food: Unknown.
Allopurinol is available by the PO and IV routes. IV
administration is usually reserved for patients with high Pregnancy: Category C.
uric acid levels resulting from cancer chemotherapy. In
2017 Duzallo, a fixed-dose combination of allopurinol and Treatment of Overdose: Overdose with allopurinol
lesinurad, was approved to treat symptomatic gout. is rare. There is no specific treatment for an overdose and
the patient is treated symptomatically.
Mechanism of Action: Allopurinol reduces uric acid
formation by selectively inhibiting the action of xanthine Nursing Responsibilities: Key nursing implications
oxidase, which is the enzyme responsible for the formation for patients receiving allopurinol are included in the Nurs-
of uric acid. Lowering the formation of uric acid prevents ing Practice Application for Patients Receiving Pharmaco-
hyperuricemia. Unlike the uricosuric drugs, allopurinol therapy for Gout.
does not increase the renal excretion of uric acid.
Drugs Similar to Allopurinol (Lopurin,
Pharmacokinetics: Zyloprim)
Route(s) PO, IV Additional drugs for gout prophylaxis and hyperuricemia
include febuxostat, lesinurad, pegloticase, and probenecid.
Absorption 80–90% absorbed in the GI tract Sulfinpyrazone is a uricosuric medication than has been
discontinued in the United States.
Distribution Widely distributed; secreted in
Febuxostat (Uloric): An alternative to allopurinol, febuxo-
breast milk; less than 1% bound stat was approved in 2009 for the chronic management of
hyperuricemia in patients with gout. The drug acts by
to plasma proteins inhibiting xanthine oxidase and offers the convenience of
once-daily dosing. Unlike some of the other medications in
Primary metabolism Hepatic to the active metabolite this class, febuxostat exhibits little nephrotoxicity or der-
matologic toxicity. Liver function tests should be monitored
oxypurinol periodically to prevent the development of hepatotoxicity.
It should not be administered concurrently with drugs
Primary excretion Primarily renal metabolized by xanthine oxidase such as mercaptopurine
or azathioprine because these drugs could accumulate to
Onset of action 24–48 h toxic levels. Febuxostat is pregnancy category C.
Duration of action 1–3 weeks after drug is Lesinurad (Zurampic): Lesinurad is a uricosuric medica-
tion approved in 2015. It is indicated when pharmacother-
discontinued apy has been unable to lower uric acid to target levels by
the use of a xanthine oxidase inhibitor alone. Lesinurad is
Adverse Effects: The most frequent and serious more selective at blocking uric acid transporters in the kid-
adverse effects are dermatologic, including micropapular ney than probenecid, thus it produces fewer drug interac-
rash, rare cases of fatal toxic epidermal necrolysis, and tions. It must be administered concurrently with a xanthine
Stevens–Johnson syndrome. A rare, sometimes fatal, hyper- oxidase inhibitor such as allopurinol. It is important for
sensitivity syndrome may occur and includes a skin rash, the patient to remain well hydrated during therapy. This
fever, hepatitis, leukocytosis, eosinophilia, and progressive drug contains a black box warning that acute kidney fail-
kidney failure. Other adverse effects include drowsiness, ure has occurred with this medication. Lesinurad has not
headache, vertigo, nausea, vomiting, malaise, diarrhea, cat- been assigned a pregnancy rating.
aracts, retinopathy, and thrombocytopenia.
Pegloticase (Krystexxa): Approved in 2010, pegloticase is
Contraindications/Precautions: Contraindications a synthetic enzyme that metabolizes uric acid to an inert
include hypersensitivity to allopurinol and idiopathic substance. It is used to lower uric acid levels in patients
hemochromatosis. Use cautiously in patients with CKD or
impaired hepatic function, history of peptic ulcers, lower
GI tract disease, bone marrow depression, and pregnancy.
Drug Interactions: Alcohol may inhibit the renal
excretion of uric acid. Ampicillin and amoxicillin may
increase the risk of skin rashes. An enhanced antico-
agulant effect may be seen with the use of warfarin, and
toxicity risks increase for azathioprine, mercaptopurine,
Chapter 72 Pharmacotherapy of Bone and Joint Disorders 1359
with chronic gout who have not responded well to con- generally minor and include headache, nausea, vomiting,
ventional therapies. It is administered over a 2-hour period and anorexia. This drug is pregnancy category C.
by IV infusion, once every 2 weeks. The drug has a black
box warning that anaphylaxis may occur during and after Unrelated to its use in treating gout, probenecid blocks
the infusion, and emergency equipment should be readily the transport of organic acids in the renal tubule. When
available to address such a reaction. Patients should also given concurrently with antibiotics such as penicillins or
be pretreated with antihistamines and corticosteroids. cephalosporins, the serum levels of antibiotics will be
Other common adverse effects include gout flares at the boosted, making them more effective. Because of its effect
initiation of therapy, infusion reactions, nausea, ecchymo- on renal transport mechanisms, probenecid has the poten-
sis, nasopharyngitis, and worsening of heart failure. This tial to interact with virtually any acidic drug. A drug guide
drug is pregnancy category C. should be consulted when administering probenecid to
patients who are taking multiple medications.
Probenecid (Probalan): Probenecid is an older drug
approved in 1951 that inhibits the reabsorption of uric acid The mobilization of uric acid may also cause or worsen
in the kidneys, thus increasing its renal excretion. Given kidney stones due to the increased amount of uric acid
PO, it is effective for prophylaxis but will not terminate being excreted by the kidneys. To prevent these adverse
acute gout episodes. Probenecid should be taken with effects of early therapy, the uricosurics are started at low
meals to decrease gastric irritation. Several combination doses and increased gradually over several weeks. During
drugs that contain probenecid and colchicine are available this initial therapy, the urine may be made more alkaline by
for long-term maintenance therapy. Adverse effects are the administration of sodium bicarbonate to prevent uric
acid crystals from forming.
CONNECTIONS: NURSING PRACTICE APPLICATION
Patients Receiving Pharmacotherapy for Gout
Assessment
Baseline assessment prior to administration:
• Understand the reason the drug has been prescribed in order to assess for therapeutic effects (e.g., decreasing acute inflammatory stage, preventing
recurrence).
• Obtain a complete health history including musculoskeletal, GI, cardiovascular, neurologic, endocrine, hepatic, or kidney disease.
• Obtain a drug history including allergies, current prescription and OTC drugs, herbal preparations, alcohol use, or smoking. Be alert to possible drug
interactions.
• Obtain a history of any current symptoms and their effect on ADLs. Assess for inflammation and location, and note any pain or discomfort on movement
or at rest.
• Obtain a dietary history, noting correlations between food intake and increase in symptoms. Assess fluid intake.
• Obtain baseline weight and vital signs.
• Evaluate appropriate laboratory findings (e.g., uric acid level, CBC, hepatic and renal function studies, urinalysis).
• 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., symptoms of acute inflammation are diminished or absent, no return of symptoms).
• Continue monitoring vital signs and urine output.
• Continue to monitor uric acid level, CBC, hepatic and renal studies.
• Assess for and promptly report adverse effects: nausea, vomiting, abdominal pain, skin rash, pruritus, paresthesia, diminished urine output, fever, or infections.
Implementation
Interventions and (Rationales) Patient-Centered Care
Ensuring therapeutic effects: • Encourage the patient to keep a food diary, noting any occurrence or
• Review the dietary history with the patient, noting any correlation between increasing of symptoms related to food or beverage intake.
diet and symptoms, especially after ingestion of purine-containing • Teach the patient to limit intake of high-purine foods and to limit or
foods (e.g., salmon, sardines, organ meats, alcohol, mushrooms, eliminate alcohol consumption.
legumes, oatmeal). Avoid large doses of vitamin C. (Gout may occur
due to overproduction or underexcretion of uric acid or a combination
of both. Correlating symptoms to intake of high-purine foods assists in
determining the most effective drug therapy. Large doses of vitamin C
may acidify the urine, leading to formation of uric acid stones.)
• Increase fluid intake to 2–4 L/day. Monitor urine output and obtain • Teach the patient to increase fluid intake to 2–4 L/day, taken throughout
periodic urinalysis. (Increased fluid intake will help increase uric acid the day.
excretion and prevent urinary uric acid crystal formation or renal calculi.)
• Continue to monitor serum and urinary uric acid levels, and note • Encourage the patient to maintain consistent drug dosing to ensure that
improvement in symptoms of acute inflammation, gouty tophi, and uric acid levels are diminishing.
improved movement with less pain in affected joints. (As uric acid levels
decrease, inflammation due to uric acid crystals should improve.) • Instruct the patient on the need to return for periodic laboratory testing
and urinalysis.
(continued )
1360 Unit 11 Additional Drug Classes
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
Minimizing adverse effects: • Instruct the patient to promptly report any continued inflammation, pain,
• Monitor serum and urinary uric acid levels and symptoms associated increased joint involvement, or general worsening of symptoms.
with acute inflammatory period. (Decreased uric acid levels should
decrease the amount of inflammation. Continued or increasing
inflammation may indicate a need for additional antigout or anti-
inflammatory medication.)
• Monitor daily weight and urinary output. Record intake and output in the • Instruct the patient to:
hospitalized patient. Immediately report any flank pain to the provider. • Report any diminished urine output or changes in urine appearance,
(Uric acid excretion may cause urate crystal formation in the kidneys and to return periodically for urinalysis.
with resulting kidney impairment. Daily weight is an accurate measure of • Weigh self daily at the same time and report any weight gain of over
overall body fluid volume and any gain of over 1 kg [2 lb] per day should 1 kg (2 lb) in a 24-h period to the healthcare provider.
be reported. Flank pain may indicate the presence of renal calculi.) • Immediately report any flank pain to the provider.
• Continue to monitor periodic hepatic and renal laboratory work. • Instruct the patient on the need to return periodically for laboratory
(Lifespan: Age-related physiologic differences may place the older adult work.
at greater risk for hepatic and nephrotoxicity.)
• Decrease intake of purine-containing foods (e.g., salmon, sardines, • Teach the patient to avoid high-purine foods, decrease or eliminate alco-
organ meat, mushrooms, legumes, oatmeal, and alcohol). Avoid hol consumption, and avoid increased vitamin C intake or supplementa-
large doses of vitamin C. (Intake of high-purine foods and alcohol may tion. Provide dietitian consult as needed.
increase production of uric acid. Large doses of vitamin C may acidify
the urine, leading to formation of uric acid stones.)
• Observe for skin rashes, fever, stomatitis, flulike symptoms, or general • Teach the patient to immediately report any flulike symptoms, fever,
malaise. (Bone marrow suppression may occur with antigout drugs and mouth irritation or soreness, or skin rashes.
result in leukopenia and an increased risk of infection. Severe dermato-
logic reactions are possible and any skin rashes, especially with the ap-
pearance of blisters and discoloration, should be reported immediately.)
Patient understanding of drug therapy: • The patient should be able to state the reason for the drug, appropriate
• Use opportunities during administration of medications and during dose and scheduling, what adverse effects to observe for and when to
report them, and the anticipated length of medication therapy.
assessments to discuss the rationale for drug therapy, desired therapeutic
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: • The patient, family, or caregiver is able to discuss appropriate dosing
• When administering the medication, instruct the patient, family, or and administration needs including taking medications at the first sign of
a gout attack.
caregiver in proper self-administration of the drug, e.g., taken on an
empty stomach or with meals or additional fluids, followed by teach- • Colchicine should be taken on an empty stomach. Other antigout medi-
back. (Utilizing time during nurse administration of these drugs helps to cations should be taken with food or meals.
reinforce teaching.)
Understanding Chapter 72
Key Concepts Summary 72.5 Vitamin D therapy is indicated for treating
osteomalacia, hypoparathyroidism, and
72.1 Adequate levels of calcium in the body are osteoporosis.
necessary to transmit nerve impulses, to prevent
muscle spasms, and for proper bone health. 72.6 Bisphosphonates increase bone density and are
used to treat osteoporosis and Paget’s disease.
72.2 Calcium balance is regulated by parathyroid
hormone, calcitonin, and vitamin D. 72.7 Selective estrogen receptor modulators increase
bone mass density and prevent fractures in
72.3 Hypocalcemia and hypercalcemia are treated with postmenopausal women.
nutritional adjustments or with pharmacotherapy.
72.4 Metabolic bone disease is characterized by
abnormal bone structure.
Chapter 72 Pharmacotherapy of Bone and Joint Disorders 1361
72.8 Calcitonin and several miscellaneous drugs are used corticosteroids, and disease-modifying
for osteoporosis and other metabolic bone diseases. antirheumatic drugs.
72.9 Osteoarthritis is treated with a combination of 72.11 Gout is treated with drugs that decrease joint pain
analgesics and nonpharmacologic therapies. and inflammation and lower uric acid levels.
72.10 Pharmacotherapy for rheumatoid arthritis 72.12 Hyperuricemia is treated with drugs that reduce
includes analgesics, anti-inflammatory drugs, serum levels of uric acid.
CASE STUDY: Making the Patient Connection
Remember the patient “Char- information, Charlene states, “I have always been short.
lene Coleman” at the beginning You should see my mother who is much shorter than I am.
of the chapter? Now read the But lately, my clothes just don’t seem to fit. I haven’t lost
remainder of the case study. any weight, but my pant legs drag on the ground. Is it pos-
Based on the information pre- sible that I’m actually getting shorter?”
sented within this chapter,
respond to the critical thinking Critical Thinking Questions
questions that follow.
1. As the nurse, how would you respond to the patient’s
Charlene Coleman is a 65-year-old Black woman who is statement?
generally in good health. She has scheduled a routine
checkup visit with her healthcare provider. While assessing 2. As you talk with Charlene, she asks you, “Is there any
Charlene’s vital signs, height, and weight, the nurse notes way to slow my declining height?” What could you
a significant deviation from the data recorded during last recommend?
year’s visit. Apparently, the patient has lost 2.5 cm (1 in.) in
height during the last year. When the nurse shares this Answers to Critical Thinking Questions are available on the
faculty resources site. Please consult with your instructor.
Additional Case Study 3. What potential adverse effects may occur in addition
to those related to the injection itself?
A female patient, age 56, has been ordered methotrexate
(Otrexup, Rheumatrex, Trexall) and etanercept (Enbrel) for 4. What is the drug classification for methotrexate? What
treatment of severe RA. She wants her daughter to admin- are potential adverse effects for this drug?
ister the etanercept because of limitations due to arthritis-
related deformities in her hands. The daughter is worried Answers to Additional Case Study questions are available on
about giving her mother the medication. the faculty resources site. Please consult with your instructor.
1. How is etanercept (Enbrel) given? How often?
2. What instructions should the nurse give the daughter
about administering this medication?
Chapter Review 2. “I will take my medication immediately before
bedtime or at 9 p.m.”
1. The patient who has been prescribed alendro-
nate (Fosamax) demonstrates an understanding 3. “I will take my medication with a full glass of
of how to correctly take the medication when water 30 minutes before breakfast.”
stating:
4. “I should lie flat for at least 30 minutes after I take
1. “I will take my medication prior to eating my this medication.”
lunch or dinner.”
1362 Unit 11 Additional Drug Classes 3. Decreasing serum calcium and increasing
phosphate levels
2. Which of the following symptoms would alert the
nurse to the possibility of the development of toxicity 4. Decreasing serum calcium and decreasing
to methotrexate (Otrexup, Rheumatrex, Trexall)? phosphate levels
1. Headache, dizziness, and blurred vision 5. Which assessment findings in a patient who is receiv-
2. Hematuria, hiccoughs, and jaundice ing calcitriol (Rocaltrol) should the nurse immediately
3. Stomatitis, constipation, and dyspepsia report to the prescriber?
4. Jaundice, ascites, and edema formation
1. Muscle weakness, nausea, and vomiting
3. The patient asks the nurse to explain how colchicine 2. Diarrhea, abdominal pain, and stomatitis
(Colcrys) works. The nurse would base the response 3. Bone pain, joint stiffness, and fever
on which physiologic principle? 4. Photosensitivity, tinnitus, and bone pain
1. It increases the deposits of uric acid in the synovial 6. A patient with rheumatoid arthritis will begin treat-
spaces of the joints. ment with adalimumab (Humira). Which of the fol-
lowing statements related to this therapy is correct?
2. It reduces the pain associated with joint (Select all that apply.) Adalimumab:
inflammation from gouty arthritis.
1. May lower immune response and increase the risk
3. It prevents the accumulation of uric acid crystals in of infections and malignancies.
the joints.
2. Is associated with osteoporosis and baseline and
4. It increases renal excretion of uric acid crystals. periodic dual-energy x-ray absorptiometry (DEXA)
scans should be conducted.
4. Which laboratory findings would the nurse monitor
to determine if pharmacotherapy is helping a 3. May reactivate latent TB.
patient taking calcium supplementation for 4. May cause local injection-site irritations such as
osteomalacia?
pain and bruising.
1. Increasing serum calcium and increasing 5. Must be taken daily for up to 6 months.
phosphate levels
See Answers to Chapter Review in Appendix A.
2. Increasing serum calcium and decreasing
phosphate levels
References Retrieved from https://nccih.nih.gov/health/
glucosaminechondroitin
Araujo, A. B., Yang, M., Suarez, E. A., Dagincourt, N., Henrotin, Y., Marty, M., & Mobasheri, A. (2014). What is
Chiu, G., Holick, M. F., . . . Zmuda, J. M. (2014). Racial/ the current status of chondroitin sulfate and
ethnic and socioeconomic differences in bone loss glucosamine for the treatment of knee osteoarthritis?
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2552–2560. doi:10.1002/jbmr.2305 2014.04.015
Jackson, R. D., & Mysiw, W. J. (2014). Insights into the
Bethel, M. (2017). Osteoporosis. Retrieved from http:// epidemiology of postmenopausal osteoporosis: The
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Kanis, J. A., Harvey, N. C., Cooper, C., Johansson, H.,
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Shepherd, J. A., & Leslie, W. D. (2015). Fracture risk review of intervention thresholds based on FRAX: A
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official positions part 1: Hip geometry. Journal of Clinical Guideline Group and the International Osteoporosis
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s11657-016-0278-z
Cass, A. R., Shepherd, A. J., Asirot, R., Mahajan, M., & Kanis, J. A., Harvey, N. C., Johansson, H., Odén. A.,
Nizami, M. (2016). Comparison of the male Leslie, W. D., & McCloskey, E. V. (2015). FRAX and
osteoporosis risk estimation score (MORES) with FRAX
in identifying men at risk for osteoporosis. Annals of
Family Medicine, 14, 365–369. doi:10.1370/afm.1945
Center for Complementary and Integrative Health.
(2016). Glucosamine and chondroitin for osteoarthritis.
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Climacteric, 18(Suppl. 2), 2–9. doi:10.3109.13697137.
2015.1092342 Pang, W. Y., & Inderjeeth, C. A. (2014). FRAX without
Lo, J. C., Zheng, P., Grimsrud, C. D., Chandra, M., bone mineral density versus osteoporosis self-
Ettinger, B., Budayr, A., . . . Neugebauer, R. (2014). assessment screening tool as predictors of osteoporosis
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fractures. Osteoporosis International, 25, 2313–2318. Journal of the American Geriatrics Society, 62, 442–446.
doi:10.1007/s00198-014-2750-1 doi:10.1111/jgs.12696
Najafi, D. A., Dahlberg, L. E., & Hansson, E. E. (2016). A
combination of clinical balance measures and FRAX to Saadeh, C. K. (2016). Calcium pyrophosphate deposition
improve identification of high-risk fallers. BMC disease. Retrieved from http://emedicine.medscape.
Geriatrics, 16, 94. doi:10.1186/s12877-016-0266-6 com/article/330936-overview#a5
Smith, H. R. (2017). Rheumatoid arthritis. Retrieved from
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sheet for health professionals. Retrieved from https://ods.
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http://www.arthritis.org/about-arthritis/
understanding-arthritis/arthritis-statistics-facts.php National Osteoporosis Foundation. (n.d.). What is
osteoporosis and what causes it? Retrieved from http://
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acr.21773
“I hate the way my skin looks.
I know people are just staring at
my face and not really listening
to me.”
Patient “Danny McBride”
Chapter 73
Pharmacotherapy of
Dermatologic Disorders
Chapter Outline Learning Outcomes
cc Anatomy of the Integumentary System After reading this chapter, the student should be able to:
cc Classification of Skin Disorders
cc Pharmacotherapy of Skin Infections 1. Identify the structure and functions of the skin and
associated structures.
Scabicides and Pediculicides
PROTOTYPE Permethrin (Acticin, Elimite, Nix), 2. Explain the process by which superficial skin cells
p. 1369 are replaced.
cc Pharmacotherapy of Acne and Rosacea
PROTOTYPE Tretinoin (Avita, Retin-A, Others), 3. Explain how skin diseases are classified.
p. 1373
cc Pharmacotherapy of Dermatitis 4. Describe the drug therapies for bacterial, fungal,
cc Pharmacotherapy of Psoriasis viral, and parasitic infections of the skin.
cc Pharmacotherapy of Minor Skin Burns
PROTOTYPE Benzocaine (Americaine, Anbesol, 5. Explain the etiology, pathogenesis, and
Others), p. 1384 pharmacotherapy for acne vulgaris, rosacea,
cc Pharmacotherapy of Alopecia dermatitis, and psoriasis.
1364 6. Outline the stepwise approach to treating psoriasis.
7. Describe the prevention and management of minor
burns.
8. Explain the pharmacotherapy of alopecia.
9. Describe the nurse’s role in the pharmacologic
management of dermatologic 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 the care of patients
receiving pharmacotherapy for dermatologic
disorders.
Chapter 73 Pharmacotherapy of Dermatologic Disorders 1365
Key Terms keratolytic, 1372 rhinophyma, 1373
nits, 1368 rosacea, 1373
acne vulgaris, 1370 pediculicides, 1369 scabicides, 1369
comedolytics, 1373 plaques, 1379 seborrhea, 1370
comedones, 1372 pruritus, 1367 urticaria, 1367
dermatitis, 1376 psoralens, 1382
eczema, 1377 retinoids, 1373
erythema, 1367
excoriation, 1376
The integumentary system consists of the skin, hair, nails, stratum corneum is referred to as the “horny layer” because
sweat glands, and sebaceous glands. The largest and most of the abundance of the protein keratin, a water-insoluble
visible of all organs, healthy skin provides an effective bar- material secreted by keratinocytes, which is also found in
rier between the outside environment and the body’s inter- the hair, hooves, and horns of many mammals. Keratin
nal tissues, helps to regulate body temperature, and assists gives the skin its tough, protective seal, forming a barrier
in maintaining fluid and electrolyte balance. At times, how- that repels bacteria and foreign matter. Most substances
ever, environmental conditions damage the skin, or condi- cannot penetrate it. The largest amount of keratin is found
tions within the body change, resulting in unhealthy skin. in those areas subject to mechanical stress, for example, the
Some of these changes can even lead to systemic changes soles of the feet and the palms of the hands.
that affect tissues outside the integumentary system. When
this occurs, pharmacotherapy may be utilized to improve The deepest epidermal sublayer, the stratum basale,
the skin’s condition. The purpose of this chapter is to exam- supplies the epidermis with new cells after older superfi-
ine the broad scope of skin disorders and the drugs used cial cells have been damaged or lost through normal wear.
for skin pharmacotherapy. Over time, these newly created cells migrate from the stra-
tum basale to the outermost layers of the skin. As these
Anatomy of the Integumentary cells are pushed to the surface, they are flattened and cov-
System ered with keratin. The outermost skin layer, called the stra-
tum corneum, is composed of these dead cells. On average,
73.1 Three layers of skin, known as the it takes a cell about 2 to 3 weeks to move from the stratum
epidermis, dermis, and subcutaneous layers, basale to the body surface.
provide effective barrier defenses for the body.
Specialized cells within the deeper layers of the epider-
To understand the actions of dermatologic drugs, it is nec- mis, called melanocytes, secrete the dark pigment melanin.
essary to have a thorough knowledge of the structure of Melanin forms a protective shield, which protects the kera-
the skin. The skin comprises three primary layers: the epi- tinocytes and the nerve endings in the dermis from the
dermis, dermis, and subcutaneous layers, as illustrated in sun’s ultraviolet (UV) rays. The number and type of mela-
Figure 73.1. The epidermis is the visible, outermost layer nocytes determine the overall pigment of the skin and
that constitutes only about 5% of the skin depth. The mid- determine racial differences in skin tone. Darker skin tones
dle layer is the dermis, which accounts for about 95% of are not caused by an increased number of melanocytes, but
the entire skin thickness. The subcutaneous layer lies by the amount of the pigment melanin that is contained in
beneath the dermis. Some textbooks consider the subcuta- each cell. The more melanin, the darker the skin color.
neous layer as being separate from the skin and not one of Freckles, birthmarks, and age spots are caused by the pro-
its layers. Each layer of skin is distinct in form and func- duction of melanin. In areas where the melanocytes are
tion and provides the basis for how drugs are injected or destroyed, there are milk-white areas of depigmented skin
topically applied. referred to as vitiligo.
Epidermis: The epidermis consists of epithelial cells The junction of the epidermis and the dermis is an area
with either four or five sublayers depending on its location. of many ridges and furrows called the rete ridges. This area
The five layers from the innermost to outermost are the anchors the epidermis to the dermis. The epidermis does
stratum basale (also referred to as the stratum germinati- not have a separate blood supply. It receives its nutrients
vum), stratum spinosum, stratum granulosum, stratum by diffusion in the rete ridges from the many blood vessels
lucidum, and the strongest layer, the stratum corneum. The in the dermis. This surface also provides for the ripples
seen on the skin surface, which on the fingertips are called
fingerprints.
1366 Unit 11 Additional Drug Classes
Hair Pore Stratum corneum
shaft Stratum lucidum
Stratum granulosum
Stratum spinosum
Stratum basale
Arrector Epidermis
pili muscle
Dermis
Oil gland
Subcutaneous
Root hair tissue
plexus
Eccrine Hair Hair Vein Nerve
sweat gland
follicle root Artery
Figure 73.1 Anatomy of the skin.
Dermis: The second primary layer of skin, called the depending on their location. Composed primarily of dead
dermis, is a layer of connective tissue that contains no cells. cells, hair consists of a root that begins in the bulb of the
The dermis is composed of collagen fibers and elastic hair follicle and grows from the dermis outward. The hair
fibers that give the skin both flexibility and strength. It shaft is the portion that projects through the epidermis and
provides a foundation for the epidermis and accessory exits the skin. Hair growth occurs in cycles; a growth phase
structures such as hair and nails. Most sensory nerves that is followed by a resting phase during which hair is shed
transmit the sensations of touch, pressure, temperature, from the body. Stressors can alter the growth cycle and
pain, and itch are located within the dermis, as well as the cause temporary hair loss. Permanent baldness is genetic
oil glands and sweat glands. A vast network of lymph and in origin and is seldom influenced by stressors. Hair color
capillary vessels is found within the dermis. is genetically determined by an individual’s rate of mela-
nin production within the hair shaft.
Subcutaneous tissue: Beneath the dermis is the subcu-
taneous tissue, or hypodermis, which lies over muscle and The sebaceous glands are distributed over the entire
bone. It consists mainly of adipose tissue, which cushions, skin surface, except for the palms of the hand and the soles
insulates, and serves as an energy reserve in the event that of the feet. Most sebaceous glands are directly connected to
extra calories are needed to fuel the body. The amount of the hair follicles; the glands of the eyelids, nipple areolae,
subcutaneous tissue varies in an individual and is deter- and genitalia are freestanding. Sebaceous glands produce
mined by body area, sex, age, nutritional status, and hered- sebum, which is emptied into the space between the hair
ity. Many blood vessels pass through the fatty layer and follicle and shaft. Sebum lubricates and softens the skin and
extend into the dermis, forming capillary networks that hair and reduces water loss from the skin surface in low
supply nutrients and remove wastes. humidity. Sebum also is mildly bacteriostatic. The secretion
of sebum is stimulated by hormones, especially androgens.
Skin appendages: Hair follicles are located in the der-
mis. Hair growth varies by race, gender, age, and heredity. The skin has two types of sweat glands: apocrine and
Individual hairs vary in both structure and rate of growth, eccrine. The apocrine glands are directly connected to the
hair follicles and are mainly found in the axillary, perineal,
Chapter 73 Pharmacotherapy of Dermatologic Disorders 1367
nipple areolae, and umbilical areas. The interaction of skin common and are frequent indications for anti-infective
bacteria with the milky secretions of apocrine glands causes pharmacotherapy. A brief overview of anti-infectives
distinct body odor. The eccrine glands are found over the most frequently prescribed for skin conditions is pre-
entire skin surface. Their ducts open directly onto the skin sented in Section 73.3, with further emphasis on para-
surface and are not associated with hair follicles. The secre- sitic infections in Section 73.4. Greater detail on the
tions of the eccrine glands are an important factor in the individual anti-infective drugs may be found in
regulation of body temperature. Sweat is released from the Chapters 46 through 54.
eccrine glands in response to elevated body temperature or • Inflammatory. Inflammatory disorders encompass a
ambient temperature and is under control of the sympa- broad range of pathology that includes acne, dermati-
thetic nervous system. tis, burns, and psoriasis. The pharmacotherapy of
inflammatory skin disorders includes many of the
Classification of Skin Disorders drugs discussed in Chapter 41, such as corticosteroids.
• Neoplastic. Malignant tumors include malignant mel-
73.2 The etiology of skin disorders may be anoma and basal cell carcinoma, which are treated
classified as infectious, inflammatory, or with the therapies described in Chapter 57. Warts are a
neoplastic. type of benign tumor.
Of the many types of skin disorders, some have vague, gen- Systemic disease processes that occur in the body may
eralized signs and symptoms, and others have specific and manifest as dermatologic signs and symptoms. Skin abnor-
easily identifiable causes. Urticaria is a hypersensitivity malities, including color, size, type, and character of sur-
response that is characterized by hives and is often accom- face lesions, and skin turgor and moisture may have
panied by pruritus, or itching. Allergies to foods often man- systemic causes such as chronic kidney disease (CKD),
ifest as urticaria. Pruritus is a general condition that is liver impairment, cardiovascular insufficiency, metastatic
associated with dry, scaly skin or a parasite infestation. Pru- tumors, recent injury, and poor nutritional status.
ritus may also be a sign of serious systemic pathology, such
as cholestatic disease and uremia. A substantial number of Although there are many skin disorders, some warrant
drugs have urticaria or pruritus listed as potential adverse only localized or short-term pharmacotherapy. Examples
effects. Local erythema or redness accompanies inflamma- include lice infestation, sunburn with minor irritation, and
tion and many other skin disorders. Inflammation is a char- acne. Eczema, dermatitis, and psoriasis are more serious dis-
acteristic of burns and trauma to the skin. orders that require extensive and more prolonged therapy.
Skin disorders are diverse and difficult to classify Pharmacotherapy of Skin
because some conditions have overlapping components. Infections
For example, lesions that are characteristic of acne may be
inflamed and become infected. One simple method, which 73.3 When the integrity of the skin is
is summarized in Table 73.1, is to group the disorders into compromised, microbes can gain entrance and
the following categories: cause infections that require anti-infective therapy.
• Infectious. Bacterial, fungal, viral, and parasitic infec- The skin is normally populated with microorganisms or
tions of the skin and mucous membranes are relatively flora that includes a diverse collection of bacteria, fungi,
Table 73.1 Classification of Skin Disorders
Type Examples
Infectious Bacterial infections: boils, impetigo, infected hair follicles
Inflammatory
Neoplastic Fungal infections: ringworm, athlete’s foot, jock itch, nail infection
Parasitic infections: ticks, mites, lice
Viral infections: cold sores, fever blisters (herpes simplex), chickenpox, warts, shingles (herpes zoster), measles (rubeola),
and German measles (rubella)
Injury and exposure to the sun
Combination of overactive glands, increased hormone production, and/or infection such as acne and rosacea
Disorders with itching, cracking, and discomfort such as atopic dermatitis, contact dermatitis, seborrheic dermatitis, stasis dermatitis,
and psoriasis
Skin cancers: squamous cell carcinoma, basal cell carcinoma, and malignant melanoma
Benign neoplasms include keratosis and keratoacanthoma
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