518 Unit 5 Pharmacology of the Cardiovascular System
arteries, an action that is important when the drug is used Drug Interactions: Verapamil is metabolized by
to treat angina. It is approved to treat variant, unstable, and hepatic CYP450 enzymes and exhibits many drug–drug
chronic angina (see Chapter 35). Off-label indications in- interactions. Verapamil has the ability to elevate blood
clude cluster headache and migraine prophylaxis. levels of digoxin. Because digoxin and verapamil both
slow conduction through the AV node, their concurrent
Verapamil is available in PO, oral extended release, use must be carefully monitored to avoid bradycardia.
and IV formulations. Covera-HS is a unique formulation Use with other antihypertensive drugs, including ACE
that delays the release of verapamil until 4 to 5 hours after inhibitors or beta-adrenergic blockers, may cause addi-
ingestion and then releases it slowly. Covera-HS should be tive hypotension or bradycardia. Concurrent administra-
taken at night so that the drug is in the bloodstream on tion of verapamil with buspirone can triple the plasma
awakening. The inert shell of the drug is sometimes found concentration of buspirone. Verapamil should not be ad-
in the stool. The therapeutic serum level of verapamil is ministered with statins because the risk of myopathy in-
0.08 to 0.3 mcg/mL. Tarka is a fixed-dose combination of creases significantly. Carbamazepine serum concentration
verapamil with trandolapril for HTN. may increase during concurrent therapy with verapamil,
causing adverse effects such as diplopia, ataxia, or dizzi-
Mechanism of Action: Verapamil acts by inhibit- ness. Use with alcohol can raise serum levels of the CCB
ing the flow of calcium ions into both cardiac muscle cells and prolong its effects. Herbal/Food: Grapefruit juice may
and vascular smooth muscle cells. Blocking calcium entry increase verapamil levels. Use with caution with herbal
causes vasodilation of peripheral arterioles and reduced supplements, such as hawthorn, which may have additive
contractility of the myocardium. hypotensive effects. High doses of calcium supplements
may diminish the effects of CCBs and should not be used
Pharmacokinetics: PO and IV without consulting the healthcare provider.
Route(s)
Absorption Well absorbed Pregnancy: Category C.
Distribution
Widely distributed; crosses the Treatment of Overdose: Treatment of overdose is
Primary metabolism placenta; secreted in breast milk aimed at reversing hypotension with vasopressors such
as dopamine or norepinephrine. Atropine, levarterenol, or
Primary excretion Hepatic; extensive first-pass isoproterenol may be administered to treat bradycardia.
metabolism Calcium salts may be administered to increase calcium
Onset of action available to the myocardium and arterioles.
Duration of action Renal (70%) with small amounts
in feces (16%) Nursing Responsibilities: Key nursing implications
for patients receiving verapamil are included in the Nurs-
PO: 1–2 h; IV: 1–5 min ing Practice Application for Patients Receiving Pharmaco-
therapy with Calcium Channel Blockers.
PO: 3–7 h (extended release:
24 h); IV: 2 h Drugs Similar to Verapamil (Calan,
Isoptin, Verelan)
Half-life: 2–8 h
The only other nondihydropyridine is diltiazem.
Adverse Effects: Most adverse effects of verapamil
are extensions of its actions on the cardiovascular system. Diltiazem (Cardizem, Dilacor, Taztia XT, Tiazac, others): Like
Peripheral vasodilation may cause flushed skin, headache, other nondihydropyridines, diltiazem has the ability to relax
dizziness, lightheadedness, and peripheral edema. High both coronary and peripheral blood vessels. Approved in
doses and IV administration may cause serious hypoten- 1982, diltiazem reduces heart rate, blood pressure, and car-
sion. The most serious adverse effects of verapamil are diac workload. The drug slows electrical conduction through
cardiac related, including worsening of HF, bradycardia, the AV node. It is useful in the treatment of atrial dysrhyth-
reflex tachycardia, and AV block. Constipation is relatively mias and HTN as well as stable and vasospastic angina.
common. CNS effects such as confusion, drowsiness, and Migraine prophylaxis is an off-label indication. When given
mood changes have been reported, though they are un- as extended release capsules (Cardizem LA, Dilacor XR, Taz-
common. Elevated hepatic enzymes and rare cases of liver tia XT), it is administered once daily. An IV formulation is
damage have been reported. available to treat atrial fibrillation. The drug is well tolerated
and serious adverse effects are uncommon and similar to
Contraindications/Precautions: Verapamil is con- those of verapamil. Like verapamil, diltiazem should be
traindicated in patients with AV heart block, sick sinus syn- used cautiously in patients with bradycardia, AV block, HF,
drome, severe hypotension, bleeding aneurysm, or those or serious hypotension.
undergoing intracranial surgery. Because verapamil can cause
bradycardia and pulmonary edema, patients with HF should
be carefully monitored, especially when the drug is admin-
istered IV. The drug should be used with caution in patients
with chronic kidney disease or hepatic impairment because
this can delay clearance of verapamil and its metabolites.
Chapter 30 Pharmacotherapy with Calcium Channel Blockers 519
There are several formulations of diltiazem and not all release,” which does not tell the prescriber which trade-name
are approved for the same indications (see Table 30.1). The product the generic is equivalent to. Caution must always be
doses among the forms are not always equivalent. Even more used when administering this drug to ensure that the patient
confusing is that generics are labeled as “diltiazem extended is receiving the correct dose and form of diltiazem.
CONNECTIONS: NURSING PRACTICE APPLICATION
Patients Receiving Pharmacotherapy with Calcium Channel Blockers
Assessment
Baseline assessment prior to administration:
• Obtain a complete health history including cardiovascular (MI or HF), musculoskeletal (preexisting conditions that might result in fatigue, weakness,
muscle or joint pain), and the possibility of pregnancy. Obtain a drug history including allergies, current prescription and over-the-counter (OTC) drugs,
herbal preparations, and alcohol use. Be alert to possible drug interactions.
• Evaluate appropriate laboratory findings: electrolytes, especially potassium level, liver function studies, and lipid profiles.
• Obtain baseline weight, vital signs (especially blood pressure and pulse), breath sounds, and cardiac monitoring (e.g., electrocardiogram [ECG],
cardiac output) if appropriate. Assess for location, character, and amount of edema, if present.
• 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., lowered blood pressure within established limits; lessened or absent angina and dysrhythmias if present).
• Continue periodic monitoring of electrolytes, especially potassium.
• Assess for adverse effects: nausea, headache, constipation, musculoskeletal fatigue or weakness, flushing, lightheadedness or dizziness, sexual
dysfunction, or impotence. Myalgia, arthralgia, peripheral edema, facial edema, significant constipation, inability to maintain activities of daily living (ADLs)
due to musculoskeletal weakness or pain, or unexplained numbness or tingling of extremities should be reported immediately to the healthcare provider.
Implementation
Interventions and (Rationales) Patient-Centered Care
Ensuring therapeutic effects: • Teach the patient, family, or caregiver how to monitor pulse and blood
• Continue frequent assessments as above for therapeutic effects. pressure. Ensure proper use and functioning of any home equipment
obtained.
(Blood pressure and pulse should be within normal limits or within
parameters set by the healthcare provider. If the drug is given for
angina or dysrhythmias, significant improvement in reports of pain,
palpitations, or ECG demonstrates improvement.)
• Encourage appropriate lifestyle changes: lowered fat intake, increased • Encourage the patient, as well as the family or caregiver, to adopt a
exercise, limited alcohol intake, and smoking cessation. Provide for healthy lifestyle of low-fat food choices, increased exercise, decreased
dietitian consultation as needed. (Healthy lifestyle changes will support alcohol consumption, and smoking cessation.
and minimize the need for drug therapy.)
Minimizing adverse effects: Instruct the patient to:
• Continue to monitor vital signs. Take the blood pressure lying, sitting, • Rise from lying or sitting to standing slowly to avoid dizziness or falls. If
and standing to detect orthostatic hypotension. Lifespan: Be dizziness occurs, the patient should sit or lie down and not attempt to
particularly cautious with older adults who are at increased risk for stand or walk, until the sensation passes.
hypotension. Ensure patient safety. (CCBs cause vasodilation, • Stop taking the medication and promptly notify the healthcare provider
resulting in lowered blood pressure. Orthostatic hypotension may if the blood pressure is 90/60 mmHg or below, or per parameters set
increase the risk of falls and injury. Diverse Patients: Because CCBs by the provider.
metabolize through the CYP450 system pathways, monitor ethnically • Call for assistance prior to getting out of bed or attempting to walk
diverse patients to ensure optimal therapeutic effects and minimize alone, and to avoid driving or other activities requiring mental alertness
adverse effects.) or physical coordination until the effects of the drug are known.
• Continue to monitor periodic electrolyte levels, especially potassium, • Instruct the patient on the need to return periodically for laboratory
ECG as appropriate, and hepatic and renal function laboratory values. work or ECGs.
(Hypokalemia may increase the risk for dysrhythmias.)
• Advise the patient to carry a wallet identification card or wear medical
identification jewelry indicating CCB therapy.
• Lifespan: The drug should not be taken during pregnancy, if
pregnancy is suspected, or while breastfeeding.
• Weigh the patient daily and report weight gain or loss of 1 kg (2 lb) or • Have the patient weigh self daily, ideally at the same time of day, and
more in a 24-h period or 2 kg (5 lb) per week. (Daily weight is an record weight along with blood pressure and pulse measurements.
accurate measure of fluid status and takes into account intake, output, Have the patient report weight loss or gain of more than 1 kg (2 lb) in a
and insensible losses. Weight gain or edema may signal blood 24-h period.
pressure has lowered too quickly, stimulating renin release or is an
adverse effect.)
• Observe for paradoxical increase in chest pain or angina symptoms. • Instruct the patient to report chest pain or other angina-like symptoms,
(Severe hypotension may cause this and may indicate blood pressure especially if increasing.
has decreased too quickly or too substantially.)
• Monitor for signs of HF (e.g., increasing dyspnea or postural nocturnal • Instruct the patient to immediately report any severe shortness of
dyspnea, rales or crackles in the lungs, and frothy pink-tinged breath, frothy sputum, profound fatigue, or swelling of extremities
sputum). (CCBs are negative inotropes and can decrease myocardial because they are possible signs of HF.
contractility, increasing the risk of, or precipitating HF.)
(continued )
520 Unit 5 Pharmacology of the Cardiovascular System
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
• Observe for hypersensitivity reaction or angioedema, especially of the • Instruct the patient to immediately seek medical attention for difficulty
facial area. breathing, throat tightness, hives or rash, muscle cramps, or tremors.
Promptly report any angioedema around the facial area.
• Observe for constipation. (CCBs may cause constipation due to • Instruct the patient to increase fluid and fiber intake to facilitate stool
decreased peristalsis. Lifespan: The older adult is at increased risk of passage.
constipation due to slowed peristalsis.)
• If constipation persists, consider use of stool softener or laxative (such
as MiraLAX) or as recommended by the healthcare provider.
• Assess the condition of gums and oral hygiene measures. (While • Instruct the patient to maintain excellent oral hygiene and keep
uncommon, CCBs may cause gingival hyperplasia, increasing the risk regularly scheduled dental appointments.
of oral infections.)
• Monitor patient diet and medications for concurrent use of alcohol, • Provide the patient with information on products to avoid while taking
grapefruit or grapefruit juice, herbal supplements, and alternative CCBs, specific to the drug ordered.
medications. (Alcohol and melatonin use may increase risk for
hypotension, drowsiness, and dizziness. Grapefruit juice may increase
drug levels with increased adverse effects.)
Patient understanding of drug therapy: • The patient, family, or caregiver should be able to state the reason for
• Use opportunities during administration of medications and during the drug, appropriate dose and scheduling, what adverse effects to
observe for and when to report them, and the anticipated length of
assessments to discuss the rationale for drug therapy, desired medication therapy.
therapeutic outcomes, 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. (Utilizing time during
nurse administration of these drugs helps to reinforce teaching.)
Understanding Chapter 30
Key Concepts Summary
30.1 Calcium channels facilitate contraction in cardiac 30.4 Calcium channel blockers are classified by their
and smooth muscles. chemical structures as dihydropyridines or
nondihydropyridines.
30.2 The calcium channel consists of multiple subunits
and is present in many tissues. 30.5 The dihydropyridines are selective for vascular
smooth muscle and are used to treat hypertension
30.3 Blocking calcium channels has significant and angina pectoris.
physiologic effects on the heart and vascular
smooth muscle. 30.6 The nondihydropyridines act on both vascular
smooth muscle and the myocardium.
CASE STUDY: Making the Patient Connection
Remember the patient Angela Rivera, a 40-year-old interior designer, had no
“Angela Rivera” at idea that her blood pressure was elevated. One day at the
the beginning of the shopping mall she saw an automatic blood pressure
chapter? Now read the machine and thought she would try it. She could hardly
remainder of the case believe the machine’s reading when it revealed her blood
study. Based on the pressure was 150/92 mmHg. She was certain that there
information presented must be something wrong with the machine. After all, she
within this chapter, respond to the critical thinking felt fine. In fact, she is rarely ill and never misses work
questions that follow. due to illness.
Chapter 30 Pharmacotherapy with Calcium Channel Blockers 521
Just to be certain, Angela made an appointment with as much about HTN as possible and felodipine in particu-
her doctor for a checkup. During her first clinic visit, her lar. With all the information about high blood pressure, she
blood pressure was 146/90 mmHg, heart rate was 78 beats/ is even more confused and anxious.
min, respiratory rate was 16 breaths/min, and temperature
was 36.8°C (98.2°F). Angela was instructed on lifestyle Critical Thinking Questions
modifications for HTN and told to return to the clinic in 1. Describe how calcium channel blockers control HTN.
1 month. The next month, Angela’s blood pressure 2. Angela asks you, the nurse, if calcium channel block-
remained elevated. Multiple diagnostic studies, which
included an ECG and blood chemistry levels, were com- ers can cure HTN. How would you respond?
pleted. Her healthcare provider prescribed felodipine 3. What adverse effects are associated with CCBs?
(Plendil) and instructed her to return in 1 week.
Answers to Critical Thinking Questions are available on the
All of this has caused Angela to be concerned and wor- faculty resources site. Please consult with your instructor.
ried about her health. She has accessed the internet to learn
Additional Case Study 2. What adverse effects related to amlodipine might
cause the patient to stop taking the medication?
Mabel Hillside was prescribed amlodipine (Norvasc) 5 mg
once daily. However, Mabel’s health insurance does not 3. List strategies that Mabel can use to remember to take
cover prescription drug costs and she will be required to her HTN medication.
self-pay for the drug. As you are talking with this patient,
she says, “Why should I take this medicine? After all, I feel Answers to Additional Case Study questions are available on
just fine and it is very expensive. Plus I keep forgetting to the faculty resources site. Please consult with your instructor.
take it.”
1. How would you respond to Mabel’s remark about
feeling “just fine”?
Chapter Review 3. Administers the medication only during waking
hours
1. Nifedipine (Procardia) is being initiated for a patient
with elevated blood pressure. What health teaching 4. Measures intake and output ratio and daily weight
would be most appropriate? The patient should:
4. The nurse determines that the patient understands an
1. Weigh daily at the same time each day. important principle in self-administration of nifedip-
2. Avoid crowds while taking this medication. ine (Procardia) when the patient makes which
3. Increase intake of calcium-containing foods. statement?
4. Take this medication only when feeling that blood
1. “The use of antacids when taking the medication
pressure is elevated. will enhance absorption.”
2. A patient is receiving felodipine (Plendil) for hyper- 2. “Grapefruit juice may enhance the absorption of
tension. In the care plan the nurse includes the need nifedipine.”
to monitor the patient for which adverse effect?
3. “If I miss a dose, I should take two nifedipine
1. Rash and chills capsules when I remember.”
2. Increased urinary output
3. Weight loss 4. “This drug will make my birth control pills
4. Reflex tachycardia ineffective.”
3. A patient with primary hypertension has started ther- 5. What health teaching should the nurse provide for a
apy with verapamil (Calan). The nurse performs what patient receiving diltiazem (Cardizem)? (Select all that
important intervention during the initial course of apply.)
this treatment?
1. Avoid driving or performing other activities
1. Uses an electric razor to shave the patient requiring mental alertness until the effects of the
2. Monitors the patient for increased thrombocyte drug are known.
levels 2. Maintain adequate fluid and fiber intake to
facilitate stool passage.
522 Unit 5 Pharmacology of the Cardiovascular System
3. Report weight gain of 2 kg (5 lb) per week. 1. A patient who is admitted for an appendectomy
in the morning
4. Rise slowly from prolonged periods of sitting or
lying down. 2. A patient who is receiving renal dialysis 3 times
per week
5. Immediately stop taking the medication if sexual
dysfunction is noted. 3. A patient who develops pulmonary edema in the
intensive care unit
6. A healthcare provider has ordered nifedipine (Procar-
dia XL) for each of the following patients. A nurse will 4. A patient who receives psychotropic drugs for
most closely monitor which patient for drug-related bipolar disease
problems?
See Answers to Chapter Review in Appendix A.
References Peters, J., Booth, A., & Peters, R. (2015). Potential for
specific dihydropyridine calcium channel blockers
Alzheimer’s Association. (2016). 2016 Alzheimer’s disease to have a positive impact on cognitive function in
facts and figures. Retrieved from http://www.alz.org/ humans: A systematic review. Therapeutic Advances
facts/overview.asp in Chronic Diseases, 6, 160–169. doi:10.1177/
2040622315582353
Lovell, M. A., Abner, E., Kryscio, R., Xu, L., Fister, S. X., &
Lynn, B. C. (2015). Calcium channel blockers, Suliburska, J., Bogdanski, P., Szulinska, M., & Pupek-
progression to dementia, and effects on amyloid beta Musialik, D. (2014). The influence of antihypertensive
peptide production. Oxidative Medicine and Cellular drugs on mineral status in hypertensive patients.
Longevity, 2015, Article ID 787805. doi:10.1155/ European Review for Medical and Pharmacological Sciences,
2015/787805 18(1), 58–65.
Mejia, L. M. (2016). Drug-induced gingival hyperplasia. doi:10.1002/2327-6924.12262. Retrieved from http://
Retrieved from http://emedicine.medscape.com/ onlinelibrary.wiley.com/enhanced/exportCitation/
article/1076264-overview doi/10.1002/2327-6924.12262
Striessnig, J., Pinggera, A., Kaur, G., Bock, G., & Tuluc, P.
Selected Bibliography (2014). L-type Ca2+ channels in heart and brain. Wiley
Interdisciplinary Reviews: Membrane Transport and
Davis, L. L. (2015). Hypertension guidelines: Evidence- Signaling, 3(2), 15–38. doi:10.1002/wmts.102
based treatments for maintaining blood pressure Zamponi, G. W. (2016). Targeting voltage-gated calcium
control. The Nurse Practitioner, 40(6), 32–37. channels in neurological and psychiatric diseases.
doi:10.1097/01.NPR.0000465116.19783.a7 Nature Reviews Drug Discovery, 15, 19–34. doi:10.1038/
nrd.2015.5
Godfraind, T. (2014). Calcium channel blockers in Zamponi, G. W., Striessnig, J., Koschak, A., & Dolphin,
cardiovascular pharmacotherapy. Journal of A. C. (2015). The physiology, pathology, and
Cardiovascular Pharmacology and Therapeutics, 19, pharmacology of voltage-gated calcium channels and
501–515. doi:10.1177/1074248414530508 their future therapeutic potential. Pharmacological
Reviews, 67, 821–870. doi:10.1124/pr.114.009654
Graudins, A., Lee, H. M., & Druda, D. (2016). Calcium
channel antagonist and beta-blocker overdose:
Antidotes and adjunct therapies. British Journal of
Clinical Pharmacology, 81(3), 453–461. doi:10.1111/
bcp.12763
Lefler, L. L., Hadley, M., Tackett, J., & Thomason, A. P.
(2015). New cardiovascular guidelines: Clinical practice
evidence for the nurse practitioner. Journal of the
American Association of Nurse Practitioners, 28, 241–248.
“When I saw my doctor, she
said my blood pressure was
still high. I’m taking my
medicine as directed. So
what’s the problem?”
Patient “Carlos Avaya”
Chapter 31
Drugs Affecting the Renin-
Angiotensin-Aldosterone
System
Chapter Outline Learning Outcomes
cc Components of the Renin-Angiotensin-Aldosterone After reading this chapter, the student should be able to:
System
1. Illustrate the steps in the renin-angiotensin-
cc Physiologic Actions of the Renin-Angiotensin- aldosterone pathway.
Aldosterone System
2. Identify the primary physiologic factors that control
cc Drugs Affecting the Renin-Angiotensin-Aldosterone renin secretion.
System
Angiotensin-Converting Enzyme Inhibitors 3. Explain the two primary functions of angiotensin-
PROTOTYPE Lisinopril (Prinivil, Zestril), p. 529 converting enzyme.
Angiotensin II Receptor Blockers
PROTOTYPE Losartan (Cozaar), p. 532 4. Describe multiple mechanisms by which angiotensin
Aldosterone Antagonists II raises blood pressure.
5. Explain how the actions of aldosterone can lead to
high blood pressure.
6. Identify the specific steps in the renin-angiotensin-
aldosterone system that can be blocked by
medications.
7. For each of the classes shown in the chapter outline,
identify the prototype and representative drugs and
explain the mechanism(s) of drug action, primary
indications, contraindications, significant drug
interactions, pregnancy category, and important
adverse effects.
8. Apply the nursing process to care for patients
receiving pharmacotherapy with angiotensin-
converting enzyme inhibitors and angiotensin
receptor blockers.
523
524 Unit 5 Pharmacology of the Cardiovascular System
Key Terms angiotensinogen, 524 juxtaglomerular (JG) cells, 525
bradykinin, 526 macula densa, 525
angioedema, 528 cardiac remodeling, 526 renin, 525
angiotensin I, 524
angiotensin II, 524
The renin-angiotensin-aldosterone system (RAAS) is a key Constantly Angioten- Produces in
homeostatic mechanism regulating blood pressure and Liver produces sinogen response
fluid balance. The RAAS is presented early in the study of in plasma to low BP
cardiovascular pharmacology because the drugs affecting
this pathway are frequently used to treat hypertension Renin
(HTN) and heart failure (HF). This chapter examines com-
ponents of the RAAS and describes how drugs affecting Kidney
this system are used for therapeutic benefit.
Angiotensin I
Components of the Renin- in plasma
Angiotensin-Aldosterone System
Angiotensin- From
31.1 The formation of angiotensin II requires converting blood vessel
two enzymatic steps.
enzyme epithelium
In the mid-1900s, scientists discovered a peptide circulat-
ing in the blood that caused profound vasoconstriction. Angiotensin II
Named angiotensin (angio 5 blood vessel; tensin 5 pres- in plasma
sure), high levels of this substance were found in people
with HTN. Thus began the search for components of what ++ ++
is now called the renin-angiotensin-aldosterone system.
Vaso- Aldosterone
We now know that there are several forms of angioten- constriction
sin. Angiotensin II is the vasopressor substance originally of arterioles ADH
isolated by scientists in the 1900s. The formation of angio- secretion
tensin II requires two key enzymatic steps, and an under- Cardiac Increased
standing of these steps is critical to learning the remodeling blood Fluid
pharmacology of drugs affecting the RAAS. The RAAS is retention
illustrated in Figure 31.1. pressure Increased
sodium
Step 1—Formation of angiotensin I: Angiotensinogen is a
protein synthesized by the liver that is continuously circulat- reabsorption
ing in the bloodstream. In the blood, angiotensinogen is split
by the enzyme renin to form angiotensin I. Neither angio- Increased
tensinogen nor angiotensin I has any significant physiologic blood
actions; they simply serve as precursors to angiotensin II.
pressure
Step 2—Formation of angiotensin II: Angiotensin I travels
through the circulation until it encounters angiotensin- Figure 31.1 The renin-angiotensin-aldosterone pathway.
converting enzyme (ACE), which cleaves two amino acids
to form angiotensin II. ACE is located on the membrane 31.2 Renin secretion is controlled by the
surface of the blood vessel endothelium. Because the lung juxtaglomerular cells of the kidney and the
possesses such an extensive number of capillaries, it is the sympathetic nervous system.
primary organ responsible for converting angiotensin I to
angiotensin II. Angiotensin II is one of the most potent nat- Because renin is responsible for the first step in the
ural vasoconstrictors known; it is approximately 40 times RAAS pathway, it is a major factor in determining the
more potent at raising blood pressure than norepinephrine. amount of angiotensin II produced in the body. There-
fore, factors affecting the secretion of renin are impor-
tant to understanding the pharmacotherapy associated
with this system.
Chapter 31 Drugs Affecting the Renin-Angiotensin-Aldosterone System 525
THE JUXTAGLOMERULAR APPARATUS
The juxtaglomerular apparatus consists of macula densa and granular cells. Paracrine signaling
between the nephron and a erent arteriole influences GFR.
(a) The nephron loops back on itself so that the (b) The macula densa cells sense distal
ascending limb of the loop of Henle passes tubule flow and release paracrines that
between the a erent and e erent arterioles. a ect a erent arteriole diameter.
E erent arteriole
Bowman’s
capsule
Ascending Glomerulus
limb of loop Proximal
tubule
of Henle
Macula
densa
cells
A erent Granular cells secrete renin, an enzyme
arteriole involved in salt and water balance.
Endothelium
Figure 31.2 The macula densa and the juxtaglomerular (JG) cells. Osmoreceptors in the macula densa sense low sodium levels, which
signals the JG cells to release renin.
From Human Physiology: An Integrated Approach (6th ed., p. 639), by D. U. Silverthorn, © 2013. Reprinted and electronically reproduced by permission of Pearson
Education, Inc., Upper Saddle River, New Jersey.
Renin is an enzyme that is synthesized, stored, and Anatomically, the JG cells and the macula densa are in
secreted by specialized cells in the kidney known as jux- proximity, as shown in Figure 31.2. The JG cells and the
taglomerular (JG) cells (also called granular cells). Found macula densa are sometimes considered a single anatomic
in the afferent arteriole that supplies blood to the glom- unit called the juxtaglomerular complex.
erulus, JG cells are specialized smooth muscle cells that
act as pressure sensors. As blood pressure falls, there is CONNECTION Checkpoint 31.1
less pressure on the JG cells, which respond by releasing
renin to the circulation. The increase in renin ultimately Substances that lower blood pressure may trigger reflex tachycar-
leads to larger amounts of circulating angiotensin II, dia. From what you learned in Chapter 28, explain the mechanism
which returns blood pressure to normal. The release of involved in this reflex. Answers to Connection Checkpoint questions
renin is caused by factors that lower blood pressure, such are available on the faculty resources site. Please consult with your
as a loss of blood volume due to dehydration or hemor- instructor.
rhage. Through negative feedback, increased blood pres-
sure is sensed by the JG cells, which then turn off renin A third mechanism for controlling the release of renin is
secretion. more direct: activation of the sympathetic nervous system.
JG cells contain beta1-adrenergic receptors, which are acti-
Several other important factors influence the release vated by the classic fight-or-flight response of the sympa-
of renin. Adjacent to the JG cells in the distal convoluted thetic nervous system (see Chapter 12). The release of renin
tubule of the nephron is a specialized cluster of cells called helps to raise blood pressure when dealing with a stressful
the macula densa. The macula densa is in a perfect loca- or harmful situation.
tion to sense the flow rate and the concentration of sodium
ions (osmolality) in the urinary filtrate. As blood pressure To summarize, factors that promote the release of renin
falls, blood flow through the kidney diminishes and the by JG cells will raise blood pressure. The three primary fac-
flow of renal tubular filtrate slows. The macula densa rec- tors causing an increase are decreased pressure in blood
ognizes the decreased flow rate (and less sodium) and flowing through the kidney, decreased tubular flow rate (or
sends a chemical message to the JG cells to release more fewer sodium ions) sensed by the macula densa, and acti-
renin. The renin release forms more angiotensin II and vation of the sympathetic nervous system. Conversely, the
blood pressure rises. factors that decrease renin secretion lower blood pressure.
These factors are illustrated in Figure 31.3.
526 Unit 5 Pharmacology of the Cardiovascular System
(a) (b) (c) responsible for some of the adverse effects of the ACE
Macula densa inhibitor medications. When referring to its actions on bra-
dykinin, ACE is sometimes called kininase II; kininase is the
Na+ general term for an enzyme that breaks down kinins. ACE
and kininase II refer to the identical enzyme.
Cardiovascular + + Kidney
center + Pharmacologically, ACE is an important enzyme in the
Blood RAAS because it serves as a target molecule for drugs in
Sympathetic flow the ACE inhibitor class of medications. Inhibition of ACE
activity will prevent the formation of angiotensin II, thus interrupt-
JG cell ing the RAAS pathway. These medications also inhibit kini-
nase II, thus preventing the breakdown of bradykinin.
Renin Accumulation of bradykinin in certain tissues can cause
release several adverse effects of ACE inhibitors, such as angio-
edema and cough.
Figure 31.3 Overview of factors affecting renin release:
(a) activation of the sympathetic nervous system; (b) low osmolarity Physiologic Actions of the Renin-
in the macula densa; (c) low blood flow through the kidney. Angiotensin-Aldosterone System
Increasing renin secretion will not always cause an 31.4 Angiotensin II has multiple effects on the
increase in blood pressure. Remember that RAAS is a two- cardiovascular system that raise blood pressure
step pathway, and both steps are essential to produce a and affect cardiac function.
physiologic response. Section 31.3 examines this second
step. The final product of the two-step renin-angiotensin path-
way is angiotensin II. Angiotensin II has several important
CONNECTION Checkpoint 31.2 physiologic effects important to homeostasis and to
pharmacotherapy.
From what you learned in Chapter 12, other than JG cells, in what
organ are beta1-adrenergic receptors predominantly located? Direct vasoconstriction: Angiotensin II acts directly on
What is the response of that organ when these receptors are vascular smooth muscle to cause vasoconstriction and
activated? Answers to Connection Checkpoint questions are avail- increased systemic blood pressure. This effect is rapid; for-
able on the faculty resources site. Please consult with your instructor. mation of angiotensin II results in a nearly instantaneous
increase in blood pressure. This vasopressor action of
31.3 Angiotensin-converting enzyme is angiotensin II is much greater on arterioles compared to
responsible for the formation of angiotensin II. veins; arterioles serving the kidneys are especially sensi-
tive to this vasopressor action.
Once angiotensin I is formed, its conversion to angiotensin
II by ACE is almost instantaneous. A single pass of the Increased sympathetic nervous system activity:
blood through lung capillaries converts most of the circu- Angiotensin II activates the sympathetic nervous system
lating angiotensin I to angiotensin II. by causing the release of norepinephrine from sympathetic
nerve terminals. The adrenal medulla is also affected by
In addition to its role in the formation of angiotensin II, angiotensin II, which responds by releasing additional epi-
ACE has a second function important to homeostasis and nephrine to the circulation. Furthermore, through largely
pharmacotherapy. ACE is one of several enzymes that unknown mechanisms, angiotensin II increases sympa-
break down bradykinin, a natural mediator of inflamma- thetic outflow from the brain. All three of these actions
tion and pain. Bradykinin has many of the same effects as increase peripheral resistance and raise blood pressure.
histamine (see Chapter 44), including increasing arteriolar
vasodilation and vascular permeability, and is likely Alteration of cardiovascular structure: The long-term
presence of angiotensin II can also cause hypertrophy of
myocardial cells (myocytes) and promote collagen depos-
its in the cardiac matrix, essentially forming scar-like tis-
sue in the heart. These changes are known as cardiac
remodeling. The hypertrophy, fibrosis, and remodeling of
cardiac structure have been correlated with increased mor-
bidity and mortality associated with HF. In blood vessels,
angiotensin II causes the release of multiple chemical
Chapter 31 Drugs Affecting the Renin-Angiotensin-Aldosterone System 527
mediators of atherosclerosis, accelerating the deposition of cells to cause its biologic actions. There are two pri-
fatty plaque on the walls of the vessels. Increased plaque mary receptor subtypes, known as AT1 and AT2 recep-
deposits lead to an increased risk for myocardial infarction tors. Blocking AT1 receptors prevents angiotensin from
(MI) and stroke. raising blood pressure and from causing cardiac
remodeling. Angiotensin receptor blockers are medi-
Release of aldosterone and effects on the renal tubule: cations that intervene at this step in the RAAS by
Angiotensin II has two primary effects on the kidney that blocking the AT1 receptor. The role of AT2 receptors,
promote an increase in blood pressure. First, angiotensin II which are found in greatest abundance in the fetus, is
has a direct effect on the nephron that increases Na+ and largely unknown but is an area of active research.
Cl− reabsorption in the proximal tubule. Second, angioten- • Aldosterone antagonists. Much of the blood pressure
sin II indirectly affects sodium reabsorption by stimulating increase resulting from the formation of angiotensin II
the adrenal cortex to synthesize and secrete additional is caused by its stimulation of aldosterone secretion.
amounts of the hormone aldosterone. Aldosterone acts on Two drugs are available that block receptors for aldo-
the distal and collecting tubules of the nephron to increase sterone in the kidney, thus preventing the aldosterone-
Na+ reabsorption and K+ and H+ excretion. The enhanced induced increase in blood pressure.
sodium reabsorption from both direct and indirect actions • Renin inhibitors. In 2007, the U.S. Food and Drug
of angiotensin II causes the body to retain water, thus Administration (FDA) approved the first renin inhibi-
increasing blood volume and raising blood pressure. Aldo- tor. Aliskiren (Tekturna) is approved to treat HTN as
sterone is a key component of the RAAS. monotherapy or in combination with other antihyper-
tensives. It is likely that other renin inhibitors will be
Unlike its immediate and direct effects on sympathetic approved in the future.
nerves, the actions of angiotensin II on the kidney develop
more slowly. This slow vasopressor response is believed to Drugs Affecting the Renin-
be responsible for producing a sustained elevation of blood Angiotensin-Aldosterone System
pressure and a gradual decline of renal function.
31.6 ACE inhibitors are key drugs in the
Students often think of angiotensin II as a “bad actor” pharmacotherapy of hypertension and heart
because it can create HTN and cause the damaging effects failure.
of cardiac remodeling. Remember, however, that the car-
diovascular and renal effects of angiotensin II serve an First detected in the venom of pit vipers in the 1960s,
essential homeostatic function. Should blood pressure fall, inhibitors of ACE have been approved for HTN since the
the increased synthesis and production of angiotensin II 1980s. Since then drugs in this class have become first-line
help return blood pressure to normal levels to maintain drugs in the treatment of HTN and HF. Doses for the ACE
blood flow to vital organs. When the body is subjected to inhibitors are listed in Table 31.1.
chronically elevated levels of angiotensin II, however, the
once vital reflex pathway becomes a detriment to the body. ACE inhibitors block the conversion of angiotensin I to
angiotensin II. The decline in angiotensin II levels causes
CONNECTION Checkpoint 31.3 blood pressure to decrease because there is less sympa-
thetic activation and, thus, lower peripheral resistance. In
From what you learned in Chapter 28, what effect would you addition, the decreased aldosterone secretion reduces
expect angiotensin II formation to have on cardiac output and blood volume, which also contributes to blood pressure
afterload? Answers to Connection Checkpoint questions are avail- reduction.
able on the faculty resources site. Please consult with your instructor.
Research studies have clearly demonstrated that ACE
31.5 The renin-angiotensin-aldosterone inhibitors can slow the progression of HF and reduce mor-
pathway offers multiple points for drug tality from this disease. This is likely due to both the reduc-
intervention. tion in systemic blood pressure and a reversal of the
angiotensin II–induced structural changes in the heart.
Having learned details of the different components in the Because of their relative safety, they have replaced digoxin
short pathway leading from angiotensinogen to angioten- (Lanoxin) as the first-line drugs for the treatment of chronic
sin II, the student should recognize several potential mech- HF. Indeed, unless specifically contraindicated, all patients
anisms by which drugs could intervene: with HF usually receive an ACE inhibitor, as discussed in
Chapter 36.
• ACE inhibitors. These are the largest and most
important class of drugs modifying the RAAS. ACE Research has also indicated a clear benefit for adminis-
inhibitors block the conversion of angiotensin I to tering ACE inhibitors to patients who have experienced a
angiotensin II. recent MI. If therapy is begun immediately after the
• Angiotensin receptor blockers. After angiotensin II is
formed, it must interact with its receptors on target
528 Unit 5 Pharmacology of the Cardiovascular System
Table 31.1 ACE Inhibitors
Drug Route and Adult Dose (Maximum Dose Where Indicated) Adverse Effects
benazepril (Lotensin) PO: 10–40 mg in 1–2 divided doses (max: 40 mg/day) Headache, dry cough, dizziness, orthostatic
hypotension, rash
captopril (Capoten) PO: 6.25–25 mg tid (max: 450 mg/day)
Angioedema, acute renal failure, first-dose
enalapril (Vasotec) PO: 5–40 mg in 1–2 divided doses (max: 40 mg/day) phenomenon, fetal toxicity
fosinopril (Monopril) PO: 5–40 mg once daily (max: 40 mg/day)
lisinopril (Prinivil, Zestril) PO: 5–10 mg daily (max: 80 mg/day)
moexipril (Univasc) PO: 7.5–30 mg once daily (max: 30 mg/day)
perindopril (Aceon) PO: 4 mg once daily (max: 16 mg/day for HTN; 4 mg/day for HF)
quinapril (Accupril) PO: 10–20 mg once daily (max: 80 mg/day)
ramipril (Altace) PO: 2.5–20 mg daily (max: 20 mg/day)
trandolapril (Mavik) PO: 1–4 mg once daily (max: 8 mg/day)
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
infarction and continued for several weeks, these drugs Though rare, the most serious adverse effect of ACE
lower the mortality associated with an acute MI. The mech- inhibitors is the development of angioedema, a rapid
anism by which these drugs improve the outcome follow- swelling of the throat, face, larynx, and tongue that can
ing an acute MI involves reduced peripheral vascular lead to airway obstruction and death. When it does occur,
resistance, improved perfusion, and a direct action on the angioedema most often develops within a few hours after
myocardium that reduces the cardiac workload. the first dose, although it may occur after several days of
ACE inhibitor therapy. Accumulation of bradykinin is
ACE inhibitors may also be prescribed as prophylaxis
therapy in patients at high risk for an adverse cardiovascu- CONNECTIONS: Community-
lar event. ACE inhibitors can reduce the incidence of a Oriented Practice
stroke or MI in these high-risk patients. They may also pre-
vent or delay the progression of renal disease and retinopa- Angiotensin-Converting Enzyme Inhibitors
thy in patients with diabetes. and Angioedema
All ACE inhibitors have very similar indications and Angioedema is the development of edema of the mouth, lips,
adverse effect profiles. All drugs in this class are approved tongue, pharynx, larynx, and epiglottis that can be fatal if respi-
to treat HTN, and a few are approved for HF and acute MI ratory distress occurs secondary to the swelling of the upper
and for prophylaxis of cardiovascular disease. With the airway. Less commonly, intestinal edema may also occur, caus-
exception of enalaprilat, ACE inhibitors are administered ing a sudden onset of abdominal pain, vomiting, and diarrhea.
orally (PO), and nearly all offer the convenience of once- Angioedema is associated with ACE inhibitors and appears to
daily dosing. Many of the ACE inhibitors are prodrugs, be related to the increase in bradykinin levels when ACE is no
which are converted to active metabolites by enzymes in longer available to break down circulating bradykinin. Although
the liver. Most ACE inhibitors are excreted by the kidneys; angioedema occurs in less than about 1% of patients taking
thus dose reductions may be required in patients with ACE inhibitors, it is more common in African Americans, partic-
advanced chronic kidney disease (CKD). ularly those of Caribbean descent, and in older adults.
The low incidence of serious adverse effects is a major In 50% of patients, angioedema occurs after the first dose
contributing factor to the widespread use of the ACE inhibi- of an ACE inhibitor, although it may occur anytime during ther-
tors. Orthostatic hypotension following the first few doses apy. Patients who have had a previous episode of angioedema
of the drug can be severe in patients who are on low-sodium after taking an ACE inhibitor are at greater risk for developing
diets or who have HF. Drug therapy is sometimes begun angioedema from other ACE inhibitors. It may also be caused
with very low doses and increased gradually to avoid by angiotensin receptor blockers, although less commonly.
orthostatic hypotension. Hyperkalemia may occur during Itching and urticaria may occur prior to the development of
ACE inhibitor therapy; however, this is predominantly a angioedema but are not good predictors as to whether or not
major concern only for patients with diabetes, those with angioedema will develop. Immediate treatment may include
CKD, and those who are taking potassium supplements or administration of epinephrine, antihistamines (both H1 and H2
potassium-sparing diuretics. Persistent, dry cough is an blockers), corticosteroids, and fresh frozen plasma. The ACE
annoying adverse effect that occurs in 5% to 20% of patients in fresh plasma accelerates the breakdown of bradykinin. The
taking ACE inhibitors. This adverse effect is likely due to a patient should be observed closely after the first dose, and any
buildup of bradykinin in the lungs. Drugs in this class have subsequent swelling of the facial, oral, or pharynx areas should
minimal or no effect on serum glucose or uric acid levels. be immediately reported to the provider.
Chapter 31 Drugs Affecting the Renin-Angiotensin-Aldosterone System 529
thought to be responsible. Treatment of angioedema is to Primary metabolism Not metabolized
discontinue the drug immediately and maintain the airway
until the effects of the drug wear off. Primary excretion Renal
All the ACE inhibitors carry a black box warning Onset of action 1 h; peak effect: 6–8 h
regarding the risk for major congenital defects if the drugs
are taken during pregnancy. This risk for fetal kidney mal- Duration of action 24 h; half-life: 12 h
formation is well documented for the second and third tri-
mesters, which has resulted in a pregnancy category D Adverse Effects: Lisinopril is well tolerated and
rating during these pregnancy periods. The risk for other adverse effects are uncommon and transient. The most
congenital defects such as heart and neural tube defects common adverse effects are cough, headache, dizziness,
during the first trimester is not as clear, causing some of the orthostatic hypotension, and rash. Hyperkalemia occurs
drugs to be rated category C during this period. Most in about 2% to 5% of patients taking ACE inhibitors,
healthcare providers will discontinue ACE inhibitors as although this usually resolves during therapy. Patients
soon as pregnancy is determined. Women with HTN with HF or CKD or who are taking potassium supple-
should be advised not to discontinue these drugs during ments or potassium-sparing diuretics are at highest risk for
pregnancy without healthcare provider knowledge because hyperkalemia. Rare, though serious, adverse effects include
HTN itself is a risk factor for congenital defects. angioedema, agranulocytosis, and hepatotoxicity. Black
Box Warning: Fetal injury and death may occur when ACE
inhibitors are taken during pregnancy. When pregnancy is
detected, they should be discontinued as soon as possible.
PROTOTYPE DRUG Lisinopril (Prinivil, Zestril) Contraindications/Precautions: Lisinopril should
be used with extreme caution in patients with hyperka-
Classification Therapeutic: Antihypertensive lemia because they may experience serious and even fa-
Pharmacologic: ACE inhibitor tal dysrhythmias. Patients with a history of angioedema
should not receive lisinopril. Caution should be used when
Therapeutic Effects and Uses: Approved for the treating patients with advanced CKD: Dosage should be
treatment of HF, HTN, and acute MI, lisinopril is one of reduced. Lisinopril is contraindicated during pregnancy.
the most frequently prescribed medications. Approved in
1987, it may be used as monotherapy or combined with Drug Interactions: Indomethacin and other nonsteroi-
other drugs: Fixed-dose combinations of lisinopril and dal anti-inflammatory drugs (NSAIDs) interact with lisino-
hydrochlorothiazide (a diuretic) are marketed for HTN as pril to decrease antihypertensive activity. The combination
Prinzide and Zestoretic. Unlike many drugs in this class, of lisinopril and NSAIDs may also worsen preexisting renal
lisinopril is active itself; it is not a prodrug. Treatment of disease. Because of synergistic hypotensive action, concur-
migraines is an off-label indication for lisinopril. rent therapy with diuretics and other antihypertensives
such as ACE inhibitors should be carefully monitored.
Although captopril was the first drug that was marketed When taken with potassium supplements or potassium-
in this class, lisinopril is more widely prescribed because it sparing diuretics, hyperkalemia may result. Lisinopril may
has a longer duration of action that allows for once-daily dos- increase lithium levels and toxicity. Herbal/Food: Haw-
ing. Like other ACE inhibitors, 2 to 3 weeks of therapy may thorn should not be taken concurrently with lisinopril due
be required to achieve maximum therapeutic outcomes. to the possibility of additive hypotensive action.
Mechanism of Action: Lisinopril binds to and in- Pregnancy: Categories C (first trimester) and D (sec-
hibits the action of ACE, thus preventing the conversion ond and third trimesters).
of angiotensin I to angiotensin II. The decrease in serum
angiotensin II reduces aldosterone secretion, which results Treatment of Overdose: Overdose will cause hypo-
in less sodium and water retention. In patients with HTN, tension, which may be treated with normal saline or a va-
blood pressure is reduced with minimal effect on heart sopressor. The drug may also be removed by hemodialysis.
rate, stroke volume, or cardiac output.
Nursing Responsibilities: Key nursing implications
Pharmacokinetics: for patients receiving lisinopril are included in the Nursing
Practice Application for Patients Receiving Pharmacother-
Route(s) PO apy with Angiotensin-Converting Enzyme Inhibitors and
Angiotensin Receptor Blockers.
Absorption 25–30% absorbed from the gas-
trointestinal (GI) tract
Distribution Small amount crosses the blood–
brain barrier; crosses the placen- Drugs Similar to Lisinopril (Prinivil, Zestril)
ta; limited amounts are secreted In addition to lisinopril, there are nine other ACE inhibi-
tors on the market. All have very similar actions and
in breast milk; not bound to adverse effects.
plasma protein
530 Unit 5 Pharmacology of the Cardiovascular System
Benazepril (Lotensin): Approved in 1991, benazepril is Moexipril (Univasc): Approved in 1995, moexipril is indi-
approved only for HTN, although an off-label indication is cated only for HTN. It is a prodrug that is metabolized to
HF. It is a prodrug that is metabolized by hepatic enzymes its active form, moexiprilat, by hepatic enzymes. An
to its active form, benazeprilat. It has a long duration of extended half-life allows for once-daily dosing. This drug
action that allows for once-daily dosing and is excreted by should be taken on an empty stomach, because food
the kidneys. Orthostatic hypotension is the most common reduces its bioavailability by 40% to 50%. It is excreted by
adverse effect, especially after the first dose. Other adverse the kidneys, and dosage should be reduced in patients
effects, contraindications, and indications are the same as with CKD. Dizziness is one of the most common adverse
those of lisinopril. Lotensin HCT is a fixed-dose combina- effects. Adverse effects, contraindications, and indications
tion of benazepril and hydrochlorothiazide. Lotrel is a are the same as those of lisinopril. Uniretic is a fixed-dose
combination of benazepril with amlodipine. This drug is combination of moexipril and hydrochlorothiazide. Moex-
pregnancy category C (first trimester) and D (second and ipril is a pregnancy category D drug.
third trimesters).
Perindopril (Aceon): Approved in 1993, perindopril is
Captopril (Capoten): Captopril, the first ACE inhibitor approved for HTN and the prophylaxis of cardiovascular
marketed in 1981, is approved for HTN, HF, left ventricu- events such as MI in patients with coronary artery disease.
lar dysfunction after an acute MI, and diabetic nephropa- HF is an off-label use. It is a prodrug that is metabolized by
thy. It has a short half-life, which requires multiple daily hepatic enzymes to its active form, perindoprilat. It is
doses for some patients. The drug should be taken on an excreted by the kidneys, and its long half-life allows for
empty stomach, because food reduces its bioavailability. once- or twice-daily dosing. Food may reduce the bioavail-
Neutropenia and agranulocytosis have occurred during ability of the drug by as much as 35%. Cough and dizzi-
captopril use. Other adverse effects, contraindications, and ness are the most frequent adverse effects of perindopril.
indications are the same as those of lisinopril. Capozide is Other adverse effects, contraindications, and indications
a fixed-dose combination of captopril and hydrochlorothi- are the same as those of lisinopril. Prestalia is a fixed-dose
azide. This is a pregnancy category D drug. combination of perindopril and amlodipine that was
approved in 2015. This is a pregnancy category D drug.
Enalapril (Vasotec): Approved in 1985, enalapril is indi-
cated for HTN, HF, and asymptomatic left ventricular dys- Quinapril (Accupril): Approved in 1991, quinapril is indi-
function in post-MI patients. Like most drugs in this class, cated for HTN and as adjunctive therapy for HF in combi-
it has an extended half-life and is excreted by the kidneys. nation with diuretics or digoxin. It is a prodrug that is
It has a shorter half-life than some other ACE inhibitors metabolized by hepatic enzymes to its active form,
and may require twice-daily dosing. Enalapril is a pro- quinaprilat, and may be dosed either once or twice daily.
drug, being converted by hepatic enzymes to enalaprilat, Because the kidney contributes to about 96% of the excre-
which is its active form. The most frequent adverse effect is tion of the drug, doses should be reduced in patients with
hypotension, which can be especially troublesome in CKD. Adverse effects are generally mild and transient and
patients with HF. Adverse effects, contraindications, and include dizziness, cough, and diarrhea. Other adverse
indications are the same as those of lisinopril. Enalaprilat effects, contraindications, and indications are the same as
(Vasotec IV) is available as a drug for severe HTN and is those of lisinopril. Accuretic is a fixed-dose combination of
the only ACE inhibitor administered parenterally. Vaser- quinapril and hydrochlorothiazide. This is a pregnancy
etic is a fixed-dose combination of enalapril and hydro- category D drug.
chlorothiazide. Both enalapril and enalaprilat are
pregnancy category D drugs. Ramipril (Altace): Approved in 1991, ramipril is indi-
cated for HTN, HF following an MI, and to reduce mortal-
Fosinopril (Monopril): Approved in 1991, fosinopril is ity and stroke in high-risk patients with left ventricular
used to treat HTN and HF. It is a prodrug that is metabo- dysfunction after an acute MI. It is a prodrug that is metab-
lized by hepatic enzymes to its active form, fosinoprilat. olized by hepatic enzymes to its active form, ramiprilat.
An extended half-life allows for once-daily dosing, and it Excretion is predominantly renal, and dosage should be
may be taken without regard to meals. It is excreted by reduced in patients with advanced CKD. It may be admin-
both the liver and kidneys and does not require a dosage istered without regard to meals. The most common
adjustment in patients with CKD. The most common adverse effects are orthostatic hypotension, dizziness, and
adverse effects of fosinopril are orthostatic hypotension, headache. Other adverse effects, contraindications, and
dizziness, and headache. Monopril HCT is a fixed-dose indications are the same as those of lisinopril. This is a
combination of Monopril and hydrochlorothiazide. This pregnancy category D drug.
drug is pregnancy category C (first trimester) and D (sec-
ond and third trimesters). Trandolapril (Mavik): Approved in 1996, trandolapril is
indicated for HTN and HF following an MI and to reduce
Chapter 31 Drugs Affecting the Renin-Angiotensin-Aldosterone System 531
Table 31.2 Angiotensin II Receptor Blockers, Aldosterone Antagonists, and Renin Inhibitors
Drug Route and Adult Dose (Maximum Dose Where Indicated) Adverse Effects
Angiotensin II Receptor Blockers Headache, dizziness, orthostatic
hypotension, fatigue, diarrhea, upper
azilsartan (Edarbi) PO: 40–80 mg once daily respiratory infection
Angioedema, acute renal failure, first-dose
candesartan (Atacand) PO: Start at 16 mg/day for HTN and 4 mg/day for HF (max: 32 mg/day) phenomenon, hyperkalemia, fetal toxicity
and neonatal mortality
eprosartan (Teveten) PO: 600 mg/day or 400 mg qid–bid (max: 800 mg/day)
Minor hyperkalemia, headache, fatigue,
irbesartan (Avapro) PO: 150–300 mg/day (max: 300 mg/day) gynecomastia (spironolactone)
Dysrhythmias (from hyperkalemia),
losartan (Cozaar) PO: 25–50 mg in 1–2 divided doses (max: 100 mg/day) dehydration, hyponatremia,
agranulocytosis and other blood
olmesartan medoxomil (Benicar) PO: 20–40 mg/day dyscrasias
telmisartan (Micardis) PO: 40–80 mg once daily Diarrhea, hypotension, cough
valsartan (Diovan) PO: 80 mg/day (max: 320 mg/day)
Aldosterone Antagonists
eplerenone (Inspra) PO: Start with 25–50 mg/day (max: 100 mg/day for HTN; 50 mg/day
for HF)
spironolactone (Aldactone) PO: 50–100 mg/day in single or divided doses (max: 400 mg/day)
Renin Inhibitor PO: 150 mg/day (max: 300 mg/day)
aliskiren (Tekturna)
Angioedema
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
the mortality in high-risk patients with left ventricular were discovered, and a new class of drugs, the angiotensin II
dysfunction after an acute MI. It is a prodrug that is metab- receptor blockers (ARBs), was developed. The ARBs are
olized by hepatic enzymes to trandolaprilat, its active selective for AT1-type receptors. Unlike the ACE inhibitors,
form. It has an extended half-life that permits once-daily ARBs do not prevent the formation of angiotensin II, but
dosing and may be administered without regard to meals. they do effectively block it from activating their target
Unlike other ACE inhibitors, a large amount of trandol- receptors. Doses for the ARBs are listed in Table 31.2.
april (66%) is excreted in the feces. Dosages should be low-
ered in patients with chronic kidney disease (CKD) or The ARBs cause vasodilation, with a resultant reduc-
hepatic impairment. The most common adverse effects are tion in peripheral resistance and fall in blood pressure, by
cough, dizziness, and fatigue. Other adverse effects, con- blocking angiotensin II receptors in arteriolar smooth
traindications, and indications are the same as those of muscle. The blockade of AT1 receptors in the adrenal
lisinopril. Tarka is a fixed-dose combination of trandolapril gland prevents secretion of aldosterone and promotes
and the calcium channel blocker verapamil SR, which is increased Na+ and excretion of water by the kidneys.
prescribed for HTN. This is a pregnancy category D drug. Blockade of AT1 receptors in the heart prevents the
destructive effects of angiotensin-induced cardiac remod-
CONNECTION Checkpoint 31.4 eling. Although they act by a different mechanism, ARBs
essentially produce the same pharmacologic actions as
ACE inhibitors decrease sympathetic activation. From what you the ACE inhibitors.
learned in Chapters 15 and 16, what type of interactions (additive or
antagonistic) would you expect from the autonomic drugs epineph- The indications for ARBs are the same as those for the
rine and propranolol? Answers to Connection Checkpoint questions ACE inhibitors. All are approved to treat HTN, and they
are available on the faculty resources site. Please consult with your are often combined with drugs from other classes. Valsar-
instructor. tan (Diovan) and candesartan (Atacand) were subsequently
approved to treat HF. Some are approved to treat MI and
31.7 Angiotensin II receptor blockers act by are used for the prophylaxis of stroke. All are administered
hinyhpiebritteinngsiothneaAnTd1hreeacertpftaoirluanred. are used for orally and have prolonged half-lives that permit once-daily
dosing. A few are prodrugs, and most are extensively
While pharmacologists were examining the mechanism of bound to plasma proteins.
action of the ACE inhibitors in the 1980s and developing
new drugs in this class, research continued on the other Are the ARBs identical to the ACE inhibitors? Not
enzymes and components of the RAAS. The receptors for exactly. Unlike the ACE inhibitors, they do not cause cough,
angiotensin II in smooth muscle, known as AT1 and AT2, and angioedema is less common. This is because ARBs do
not promote the accumulation of bradykinin, as do the
ACE inhibitors. ARBs can, however, cause dizziness,
532 Unit 5 Pharmacology of the Cardiovascular System
hypotension, and hyperkalemia, especially in patients with Onset of action 6h
CKD or who are concurrently taking potassium supple- Duration of action
ments or potassium-sparing diuretics. Caution should be Half-life: 1.5–2 h (losartan), 6–9
used with concurrent administration of ARBs and ACE h (highly active metabolite)
inhibitors due to an increased risk for hypotension, hyper-
kalemia, and diminished renal function. Adverse Effects: The incidence of adverse effects of
losartan is very low. The most common adverse effects are
If ARBs have the same pharmacologic actions and an headache, dizziness, nasal congestion, fatigue, and insom-
improved safety profile, why have they not replaced the nia. Serious adverse effects include angioedema and acute
ACE inhibitors? The answer is because the ACE inhibitors renal failure. Black Box Warning: Fetal injury and death
are generally less expensive, and healthcare providers have may occur when ARBs are taken during pregnancy. When
much more clinical experience prescribing them. Because pregnancy is detected, they should be discontinued as
the ARBs are newer, a significant body of research has not soon as possible.
yet accumulated that demonstrates clear benefits over the
ACE inhibitors. Because of these factors, the ARBs are usu- Contraindications/Precautions: Losartan is con-
ally reserved for patients unable to tolerate the adverse traindicated in patients with prior hypersensitivity to the
effects of ACE inhibitors. drug. Because ARBs exhibit the same teratogenic effects as
ACE inhibitors, they should not be used during pregnancy
PROTOTYPE DRUG Losartan (Cozaar) and lactation. Caution should be used in treating patients
with serious hepatic impairment or advanced CKD; dos-
Classification Therapeutic: Antihypertensive age may need to be reduced. Patients with a history of
Pharmacologic: Angiotensin II receptor angioedema should be monitored carefully. Patients with
hypovolemia are at high risk of symptomatic hypotension
blocker during therapy. Hypovolemia should be corrected prior to
administration of losartan.
Therapeutic Effects and Uses: Approved for the
treatment of HTN, stroke prophylaxis in patients with Drug Interactions: The drug interactions of losartan
left ventricular hypertrophy, and the prevention of type 2 and other ARBs are similar to those of the ACE inhibitors.
diabetic nephropathy, losartan was the first ARB marketed Indomethacin and other NSAIDs may decrease the antihy-
in 1995. An off-label use is for HF. Although losartan pertensive activity of losartan. When taken concurrently
undergoes extensive first-pass metabolism and has a short with potassium supplements or potassium-sparing diuret-
half-life, it is metabolized to an active intermediate that ics, care must be taken to avoid hyperkalemia. Concurrent
prolongs the drug’s action, allowing for once-daily dosing. use of losartan with diuretics and other antihypertensives
Two daily doses may be necessary in some patients. Its may cause additive hypotensive effects. Use with alcohol
actions include vasodilation and reduced blood volume, due may also add to the hypotensive effects of losartan. Losar-
to the drug blocking the release of aldosterone by angio- tan may increase lithium levels and toxicity. In patients
tensin II. Hyzaar is a fixed-dose combination of losartan with diabetes, losartan should not be administered concur-
and hydrochlorothiazide. rently with aliskiren. Herbal/Food: Hawthorn should not
be taken concurrently with losartan due to the possibility
Mechanism of Action: Losartan selectively blocks of additive hypotensive action.
angiotensin AT1 receptors, resulting in a decline in blood
pressure. The blockade of angiotensin II receptors prevents Pregnancy: Categories C (first trimester) and D (sec-
cardiac remodeling and deterioration of renal function in ond and third trimesters).
patients with diabetes.
Treatment of Overdose: Overdose will cause hy-
Pharmacokinetics: PO potension, which may be treated with an infusion of nor-
Route(s) mal saline or a vasopressor. The drug is not removed by
Absorption Well absorbed from the GI tract hemodialysis.
Distribution
Does not appear to cross the Nursing Responsibilities: Key nursing implications
Primary metabolism blood–brain barrier or the pla- for patients receiving losartan are included in the Nursing
centa or to be secreted in breast Practice Application for Patients Receiving Pharmacother-
Primary excretion milk; approximately 99% bound apy with Angiotensin-Converting Enzyme Inhibitors and
to protein Angiotensin Receptor Blockers.
Hepatic: extensive first-pass Drugs Similar to Losartan (Cozaar)
metabolism; converted to active
metabolite In addition to losartan, seven other ARBs are available. They
all have similar indications, actions, and adverse effects.
35% renal, 60% in feces
Chapter 31 Drugs Affecting the Renin-Angiotensin-Aldosterone System 533
Azilsartan medoxomil (Edarbi): One of the newer ARBs, form (olmesartan) during its absorption from the GI tract.
azilsartan was approved in 2011 for the treatment of Olmesartan is 99% protein bound and excreted equally in
HTN, either as monotherapy or in combination with urine and the feces. The drug is administered once daily,
other antihypertensives. The drug is sometimes listed by and optimal blood pressure reduction may require
its potassium salt, azilsartan kamedoxomil. Both the 2 weeks of therapy. The drug exhibits few adverse effects,
medoxomil and kamedoxomil salts are prodrugs that are with dizziness being the most common complaint. Other
converted to their active form (azilsartan) when absorbed adverse effects, contraindications, and indications are the
across the GI tract. Azilsartan appears to lower blood same as those of losartan. There are three fixed-dose com-
pressure faster than other drugs in its class. The drug is binations of olmesartan: Benicar HCT (with hydrochloro-
well tolerated, with diarrhea being the most frequent thiazide), Azor (with amlodipine), and Tribenzor (with
adverse effect. Caution should be used in treating volume amlodipine and hydrochlorothiazide). This drug is preg-
or salt-depleted patients because transient hypotension nancy category D.
may occur. Edarbyclor is a fixed-dose combination of
azilsartan with chlorthalidone approved to treat HTN. CONNECTIONS: Complementary
This drug is pregnancy category C (first trimester) and D and Alternative Therapies
(second and third trimesters).
Hawthorn
Candesartan (Atacand): Approved in 1998, candesartan
is indicated for HTN and HF in patients with left ventric- Description
ular dysfunction. It is a prodrug that is metabolized to its
active form during its absorption from the GI tract. Opti- Hawthorn (Crataegus) is a thorny shrub or small tree that is
mal therapeutic effects may take up to 4 weeks. The drug widespread in North America, Europe, and Asia. Leaves, flow-
is 99% protein bound and is primarily excreted in the bile ers, and berries of the plant are dried or extracted in liquid form.
(66%). Adverse effects are generally mild and include
headache and dizziness. Other adverse effects, contrain- History and Claims
dications, and indications are the same as those of losar-
tan. Atacand HCT is a fixed-dose combination of Hawthorn, sometimes called May bush, was used in ancient
candesartan and hydrochlorothiazide. This drug is preg- Greece. In traditional Chinese medicine, hawthorn is used as a
nancy category D. digestive aid. European and American interest in the herb
began in the late 1800s. It has been widely used in European
Eprosartan (Teveten): Approved in 1997, eprosartan is countries to treat HTN and HF. The berries may be consumed
indicated only for HTN. It is mostly unmetabolized and raw or made into jellies, juices, and alcoholic beverages. Some
primarily excreted in the feces (90%). Optimal blood pres- cultures believe that the shrub is magical, and it is used in
sure reduction may require 2 to 3 weeks of therapy. The religious rites to ward off evil spirits.
most common adverse effects are upper respiratory infec-
tion, cough, abdominal pain, and fatigue. Other adverse Standardization
effects, contraindications, and indications are the same as
those of losartan. Teveten HCT is a fixed-dose combination Active ingredients in hawthorn include flavonoids and procy-
of eprosartan and hydrochlorothiazide. This drug is preg- anidins. A typical dose is 4.5 to 6 g of dried leaves or flowers
nancy category D. or 160 to 900 mg of extract per day.
Irbesartan (Avapro): Approved in 1997, irbesartan is indi- Evidence
cated for HTN and type 2 diabetic nephropathy. The drug
is 90% protein bound and is primarily excreted in the feces Hawthorn has been well studied (National Center for Comple-
(80%). Adverse effects are generally mild and include diz- mentary and Integrative Health, 2016). Some studies have
ziness, upper respiratory infection, orthostatic hypoten- reported positive effects in patients with HF, although the
sion, diarrhea, dyspepsia, and fatigue. Hyperkalemia may mechanism has not been determined. Hawthorn is known to
occur in 19% of patients taking this medication. Other contain flavonoids and studies have suggested that it has
adverse effects, contraindications, and indications are the antioxidant, antilipid, cardioprotective, and antitumor, partic-
same as those of losartan. Avalide is a fixed-dose combina- ularly melanoma, effects (Diane et al., 2016; Mustapha et al.,
tion of irbesartan and hydrochlorothiazide. This drug is 2016). Hawthorn has few adverse effects at normal doses
pregnancy category D. but has been noted to increase the risk of postoperative
bleeding (Rababa’h et al., 2016). This product should be
Olmesartan medoxomil (Benicar): Approved in 2002, used with caution in patients taking cardiac glycosides and
olmesartan is indicated only for HTN. Olmesartan other prescription medications for cardiovascular disease.
medoxomil is a prodrug that is metabolized to its active Because hypotension may occur, frequent blood pressure
measurements, and observation for any increased bleeding,
particularly occult bleeding, should be monitored when using
this therapy.
534 Unit 5 Pharmacology of the Cardiovascular System
Telmisartan (Micardis): Approved in 1998, telmisartan is to treat edema and HTN. Doses for these drugs are listed
indicated for HTN and for cardiovascular risk reduction in in Table 31.2.
patients unable to take ACE inhibitors. An off-label use is
for the treatment of renal dysfunction in patients with dia- Spironolactone is an aldosterone antagonist that has
betic nephropathy. It is mostly unmetabolized, 99% protein been used for its diuretic action for many decades. By
bound, and excreted primarily in the feces. Initial doses binding to aldosterone receptors, spironolactone produces
should be reduced in patients with hepatic impairment. a mild diuresis by promoting Na+ and Cl− excretion.
The drug is well tolerated and serious adverse effects are Because it has little or no effect on the excretion of potas-
uncommon. Adverse effects, contraindications, and indica- sium, spironolactone is also classified as a potassium-
tions are the same as those of losartan. Fixed-dose combi- sparing diuretic and is featured as a prototype diuretic in
nations include Micardis HCT (with hydrochlorothiazide) Chapter 32. Because spironolactone produces only a mild
and Twynsta (with amlodipine). This drug is pregnancy diuresis, it is often combined with drugs from other
category D. diuretic classes when used for HTN. It is also useful in
treating primary aldosteronism, a rare condition in which
Valsartan (Diovan): Approved in 1996, valsartan is indi- the body produces an overabundance of aldosterone, usu-
cated for HTN, HF, and MI when the patient is unable to ally due to a tumor of the adrenal gland. Spironolactone
tolerate an ACE inhibitor. It undergoes hepatic metabo- has been shown to reduce morbidity, mortality, and dys-
lism, is 95% protein bound, and is eliminated in the feces. rhythmias associated with HF.
Because food can reduce drug absorption by as much as
40%, the drug should be given on an empty stomach. The primary concern with spironolactone is potas-
Headache and dizziness are common adverse effects. sium retention, which can result in serious hyperkalemia.
Other adverse effects, contraindications, and indications Some patients experience GI-related adverse effects such
are the same as those of losartan. Fixed-dose combinations as nausea, vomiting, and diarrhea. Because spironolactone
include Diovan HCT (with hydrochlorothiazide), Byval- has a chemical structure similar to that of steroid hor-
son (with nebivolol), and Exforge (with amlodipine). This mones, it sometimes causes endocrine adverse effects in
drug is pregnancy category D. men, such as gynecomastia and erectile dysfunction.
Women may experience menstrual irregularities and
31.8 Aldosterone antagonists block the breast tenderness.
biological effects of aldosterone in the renal
tubule. Eplerenone (Inspra) is a second aldosterone antago-
nist that has a very different chemical structure than spi-
As described in Section 31.3, angiotensin II causes the ronolactone. It is more selective for aldosterone receptors
release of aldosterone, which subsequently contributes to and has a very low incidence of endocrine-related adverse
increased blood pressure due to sodium and water reten- effects. Like spironolactone, hyperkalemia is a poten-
tion. Receptors for aldosterone are located in the distal tially serious adverse effect. Headache and dizziness are
tubule and collecting ducts of the nephron. Two drugs are common adverse effects. Eplerenone is approved to treat
available that block these receptors in the kidney, thus HTN and HF and to reduce morbidity and mortality
inhibiting the physiologic actions of aldosterone. Both spi- associated with post-MI in patients with left ventricular
ronolactone (Aldactone) and eplerenone (Inspra) are used dysfunction.
For additional information on aldosterone antagonists,
see Chapter 32.
CONNECTIONS: NURSING PRACTICE APPLICATION
Patients Receiving Pharmacotherapy with Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers
Assessment
Baseline assessment prior to administration:
• Obtain a complete health history including cardiovascular (MI, HF), diabetes, CKD, and the possibility of pregnancy. Obtain a drug history including
allergies, current prescription and over-the-counter (OTC) drugs, herbal preparations, and alcohol use. Be alert to possible drug interactions.
• Evaluate appropriate laboratory findings, electrolytes, especially potassium level, liver function studies, and lipid profiles.
• Obtain baseline weight, vital signs (especially blood pressure and pulse), breath sounds, and cardiac monitoring (e.g., electrocardiogram [ECG], car-
diac output) if appropriate. Assess for location, character, and amount of edema, if present.
• 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., lowered blood pressure within established limits).
• Continue periodic monitoring of electrolytes, especially potassium.
• Assess for adverse effects: headache, cough, orthostatic hypotension, fatigue or weakness, lightheadedness or dizziness, symptoms of hyperkalemia,
sexual dysfunction, or impotence. Angioedema should be immediately reported to the healthcare provider.
(continued )
Chapter 31 Drugs Affecting the Renin-Angiotensin-Aldosterone System 535
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
Ensuring therapeutic effects: • Teach the patient, family, or caregiver how to monitor pulse and blood
• Continue frequent assessments as above for therapeutic effects. pressure. Ensure proper use and functioning of any home equipment
obtained.
(Blood pressure and pulse should be within normal limits or within
parameters set by the healthcare provider.)
• Encourage appropriate lifestyle changes: lowered fat intake, increased • Encourage the patient to adopt a healthy lifestyle of low-fat food
exercise, limited alcohol intake, and smoking cessation. Provide for choices, increased exercise, decreased alcohol consumption, and
dietitian consultation as needed. (Healthy lifestyle changes will support smoking cessation.
and minimize the need for drug therapy.)
Minimizing adverse effects: Instruct the patient to:
• Continue to monitor vital signs. Take the blood pressure lying, sit- • Take the first dose of the new prescription in the evening before bed
ting, and standing to detect orthostatic hypotension. Lifespan: Be and to be cautious during the next few doses until drug effects are
particularly cautious with the first few doses of the drug and with older known.
adults who are at increased risk for hypotension. Ensure patient safety. • Rise from lying or sitting to standing slowly to avoid dizziness or falls. If
(ACE inhibitors and ARBs cause vasodilation, resulting in lowered dizziness occurs, the patient should sit or lie down and not attempt to
blood pressure. A first-dose effect may occur with a significant drop in stand or walk, until the sensation passes.
blood pressure with the first few doses. Orthostatic hypotension may • Stop taking the medication if the blood pressure is 90/60 mmHg or
increase the risk of falls and injury.) below, or per parameters set by the healthcare provider, and promptly
notify the provider.
• Call for assistance prior to getting out of bed or attempting to walk
alone, and to avoid driving or other activities requiring mental alertness
or physical coordination until the effects of the drug are known.
• Continue to monitor periodic electrolyte levels, especially potassium, Instruct the patient on the need to:
hepatic and renal function laboratory values, and ECG as appropriate. • Return periodically for laboratory work.
(Hyperkalemia may occur and may increase the risk of dysrhythmias.) • Carry a wallet identification card or wear medical identification jewelry
indicating ACE inhibitor or ARB therapy.
• Monitor for persistent dry cough or increasing cough severity. (ACE Teach the patient:
inhibitors increase bradykinin levels, which results in a dry cough. A • To anticipate a dry cough that may persist and to use nonmedicinal
change in the severity of the cough may indicate another disease
process or may result in the need to consider other medications.) measures to treat (e.g., OTC cough lozenges, hard candy, or increased
fluid intake).
• That if the cough becomes troublesome when in a supine position,
sleep with the head elevated on additional pillows.
• To consult with the healthcare provider about the use of antihistamines
to treat a persistent cough unrelieved by nonmedicinal measures.
• To promptly report any change in the severity or frequency of a cough.
Any cough accompanied by shortness of breath, fever, or chest pain
should be reported immediately because it may indicate more severe
pathologic conditions.
• Monitor for hyperkalemia. (Reduced aldosterone levels may cause Instruct the patient:
hyperkalemia, especially in patients with diabetes or impaired kidney • On the signs of hyperkalemia (nausea, irregular heartbeat, profound
function. Lifespan: The older adult may be at greater risk for hyperka-
lemia related to renal effects of aging.) fatigue or muscle weakness, and slow or faint pulse) and to report
them immediately.
• To avoid salt substitutes containing potassium chloride, consuming
snacks advertised as “electrolyte-fortified,” specialized sports drinks
that contain high levels of potassium, or excessive intake of foods high
in potassium different from their normal diet.
• Monitor for the development of angioedema. (Lifespan and Diverse • Teach the patient to observe for and immediately report swelling of the
Patients: The older adult and patients of African American heritage are mouth, lips, tongue, or throat, hoarseness, or sudden difficulty with
at higher risk for the development of angioedema.) breathing.
• Assess for the possibility of pregnancy or breastfeeding. (Lifespan: • Lifespan: The drug should not be taken during pregnancy, if preg-
The drugs may cause birth defects if taken during pregnancy and may nancy is suspected, or while breastfeeding.
have adverse effects on the breastfeeding child.)
Patient understanding of drug therapy: • The patient, family, or caregiver should be able to state the reason for
• Use opportunities during the administration of medications the drug, appropriate dose and scheduling, what adverse effects to
observe for and when to report them, and the anticipated length of
and during assessments to discuss the rationale for the drug medication therapy.
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., take the first
dose of the new prescription at bedtime. (Utilizing time during nurse
administration of these drugs helps to reinforce teaching.)
536 Unit 5 Pharmacology of the Cardiovascular System
Understanding Chapter 31
Key Concepts Summary 31.5 The renin-angiotensin-aldosterone pathway offers
multiple points for drug intervention.
31.1 The formation of angiotensin II requires two
enzymatic steps. 31.6 ACE inhibitors are key drugs in the
pharmacotherapy of hypertension and heart failure.
31.2 Renin secretion is controlled by the juxtaglomerular
cells of the kidney and the sympathetic nervous 31.7 Angiotensin II receptor blockers act by inhibiting
system. the AT1 receptor and are used for hypertension and
heart failure.
31.3 Angiotensin-converting enzyme is responsible for
the formation of angiotensin II. 31.8 Aldosterone antagonists block the biological effects
of aldosterone in the renal tubule.
31.4 Angiotensin II has multiple effects on the
cardiovascular system that raise blood pressure and
affect cardiac function.
CASE STUDY: Making the Patient Connection
Remember the patient The nurse asks Carlos to describe a typical day. During
“Carlos Avaya” at the the description the nurse notices a concerning pattern.
beginning of the chapter? Because Carlos lives alone, he frequently cooks for himself.
Now read the remainder of He admits that he enjoys salty foods such as pretzels and
the case study. Based on the popcorn. He denies having consumed either prior to the
information presented visit to the clinic. However, to Carlos, cooking a meal
within this chapter, respond to the critical thinking involves preparing canned processed foods and frozen din-
questions that follow. ners. He never reads food labels. Without recording a com-
plete dietary history, the nurse is able to determine that
Carlos Avaya is a 26-year-old single man who was diag- Carlos’s intake of sodium-rich foods is quite extensive.
nosed with primary HTN 4 months ago. Carlos has been
taking losartan (Cozaar) 50 mg daily PO and has been Critical Thinking Questions
faithful in taking the medication as prescribed. When Car-
los was told that his blood pressure was still elevated dur- 1. How does losartan (Cozaar) work to reduce blood
ing this clinic visit, he was obviously distressed and pressure?
concerned.
2. Considering the adverse effects of losartan (Cozaar),
The healthcare team begins to investigate external fac- when would you instruct Carlos to notify the
tors that may be causing his blood pressure to remain ele- prescriber?
vated. Carlos has never smoked or used alcohol. He does
not like to exercise but participates in a weekly game of 3. In addition to teaching Carlos about losartan (Cozaar),
soccer at the nearby community center. He denies being what additional health teaching should he receive?
overly stressed with work or home life. Furthermore, he
claims that he rarely salts his food. Answers to Critical Thinking Questions are available on the
faculty resources site. Please consult with your instructor.
Additional Case Study 2. What are the main precautions specific to spironolac-
tone that should be included in the teaching plan?
Ella Daniels, a middle-aged African American woman,
takes spironolactone (Aldactone) for HTN. As the nurse Answers to Additional Case Study questions are available on
responsible for providing her with health information, you the faculty resources site. Please consult with your instructor.
plan to talk with her about this drug.
1. How does the mechanism of action of spironolactone
differ from that of lisinopril (Prinivil, Zestril)?
Chapter 31 Drugs Affecting the Renin-Angiotensin-Aldosterone System 537
Chapter Review 4. The nurse is caring for a patient with chronic hyper-
tension. The patient is receiving losartan (Cozaar)
1. The community health nurse teaches a patient at daily. Which patient manifestations would the nurse
home. Lisinopril (Prinivil) has been prescribed for the conclude is an adverse effect of this medication?
patient. Which statement, if made by the patient, indi-
cates that further teaching is necessary? 1. Irritability and tremors
2. Headache and dizziness
1. “I should notify my healthcare provider of 3. Sleepiness and slurred speech
symptoms of hypotension such as dizziness or 4. Pruritus and rash
fainting.”
5. Irbesartan (Avapro) is prescribed for each of the fol-
2. “I should avoid the use of salt substitutes lowing patients. A nurse should question the order for
containing potassium.” a patient who has:
3. “If a dose is missed, I will take it as soon as 1. Severe dehydration from diuretic therapy.
possible but not too close to the next dose.” 2. Long-term diabetes mellitus.
3. A systolic blood pressure of 162.
4. “Too much calcium in my diet will elevate my 4. A 5-year history of heart failure.
blood pressure.”
6. The nurse determines that the patient does not under-
2. The patient states, “I always keep my lisinopril (Prini- stand an important principle in self-administration of
vil) on my kitchen window sill. It helps me to remem- benazepril (Lotensin) when the patient makes which
ber to take it.” The nurse’s response would be based statement?
on which pharmacologic concept about heat and
moisture? 1. “I will learn to monitor my own blood pressure
and write down all my daily measurements.”
1. They cause the medicine to break down.
2. They enhance the strength of the drug. 2. “While taking this medication, I should avoid over-
3. They crystallize the medication. the-counter medications for colds, sinus, or
4. They convert the medicine to toxic metabolites. appetite control.”
3. A patient is hospitalized for uncontrolled hyperten- 3. “This drug will not impair thinking and reaction
sion and is receiving enalapril (Vasotec). The nurse time. I don’t need to wait to start driving my car.”
should notify the healthcare provider if the patient
exhibits: 4. “Drinking alcohol while on this medication can
lower my blood pressure and lead to dizziness and
1. Dry mucous membranes. faintness.”
2. A decline in systolic blood pressure.
3. Nonproductive cough. See Answers to Chapter Review in Appendix A.
4. A reduction of diastolic blood pressure.
References National Center for Complementary and Integrative
Health. (2016). Hawthorn. Retrieved from https://nccih.
Diane, A., Borthwick, F., Wu, S., Lee, J., Brown, P. N., nih.gov/health/hawthorn
Dickinson, T. A., … Proctor, S. D. (2016). Hypolipidemic
and cardioprotective benefits of a novel fireberry Rababa’h, A. M., Altarabsheh, S. E., Haddad, O., Deo, S.
hawthorn fruit extract in the JCR:LA-cp rodent model V., Obeidat, Y., & Al-Azzam, S. (2016). Hawthorn herb
of dyslipidemia and cardiac dysfunction. Food & increases the risk of bleeding after cardiac surgery: An
Function, 7, 3943–3952. doi:10.1039/c6fo01023g evidence-based approach. The Heart Surgery Forum, 19,
E175–E179. doi:10.1532/hsf.1570
Mustapha, N., Mokdad-Bzéouich, I., Maatouk, M.,
Ghedira, K., Hennebelle, T., & Chekir-Ghedira, L. (2016). Silverthorn, D. U. (2013). Human physiology: An integrated
Antitumoral, antioxidant, and antimelanogenesis approach (6th ed.). Upper Saddle River, NJ: Pearson.
potencies of hawthorn, a potential natural agent in the
treatment of melanoma. Melanoma Research, 26, 211–222.
doi:10/1097/CMR.0000000000000240
538 Unit 5 Pharmacology of the Cardiovascular System
Selected Bibliography Li, E. C., Heran, B. S., & Wright, J. M. (2014). Angiotensin
converting enzyme (ACE) inhibitors versus angiotensin
Cheng, J., Zhang, W., Zhang, X., Han, F., Li, X., He, X., … receptor blockers for primary hypertension. Cochrane
Chen, J. (2014). Effect of angiotensin-converting Database of Systematic Reviews, 8, Art. No. CD009096.
enzyme inhibitors and angiotensin II receptor blockers doi:10.1002/14651858.CD009096.pub2
on all-cause mortality, cardiovascular deaths, and
cardiovascular events in patients with diabetes Palla, M., Ando, T., Androulakis, E., Telila, T., & Briasoulis,
mellitus: A meta-analysis. JAMA Internal Medicine, 174, A. (2017). Renin-angiotensin system inhibitors vs other
773–785. doi:10.1001/jamainternmed.2014.348 antihypertensives in hypertensive blacks: A meta-
analysis. The Journal of Clinical Hypertension, 19, 344–350.
Davis, L. L. (2015). Hypertension guidelines: Evidence- doi:10.1111/jch.12867
based treatments for maintaining blood pressure
control. The Nurse Practitioner, 40(6), 32–37. Sayer, G., & Bhat, G. (2014). The renin-angiotensin-
doi:10.1097/01.NPR.0000465116.19783.a7 aldosterone system and heart failure. Cardiology Clinics,
32, 21–32. doi:10.1016/j.ccl.2013.09.002
Lee, H.-Y., Sakuma, I., Ihm, S.-H., Goh, C.-W., & Koh, K. K.
(2014). Statins and renin-angiotensin system inhibitor Silverthorn, D. U. (2016). Human physiology: An integrated
combination treatment to prevent cardiovascular approach (7th ed.). Hoboken, NJ: Pearson.
disease. Circulation Journal, 78, 281–287. doi:10.1253/
circj.CJ-13-1494 Xue, H., Lu, Z., Tang, W. L., Pang, L. W., Wang, G. M.,
Wong, G. W., & Wright, J. M. (2015). First-line drugs
Lefler, L. L., Hadley, M., Tackett, J., & Thomason, A. P. inhibiting the renin angiotensin system versus other
(2015). New cardiovascular guidelines: Clinical practice first-line antihypertensive drug classes for hypertension.
evidence for the nurse practitioner. Journal of the Cochrane Database of Systematic Reviews, 1, Art.
American Association of Nurse Practitioners, 28(5), 241–248. No. CD008170. doi:10.1002/14651858.CD008170.pub2
doi:10.1002/2327-6924.12262
“I feel terrible. I have no
energy and I feel as weak as
a kitten. Lately, I don’t even
feel like getting out of bed in
the mornings. I try to take
my medications just as
I was told to do.”
Patient “Katherine Crosland”
Chapter 32
Diuretic Therapy and the
Pharmacotherapy of Chronic
Kidney Disease
Chapter Outline Learning Outcomes
cc Review of Renal Physiology After reading this chapter, the student should be able to:
cc Pharmacotherapy for Patients with Chronic Kidney
1. Explain the role of the urinary system in maintaining
Disease fluid, electrolyte, and acid–base homeostasis.
cc Diuretic Therapy
2. Explain the physiologic processes that change the
Loop (High-Ceiling) Diuretics composition of filtrate as it travels through the
PROTOTYPE Furosemide (Lasix), p. 546 nephrons.
Thiazide and Thiazide-Like Diuretics
PROTOTYPE Hydrochlorothiazide (Microzide), p. 549 3. Explain how pharmacotherapy is modified in
Potassium-Sparing Diuretics patients with chronic kidney disease.
PROTOTYPE Spironolactone (Aldactone), p. 551
Osmotic Diuretics 4. Identify indications for diuretics.
PROTOTYPE Mannitol (Osmitrol), p. 553
Carbonic Anhydrase Inhibitors 5. Compare and contrast the loop, thiazide, potassium-
PROTOTYPE Acetazolamide (Diamox), p. 554 sparing, osmotic, and carbonic anhydrase inhibitor
diuretics.
6. Describe the nurse’s role in the pharmacologic
management of chronic kidney disease and in
diuretic therapy.
7. For each of the classes shown in the chapter outline,
identify the prototype and representative drugs and
explain the mechanism(s) of drug action, primary
indications, contraindications, significant drug
interactions, pregnancy category, and important
adverse effects.
8. Apply the nursing process to care for patients who
are receiving pharmacotherapy with diuretics.
539
540 Unit 5 Pharmacology of the Cardiovascular System
Key Terms glomerular filtration rate osmotic pressure, 552
(GFR), 542 reabsorption, 541
carbonic anhydrase, 554 secretion, 541
chronic kidney disease, 541 glomerulus, 540 symporter, 545
diuretic, 543
filtrate, 540 natriuresis, 543
nephrons, 540
The kidneys serve an amazing role in maintaining homeo- glomerular pores and collected by Bowman’s capsule, the
stasis. By filtering a volume equivalent to all of the body’s first portion of the collecting system of the nephron.
extracellular fluid every 100 minutes, the kidneys are able Together, the glomerulus and Bowman’s capsule are called
to make immediate adjustments to fluid volume, electro- the renal corpuscle. During filtration, not all substances
lyte composition, and acid–base balance. Failure of the kid- in the blood reach Bowman’s capsule. Plasma proteins and
neys to adjust to changing internal conditions of the body the formed elements of the blood—the erythrocytes, leuko-
may result in dire consequences, and pharmacotherapy is cytes, and platelets—are too large to pass through the pores
often used to correct these imbalances. This chapter exam- of the glomerulus and thus continue circulating through
ines diuretics, drugs that increase urine output, and other the bloodstream. Water and other small molecules in
medications used to treat patients with renal dysfunction. plasma, however, readily pass through the glomerular
pores and enter the next section of the nephron.
PharmFACT
The fluid filtered into Bowman’s capsule is called filtrate.
More than 17,000 kidney transplants were performed in Essentially, the initial composition of filtrate may be thought
2014. Over 100,000 people are on the waiting list for kidney of as plasma minus proteins. After leaving Bowman’s cap-
transplants (National Kidney Foundation, 2016). sule, the filtrate enters the proximal tubule, travels through
the loop of Henle and, subsequently, the distal tubule. The
Review of Renal Physiology proximal and distal tubules are twisted and highly convo-
luted, which greatly increases the length of the nephron,
32.1 The kidneys are major organs of excretion allowing for enhanced processing of substances in the filtrate.
and body homeostasis. The filtrate eventually reaches common collecting ducts,
which empty into increasingly larger collecting structures
When most people think of the kidneys, they think of inside the kidney. Fluid leaving the collecting ducts and enter-
excretion. Although this is certainly true, the kidneys have ing subsequent portions of the kidney is called urine. Approx-
many other essential homeostatic functions. The kidneys imately 1 mL of urine is produced each minute. Parts of the
are the primary organs for regulating fluid balance, elec- nephron and their functions are illustrated in Figure 32.1.
trolyte composition, and the pH of body fluids. They also
secrete the enzyme renin, which helps to regulate blood Efferent
pressure (see Chapter 31), and erythropoietin, a hormone arteriole Proximal tubule
that stimulates red blood cell production (see Chapter 39).
In addition, the kidneys are responsible for the production Bowman's
of calcitriol, the active form of vitamin D, which helps capsule
maintain bone homeostasis (see Chapter 72). It is not sur-
prising that our overall health is strongly dependent on Glomerulus
the proper functioning of the kidneys.
Afferent
The urinary system consists of two kidneys, two ure- arteriole
ters, one urinary bladder, and a urethra. Blood enters the
kidneys through the large renal arteries, bringing 25% of Arcuate artery
the total cardiac output to the kidneys each minute. After a
series of branches, blood enters the nephrons, the func- Distal tubule
tional units of the kidney. Each kidney contains over 1 mil-
lion nephrons. Arcuate Descending
vein and
In the nephron, blood travels at high pressure through ascending
the glomerulus, a specialized capillary containing pores. Collecting loop of
The fluid portion of the blood is filtered through the duct Henle
Figure 32.1 The nephron. Peritubular
capillaries
Chapter 32 Diuretic Therapy and the Pharmacotherapy of Chronic Kidney Disease 541
Many drugs are small enough to pass through the Table 32.1 Substances Filtered, Reabsorbed, and
glomerulus and enter the filtrate. If the drug is bound to a
plasma protein, however, the drug–protein complex will be Excreted by the Kidneys
too large to be filtered and will continue circulating in the
blood. Plasma proteins such as albumin are also too large Substance Filtered Reabsorbed Excreted
to pass through the filter and will not be present in the fil- 178–179 L 1–2 L
trate or in the urine of healthy patients. The appearance of Water 180 L 162 g 0g
excess plasma proteins in urine (proteinuria or albumin- 1.9 g 0.1 g
uria) is a sign of kidney pathology. For example, during Glucose 162 g
glomerulonephritis the glomeruli become inflamed and 575 g 4g
the size of the pores increases, allowing larger substances Proteins 2g 29.6 g 2g
such as proteins to enter the filtrate. 274.97 g 0.03 g
Ions
CONNECTION Checkpoint 32.1 0g 1.6 g
Sodium 579 g 24 g 30 g
From what you learned in Chapter 3, explain how plasma protein 7.7 g 0.8 g
binding markedly affects the excretion of a drug. Answers to Con- Potassium 29.6 g
nection Checkpoint questions are available on the faculty resources site.
Please consult with your instructor. Bicarbonate 275 g
32.2 The composition of filtrate changes Metabolic Waste Products
dramatically as a result of the processes
of reabsorption and secretion. Creatine 1.6 g
The filtrate’s composition changes dramatically as it makes Urea 54 g
its long journey through the nephron. Some substances in
the filtrate cross the tubule walls to reenter the blood; this Uric acid 8.5 g
process is known as tubular reabsorption. Water is the
most important molecule reabsorbed in the tubule. For neostigmine, and trimethoprim. Potassium, phosphate,
every 180 L of water entering the filtrate each day, approxi- hydrogen, and ammonium ions also enter the filtrate
mately 178.5 L are reabsorbed, leaving only 1.5 L to be through active secretion. The amounts of selected substances
excreted in the urine. Over 65% of the filtered sodium is filtered, reabsorbed, and excreted are shown in Table 32.1.
reabsorbed in the proximal tubule, and 25% in the loop of
Henle. Glucose, amino acids, and essential ions such as Reabsorption and secretion are critical to the pharma-
chloride, calcium, and bicarbonate are also reabsorbed. cokinetics of drugs. Some drugs are reabsorbed, whereas
others are secreted into the filtrate. For example, approxi-
Hormones can markedly affect the degree of reabsorp- mately 90% of a dose of penicillin G enters the urine
tion in the renal tubule. Aldosterone, for example, exerts a through secretion. When the kidney is diseased, reabsorp-
major effect on the tubule by stimulating sodium reabsorp- tion and secretion mechanisms are impaired and serum
tion in the distal portions of the nephron. Under the influ- drug levels may be dramatically affected. Figure 32.2 illus-
ence of aldosterone, potassium excretion is increased trates the possible fates of drugs entering the glomerulus.
because this ion is “exchanged” for sodium ions, which are
reabsorbed. Antidiuretic hormone (ADH) also affects kid- CONNECTION Checkpoint 32.2
ney function, increasing water reabsorption by making the
collecting ducts become more permeable to water. The for- From what you learned in Chapter 31, explain the relationship be-
mation of urine is indeed a dynamic process that under- tween angiotensin II and the release of aldosterone by the adrenal
goes continuous modification as the filtrate travels down gland and its significance to pharmacology. Answers to Connection
the tubule. Many drugs have the ability to either enhance Checkpoint questions are available on the faculty resources site. Please
or block the effects of hormones on tubular processes. consult with your instructor.
Certain ions and molecules too large to pass through Pharmacotherapy for Patients
Bowman’s capsule may still enter the urine by crossing from with Chronic Kidney Disease
the blood to the filtrate using a process known as tubular
secretion. The tubule contains molecular pumps for organic 32.3 Chronic kidney disease may significantly
acids and bases. Acidic drugs secreted in the proximal tubule impact the success of pharmacotherapy.
include penicillin G, ampicillin, sulfisoxazole, nonsteroidal
anti-inflammatory drugs (NSAIDs), and furosemide. Basic Chronic kidney disease (CKD), sometimes called renal
drugs include procainamide, epinephrine, dopamine, failure, is a condition characterized by a gradual loss of
kidney function, usually over a period of months or years.
The kidneys lose their ability to maintain electrolyte and
fluid balance and excrete waste products. Due to its pro-
longed, gradual development and its nonspecific symp-
toms, CKD may go undetected for many years. By the time
the disease is diagnosed, the loss of renal function may be
irreversible. The leading causes of CKD are diabetes and
uncontrolled hypertension (HTN).
Pharmacotherapy with nephrotoxic drugs can lead to
either CKD or acute renal failure. It is good practice for the
542 Unit 5 Pharmacology of the Cardiovascular System Collecting
tubule
Peritubular capillaries
-P -P
Renal artery -P -P -P
-P
-P
-P
Bowman’s
capsule
Return to Renal
circulation vein
-P
-P To urine
Loop of Henle
Filtered and excreted in urine
Filtered and reabsorbed in proximal tubule
Not filtered, secreted in distal tubule
-P Protein bound, not filtered
Figure 32.2 Fates of drugs entering the glomerulus: filtration, reabsorption,
secretion, and excretion.
nurse to remember common nephrotoxic drugs, which are PharmFACT
listed in Table 32.2, so that kidney function may be continu-
ously monitored during therapy with these drugs. More than 661,000 Americans have CKD—about 14% of the
general population. African Americans have a 3 to 4 times
The last stage of CKD, which requires dialysis or a trans- greater risk for CKD than Caucasians (National Institute of
plant for survival, is called end-stage renal disease (ESRD). Diabetes and Digestive and Kidney Diseases, 2016).
The primary treatment goal for a patient with CKD is to main-
tain blood flow through the kidneys and adequate urine out- The most basic diagnostic test of kidney function is a
put so that metabolic wastes can be removed from the body. urinalysis, which examines urine for the presence of blood
cells, proteins, pH, specific gravity, ketones, glucose, and
Table 32.2 Selected Nephrotoxic Drugs microorganisms. The urinalysis can detect proteinuria and
albuminuria, which are the primary measures of structural
Drug or Class Indication/Classification kidney damage. Although easy to perform, the urinalysis is
nonspecific: Many diverse diseases and conditions can
aminoglycosides Antibiotics cause abnormal urinalysis values. Serum creatinine and
Systemic antifungal blood urea nitrogen (BUN) are additional laboratory mea-
amphotericin B (Amphotec, AmBisome) HTN, HF sures for detecting kidney disease. To provide a more
definitive diagnosis, diagnostic imaging such as computed
angiotensin-converting enzyme (ACE) Antineoplastics tomography, sonography, or magnetic resonance imaging
inhibitors Immunosuppressants may be necessary. Renal biopsy may be performed to
obtain a more specific diagnosis.
cisplatin (Platinol), carboplatin (Paraplatin) Antiviral
Inflammation and pain The best marker for estimating kidney function is the
cyclosporine (Neoral, Sandimmune), glomerular filtration rate (GFR), which is the volume of
tacrolimus (Prograf) Anti-infective (Pneumocystis) water filtered through the Bowman’s capsules per minute.
Diagnosis of kidney and The GFR can be used to predict the onset and progression
foscarnet (Foscavir) vascular disorders of CKD and it is a measure of the kidneys’ ability to excrete
nonsteroidal anti-inflammatory drugs
(NSAIDs)
pentamidine (NebuPent, Pentam)
radiographic intravenous (IV) contrast
agents
Chapter 32 Diuretic Therapy and the Pharmacotherapy of Chronic Kidney Disease 543
drugs from the body. With normal values ranging from the kidneys excrete most drugs or their metabolites, many
90 to 120 mL/min, a progressive decline in GFR indicates a medications will require a significant dosage reduction in
reduction in the number of functioning nephrons. As neph- patients with moderate to severe renal disease. The impor-
rons “die,” however, the remaining healthy ones have the tance of this cannot be overemphasized: Administering the
ability to compensate by increasing their filtration capacity. “average” dose to a patient with severe kidney disease can
Because of this, patients with significant kidney damage have fatal consequences.
may be asymptomatic until 50% or more of the nephrons
have become nonfunctional and the GFR has fallen to less Diuretic Therapy
than half its normal value.
32.4 Diuretics are used to treat hypertension,
Kidney disease may also be acute. Acute kidney injury heart failure, accumulation of edema fluid,
(AKI) (also called acute renal failure) requires immediate and chronic kidney disease.
treatment because retention of nitrogenous waste prod-
ucts in the body such as urea and creatinine can result in A diuretic is a drug that increases the formation of urine by
death if left untreated. The most common cause of acute the body. Diuretics do more than increase urine flow; they
kidney injury is renal hypoperfusion, the lack of sufficient also change the rate of excretion of specific electrolytes,
blood flow through the kidneys. Hypoperfusion can lead most importantly sodium and potassium. The goal of most
to permanent destruction of kidney cells and nephrons. To diuretic therapy is to reduce extracellular fluid volume, so
prevent AKI, the cause of the hypoperfusion must be that abnormal fluid retention (edema) by the body may be
quickly identified and corrected. Potential causes include reversed. Excretion of excess fluid in the body is particularly
heart failure (HF), dysrhythmias, hemorrhage, toxins, and important in the management of the following conditions:
dehydration.
• HTN
Pharmacotherapy of CKD attempts to find and cor- • HF
rect the cause of the dysfunction. Diuretics are given to • CKD
increase urine output, and cardiovascular drugs are • Liver failure or cirrhosis
administered to treat underlying HTN or HF. Dietary • Pulmonary edema.
management is often necessary to prevent worsening of
CKD. Depending on the stage of the disease, dietary man- The most common mechanism by which diuretics act
agement may include restriction of protein and reduction is by blocking sodium ion (Na1) reabsorption in the neph-
of sodium, potassium, phosphorous, and magnesium ron, thus sending more Na1 to the urine (natriuresis). The
intake. For patients with diabetes, control of blood glu- human body is particularly sensitive to sodium imbal-
cose through intensive insulin therapy may reduce the ances; dietary intake must be balanced with excretion
risk of renal damage. See Table 32.3 for a summary of mechanisms. For example, a 1% increase in sodium reab-
selected medications used to prevent and treat the com- sorption (retention) could potentially cause a 1.8-L net gain
plications of CKD. of water each day, which is equivalent to 4 lb of body
weight. On the other hand, even small decreases in sodium
The nurse serves a key role in assessing and providing reabsorption can cause net losses of sodium from the body,
interventions for patients with CKD. Once a diagnosis has resulting in volume depletion and circulatory collapse.
been established, all nephrotoxic medications should be
either discontinued or used with extreme caution. Because
Table 32.3 Pharmacologic Management of Chronic Kidney Disease
Complication Pathogenesis Selected Therapies
Anemia Kidneys are unable to synthesize sufficient Epoetin alfa (Epogen, Procrit)
Hyperkalemia erythropoietin for red blood cell production.
Hyperphosphatemia Kidneys are unable to adequately excrete potassium. Dietary restriction of potassium; polystyrene sulfate (Kayexalate) with sorbitol
Kidneys are unable to adequately excrete
Hypervolemia phosphate. Dietary restriction of phosphate; phosphate binders such as calcium
Hypocalcemia carbonate (Os-Cal 500, others), calcium acetate (Calphron, PhosLo),
Metabolic acidosis Kidneys are unable to excrete sufficient sodium and lanthanum carbonate (Fosrenol), sucroferric oxyhydroxide (Velphoro), or
water, leading to water retention. sevelamer (Renagel)
Hyperphosphatemia leads to loss of calcium.
Dietary restriction of sodium; loop diuretics in acute conditions, thiazide
Kidneys are unable to adequately excrete metabolic diuretics in mild conditions
acids.
Usually corrected by reversing the hyperphosphatemia, but additional
calcium supplements may be necessary
Sodium bicarbonate or sodium citrate
544 Unit 5 Pharmacology of the Cardiovascular System
Pharmacotherapy Illustrated 32.1
Sites of Action of the Diuretics
Carbonic anhydrase inhibitors
Inhibit reabsorption of
bicarbonate ion in proximal tubule.
Proximal Thiazide diuretics
convoluted Act on the early distal tubule to
block the reabsorption of sodium,
tubule chloride, and water. Excretion of
potassium is increased.
Distal
convoluted
tubule
Osmotic diuretics Ascending Collecting
Act on the proximal tubule and loop of duct
the loop of Henle to create an Henle
osmotic force that pulls water
into the nephron and increases
the excretion of nearly all
electrolytes.
Loop diuretics Potassium-sparing diuretics
Act on the ascending limb of the Act on the late distal tubule and
loop of Henle to block the collecting ducts to block the
reabsorption of sodium, chloride, reabsorption of sodium and
and water. Excretion of reduce the secretion of
potassium is increased. potassium (sodium–potassium
exchange). Excretion of
potassium is not increased.
These examples illustrate the need for patients to monitor • Loop or high-ceiling. These drugs prevent the reabsorp-
their weight daily when taking diuretics. tion of Na1 in the loop of Henle; thus, they are called
loop diuretics. Because there is an abundance of Na1 in
Natriuresis results in two other important effects. Chlo- the filtrate within the loop of Henle, drugs in this class
ride ions (Cl−) follow sodium, potentially causing hypo- are capable of producing large increases in urine output.
chloremia, a net loss of chloride from the body. In addition,
because water molecules travel passively with sodium ions, • Thiazides. The largest diuretic class, the thiazides act
blocking the reabsorption of Na1 increases the total volume by blocking Na1 in the distal tubule. Because most
of urination, or diuresis. The amount of diuresis produced Na1 has already been reabsorbed from the filtrate by
by a diuretic is directly related to the amount of sodium the time it reaches this part of the nephron, the thia-
reabsorption that is blocked: Those that block the most zides produce less diuresis than loop diuretics.
sodium are the most effective at increasing urine output.
Diuretics also affect the renal excretion of ions such as mag- • Potassium-sparing. The third major class is named
nesium, potassium, phosphate, calcium, and bicarbonate. It potassium-sparing diuretics, because they have mini-
is important to remember that imbalances may occur in vir- mal effect on potassium ion (K1) excretion. These
tually any electrolyte during diuretic therapy. drugs produce a mild diuresis.
Diuretics are classified into five major groups, based • Osmotic. These drugs are relatively inert drugs that
on differences in their chemical nature and mechanism of change the osmolality of filtrate, causing water to
action. The sites in the nephron at which the various diuret- remain in the nephron for excretion. These drugs are
ics act are shown in Pharmacotherapy Illustrated 32.1. very effective but are rarely prescribed because they
can produce potentially serious adverse effects.
Chapter 32 Diuretic Therapy and the Pharmacotherapy of Chronic Kidney Disease 545
Peritubular Peritubular
capillary
Renal tubule Renal tubule capillary
Na+
(a) Symporter KC+l- (b) Symporter
protein in
loop of Henle: protein inhibited by
normal
reabsorption loop diuretic (F): loss KN+a+ F
of sodium ions, Cl-
potassium ions, and
chloride ions
Cl- K+ Na+
Reabsorbed to circulation To urine
Figure 32.3 Symporter protein in the loop of Henle: (a) normal reabsorption of the Na1, K1, and Cl2 ions; (b) inhibition of symporter by
furosemide causes excretion of Na1, K1, and Cl2 ions.
• Carbonic anhydrase inhibitors. These drugs block the chloride in the loop of Henle. This occurs when the drug
enzyme in the nephron responsible for bicarbonate inhibits the molecule responsible for transporting sodium
reabsorption. They produce a weak diuresis and are and chloride from the filtrate to the blood, known as the
rarely used. Na1-K1-2Cl2 symporter. A symporter is a membrane pro-
tein that transports two molecules at the same time. When
It is common practice to combine two or more drugs the loop diuretics block this symporter, sodium and chlo-
in the pharmacotherapy of HTN and fluid retention disor- ride are prevented from being reabsorbed, and diuresis is
ders. Diuretics are often a component of fixed-dose combi- increased. All loop diuretics have an additional action that
nations with drugs from other classes. The primary is responsible for a major adverse effect of drugs in this
rationales for combination therapy are that the incidence class: increasing potassium excretion. An illustration
of adverse effects is decreased and the pharmacologic showing the effects caused when this symporter is inhib-
effects (such as diuresis or blood pressure reduction) may ited is shown in Figure 32.3.
be enhanced. For patient convenience, some of these drugs
are available in single-tablet formulations. Examples of All loop diuretics are available for either oral (PO) or
single-tablet diuretic combinations include the following: parenteral administration and are extensively bound to
plasma proteins. They have relatively short half-lives, and
• Aldactazide. Hydrochlorothiazide and spironolactone extended release preparations are not available. When
• Apresazide. Hydrochlorothiazide and hydralazine given intravenously (IV), loop diuretics have the ability to
• Dyazide. Hydrochlorothiazide and triamterene cause large amounts of fluid to be excreted by the kidney
• Moduretic. Hydrochlorothiazide and amiloride. in a very short time. Loop diuretics are used to reduce the
edema associated with HF, hepatic cirrhosis, or CKD.
Loop (High-Ceiling) Diuretics Furosemide and torsemide are also approved for HTN,
although their short half-lives make them less suitable for
32.5 The most effective diuretics are the loop this indication than thiazide diuretics. Occasionally, loop
diuretics that block sodium reabsorption in the diuretics are given to speed the renal excretion of a drug
loop of Henle. that has been overdosed or a toxin that has been uninten-
tionally ingested. Doses of the loop diuretics are listed in
The most effective diuretics, the loop or high-ceiling Table 32.4.
diuretics, act by blocking the reabsorption of sodium and
Table 32.4 Loop Diuretics
Drug Route and Adult Dose (Maximum Dose Where Indicated) Adverse Effects
bumetanide (Bumex)
ethacrynic acid (Edecrin) PO: 0.5–2 mg/day, may repeat at 4- to 5-h intervals if needed (max: 10 mg/day) Minor hypokalemia, orthostatic hypotension,
IV/IM: 0.5–1 mg over 1–2 min, repeated q2–3h prn (max: 10 mg/day) tinnitus, nausea, diarrhea, dizziness, fatigue
furosemide (Lasix)
torsemide (Demadex) PO: 50–100 mg 1–2 times/day; may increase by 25–50 mg prn (max: 400 mg/ Serious hypokalemia, blood dyscrasias,
day) dehydration, ototoxicity, electrolyte
IV: 0.5–1 mg/kg or 50 mg (max: 100 mg/dose) imbalances, circulatory collapse
PO: 20–80 mg in 1 or more divided doses (max: 600 mg/day)
IV/IM: 20–40 mg in 1 or more divided doses (max: 600 mg/day)
PO/IV: 10–20 mg/day (max: 200 mg/day)
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
546 Unit 5 Pharmacology of the Cardiovascular System
CONNECTIONS: Preparing for Advanced Practice
Chronic Kidney Disease and Prescribing Considerations
Case with CKD and AKI therefore require more thought, especially for
medications that are renally excreted. For prescribing purposes,
Nolan is a 71-year-old African American man who was admitted CKD is divided into three grades:
to the hospital for altered mental status. His daughter Renee
reported that her father had become progressively confused • Mild: GFR 20–50 mL/min; serum creatinine 150–300 μmol/L
and had been having visual and auditory hallucinations, seeing • Moderate: GFR 10–20 mL/min; serum creatinine 300–700
and hearing people and animals that were not really there. In the
past 24 hours, Nolan’s symptoms had become more persistent μmol/L
and she became more and more concerned. Nolan has a 9-year • Severe: GFR less than 10 mL/min; serum creatinine more
history of HF and type 2 diabetes, and was diagnosed
10 months ago with stage V CKD, thought to be primarily due to than 700 μmol/L (GFR above 50 mL/min does not usually
his diabetic nephropathy. require any dosage adjustment.)
On admission, the nurse practitioner hospitalist, his bed- Drugs to which particular attention should be given include
side nurse, and the unit’s Pharm D. reviewed his medications histamine H2-receptor antagonists, specific antibiotics, anticon-
with Renee. Nolan was taking 81 mg of aspirin, atenolol, atorv- vulsants, digoxin, and NSAIDs. Prescribing any medication that
astatin, calcium acetate, insulin, and had recently started increases potassium levels, such as potassium supplements and
300 mg of gabapentin 3 times daily for the diabetic neuropathy. potassium-sparing diuretics, is potentially very dangerous.
On physical examination, he was sleepy but arousable. His Additionally, methotrexate, enoxaparin, and metformin should no
blood pressure was 136/86 mmHg; pulse was 72 beats/min longer be prescribed even with a mild grade of CKD. With cardio-
(regular); respiratory rate was 14 breaths/min; and oxygen satu- vascular (e.g., atenolol), antidiabetic (e.g., glibenclamide), or anti-
ration 96%. What pharmacologic factors should the team be convulsive (e.g., gabapentin) drugs, the recommendation is to
considering for Nolan? use alternative medications, such as metoprolol, gliquidone, or
carbamazepine, that are not renally excreted or are independent
Discussion of kidney function. Drug dose adjustments should be considered
with antimicrobial (e.g., ampicillin), antiviral (e.g., acyclovir), and
Kidney disease, both acute kidney injury (AKI) and CKD, affects some chemotherapeutic and cytotoxic drugs (e.g., cisplatin).
every organ system in the body. The number of patients with Products with a high sodium content (e.g., antacids) should be
AKI and CKD has increased due to the aging populations and avoided because they may cause sodium and water retention in
medical advancements. Prescribing considerations for patients patients with CKD (Carville, Wonderling, & Stevens, 2014).
The rapid excretion of large amounts of fluid has the prescribed for patients with moderate to severe fluid reten-
potential to produce serious adverse effects, including tion, such as acute pulmonary edema, or when thiazide
dehydration and electrolyte imbalances. Signs of dehydra- diuretics have failed to achieve therapeutic goals.
tion include thirst, dry mouth, weight loss, and headache.
Dizziness and fainting can result from the fall in blood PROTOTYPE DRUG Furosemide (Lasix)
pressure caused by the rapid fluid loss. Potassium deple-
tion can be serious and result in dysrhythmias. Potassium Classification T herapeutic: Antihypertensive drug for
supplements are often prescribed concurrently with these heart failure and edema
diuretics to prevent hypokalemia. Potassium loss is of par-
ticular concern to those concurrently taking digoxin (Lan- Pharmacologic: Loop- or high-ceiling-
oxin), because hypokalemia predisposes these patients to type diuretic
dysrhythmias. With large doses, significant loss of sodium,
magnesium, and calcium is possible. Continuous use of Therapeutic Effects and Uses: An established diuretic
loop diuretics in postmenopausal women may affect bone approved in 1966, furosemide is frequently used in the treat-
metabolism due to excessive calcium loss. Loop diuretics ment of acute edema associated with liver cirrhosis, CKD,
can cause gout in some patients due to hyperuricemia, the or HF because it has the ability to remove large amounts of
accumulation of uric acid in the blood. edema fluid from the patient in a short time. When given IV,
diuresis begins within 5 minutes, providing rapid relief from
Although rare, loop diuretics may cause ototoxicity, distressing symptoms such as dyspnea. Unlike the thiazide
which may manifest as tinnitus, vertigo, or deafness. Use of diuretics, furosemide is able to increase urine output even
other ototoxic drugs such as the aminoglycoside antibiotics when blood flow to the kidneys is diminished, which makes
should be avoided during loop diuretic therapy due to the it of particular value in patients with low cardiac output or
potential for additive hearing impairment. Due to the risk CKD. It is also approved for HTN, although it is not a pre-
for serious adverse effects, loop diuretics are normally ferred drug for this indication because of its short half-life
and potential for serious adverse effects.
Chapter 32 Diuretic Therapy and the Pharmacotherapy of Chronic Kidney Disease 547
Mechanism of Action: Furosemide prevents the a diminished diuretic effect. Additive hypotension will
reabsorption of sodium and chloride by blocking the Na−- occur if furosemide is given concurrently with antihyper-
K−-2Cl− symporter in the loop of Henle. Because this is tensives, including other diuretics. Use of ethanol should
the region of the nephron that normally filters the bulk of be restricted because it may add to the hypotensive and
sodium, furosemide can cause a profound diuresis. The diuretic actions of furosemide. Furosemide should not
e xtensive diuresis results in the increased urinary excre- be used concurrently with aminoglycoside antibiotics
tion of sodium, chloride, potassium, and hydrogen ions. due to the possibility of additive nephrotoxicity and oto-
toxicity. Herbal/Food: Oral aloe can decrease the levels
Pharmacokinetics: PO, IV, intramuscular (IM) of potassium and should not be used concurrently with
Route(s) loop diuretics. Use with hawthorn could result in additive
Absorption 60% absorbed PO hypotensive effects. Ginseng may decrease the effective-
Distribution ness of loop diuretics. High sodium intake can reduce the
Distributed to most tissues; e ffectiveness of diuretics; patients should be placed on a
Primary metabolism crosses the placenta; secreted sodium-restricted intake of 1500 to 2300 mg/day.
Primary excretion in breast milk; 95% bound to
Onset of action plasma protein Treatment of Overdose: Overdose with furosemide
can result in serious hypotension, fluid loss, and electro-
Duration of action Hepatic (small amounts) lyte imbalances. Treatment is supportive with replacement
of fluids and electrolytes and the possible administration
Renal of a vasopressor.
PO: 30–60 min; IV: 5 min; IM: Pregnancy: Category C.
10–30 min
Nursing Responsibilities: Key nursing implications
PO: 6–8 h; IV: 2 h; IM: 4–8 h for patients receiving furosemide are included in the Nurs-
ing Practice Application for Patients Receiving Pharmaco-
Adverse Effects: The greatest concerns during furo- therapy with Diuretics.
semide therapy are excessive fluid loss and electrolyte
imbalances. Hypovolemia may cause orthostatic hypoten- Drugs Similar to Furosemide (Lasix)
sion and syncope. Imbalances may occur in any or all electro-
lytes, causing symptoms such as tachycardia, dysrhythmias, Furosemide is the most commonly prescribed drug in this
nausea, and vomiting. Ototoxicity is rare but may result in class. Other loop diuretics include bumetanide, ethacrynic
permanent hearing deficit. Hyperuricemia caused by the acid, and torsemide.
drug may cause exacerbations of gout. In patients with
hypokalemia and hypochloremia, furosemide may induce Bumetanide (Bumex): Approved in 1983, bumetanide is
metabolic alkalosis. Black Box Warning: Furosemide is a indicated for ascites (excess fluid in the abdomen) and the
potent diuretic that, if given in excessive amounts, may lead treatment of peripheral edema, usually associated with HF
to profound diuresis with water and electrolyte depletion. or CKD. This drug is available by the PO, IV, and IM routes
Careful medical supervision is required. and is 40 times more potent than furosemide but has a
shorter duration of action. It may be used in acute clinical
Contraindications/Precautions: Contraindications situations when furosemide has proved ineffective in
include hypersensitivity to furosemide or sulfonamide patients with severe CKD. Like furosemide, bumetanide
antibiotics, anuria, hepatic coma, or severe fluid or electrolyte can cause electrolyte imbalances, hypotension, and dehy-
depletion. Due to its high potency, fluid loss must be care- dration. Unlike furosemide and torsemide, bumetanide is
fully monitored to avoid possible dehydration and hypoten- not approved for HTN, although it may be used off-label
sion. Any preexisting hypovolemia or hypotension should for that indication. This drug is pregnancy category C.
be corrected before furosemide therapy is initiated. Because
loop diuretics can increase blood glucose, serum glucose lev- Ethacrynic acid (Edecrin): Approved in 1967, ethacrynic
els should be assessed in patients with diabetes mellitus. acid is indicated for the treatment of edema, usually asso-
ciated with HF, hepatic cirrhosis, or CKD. Given by either
Drug Interactions: Hypokalemia from the use of the oral or IV route, ethacrynic acid is the only loop
furosemide may cause dysrhythmias in patients taking diuretic that does not contain a sulfur group in its struc-
digoxin; therefore, combination therapy with furosemide ture; thus it can safely be used in patients allergic to sul-
and digoxin should be avoided or carefully monitored. fonamides. Of the loop diuretics, ethacrynic acid causes
Concurrent use with corticosteroids, amphotericin B, or the most severe hearing loss, which may be irreversible.
other potassium-depleting drugs can result in hypokale- The patient must be carefully monitored to prevent exces-
mia. When given with lithium, elimination of lithium is sive electrolyte and fluid losses. Although ethacrynic acid
decreased, causing a higher risk of toxicity. Furosemide
may diminish the hypoglycemic effects of sulfonylureas
and insulin. Concurrent use with NSAIDs can result in
548 Unit 5 Pharmacology of the Cardiovascular System
CONNECTIONS: Community- Thiazide and Thiazide-Like Diuretics
Oriented Practice
32.6 The thiazides are the most commonly
Diuretics: A Banned Substance? prescribed class of diuretics.
Diuretics are included in the banned substance list by the The thiazides comprise the largest and most commonly
International Olympic Committee (IOC) and the World Anti- prescribed class of diuretics. Like the loop diuretics, the
Doping Agency (WADA, 2017) except under highly regulated thiazides block a symport protein in the renal tubule wall
use for clinical conditions. Elite athletes seeking a competitive that is responsible for reabsorbing sodium and chloride
edge may use diuretics to achieve rapid weight loss to meet ions from the filtrate. However, the thiazides block a differ-
specific weight categories in some sports. Diuretics have also ent symport protein and in a different location than the
been used illicitly to mask the presence of other banned sub- loop diuretics. The thiazides act on the Na1Cl2 symporter
stances by reducing their concentration in urine (by increasing in the distal tubule to block Na1 reabsorption and increase
urine volume) or increasing their excretion (by altering urine K1 and water excretion. The thiazides are less effective
pH). Hydrochlorothiazide and furosemide are the most com- than the loop diuretics because over 90% of the Na1 has
monly detected diuretics, although all classifications have already been reabsorbed by the time the filtrate reaches the
been detected. Not all drugs are able to be detected, how- distal tubule. There are simply fewer Na1 to block; thus
ever, and until better drug detection techniques are devel- the maximum diuresis produced by thiazides is less than
oped, drug use in athletics for competitive advantage, the loop diuretics.
including the use of diuretics, will continue.
The primary indication for thiazide diuretics is the
is not approved for HTN, it may be prescribed off-label for treatment of mild to moderate HTN. Mild HTN can often
this indication. This drug is pregnancy category B. be managed with only a thiazide diuretic, whereas moder-
ate to severe HTN often requires two or more antihyperten-
Torsemide (Demadex): Approved in 1993, torsemide is sive drugs. Thiazides are also indicated for mild to
indicated for the treatment of HTN and edema, usually moderate edema due to HF, hepatic cirrhosis, or CKD.
associated with HF, hepatic cirrhosis, or CKD. Given by They are not effective in patients with severe organ impair-
either the oral or IV route, torsemide is twice as potent as ment because their ability to produce a diuresis diminishes
furosemide and has a longer half-life, which offers the as blood flow through the kidneys is reduced. Doses of the
advantage of once-a-day dosing. The incidence of ototoxic- thiazide diuretics are listed in Table 32.5.
ity with torsemide is low, and the risk of hypokalemia is
less than that of other drugs in this class. At higher doses, Thiazides are available only by the PO route with the
however, torsemide carries the same potential risks as exception of chlorothiazide (Diuril), which may be
furosemide and other loop diuretics, including electrolyte administered PO or parenterally. All the thiazide diuret-
imbalances and hypovolemia. Torsemide is contraindi- ics have equivalent effectiveness and safety profiles.
cated in patients with sensitivity to sulfonylureas. This They differ, however, in their potency and duration of
drug is pregnancy category B. action. For example, metolazone (Zaroxolyn) is 10 times
more potent than hydrochlorothiazide (Microzide). At
Table 32.5 Thiazide and Thiazide-Like Diuretics
Drug Route and Adult Dose (Maximum Dose Where Indicated) Adverse Effects
Short Acting
chlorothiazide (Diuril) PO: 250 mg–1 g/day in 1–2 divided doses Minor hypokalemia, fatigue
IV: 250 mg–1 g/day in 1–2 divided doses (max: 2 g/day) Serious hypokalemia, electrolyte depletion,
hydrochlorothiazide (Microzide) PO: 25–100 mg/day as a single or divided dose (max: 50 mg/day for dehydration, hypotension, hyponatremia,
HTN; 100 mg/day for edema) hyperglycemia, coma, blood dyscrasias
Intermediate Acting
bendroflumethiazide and nadolol PO: 1 tablet/day (40–80 mg nadolol and 5 mg bendroflumethiazide)
(Corzide)
metolazone (Zaroxolyn) PO: 2.5–10 mg once daily (max: 20 mg/day)
Long Acting
chlorthalidone PO: 50–100 mg/day (max: 50 mg/day for HTN; 200 mg/day for edema)
indapamide PO: 1.25–2.5 mg once daily (max: 5 mg/day)
methyclothiazide (Enduron) PO: 2.5–5 mg once daily (max: 5 mg/day for HTN; 10 mg/day for edema)
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
Chapter 32 Diuretic Therapy and the Pharmacotherapy of Chronic Kidney Disease 549
therapeutic doses all thiazides produce the same level of Pharmacokinetics: PO
diuresis. Route(s) Variable; incompletely absorbed
Absorption Distributed to most tissues;
Three drugs in Table 32.5, chlorthalidone, indapamide, Distribution crosses the placenta and is
and metolazone (Zaroxolyn), are not true thiazides because secreted in breast milk
they do not contain the two-ring structure that chemically Primary metabolism Not metabolized
defines a thiazide. However, these drugs block the same Primary excretion Renal
symport protein and have the same pharmacologic effects Onset of action 2 h; peak effect: 4 h
as thiazides. They are sometimes called “thiazide-like” and Duration of action 6–12 h; half-life: 45–120 min
are always considered along with the true thiazides because
of their similar mechanism of action, indications, and Adverse Effects: Hydrochlorothiazide is generally
adverse effects. well tolerated and exhibits few serious adverse effects.
Hypotension may cause dizziness or headache. Electro-
The adverse effects of thiazides are similar to those of lyte imbalances such as hypochloremia, hypomagnesemia,
the loop diuretics, though their frequency is less and they h ypokalemia, and hyponatremia may occur. Dysrhyth-
do not cause ototoxicity. Dehydration and excessive loss of mias due to hypokalemia may be serious if not prevented
sodium, potassium, or chloride ions may occur with over- by maintaining normal serum potassium levels, usually by
treatment: Hypokalemia and hypochloremia can cause the administration of potassium supplements during ther-
metabolic alkalosis. Concurrent therapy with digoxin apy. Hydrochlorothiazide may precipitate gout attacks due
requires careful monitoring to avoid dysrhythmias caused to its tendency to cause hyperuricemia. Blood dyscrasias
by excessive potassium loss. Potassium supplements are such as leukopenia, agranulocytosis, and aplastic anemia
sometimes prescribed during thiazide therapy to prevent are rare, though serious, adverse effects.
hypokalemia. Patients with diabetes should be aware that
thiazide diuretics sometimes increase blood glucose levels. Contraindications/Precautions: Contraindica-
Like the loop diuretics, thiazides can increase serum levels tions include anuria and prior hypersensitivity to thiazide
of uric acid, although this is only clinically significant in diuretics or sulfonamide antibiotics. Because hydrochloro-
patients with a history of gout. thiazide can cause glycosuria and hyperglycemia, serum
glucose levels must be carefully monitored in patients with
PROTOTYPE DRUG Hydrochlorothiazide (Microzide) diabetes. Preexisting hypovolemia or hypotension should
be corrected before thiazide therapy is initiated because di-
Classification Therapeutic: Antihypertensive uretics can worsen these conditions. Hydrochlorothiazide
Pharmacologic: Thiazide-type diuretic should not be used in neonates with jaundice because it
can cause hyperbilirubinemia.
Therapeutic Effects and Uses: Approved in 1959,
hydrochlorothiazide (sometimes abbreviated HCTZ) is Drug Interactions: When given concurrently with
the most widely prescribed diuretic for HTN. Like many other antihypertensives, additive effects on blood pres-
diuretics, it produces few adverse effects and is effective at sure usually occur. Thiazides may reduce the effective-
producing a 10- to 20-mmHg reduction in blood pressure. ness of anticoagulants, sulfonylureas, and antidiabetic
Patients with severe HTN or a compelling condition such drugs, including insulin. Cholestyramine and colestipol
as HF, postmyocardial infarction (post-MI), high risk for bind to and decrease the absorption of HCTZ, thus reduc-
coronary artery disease, diabetes, CKD, or recurrent stroke ing its effectiveness. Hydrochlorothiazide increases the
prevention may require the addition of a second drug from risk of renal toxicity from NSAIDs. Corticosteroids and
a different class to control the disease. amphotericin B increase potassium loss when given with
HCTZ. Hypokalemia caused by HCTZ may increase di-
Hydrochlorothiazide is approved to treat ascites, goxin toxicity and the possibility of dysrhythmias. Hy-
edema, HF, HTN, and nephrotic syndrome. Off-label indi- drochlorothiazide decreases the excretion of lithium and
cations include premenstrual syndrome (PMS), diabetes can lead to lithium toxicity. Because thiazides decrease
insipidus, hypercalciuria, and nephrolithiasis. Hydrochlo- the renal excretion of calcium, concurrent administration
rothiazide is the most common agent found in fixed-dose with calcium supplements may lead to hypercalcemia.
combination drugs for HTN. Herbal/Food: Ginkgo biloba may produce a paradoxical
increase in blood pressure. Oral aloe can decrease levels of
Mechanism of Action: Hydrochlorothiazide acts potassium and should not be used concurrently with thia-
on the distal tubule to decrease the reabsorption of Na1. zide diuretics. Use with hawthorn could result in additive
This results in less water reabsorption, increased diuresis,
and removal of edema fluid. Blood volume decreases and
blood pressure falls. Increasing the amount of sodium in
the distal tubule also increases potassium excretion via a
sodium–potassium exchange mechanism.
550 Unit 5 Pharmacology of the Cardiovascular System
hypotensive effects. High sodium intake can reduce the Potassium-Sparing Diuretics
effectiveness of diuretics; patients should be placed on a
sodium-restricted diet of 1500 to 2300 mg/day. 32.7 Potassium-sparing diuretics have low
effectiveness but can help prevent hypokalemia.
Treatment of Overdose: Overdose is manifested as
electrolyte depletion, which is treated with infusions of As discussed in Sections 32.5 and 32.6, hypokalemia is a
fluids containing electrolytes. Infusion of fluids also pre- potentially serious adverse effect of the loop and thiazide
vents dehydration and hypotension. diuretics. The therapeutic advantage of the potassium-
sparing diuretics is that increased diuresis can be obtained
Pregnancy: Category B. without lowering blood potassium levels. The potassium-
sparing diuretics are listed in Table 32.6. There are two
Nursing Responsibilities: Key nursing implications subclasses of potassium-sparing diuretics: sodium ion
for patients receiving hydrochlorothiazide are included in channel inhibitors and aldosterone antagonists.
the Nursing Practice Application for Patients Receiving
Pharmacotherapy with Diuretics. Sodium ion channel inhibitors: In the distal tubule,
Na1 is reabsorbed from the filtrate through sodium ion
Drugs Similar to Hydrochlorothiazide channels. As the sodium ion in the filtrate travels across
(Microzide) the renal tubule cell and returns to the bloodstream, potas-
sium ion moves in the opposite direction. In other words,
Many thiazide and thiazide-like diuretics are available. as sodium ion is reabsorbed, potassium ion is secreted.
They may be grouped into subclasses based on their rela-
tive duration of action. Triamterene (Dyrenium) and amiloride (Midamor)
block the Na1 channel, causing sodium to stay in the fil-
Short-acting thiazides: This group includes chlorothia- trate. Because water always follows sodium ions, addi-
zide (Diuril) and hydrochlorothiazide (Microzide). These tional water is retained in the filtrate and ultimately leaves
drugs have a rapid onset of 1 to 2 hours with a duration of in the urine. When the sodium ion channel is blocked,
action of 6 to 12 hours. Chlorothiazide is available by the another important action occurs: The potassium ion is no
IV route for patients who are unable to take PO thiazides. longer secreted to the filtrate. The body, therefore, does not
lose potassium, as is the case with the thiazide and loop
Intermediate-acting thiazides: This group includes meto- diuretics. Because most of the sodium ion has already been
lazone (Zaroxolyn) and Corzide, a fixed-dose combination removed before the filtrate reaches the distal tubule, these
of bendroflumethiazide (a thiazide) with nadolol (a beta- potassium-sparing diuretics produce only a mild diuresis.
adrenergic blocker). These drugs have an onset time of Drugs in this class are rarely prescribed alone, but they
about 2 hours with a duration of action of 12 to 24 hours. may be used in combination with thiazide or loop diuretics
to minimize loss of potassium ions in the pharmacotherapy
Long-acting thiazides: This group includes chlorthali- of HTN or edema.
done, indapamide, and methyclothiazide (Enduron).
These drugs have a 2-hour onset with a duration of action Aldosterone antagonists: Aldosterone is the primary
ranging from 24 to 72 hours. mineralocorticoid hormone secreted by the adrenal gland.
The physiologic targets, or membrane receptors (MRs), for
CONNECTION Checkpoint 32.3 aldosterone are located in the distal tubule and collecting
ducts of the nephron. Once bound to its receptors, the MR–
The use of lithium is often contraindicated when a patient is taking aldosterone complex causes the renal tubule cells to syn-
diuretics. From what you learned in Chapter 19, identify the indica- thesize more Na1 channels, thereby allowing for more
tions for lithium and explain how the use of a diuretic can lead to
lithium toxicity. Answers to Connection Checkpoint questions are avail-
able on the faculty resources site. Please consult with your instructor.
Table 32.6 Potassium-Sparing Diuretics
Drug Route and Adult Dose (Maximum Dose Where Indicated) Adverse Effects
Sodium Ion Channel Inhibitors Minor hyperkalemia, headache, fatigue,
gynecomastia (spironolactone)
amiloride (Midamor) PO: 5–10 mg/day (max: 20 mg/day) Dysrhythmias (from hyperkalemia), dehydration,
hyponatremia, agranulocytosis, and other blood
triamterene (Dyrenium) PO: 50–100 mg bid (max: 300 mg/day) dyscrasias
Aldosterone Antagonists
eplerenone (Inspra) PO: 25–50 mg once daily (max: 100 mg/day for HTN; 50 mg/day for HF)
spironolactone (Aldactone) PO: 25–100 mg 1–2 times/day (max: 400 mg/day)
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
Chapter 32 Diuretic Therapy and the Pharmacotherapy of Chronic Kidney Disease 551
reabsorption of Na1 from the filtrate. Simply stated, aldo- off-label indication is to improve survival and reduce hospi-
sterone increases sodium reabsorption. talizations in patients with severe HF. Other off-label indi-
cations include treatment of minor edema associated with
Spironolactone (Aldactone) and eplerenone (Inspra) PMS, polycystic ovary, acne, and hirsutism in females.
prevent the formation of the MR–aldosterone complex and Aldactazide is a fixed-dose combination of spironolactone
are called aldosterone antagonists. By blocking the actions with hydrochlorothiazide.
of aldosterone, these drugs enhance the excretion of sodium
and the retention of potassium. Like the sodium ion chan- Mechanism of Action: Spironolactone acts by inhibit-
nel inhibitors, spironolactone and eplerenone produce only ing the actions of aldosterone in the distal tubule and collect-
a weak diuresis, and they are normally combined with ing ducts of the nephron. When the actions of aldosterone
drugs from other classes when treating HTN or edema. are blocked by spironolactone, sodium, chloride, and water
Spironolactone has also been found to significantly reduce excretion are increased and the body retains potassium.
mortality in patients with HF and, because of this impor-
tant beneficial effect, its use has increased. The aldosterone Pharmacokinetics: PO
antagonists are also used to treat hyperaldosteronism, a Route(s)
rare disorder in which a tumor of the adrenal gland secretes Absorption Rapid absorption; 73% absorbed
large amounts of aldosterone. Distribution
Distributed to most tissues;
Using potassium supplements or adding potassium- Primary metabolism crosses the placenta; secreted
rich foods to the diet when taking these medications may Primary excretion in breast milk; more than 90%
lead to life-threatening hyperkalemia. Signs and symptoms Onset of action bound to plasma protein
of hyperkalemia include muscle weakness, ventricular Duration of action
tachycardia, or fibrillation. Minor adverse effects of the Hepatic and renal; converted to
drugs include headache, dizziness, nausea, and vomiting. active metabolites
Spironolactone binds to progesterone and androgen recep-
tors, resulting in a small incidence of gynecomastia, men- Renal (40–57%) and feces
strual abnormalities, and impotence. Gynecomastia, (35–40%)
abnormal enlargement of the breasts in men, appears to be
related to dosage level and duration of therapy; it may per- 2–3 days; may take 2 weeks for
sist after the drug is discontinued. The incidence of adverse maximum effect
reproductive system effects is lower with eplerenone.
2–3 days; half-life: 1.3–2.4 h for
PROTOTYPE DRUG Spironolactone (Aldactone) parent compound, and 18–23 h
for active metabolites
Classification Therapeutic: Antihypertensive
Pharmacologic: Potassium-sparing Adverse Effects: Hyperkalemia induced by spironolac-
tone can cause life-threatening cardiac dysrhythmias. Signs
diuretic/aldosterone antagonist and symptoms associated with spironolactone-induced
hyperkalemia include muscle weakness, paresthesia,
Therapeutic Effects and Uses: Approved in 1960, fatigue, bradycardia, flaccid paralysis of the extremities,
spironolactone is the most frequently prescribed potassium- and shock. In men, spironolactone can cause gynecomastia,
sparing diuretic. The most common indication for spirono- impotence, and diminished libido. Women may experience
lactone is mild HTN. Because it does not cause potassium menstrual irregularities, hirsutism, and breast tenderness.
depletion, the drug is particularly useful in patients who are Fertility may decrease during therapy. Agranulocytosis and
at high risk for hypokalemia. However, spironolactone does other blood dyscrasias are rare adverse effects. Black Box
such an efficient job of retaining potassium that hyperkale- Warning: Spironolactone produces tumors in laboratory
mia may develop, especially if the patient is taking potas- animals; unnecessary use of the drug should be avoided.
sium supplements or is receiving angiotensin-converting
enzyme (ACE) inhibitors. When serum potassium levels are Contraindications/Precautions: Contraindications
monitored carefully and maintained within normal values, include anuria, severe CKD, pregnancy, and hyperkalemia.
serious adverse effects from spironolactone are uncommon. Older patients and those with renal insufficiency or diabetes
mellitus are at greatest risk for hyperkalemia. At high doses,
Spironolactone is approved for the management of spironolactone produces teratogenic effects in laboratory
edema associated with hepatic cirrhosis, HF, or nephrotic animals; thus it should not be used during pregnancy. A ma-
syndrome. It is particularly useful in treating edema or asci- jor metabolite of spironolactone is secreted in breast milk;
tes in patients with hepatic cirrhosis, because it counteracts thus this drug should not be given during lactation.
the large amount of aldosterone secreted by these patients.
Spironolactone may also be used for the short-term, preop- Drug Interactions: Spironolactone should not be ad-
erative treatment of primary hyperaldosteronism. An ministered concurrently with eplerenone due to the poten-
tial for hyperkalemia. Aspirin and other salicylates may
decrease the diuretic effect of the medication. Concurrent
552 Unit 5 Pharmacology of the Cardiovascular System
use with digoxin may decrease the effects of digoxin. When class, however, the development of hyperkalemia is a
taken with potassium supplements, ACE inhibitors, angio- potentially serious adverse effect, especially if the drug is
tensin receptor blockers (ARBs), or the potassium salts of used concurrently with ACE inhibitors. Eplerenone is
other drugs (such as penicillin G potassium), s evere hyper- sometimes referred to as a selective aldosterone receptor
kalemia and possible dysrhythmias may result. Concurrent antagonist. This drug is pregnancy category B.
use with other antihypertensives will result in an additive
hypotensive effect. Herbal/Food: Licorice extract contains Triamterene (Dyrenium): Approved in 1964, triamterene
a substance with aldosterone-like actions and should be is an oral drug that acts by the same mechanism as
avoided. Use with hawthorn may result in hypotension. amiloride and has the same indications and adverse
effects. It is a relatively weak diuretic and is sometimes
Treatment of Overdose: Acute overdoses produce used to manage hypokalemia in patients who are unable
drowsiness, mental confusion, rash, nausea, vomiting, dizzi- to tolerate potassium supplements. Triamterene is rarely
ness, or diarrhea. The most serious symptoms of spironolac- prescribed as monotherapy and should not be used con-
tone overdose are related to hyperkalemia. If severe, therapies currently with other potassium-sparing diuretics due to
are administered to counteract the hyperkalemia. These the potential for hyperkalemia. Dyazide is a fixed-dose
include IV calcium chloride, calcium gluconate, sodium bi- combination of triamterene and hydrochlorothiazide. This
carbonate, or the administration of glucose with rapid-acting drug is pregnancy category C.
insulin. Cationic exchange resins such as sodium polystyrene
sulfonate (Kayexalate) may be administered. CONNECTION Checkpoint 32.4
Pregnancy: Category D. From what you learned in Chapter 31, explain why patients who are
taking an ACE inhibitor should probably not receive an aldosterone
Nursing Responsibilities: Key nursing implications antagonist. Answers to Connection Checkpoint questions are available
for patients receiving spironolactone are included in the on the faculty resources site. Please consult with your instructor.
Nursing Practice Application for Patients Receiving Phar-
macotherapy with Diuretics. Osmotic Diuretics
Drugs Similar to Spironolactone (Aldactone) 32.8 Osmotic diuretics cause diuresis by
increasing the osmolality of the filtrate.
The three other potassium-sparing diuretics include
amiloride, eplerenone, and triamterene. The osmotic diuretics, shown in Table 32.7, are a small
class of drugs that are reserved for very specific indica-
Amiloride (Midamor): Approved in 1981, amiloride is an tions. Unlike the thiazides and loop diuretics that block
oral Na1 channel inhibitor with weak diuretic activity transport proteins, osmotic diuretics are mostly inert and
whose major indication is HTN. It is also used to treat act by raising the osmolality, which is a measure of the
peripheral edema due to HF and to reverse thiazide- amount of dissolved particles, or solutes in a solution. This
induced hypokalemia. When combined with a thiazide in turn increases the osmotic pressure, which creates a
diuretic, additive hypotensive action is achieved, and force that moves substances between compartments.
potassium balance is maintained. It should not be used as Osmotic diuretics cause water to shift compartments by
monotherapy or in combination with other potassium- creating a difference in osmotic pressure across a mem-
sparing diuretics because hyperkalemia may develop. brane or between two body compartments.
Contraindications and adverse effects are similar to those
of spironolactone, including a black box warning for the When given IV, osmotic diuretics are filtered at the
risk of severe hyperkalemia in patients receiving other glomerulus and readily enter the renal filtrate. Once in the
potassium-containing drugs. Moduretic is a fixed-dose tubule, they remain unchanged. As normal sodium and
combination of amiloride and hydrochlorothiazide. water reabsorption progresses in the proximal tubule, the
Amiloride is pregnancy category B. diuretic remains behind, and its concentration in the tubule
begins to increase. The osmolality of the filtrate increases
Eplerenone (Inspra): Approved in 2002, eplerenone is an due to the presence of the osmotic diuretic in the tubule. This
aldosterone antagonist administered by the oral route that osmotic force draws water into the filtrate, resulting in
is approved for HTN and the post-MI management of HF. increased diuresis. The influence of osmotic pressure on
Two to four weeks of therapy are required to achieve maxi- water movement is presented in greater detail in Chapter 33.
mum therapeutic effects. Eplerenone is more selective for
the aldosterone receptor than spironolactone, and it has A second action of osmotic diuretics is their ability to
the advantage of producing a lower incidence of endo- raise the osmolality of the plasma. This creates an osmotic
crine-related adverse effects such as gynecomastia, impo- force that moves water from the intracellular and extravas-
tence, or menstrual irregularities. Like other drugs in this cular spaces to the plasma. The increased volume of water
in the plasma is filtered by the kidney, resulting in enhanced
Chapter 32 Diuretic Therapy and the Pharmacotherapy of Chronic Kidney Disease 553
Table 32.7 Miscellaneous Diuretics
Drug Route and Adult Dose Adverse Effects
(Maximum Dose Where Indicated)
Electrolyte imbalances, fatigue, nausea, vomiting, dizziness
Carbonic Anhydrase Inhibitors Dehydration, blood dyscrasias, pancytopenia, flaccid paralysis, hemolytic
anemia, aplastic anemia
acetazolamide (Diamox) PO: 250–375 mg/day (max: 1500 mg/day)
IM/IV: 250–375 mg/day Electrolyte imbalances, fatigue, nausea, vomiting, dizziness
Hyponatremia, edema, convulsions, tachycardia
methazolamide (Neptazane) PO: 50–100 mg bid–tid (max: 300 mg/day)
Osmotic Diuretics
glycerin PO: 1–1.8 g/kg, 1–2 h before ocular surgery
mannitol (Osmitrol) IV: 100 g infused over 2–6 h
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
diuresis. This action is used to advantage in the treatment Mannitol has nondrug uses as a sweetener and food
of two conditions where fluid has accumulated in extravas- stabilizer. When taken PO, it is absorbed so slowly that it
cular spaces. For example, following a traumatic head has no effect on insulin levels, making it an alternative
injury, fluid accumulates in the brain, causing dangerously sweetener in foods for patients with diabetes. The drug has
high intracranial pressure. Osmotic diuretics create an a laxative effect when taken in large quantities.
osmotic force that promotes the fluid to leave the brain and
enter the blood, thus reducing cerebral edema. A second Mechanism of Action: Administered by the IV route,
example is high intraocular pressure caused by excess fluid mannitol is filtered by the glomerulus of the kidney but is
accumulation in the eye (glaucoma). Osmotic diuretics can incapable of being reabsorbed from the renal tubule. This
cause the fluid to leave the eye and enter the blood, thus creates an osmotic gradient, resulting in decreased water
relieving the high intraocular pressure. and Na1 reabsorption and increased diuresis.
Osmotic diuretics are rarely the drugs of first choice due Pharmacokinetics: IV
to their potential toxicity. Although as diuretics they are use- Route(s)
ful in increasing urine output, they are contraindicated in Absorption Does not cross biological
patients with severe kidney disease. The rapid movement of m embranes
water from the extravascular spaces to the blood can result in Distribution
severe dehydration in the tissues and cause a serious fluid Remains in extracellular space;
overload in patients with severe HF. Electrolyte imbalances, Primary metabolism does not cross the blood–brain
especially hyponatremia, may occur with these drugs. Primary excretion barrier
Onset of action
PROTOTYPE DRUG Mannitol (Osmitrol) Duration of action Hepatic (small amounts)
Classification T herapeutic: Drug for acute kidney Renal
injury
1–3 h
Pharmacologic: Osmotic diuretic
4–6 h; half-life: 100 min
Therapeutic Effects and Uses: Approved in 1944,
mannitol is a parenteral diuretic primarily used to prevent Adverse Effects: Electrolyte imbalances, either defi-
or treat AKI in patients experiencing oliguria before the ciencies or excesses, can occur during mannitol therapy.
loss of renal function becomes irreversible. In addition, by For example, as mannitol draws fluid from the intravas-
its ability to increase the osmolality of plasma, this drug cular spaces, hyperkalemia or hypernatremia may occur.
is able to “pull” fluid out of extravascular spaces; thus it However, mannitol also increases the excretion of sodium
is used to reduce intracranial pressure following head and potassium ions, which can result in hypokalemia or
trauma and to lower intraocular pressure in patients with hyponatremia. The same holds true for fluid balance. As
acute glaucoma. Reduction in the amount and pressure of mannitol draws fluid into the extracellular spaces, periph-
cerebrospinal fluid can occur as quickly as 15 minutes after eral edema, HF, or pulmonary edema may occur. As diure-
initiating the infusion; intraocular pressure reduction may sis progresses, the patient may become hypovolemic and
take up to an hour. Mannitol may be administered concur- dehydrated. Other adverse effects include fatigue, nausea,
rently with nephrotoxic drugs such as cisplatin (an anti- vomiting, dizziness, convulsions, and tachycardia.
neoplastic drug) to speed them through the kidney and
reduce damage to the walls of the renal tubules. Contraindications/Precautions: Contraindications
include anuria, severe HF, organic central nervous system
(CNS) disease or intracranial bleeding, severe dehydration,
and shock. A test dose may be given to patients with oli-
guria to determine renal function. Function is considered
554 Unit 5 Pharmacology of the Cardiovascular System
satisfactory if urine flow is at least 30 to 50 mL/h over dissociates to bicarbonate ion (HCO3−). Note that these
2 to 3 hours following an IV test dose of 0.2 g/kg. If this reactions are reversible.
response is not achieved, the kidneys are too impaired to
administer a full dose of mannitol. CO2 1 H2O ←→H2CO3 ←→ HCO32 1 H1
There is evidence that high doses of mannitol may open Carbonic acid is present in multiple tissues. In red
the blood–brain barrier by temporarily shrinking the endo- blood cells, it converts CO2 (an acidic, poorly soluble gas) to
thelial cells that line the barrier. Should this happen, man- bicarbonate, which can be transported to the lungs, recon-
nitol will enter the brain (bringing water with it) and verted to CO2, and exhaled. In the mucosa of the stomach,
increase intracranial pressure. Extreme precautions must be carbonic anhydrase is responsible for forming gastric acid
taken when treating patients with high intracranial pres- (H1). For this chapter, the most important action of carbonic
sure. Experimentally, mannitol is used to intentionally open anhydrase occurs in the renal tubule cells.
the blood–brain barrier to deliver higher doses of various
drugs, such as antineoplastic drugs, directly to the brain. In the kidney tubules, carbonic anhydrase is necessary
for the formation and reabsorption of bicarbonate ion,
Drug Interactions: Because of its intense diuretic which is essential for maintaining proper acid–base bal-
effect, mannitol can increase the excretion of many drugs. ance. Sodium ions are reabsorbed with bicarbonate ion in
This results in a decreased effect for drugs such as lithium, the proximal tubule using a symporter protein.
imipramine, salicylates, barbiturates, and potassium sup-
plements. Herbal/Food: Unknown. Several drugs that inhibit carbonic anhydrase are
available as shown in Table 32.7. Blocking carbonic anhy-
Pregnancy: Category C. drase prevents bicarbonate formation and reabsorption in
the renal tubule. Without bicarbonate ion, sodium reab-
Treatment of Overdose: Overdose will result in a sorption does not occur, more water remains in the filtrate,
shift of fluid to the vascular compartment, resulting in HF and diuresis is promoted. The reduction in plasma bicar-
and pulmonary edema. Intense diuresis may cause signifi- bonate eventually causes metabolic acidosis, which tends
cant electrolyte imbalances, especially hyponatremia. No to reverse the diuretic action of this drug.
specific antidote is available and treatment is supportive to
the presenting symptoms. The carbonic anhydrase inhibitors are rarely prescribed
as diuretics because they produce only a weak, short-lived
Nursing Responsibilities: Key nursing implications diuresis and can contribute to metabolic acidosis. Carbonic
for patients receiving mannitol are included in the Nurs- anhydrase inhibitors that are given by the oral route include
ing Practice Application for Patients Receiving Pharmaco- acetazolamide (Diamox) and methazolamide (Neptazane).
therapy with Diuretics. Methazolamide is approved only for reducing intraocular
pressure in patients with open-angle glaucoma. Acetazol-
Drugs Similar to Mannitol (Osmitrol) amide (Diamox), also used to decrease intraocular fluid pres-
sure, has several other indications. Two drugs in this class,
There is only one other osmotic diuretic, glycerin. dorzolamide (Trusopt) and brinzolamide (Azopt), are admin-
istered topically to the eye for open-angle glaucoma. The
Glycerin: Also known as glycerol, glycerin is given for a antiglaucoma drugs in this class are discussed in Chapter 74.
large number of indications. When given by the oral route,
glycerin creates an osmotic gradient like mannitol that can PROTOTYPE DRUG Acetazolamide (Diamox)
reduce intraocular and intracranial pressure. As a laxative
suppository, glycerin draws water into the colon, creating Classification T herapeutic: Drug for edema, antiglau-
more bulk and promoting defecation. It is used in a variety of coma drug
over-the-counter (OTC) products as an emollient or lubricant,
including toothpaste, shaving cream, hair products, soaps, Pharmacologic: Carbonic anhydrase
and skin care products. Like mannitol, it tastes sweet and is inhibitor
used as a food additive to sweeten and keep products moist.
Therapeutic Effects and Uses: Given by either the
Carbonic Anhydrase Inhibitors oral or parenteral route, acetazolamide produces a mild di-
uresis and is occasionally used to reduce edema fluid in
32.9 Carbonic anhydrase inhibitors are weak patients with HF. An older drug approved in 1953, it has
diuretics that have specific indications. largely been replaced by thiazide diuretics.
Carbonic anhydrase is an essential enzyme that helps reg- Acetazolamide also has applications for treating
ulate acid–base balance in the body. Carbonic anhydrase absence seizures and in relieving motion sickness. It has
converts CO2 to carbonic acid (H2CO3), which immediately been used to acclimatize people to high altitudes to prevent
or treat acute mountain sickness. It accomplishes this by
increasing the renal excretion of bicarbonate, which accu-
mulates in the body because of the hyperventilation that
Chapter 32 Diuretic Therapy and the Pharmacotherapy of Chronic Kidney Disease 555
occurs at high altitude. Acetazolamide is effective in treat- sulfonamides and similar drugs such as thiazide diuret-
ing open-angle glaucoma and for preoperative treatment of ics. Other contraindications include severe renal or hepatic
acute closed-angle glaucoma, although it is not a preferred impairment and adrenocortical insufficiency. Patients with
drug for these disorders. preexisting electrolyte imbalances such as hyponatremia,
hypokalemia, or hypochloremic acidosis should be treated
Mechanism of Action: Acetazolamide produces its with caution because acetazolamide may worsen these
diuretic effect by inhibiting carbonic anhydrase activity in conditions.
the proximal renal tubule, causing increased excretion of
sodium and bicarbonate. In the eye, the inhibition of car- Drug Interactions: The potential for hypokalemia is
bonic anhydrase reduces the rate of aqueous humor for- greatest early in the course of acetazolamide therapy and is
mation and consequently lowers intraocular pressure. accelerated by amphotericin B and corticosteroids. Because
acetazolamide alkalinizes the urine, the renal excretion of
Pharmacokinetics: PO, IV many drugs may be decreased, including tricyclic antide-
Route(s) pressants, procainamide, amphetamines, ephedrine, and
Absorption 75% absorbed when given quinidine. Renal excretion of lithium and phenobarbital
with food may be increased. High-dose aspirin therapy can compete
Distribution with tubular secretory mechanisms with acetazolamide,
Distributed to most tissues; causing the carbonic anhydrase inhibitor to accumulate to
Primary metabolism crosses the placenta and is toxic levels. Herbal/Food: Unknown.
Primary excretion secreted in breast milk
Onset of action Pregnancy: Category C.
Duration of action Not metabolized
Treatment of Overdose: Overdose with acetazol-
Renal amide results in metabolic acidosis, which may be treated
by administering sodium bicarbonate. Electrolyte deple-
PO: 90 min; IV: 2 min tion and dehydration are treated with infusions of fluids
containing electrolytes.
PO: 8–12 h; PO extended
release: 18–24 h; IV: 15 min; Nursing Responsibilities: Key nursing implications
half-life: 2.4–5.8 h for patients receiving acetazolamide are included in the
Nursing Practice Application for Patients Receiving Phar-
Adverse Effects: Acetazolamide can cause various macotherapy with Diuretics.
electrolyte imbalances, including hyperchloremia and
hypokalemia. Gastrointestinal adverse effects include nau- Drugs Similar to Acetazolamide (Diamox)
sea, vomiting, diarrhea, and anorexia. CNS effects may
occur, such as dizziness, fatigue, and numbness in the The other oral carbonic anhydrase inhibitor is methazol-
extremities, lips, or facial muscles. Metabolic acidosis may amide (Neptazane), which is used as a systemic antiglau-
result from excess bicarbonate loss. coma drug (see Chapter 74) rather than a diuretic.
Contraindications/Precautions: Acetazolamide is
contraindicated in patients who have hypersensitivity to
CONNECTIONS: NURSING PRACTICE APPLICATION
Patients Receiving Pharmacotherapy with Diuretics
Assessment
Baseline assessment prior to administration:
• Obtain a complete health history including cardiovascular disease, diabetes, pregnancy, or breastfeeding. Obtain a drug history including allergies,
current prescription and OTC drugs, herbal preparations, use of digoxin, lithium, or antihypertensive drugs, and alcohol use. Be alert to possible drug
interactions.
• Evaluate appropriate laboratory findings such as electrolytes, glucose, complete blood count (CBC), hepatic or renal function studies, uric acid levels,
and lipid profiles.
• Obtain baseline weight, vital signs (especially blood pressure and pulse), breath sounds, and cardiac monitoring (e.g., electrocardiogram [ECG],
cardiac output) if appropriate. Assess for location, character, and amount of edema, if present. Assess baseline hearing and balance.
• 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., adequate urine output, decreased edema or lowered blood pressure if given for HTN).
• Continue periodic monitoring of electrolytes, glucose, CBC, lipid profiles, liver function studies, creatinine, and uric acid levels.
• Assess for and promptly report adverse effects: hypotension, palpitations, dizziness or lightheadedness, musculoskeletal weakness or cramping,
nausea, vomiting, abdominal cramping, diarrhea, or headache. Immediately report tinnitus or hearing loss, loss of balance or incoordination, severe
hypotension accompanied by reflex tachycardia, dysrhythmias, decreased urine output, or weight gain or loss over 1 kg (2 lb) in a 24-h period.
(continued )
556 Unit 5 Pharmacology of the Cardiovascular System
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
Ensuring therapeutic effects: • Teach the patient, family, or caregiver how to monitor the pulse and
• Continue frequent assessments as above for therapeutic effects: Urine blood pressure. Ensure proper use and functioning of any home
equipment obtained.
output is increased, blood pressure and pulse are within normal limits
or within the parameters set by the healthcare provider. (Diuresis may • Have the patient weigh self daily and record weight along with blood
be moderate to extreme depending on the type of diuretic given. Blood pressure and pulse measurements.
pressure should be within normal limits without the presence of reflex
tachycardia.)
• Daily weights should remain at or close to baseline weight. (An
increase in weight over 1 kg [2 lb] per day may indicate excessive fluid
gain. A decrease of over 1 kg [2 lb] per day may indicate excessive
diuresis and dehydration.)
Minimizing adverse effects: Teach the patient to:
• Continue to monitor vital signs. Take blood pressure lying, sitting, • Rise from lying or sitting to standing slowly to avoid dizziness or falls. If
and standing to detect orthostatic hypotension. Lifespan: Be dizziness occurs, the patient should sit or lie down, and not attempt to
particularly cautious with the older adult who is at increased risk for stand or walk, until the sensation passes.
hypotension. (Diuretics reduce circulating blood volume, resulting in • Stop taking the medication and promptly notify the healthcare provider
lowered blood pressure. Orthostatic hypotension may increase the if blood pressure is 90/60 mmHg or lower, or is below the parameters
risk of falls and injury.) set by the provider.
• Continue to monitor electrolytes, glucose, CBC, lipid profiles, liver • Instruct the patient on the need to return periodically for laboratory
function studies, creatinine, and uric acid levels. (Most diuretics cause work and to inform laboratory personnel of diuretic therapy when
loss of Na1 and K1 and may increase lipid, glucose, and uric acid providing blood or urine samples.
levels.)
• Advise the patient to carry a wallet identification card or wear medical
identification jewelry indicating diuretic therapy.
• Continue to monitor hearing and balance, reporting persistent tinnitus • Have the patient report persistent tinnitus or balance or coordination
or vertigo promptly. (Ototoxicity of cranial nerve VIII may occur, problems immediately.
especially with loop diuretics. Lifespan: Because of pharmacokinetic
differences, exercise additional caution when administering diuretics to
infants and very young children. Audiology and additional monitoring
may be ordered.)
• Ensure patient safety, especially in the older adult. Observe for • Instruct the patient to call for assistance prior to getting out of bed
lightheadedness or dizziness. Monitor ambulation until the effects or attempting to walk alone, and to avoid driving or other activities
of the drug are known. (Dizziness from orthostatic hypotension may requiring mental alertness or physical coordination until the effects of
occur.) the drug are known.
• Weigh the patient daily and report weight gain or loss of 1 kg (2 lb) or • Have the patient weigh self daily, ideally at the same time of day, and
more in a 24-h period. Measure intake and output in the hospitalized record weight along with blood pressure and pulse measurements.
patient. (Daily weight is an accurate measure of fluid status and takes Have the patient report weight loss or gain of more than 1 kg (2 lb) in a
into account intake, output, and insensible losses. Diuresis is indicated 24-h period.
by output significantly greater than intake.)
• Advise the patient to continue to consume enough liquids to
remain adequately, but not overly, hydrated. Drinking when
thirsty, avoiding alcoholic beverages, and ensuring adequate
but not excessive salt intake will assist in maintaining normal
fluid balance.
• Teach the patient that excessive heat conditions contribute to
excessive sweating and fluid and electrolyte loss. Extra caution is
warranted in these conditions.
• Monitor nutritional status and encourage appropriate intake to prevent • Instruct patients taking potassium-wasting diuretics (e.g., thiazide,
electrolyte imbalances. (Electrolyte imbalances may occur dependent thiazide-like, and loop diuretics) to consume foods high in potassium:
on the type of diuretic used. Most diuretics cause Na1 and K1 loss. fresh fruits such as strawberries and bananas; dried fruits such as
Potassium-sparing diuretics may result in Na1 loss but K1 increase. apricots and prunes; vegetables and legumes such as tomatoes,
Lifespan: Monitor electrolyte levels frequently in older adults, who beets, and dried beans; juices such as orange, grapefruit, or prune;
are at greater risk for derangement related to age-related physiologic and fresh meats.
changes.)
• Instruct patients taking potassium-sparing diuretics to avoid foods
high in potassium such as above, not to use salt substitutes (which
often contain potassium salts), and to consult with a healthcare
provider before taking vitamin and mineral supplements or
specialized sports beverages. (Typical OTC sports beverages, e.g.,
Gatorade and Powerade, may have lesser amounts of potassium
but have high carbohydrate amounts that may lead to increased
diuresis, diarrhea, and the potential for dehydration from the
hyperosmolarity.)
Chapter 32 Diuretic Therapy and the Pharmacotherapy of Chronic Kidney Disease 557
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
• Observe for signs of hypokalemia or hyperkalemia. Use with caution • Instruct the patient to report signs and symptoms of hypokalemia or
in patients taking corticosteroids, ACE inhibitors, ARBs, digoxin, hyperkalemia immediately to the healthcare provider.
or lithium. Report symptoms to the healthcare provider promptly.
(Thiazide, thiazide-like, and loop diuretics can cause hypokalemia; • Teach the patient to follow recommended dietary intake of high- or
potassium-sparing diuretics may cause hyperkalemia. Symptoms of low-potassium foods as appropriate to the type of diuretic taken to
hypokalemia include muscle weakness or cramping and palpitations. avoid hypokalemia or hyperkalemia.
Symptoms of hyperkalemia include irritability or anxiety, fatigue,
palpitations, nausea, and abdominal cramping. Concurrent use with
corticosteroids may increase the risk of hypokalemia. Concurrent use
with ACE inhibitors or ARBs may increase the risk of hyperkalemia.
Concurrent use with digoxin increases the risk of potentially fatal
dysrhythmias and with lithium may cause toxic levels of the drug.)
• Observe for signs of hyperglycemia. Use with caution in patients • Instruct the patient to report signs and symptoms of diabetes mellitus
with diabetes. (Thiazide, thiazide-like, and loop diuretics may cause (e.g., polydipsia, polyphagia) or elevated blood glucose to the healthcare
hyperglycemia, especially in patients with diabetes.) provider. Patients with diabetes may need to monitor their blood glucose
levels more frequently until the effects of the diuretic are known.
• Observe for symptoms of gout. (Diuretics may cause hyperuricemia, • Instruct the patient to report signs and symptoms of gout promptly to
which may result in gout-like symptoms including warmth, pain, the healthcare provider.
tenderness, swelling, and redness around the joints, especially great
toes, hand joints, elbows, and around ears; tophi [nodules]; arthritis- • Teach gout-prone patients to increase fluid intake and to avoid
like symptoms; and limited movement in affected joints.) shellfish, organ meats (e.g., liver, kidneys), alcohol, and high-fructose
beverages.
• Observe for sunburning if prolonged sun exposure has occurred. (Many • Instruct patients to wear sunscreen and protective clothing if prolonged
diuretics cause photosensitivity and an increased risk of sunburning.) sun exposure is anticipated.
• Observe for signs of infection. (Some diuretics may decrease • Instruct the patient to report any flulike symptoms: shortness of breath,
white blood cell counts and the body’s ability to fight infection. fever, sore throat, malaise, joint pain, or profound fatigue.
Agranulocytosis is a possible adverse effect of diuretic therapy.)
• Lifespan: Assess for the possibility of pregnancy or breastfeeding • Instruct female patients who may be considering pregnancy, or are
before beginning the drug. (Some diuretics are pregnancy category D pregnant or breastfeeding, to notify their provider before starting the
drugs and should not be used during pregnancy.) drug.
Patient understanding of drug therapy: • The patient, family, or caregiver should be able to state the reason for
• Use opportunities during administration of medications and during the drug, appropriate dose and scheduling, what adverse effects to
observe for and when to report them, and the anticipated length of
assessments to discuss the rationale for the drug therapy, desired medication therapy.
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., early in the day
to prevent disruption of sleep from nocturia. (Utilizing time during nurse
administration of these drugs helps to reinforce teaching.)
Understanding Chapter 32
Key Concepts Summary 32.3 Chronic kidney disease may significantly impact
the success of pharmacotherapy.
32.1 The kidneys are major organs of excretion and body
homeostasis. 32.4 Diuretics are used to treat hypertension, heart
failure, accumulation of edema fluid, and chronic
32.2 The composition of filtrate changes dramatically kidney disease.
as a result of the processes of reabsorption and
secretion.
558 Unit 5 Pharmacology of the Cardiovascular System 32.8 Osmotic diuretics cause diuresis by increasing the
osmolality of the filtrate.
32.5 The most effective diuretics are the loop diuretics
that block sodium reabsorption in the loop of Henle. 32.9 Carbonic anhydrase inhibitors are weak diuretics
that have specific indications.
32.6 The thiazides are the most commonly prescribed
class of diuretics.
32.7 Potassium-sparing diuretics have low effectiveness
but can help prevent hypokalemia.
CASE STUDY: Making the Patient Connection
Remember the patient wait until her neighbor returned to get the medication
“Katherine Crosland” at the refilled.
beginning of the chapter?
Now read the remainder of Today, she presents to the clinic with generalized weak-
the case study. Based on the ness and fatigue. She has lost 3.6 kg (8 lb) since her last clinic
information presented within visit 6 weeks ago. Her blood pressure is 104/62 mmHg, her
this chapter, respond to the critical thinking questions heart rate is 98 beats/min, and she has a slightly irregular,
that follow. respiratory rate of 20 breaths/min. Body temperature is
97.2°F (36.2°C). The blood specimen collected for diagnostic
Katherine Crosland, a 79-year-old widow, has lived alone studies showed several outstanding findings such as a
for the past 5 years. Although her son and daughters all serum sodium level of 150 mEq/L and potassium level of
reside in distant locations, they check on her at least weekly 3.2 mEq/L. Katherine is diagnosed with dehydration and
by telephoning. Katherine is fairly independent; however, hypokalemia induced by diuretic therapy.
she does not drive and is dependent on a neighbor to get
her groceries and medications. Critical Thinking Questions
Three years ago, Katherine was hospitalized for an MI, 1. Discuss fluid and electrolyte imbalances related to the
which resulted in heart failure. She is adherent with her following diuretic therapies:
medications, which include digoxin (Lanoxin) 0.125 mg a. Loop diuretics
daily, furosemide (Lasix) 20 mg/day, and potassium sup- b. Thiazide diuretics
plements (K-Dur) 20 mEq daily. c. Potassium-sparing diuretics
d. Osmotic diuretics
Recently Katherine’s neighbor went on an extended,
out-of-town trip. Katherine was certain that she had 2. What relationship exists between this patient’s diuretic
enough of her medicine to last through that time. However, therapy, digoxin therapy, and hypokalemia?
before the neighbor returned, Katherine discovered she
had miscalculated her potassium supplement and only had 3. What patient education should the nurse provide
enough for 10 days. Katherine figured that because the about diuretic therapy?
potassium was only a “supplement,” she would be able to
Answers to Critical Thinking Questions are available on the
faculty resources site. Please consult with your instructor.
Additional Case Study 3. List the symptoms of hyperkalemia that Miles needs to
know to manage his disease and medications.
During a recent visit to the clinic, Miles Davenport
learned that his antihypertensive medication was not Answers to Additional Case Study questions are available on the
maintaining his blood pressure at the desired level. The faculty resources site. Please consult with your instructor.
nurse practitioner prescribed spironolactone (Aldactone)
50 mg twice daily in addition to his regular antihyperten-
sive medications.
1. Discuss the mechanism of action for spironolactone.
2. Prepare a list of foods that should be eaten sparingly
while taking spironolactone.
Chapter 32 Diuretic Therapy and the Pharmacotherapy of Chronic Kidney Disease 559
Chapter Review 4. Patients prescribed spironolactone (Aldactone) are
often at risk for electrolyte imbalance. The nurse
1. The nurse is teaching a group of patients with cardiac assesses for this adverse effect because this drug may
conditions who are taking diuretic therapy. The nurse cause the body to:
explains that individuals prescribed furosemide
(Lasix) should: 1. Retain potassium.
2. Release magnesium.
1. Avoid consuming large amounts of cabbage, 3. Excrete potassium.
cauliflower, and kale. 4. Bind calcium.
2. Rise slowly from sitting or lying positions. 5. Which nursing measures should be a nursing priority
3. Count their pulse for 1 full minute before taking for a patient when first beginning mannitol
(Osmitrol)?
the medication.
4. Restrict fluid intake to no more than 1000 mL in a 1. Keep the urinal or bedpan available for patients
with limited mobility.
24-hour period.
2. Assess for hypokalemia and encourage foods high
2. The patient who is receiving bumetanide (Bumex) is in potassium.
instructed to watch for symptoms associated with
electrolyte imbalances. Which condition would the 3. Monitor intake and output ratio, and weigh the
patient most likely experience? patient daily.
1. Hypernatremia 4. Monitor blood pressure and assess for level of
2. Hypokalemia consciousness.
3. Hyperkalemia
4. Hypocalcemia 6. The nurse is monitoring a patient receiving acetazol-
amide (Diamox). Which acid–base imbalance is a
3. While preparing a patient for discharge, which of the potential risk for this patient?
following statements should the nurse include in the
instructions regarding the patient’s new prescription 1. Metabolic acidosis
of hydrochlorothiazide (Microzide)? 2. Metabolic alkalosis
3. Respiratory acidosis
1. “There are no limitations on the amount of salt and 4. Respiratory alkalosis
fluid intake.”
See Answers to Chapter Review in Appendix A.
2. “Ingest vitamin K–rich foods daily, such as green,
leafy vegetables and broccoli.”
3. “Report muscle cramps or weakness to the
healthcare provider.”
4. “Antihypertensive drugs taken concurrently may
produce sleepiness.”
References National Kidney Foundation. (2016). Organ donation and
transplantation statistics. Retrieved from https://www.
Carville, S., Wonderling, D., & Stevens, P. (2014). Early kidney.org/news/newsroom/factsheets/
identification and management of chronic kidney Organ-Donation-and-Transplantation-Stats
disease in adults: Summary of updated NICE guidance.
BMJ, 349, g4507. doi:10.1136/bmj.g4507 World Anti-Doping Agency. (2017). The world anti-doping
code: The 2017 prohibited list. Retrieved from https://
National Institute of Diabetes and Digestive and Kidney www.wada-ama.org/en/resources/science-medicine/
Diseases. (2016). Kidney disease statistics for the United prohibited-list
States. Retrieved from http://www.niddk.nih.gov/
health-information/health-statistics/Pages/kidney-
disease-statistics-united-states.aspx
560 Unit 5 Pharmacology of the Cardiovascular System
Selected Bibliography A meta-analysis. Journal of Human Hypertension, 29,
159–166. doi:10.1038/jhh.2014.64
Armstrong, A. (2013). Practical tips for prescribing in renal National Kidney Foundation. (2015). Herbal supplements
impairment. Nurse Prescribing, 11, 222–227. and kidney disease. Retrieved from http://www.kidney.
doi:10.12968/npre.2013.11.5.222 org/atoz/content/herbalsupp.cfm
Pazhayattil, G. S., & Shirali, A. C. (2014). Drug-induced
Blue, L. (2015). Delivering intravenous diuretics in the impairment of renal function. International Journal of
community. Journal of Community Nursing, 29(6), Nephrology and Renovascular Disease, 7, 457–468.
41–44. doi:10.2147/IJNRD.S39747
Roush, G. C., & Sica, D. A. (2016). Diuretics for
Bolignano, D., Palmer, S. C., Navaneethan, S. D., & hypertension: A review and update. American Journal of
Strippoli, G. F. (2014). Aldosterone antagonists for Hypertension, 29(10), 1130–1137. doi:10.1093/ajh/hpw030
preventing the progression of chronic kidney disease. Shahrbaf, F. G., & Assadi, F. (2015). Drug-induced renal
Cochrane Database of Systematic Reviews, 4, Art. No. disorders. Journal of Renal Injury Prevention, 4, 57–60.
CD007004. doi:10.1002/14651858.CD007004.pub3 doi:10.12861/jrip.2015.12
Tamargo, J., Segura, J., & Ruilope, L. M. (2014). Diuretics in
Cadwallader, A. B., & Murray, B. (2015). Performance- the treatment of hypertension. Part 1: Thiazide and
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doi:10.1123/ijsnem.2014-0185 the treatment of hypertension. Part 2: Loop diuretics and
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“I don’t understand why I need
an IV. I was told this was going
to be a quick procedure.”
Patient “Peggy Hoover”
Chapter 33
Pharmacotherapy of Fluid
Imbalance, Electrolyte,
and Acid–Base Disorders
Chapter Outline Learning Outcomes
cc Principles of Fluid Balance After reading this chapter, the student should be able to:
cc Fluid Replacement Agents 1. Describe the exchange of fluids that occurs among
Blood Products the different fluid compartments in the body.
PROTOTYPE Normal Serum Albumin (Albuminar,
Plasbumin, Others), p. 565 2. Identify conditions for which intravenous fluid
Crystalloids therapy may be indicated.
PROTOTYPE 5% Dextrose in Water (D5W), p. 566
Colloids 3. Explain how changes in the osmolality or tonicity of
PROTOTYPE Dextran 40 (Gentran 40, Others), p. 567 a fluid can cause water to move to a different
cc Physiology of Electrolytes compartment.
cc Pharmacotherapy of Electrolyte Imbalances 4. Compare and contrast the use of blood products,
PROTOTYPE Sodium Chloride (NaCl), p. 571 crystalloids, and colloids in intravenous therapy.
PROTOTYPE Potassium Chloride (KCl), p. 572
PROTOTYPE Magnesium Sulfate (MgSO4), p. 574 5. Explain the importance of electrolyte balance in the
body.
cc Pharmacotherapy of Acid–Base Imbalances
PROTOTYPE Sodium Bicarbonate, p. 576 6. Explain the pharmacotherapy of sodium and
PROTOTYPE Ammonium Chloride, p. 577 potassium imbalances.
7. Discuss medications used to treat acidosis and alkalosis.
8. Describe the nurse’s role in the pharmacologic
management of fluid imbalance, electrolyte, and
acid–base disorders.
9. 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.
10. Apply the nursing process to care for patients receiving
pharmacotherapy for fluid imbalance, electrolyte, and
acid–base disorders. 561
562 Unit 5 Pharmacology of the Cardiovascular System
Key Terms extracellular fluid (ECF) intracellular fluid (ICF)
compartment, 562 compartment, 562
acidosis, 575
alkalosis, 577 hyperkalemia, 572 ion trapping, 575
buffers, 575 hypernatremia, 569 osmolality, 563
colloids, 567 hypokalemia, 572 osmosis, 563
crystalloids, 566 hyponatremia, 570 tonicity, 563
electrolyte, 568
Can too much pure, sparkling water hurt you? As often as Cells: 25 L Interstitial Plasma:
people hear “drink plenty of fluids,” too much (or too little) fluid: 12 L 3L
can definitely be harmful. The volume and composition of Water and
fluids in the body must be maintained within narrow lim- electrolytes
its. Excess fluid volume can lead to hypertension (HTN),
heart failure, or peripheral edema, while depletion results Intracellular fluid Extracellular fluid
in dehydration. compartment compartment
Body fluids must also contain specific amounts of 40% of body weight 20% of body weight
essential ions or electrolytes and be maintained at particu-
lar pH values. Imbalances in electrolytes or changes in the Figure 33.1 Major fluid compartments in the body.
pH of body fluids may have fatal consequences if left
untreated. This chapter will examine drugs used to reverse compartments, as molecules travel across the membranes
fluid imbalance, electrolyte, or acid–base disorders. that separate them. For example, the plasma membranes of
cells separate the ICF from the ECF. The capillary mem-
Principles of Fluid Balance branes separate plasma from the interstitial fluid. Although
water travels freely among the compartments, processes of
33.1 Body fluids are exchanged between diffusion and active transport govern the movement of
intracellular and extracellular compartments. large molecules and those with electrical charges. Move-
ment of ions and drugs across membranes is a primary
Body fluids travel between compartments separated by topic of pharmacokinetics (see Chapter 3).
semipermeable membranes. Control of water balance in the
various compartments is essential to homeostasis. Fluid CONNECTION Checkpoint 33.1
imbalances are frequent indications for pharmacotherapy.
From what you learned in Chapter 3, what barriers does an oral drug
Not surprisingly, the greatest bulk of body fluid con- face in moving from the gastrointestinal (GI) tract to the extracellular
sists of water, which serves as the universal solvent in fluid compartment (plasma)? Answers to Connection Checkpoint
which electrolytes, minerals, and most nutrients are dis- questions are available on the faculty resources site. Please consult
solved. Water alone is responsible for about 60% of the total with your instructor.
body weight in a young adult. A newborn may contain 80%
water, while an older adult may contain only 40%. 33.2 Osmolality or tonicity determines
the movement of body fluids.
In a simple model, water in the body can be located in
one of two places, or compartments. The intracellular fluid Osmolality and tonicity are two related terms central to
(ICF) compartment, which contains water that is inside understanding the pharmacotherapy of fluid imbalance
cells, accounts for about two thirds of the total body water. disorders. Abnormalities in the osmolality or tonicity of a
The remaining one third of body fluid resides outside cells body fluid can cause significant shifts in water balance
in the extracellular fluid (ECF) compartment. The ECF between compartments. The nurse will often administer
compartment is further divided into two parts: fluid in the intravenous (IV) fluids to compensate for these changes.
plasma, or intravascular space, and fluid in the interstitial
spaces between cells. The relationship between these fluid
compartments is illustrated in Figure 33.1.
Once contained in a compartment, water and minerals
do not stay there for very long. There is a continuous
exchange, turnover, and mixing of fluids between
Chapter 33 Pharmacotherapy of Fluid Imbalance, Electrolyte, and Acid–Base Disorders 563
The osmolality is a measure of the number of dis- the distal tubules of the kidney to increase water reabsorp-
solved particles, or solutes, in 1 kg (1 L) of water. In most tion. This increased water in the intravascular space dilutes
body fluids, three solutes determine the osmolality: the plasma, thus lowering its osmolality. In high concentra-
sodium, glucose, and urea. Sodium is the greatest contribu- tions ADH, also called vasopressin, can cause vasoconstric-
tor to osmolality due to its abundance in most body fluids. tion, which serves as an important compensatory
The normal osmolality of body fluids ranges from 275 to mechanism during hypovolemic shock.
295 milliosmoles per kilogram (mOsm/kg).
A second set of hormones assists in the maintenance of
The term tonicity is sometimes used interchangeably fluid balance. Through the renin-angiotensin-aldosterone
with osmolality, although they are somewhat different. system (RAAS) (see Chapter 31), the hormone aldosterone
Tonicity is the ability of a solution to cause a change in water is secreted by the adrenal cortex. Aldosterone causes the
movement across a membrane due to osmotic forces. kidneys to retain sodium and water in the body, thus
Whereas osmolality is a laboratory value that can be pre- increasing the osmolality of the ECF.
cisely measured, tonicity is a general term used to describe
the relative concentration of IV fluids. The tonicity of normal Failure to maintain adequate intake or output can lead
plasma is considered isotonic and is used as the reference to fluid imbalance disorders that are indications for phar-
point when administering IV solutions. Solutions that are macologic intervention. Fluid deficit disorders can cause
isotonic have the same concentration of solutes (same osmo- dehydration or shock, which are treated by administering
lality) as plasma. Hypertonic solutions contain a greater oral (PO) or IV fluids. Fluid excess disorders are treated
concentration of solutes than plasma, whereas hypotonic with diuretics (see Chapter 32). When treating fluid imbal-
solutions have a lesser concentration of solutes than plasma. ances, the ultimate goal is to diagnose and correct the
underlying cause of the disorder, while administering sup-
Through osmosis, water moves from areas of low sol- porting fluids and medications to stabilize the patient.
ute concentration (low osmolality) to areas of high solute
concentration (high osmolality). If a hypertonic (hyperos- CONNECTION Checkpoint 33.2
molar) IV solution is administered, water will move, by
osmosis, from the cells, to the interstitial fluid compart- From what you learned in Chapter 31, name the two aldosterone
ment, to the plasma compartment. If a hypotonic solution antagonists and provide their indications. Answers to Connection
is administered, water will move in the opposite direction, Checkpoint questions are available on the faculty resources site.
from plasma to the interstitial fluid, and eventually into Please consult with your instructor.
cells. Isotonic solutions produce no net fluid shift. From a
pharmacologic perspective, water movement between Fluid Replacement Agents
compartments following an IV infusion can be either a
therapeutic effect or an adverse effect depending on the 33.4 Dehydration may be treated with fluid
patient’s condition and the expected outcomes of the drug volume expanders.
administration.
When fluid output exceeds fluid intake, volume deficits
33.3 Overall fluid balance is regulated primarily may result in shock, dehydration, or electrolyte loss. Left
by hormones acting on the kidneys. untreated, large-volume deficits may turn fatal. The fol-
lowing are common causes of fluid depletion:
The average adult has a water intake of approximately
2500 mL per day, most of which comes from ingested food • Loss of GI fluids due to vomiting, diarrhea, chronic
and beverages. Water output occurs through the kidneys, laxative use, or GI suctioning
lungs, skin, feces, and sweat. To maintain water balance,
water intake must equal water output. Net gains or losses • Excessive sweating during hot weather, athletic activ-
of water can be estimated by changes in total body weight. ity, or prolonged fever
The most important physiologic mechanism regulat- • Severe burns
ing fluid intake is thirst. The sensation of thirst occurs • Hemorrhage
when osmoreceptors in the hypothalamus sense that the • Excessive diuresis due to diuretic therapy or uncon-
ECF has become hypertonic. Saliva secretion diminishes
and the mouth dries, motivating the individual to drink trolled diabetic ketoacidosis.
fluids. As the ingested water is absorbed, the osmolality of
the ECF falls and the thirst center in the hypothalamus is The immediate goal in treating a volume deficit disor-
no longer stimulated. der is to replace the depleted fluid so that blood volume
and blood pressure can be maintained. In nonacute circum-
In addition to triggering thirst, the hypothalamus also stances, this may be achieved by drinking more liquids or
directs the pituitary gland to release antidiuretic hormone by administering fluids via a feeding tube. In acute situa-
(ADH) when plasma osmolality rises. ADH acts directly on tions, IV fluid therapy is indicated.
Choice of IV fluid therapy depends on the nature of the
volume deficit. Careful attention must be paid to restoring
564 Unit 5 Pharmacology of the Cardiovascular System
Table 33.1 Types of Dehydration Disorders and Their Treatment
Type Isotonic Contraction Hypotonic Contraction Hypertonic Contraction
Fluid lost Water and sodium in equal proportions Sodium, without a corresponding loss of Water, without a corresponding loss of sodium
water
Pathophysiology ECF remains isotonic; no net fluid shift ECF becomes hypotonic; fluid shifts from ECF becomes hypertonic; fluid shifts from ICF
ECF to ICF, lowering plasma fluid volume to ECF, causing cellular dehydration
Causes Vomiting, diarrhea, renal disease, diuretics Diuretics, renal disease Excessive sweating without replenishment,
osmotic diuresis, burns
Treatment Administer isotonic fluids; e.g., isotonic Administer hypertonic fluids; e.g., Administer hypotonic fluids; e.g., hypotonic
saline (0.9%) hypertonic saline (3%) saline or 5% dextrose
normal levels of blood elements (erythrocytes, leukocytes, replacement agents are blood products, crystalloids, and
and thrombocytes) and electrolytes as well as total fluid vol- colloids.
ume. If significant blood loss has occurred, blood products
may be indicated. Loss of substantial sodium and other 33.5 Transfusions of blood products are used to
salts involves replacement therapy with hypertonic fluids. treat serious conditions that cannot be managed
Excessive sweating can result in water loss that requires effectively by other means.
hypotonic IV fluids. Treating dehydration with an IV fluid
with the incorrect tonicity may worsen the condition. Blood products include whole blood, packed red cells,
fresh frozen plasma, cryoprecipitate, immune globulins,
Fluid replacement should always be conducted in a and platelet infusions. A single unit of whole blood can be
controlled, stepwise manner. Rapid infusions can cause separated into its specific constituents (erythrocytes, leu-
fluid overload, pulmonary edema, and cardiovascular kocytes, platelets, plasma proteins, fresh frozen plasma,
stress. Vital signs and plasma electrolytes should be care- and globulins), which can be used to treat multiple
fully monitored during therapy. Therapy for dehydration patients. Indications for the various blood products are
is summarized in Table 33.1. The three basic classes of fluid shown in Table 33.2.
Table 33.2 Indications for Blood Products
Product Description Indication(s)
Whole blood Contains all blood components Rapid, massive blood loss when safer agents are not available
Packed RBCs One unit of packed RBCs increases hemoglobin by about
Fresh frozen plasma (FFP) 1 g/dL and hematocrit by about 3% Preferred product to increase serum hemoglobin level
Cryoprecipitate Washed RBCs are nearly free of plasma, white blood cells,
Immune globulins and platelets and are reserved for patients who have severe Correction of bleeding secondary to factor deficiencies for
reactions to plasma components which specific factor replacements are unavailable, multifactor
Platelets An unconcentrated source of all clotting factors, without deficiency states, and rapid warfarin reversal
platelets FFP should not be used for simple volume expansion
A concentrate prepared from FFP Originally used for hemophilia and von Willebrand’s disease, it
Each concentrate contains about 80 units each of Factor VIII is also used as a source of fibrinogen in acute disseminated
and von Willebrand’s factor and about 250 mg of fibrinogen intravascular coagulation with bleeding, treatment of uremic
It also contains fibronectin and Factor XIII bleeding, cardiothoracic surgery, and obstetric emergencies
such as abruptio placentae
Antibody preparations used to provide an immediate boost to
the immune system Rho(D) immune globulin (RhoGAM) prevents development of
maternal Rh antibodies that can result from fetomaternal
One platelet concentrate increases the platelet count by hemorrhage
about 10,000/mcL Other immune globulins are available for postexposure
prophylaxis for patients exposed to certain infectious diseases,
including cytomegalovirus, hepatitis A and B, measles, rabies,
respiratory syncytial virus, rubella, tetanus, smallpox, and
varicella
Used to prevent bleeding in asymptomatic severe
thrombocytopenia, for bleeding patients with less severe
thrombocytopenia or with platelet dysfunction due to
antiplatelet drugs but with normal platelet count, for patients
receiving a massive transfusion that causes dilutional
thrombocytopenia, and before invasive surgery
Chapter 33 Pharmacotherapy of Fluid Imbalance, Electrolyte, and Acid–Base Disorders 565
Blood products may be administered to restore deficient Therapeutic Effects and Uses: Normal serum
numbers of blood cells or proteins, or to increase fluid vol- albumin is a protein extracted from whole human blood,
ume depending on the clinical situation. Whole blood is plasma, or placental plasma that contains 96% albumin
indicated for the treatment of acute, massive blood loss and 4% globulins and other proteins. After extraction from
(depletion of more than 30% of the total volume) when there blood or plasma, the albumin is sterilized to remove possi-
is a need to replace plasma volume and to supply erythro- ble contamination by hepatitis viruses or HIV. Plasma pro-
cytes to increase the blood’s oxygen-carrying capacity. tein fraction (Plasmanate) is another albumin product that
contains 83% albumin and 17% plasma globulins. Albumin
PharmFACT is classified as both a blood product and a colloid.
In the United States, over 13 million units of whole blood and The functions of endogenous albumin are to maintain
red blood cells are donated each year. About 36,000 units of red plasma osmotic pressure and to bind certain substances
blood cells are needed every day (American Red Cross, n.d.). traveling through the blood, including fatty acids, hor-
mones, enzymes, and a substantial number of drug mole-
The administration of whole blood has been largely cules. Binding to albumin renders these substances inactive
replaced by the use of blood components. Whole blood is until they become unbound.
rarely administered for several reasons. If the patient needs
only one specific component in blood, there is no need to Normal serum albumin may be administered to
expose the patient to unnecessary components that could restore plasma volume and maintain cardiac output in
potentially trigger an adverse effect. The supply of blood patients with hypovolemic shock. It may also be adminis-
products depends on human donors and requires careful tered to restore the level of blood proteins in patients with
crossmatching to ensure compatibility between the donor hypoproteinemia, which occurs with hepatic cirrhosis.
and the recipient. Albumin is occasionally administered to bind and remove
toxic bilirubin in hemolytic disease of the newborn. It may
The most common complications of whole blood trans- also offer protection against kernicterus, a toxic accumula-
fusion include febrile nonhemolytic and chill-rigor reac- tion of bilirubin in infants that causes brain injury. It has an
tions. The patient experiences symptoms of an allergic immediate onset of action and is available in concentra-
reaction that include back pain and low-grade fever and tions of 5% and 25%.
chills. Dizziness, urticaria, and headache may occur during
or immediately after the transfusion. Symptoms are gener- Mechanism of Action: Administered IV, normal
ally mild and treated with acetaminophen (Tylenol) and serum albumin rapidly increases the osmotic pressure of
diphenhydramine (Benadryl) as needed. the blood and causes fluid to move from the tissues to the
general circulation.
The most serious adverse effect from administration of
whole blood is an acute hemolytic transfusion reaction. Pharmacokinetics: Because human albumin is a nat-
This occurs when the patient receiving the transfusion ural substance, it is not possible to obtain accurate phar-
develops antibodies against donor red blood cell (RBC) macokinetic values. Endogenous albumin has a half-life of
antigens. ABO blood type incompatibility is the most com- 17 to 19 days.
mon cause of this rare, though sometimes fatal, disorder.
Another uncommon, though serious, adverse effect from Adverse Effects: Hypervolemia may occur if the dos-
whole blood is transfusion-related acute lung injury. This age and rate of infusion are not carefully adjusted to the
injury occurs when the patient receives donor antibodies patient’s volume status. Signs of fluid overload include
that attack normal granulocytes in the lung. Acute respira- headache, dyspnea, rising blood pressure, and pulmonary
tory symptoms develop and may be fatal. edema. Normal serum albumin is a natural blood product
and the patient may have antibodies to the donor’s albu-
Whole blood, despite being carefully screened, also min that cause allergic reactions. Because coagulation fac-
has the potential to transmit serious infections such as hep- tors, antibodies, and most other blood proteins have been
atitis, cytomegalovirus, malaria, or HIV. In addition, plate- removed, such allergic reactions from albumin are rare.
let concentrates are stored at room temperature, which may Signs of allergy include fever, chills, urticaria, rash, dys-
promote the growth of bacteria in the sample. Although pnea, and, possibly, hypotension.
disease transmission from donor to recipient is possible,
the risk is very low. Contraindications/Precautions: The drug is contra-
indicated in patients with severe anemia or cardiac failure
PROTOTYPE DRUG Normal Serum Albumin in the presence of normal or increased intravascular vol-
(Albuminar, Plasbumin, Others) ume and in those with known allergy to albumin.
Classification Therapeutic: Fluid replacement agent Drug Interactions: There are no clinically significant
Pharmacologic: Blood product, colloid interactions. Herbal/Food: Unknown.
566 Unit 5 Pharmacology of the Cardiovascular System
Pregnancy: Category C. Table 33.3 Selected Crystalloid IV Solutions
Treatment of Overdose: Protein overload may occur Drug Tonicity
if excessive albumin is infused. There is no treatment for
overdose. normal saline (0.9% NaCl) Isotonic
Nursing Responsibilities: Key nursing implications hypertonic saline (3% NaCl) Hypertonic
for patients receiving normal serum albumin are included
in the Nursing Practice Application for Patients Receiving hypotonic saline (0.45% NaCl) Hypotonic
Pharmacotherapy for Fluid and Electrolyte Imbalances.
lactated Ringer’s Isotonic
Drugs Similar to Normal Serum Albumin
(Albuminar, Plasbumin, Others) Plasma-Lyte 148 Isotonic
Other blood products are described in Table 33.2 and Plasma-Lyte 56 Hypotonic
include whole blood, packed RBCs, fresh frozen plasma,
cryoprecipitate, immune globulins, and platelet infusions. Dextrose Solutions
33.6 Crystalloids are intravenous solutions 5% dextrose in water (D5W) Isotonic*
that closely resemble the composition of 5% dextrose in normal saline Hypertonic
extracellular fluid.
5% dextrose in 0.2% saline Isotonic
Crystalloids are IV solutions that contain electrolytes
and other substances in concentrations that closely 5% dextrose in lactated Ringer’s Hypertonic
mimic the body’s extracellular fluid. They are used to
replace depleted fluids and to promote urine output. 5% dextrose in Plasma-Lyte 56 Hypertonic
Crystalloid solutions are capable of quickly diffusing
across membranes, leaving the plasma, and entering the *Because dextrose is metabolized quickly, the solution is sometimes considered
interstitial fluid and ICF. Isotonic, hypotonic, and hyper- hypotonic.
tonic solutions are available. Sodium is the most com-
mon crystalloid added to solutions, although some tissues. These drugs may be used to relieve cellular edema,
crystalloids contain dextrose, a form of glucose. Com- especially cerebral edema. When patients are dehydrated
mon crystalloids used to treat shock include normal and have hypertonic plasma, hypertonic solutions match
saline, lactated Ringer ’s, Plasma-Lyte, and hypertonic the tonicity of the plasma as it is infused, but the dextrose
saline. Selected crystalloids are listed in Table 33.3. in the IV solution is subsequently metabolized and the
Infusion of crystalloids will increase the total fluid vol- solution becomes hypotonic. This hypotonic solution then
ume in the body, but the compartment that is most causes water to shift into the intracellular space, relieving
expanded depends on the solute concentration of the the dehydration within the cells. Overtreatment with
fluid administered. hypertonic crystalloids such as 3% normal saline can lead
to excessive expansion of the intravascular (plasma) com-
Isotonic crystalloids: Isotonic crystalloids expand the partment, fluid overload, and HTN.
circulating intravascular (plasma) fluid volume, without
causing major fluid shifts between compartments. This is Hypotonic crystalloids: Hypotonic crystalloid infu-
because the osmotic pressures of the intravascular and sions lower the serum osmolality. This causes water to
extravascular compartments are equal. Isotonic crystal- move out of the plasma to the tissues and cells in the intra-
loids such as normal saline are often used to treat fluid loss cellular compartment; thus, these solutions are not plasma
due to vomiting, diarrhea, or surgical procedures, espe- volume expanders. Hypotonic crystalloids are indicated
cially when blood pressure is low. The isotonic saline solu- for patients with hypernatremia and cellular dehydration.
tions may also be used to treat sodium deficiency Care must be taken not to cause depletion of the intravas-
(hyponatremia) because they contain sodium chloride. cular compartment, which can result in hypotension, or
Because isotonic crystalloids can rapidly expand circulat- too much expansion of the extracellular compartment,
ing blood volume, care must be taken not to cause fluid which can cause peripheral edema. Patients who are dehy-
overload in the patient. drated with low blood pressure should be given normal
saline; the isotonic saline will expand plasma volume and
Hypertonic crystalloids: Infusion of hypertonic crystal- increase blood pressure while hydrating the patient.
loids raises the osmolality of the plasma and expands Patients who are dehydrated with normal blood pressure
plasma volume by drawing water away from the cells and should be given a hypotonic solution; this infusion will
hydrate cells without expanding plasma volume.
PROTOTYPE DRUG 5% Dextrose in Water (D5W)
Classification Therapeutic: Fluid expander
Pharmacologic: Crystalloid
Therapeutic Effects and Uses: Commonly found
in concentrations of 2.5%, 5%, or 10%, dextrose solu-
tions are infused to replace lost water and to enhance
Chapter 33 Pharmacotherapy of Fluid Imbalance, Electrolyte, and Acid–Base Disorders 567
renal function. Being a form of glucose, dextrose provides Nursing Responsibilities: Key nursing implications
nutritional value: 1 L of 5% dextrose supplies 170 calo- for patients receiving 5% dextrose in water are included
ries. In addition, water is formed during the metabolism in the Nursing Practice Application for Patients Receiving
of dextrose, adding to the rehydration of the patient. D5W Pharmacotherapy for Fluid and Electrolyte Imbalances.
is also used as a diluent for mixing other medications
for IV delivery. Dextrose 50% is indicated for the emer- Drugs Similar to 5% Dextrose in Water (D5W)
gency treatment of insulin hypoglycemia to restore blood
glucose levels. Other crystalloids include Ringer’s solution and
Plasma-Lyte.
D5W is isotonic in the container. When infused, how-
ever, the dextrose is quickly metabolized in the body, leav- Ringer’s and lactated Ringer’s: Ringer’s solution is named
ing only water, and the solution becomes hypotonic. Water after the pharmacologist Sydney Ringer who created the
may then move from the plasma to the intracellular spaces, drug in the mid-1800s. Ringer’s solution is an isotonic
relieving cellular dehydration. Essentially, the infusion of fluid that contains sodium, chloride, potassium, and cal-
D5W has the same effect as administration of water. Because cium ions in concentrations similar to those found in
this may result in a lower plasma volume, patients needing plasma. Lactated Ringer’s solution also contains lactate,
fluid replacement for hypovolemia should receive lactated which serves as a chemical buffer in the blood to prevent
Ringer’s or normal saline rather than D5W. acidosis. Lactated Ringer’s is also available with 5% dex-
trose. Ringer’s solutions are widely administered IV for
Dextrose is added to other IV solutions, as shown in fluid resuscitation following hemorrhage caused by
Table 33.3. It is also available in other concentrations. In all trauma, surgery, or burns.
cases, the dextrose is simply added as a source of calories
and nutrition. Plasma-Lyte: Plasma-Lyte solutions are electrolyte solu-
tions used to correct volume and electrolyte deficiencies.
Mechanism of Action: There are two forms of glu- The solutions also contain buffers such as lactate, acetate,
cose in nature: L-glucose and D-glucose. Only D-glucose, or gluconate, which help to correct or prevent acidosis.
also called dextrose, can be used by the human body for Several formulations are available that differ in electrolyte
energy. If insulin is present, glucose (dextrose) enters cells composition and osmolarity. These include Plasma-Lyte-R,
and is converted into adenosine triphosphate (ATP), CO2, Plasma-Lyte-A, Plasma-Lyte 56, and Plasma-Lyte 148.
and water.
33.7 Colloids are intravenous solutions
Pharmacokinetics: Because dextrose and water are containing large molecules that remain
natural substances, it is not possible to obtain accurate in the blood.
pharmacokinetic values.
Colloids are proteins, starches, or other large molecules
Adverse Effects: Infusion of too much D5W may cause that remain in the blood for a long time because they are
fluid overload, thus worsening peripheral edema, pulmo- too large to easily cross the capillary membranes. While cir-
nary edema, and heart failure. Hyperglycemia is possible, culating, they have the same effect as hypertonic solutions,
especially in patients with deficient insulin secretion. Pain drawing water molecules from the cells and tissues into the
may occur at the injection site. As D5W dilutes the plasma, plasma through their ability to increase plasma osmolality
the concentration of sodium in the plasma may fall, result- and osmotic pressure. These drugs are sometimes called
ing in hyponatremia. Hyponatremia in children is espe- plasma volume expanders. Blood product colloids include
cially dangerous because it can lead to encephalopathy as normal serum albumin, plasma protein fraction, and serum
the brain swells. globulins. The non–blood product colloids are dextran (40,
70, and high molecular weight) and hetastarch (Hespan).
Contraindications/Precautions: Caution must be These medications are administered to provide life-sustain-
used when using D5W in patients with heart failure or ing support following massive hemorrhage and to treat
who are hyperglycemic. Patients with increased intracra- shock, burns, acute liver failure, and neonatal hemolytic
nial pressure should not receive hypotonic agents such as disease. Selected colloid solutions are given in Table 33.4.
D5W because they may worsen this condition. Dextrose is
obtained from corn and patients allergic to this food may PROTOTYPE DRUG Dextran 40 (Gentran 40, Others)
be hypersensitive to the drug.
Classification Therapeutic: Plasma volume expander
Drug Interactions: There are no significant drug inter- Pharmacologic: Colloid
actions with D5W. Herbal/Food: Unknown.
Therapeutic Effects and Uses: Dextran 40 is a syn-
Pregnancy: Category C. thetic polysaccharide that is too large to pass through
Treatment of Overdose: Overdose is uncommon,
but diuretics may be indicated in cases of fluid overload.
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