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Home , ACE inhibitor, Moexipril

-CONVERTING ENZYME INHIBITORS

Dana Bartlett, RN, BSN, MSN, MA, CSPI

Dana Bartlett is a professional nurse and author. His clinical experience includes 16 years of ICU and ER experience and over 20 years of as a poison control

center information specialist. Dana has published numerous CE and journal articles, written NCLEX material, written textbook chapters, and done editing and reviewing for publishers such as Elsevier, Lippincott, and Thieme. He has written widely on the subject of toxicology and was a contributing editor, toxicology section, for Critical Care Nurse journal. He is currently employed at the Rocky Mountain Poison Control Center.

ABSTRACT

The class of angiotensin converting enzyme (ACE) inhibitors are widely prescribed for conditions of primary . Hypertension is a very common that affects approximately 75 million Americans or roughly 1 in 3 adults. ACE inhibitors also have distinct, specific advantages for treating hypertensive patients who have chronic disease, mellitus, failure, and . They are known to prevent mortality related to a cardiovascular event. Except for and , the ACE inhibitors are pro-, changed in the to a pharmacologically active metabolite. ACE inhibitors may differ in their pharmacokinetic properties, such as peak levels and effect on depending on the .

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1 Policy Statement

This activity has been planned and implemented in accordance with the policies of NurseCe4Less.com and the continuing nursing education requirements of the American Nurses Credentialing Center's Commission on Accreditation for registered nurses. It is the policy of NurseCe4Less.com to ensure objectivity, transparency, and best practice in clinical education for all continuing nursing education (CNE) activities.

Continuing Education Credit Designation

This educational activity is credited for 2.5 hours. Nurses may only claim credit commensurate with the credit awarded for completion of this course activity. content is 2.5 hours.

Statement of Learning Need

It is important for health clinicians to have current information about ACE inhibitors, specifically, the pharmacological profile, therapeutic uses, adverse effects, contraindications, warnings, and for the treatment of certain disease states. Additionally, patient monitoring during therapy with an ACE inhibitor, and how to manage ACE inhibitor-induced and ACE inhibitor overdose will impact patient care outcomes.

Course Purpose

To increase health clinician knowledge of the recommended use, benefits and risks of ACE Inhibitor use.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 2 Target Audience

Advanced Practice Registered Nurses and Registered Nurses

(Interdisciplinary Health Team Members, including Vocational Nurses and Medical Assistants may obtain a Certificate of Completion)

Course Author & Planning Team Conflict of Interest Disclosures

Dana Bartlett, RN, BSN, MSN, MA, CSPI, William S. Cook, PhD, Douglas Lawrence, MA, Susan DePasquale, MSN, FPMHNP-BC All have no disclosures

Acknowledgement of Commercial Support

There is no commercial support for this course.

Please take time to complete a self-assessment of knowledge, on page 4, sample questions before reading the article. Opportunity to complete a self-assessment of knowledge learned will be provided at the end of the course.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 3 1. The -angiotensin system (RAS) regulates blood pressure by, among other things,

a. causing the kidneys to convert pre-renin to renin. b. synthesizing renin to angiotensin I in the kidneys. c. increasing renal blood flow. d. increasing serum sodium.

2. ______binds to specific receptors, and it increases blood pressure by its action as a potent vasoconstrictor.

a. Angiotensin I b. Renin c. Angiotensin II d. Sodium

3. The angiotensin converting enzyme (ACE) inhibitors have the net effect of

a. decreasing the activity of renin. b. lowering blood pressure. c. increasing the vasoconstrictive action of angiotensin II. d. increasing serum sodium levels in the body.

4. True or False: The ACE inhibitors and the angiotensin receptors blockers (ARBs) both lower blood pressure by their effects on the RAS using the same methods.

a. True b. False

5. Treatment of ______is a primary use of ACE inhibitors.

a. b. c. cholestatic jaundice d. cardiovascular

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 4 Introduction

The angiotensin converting enzyme inhibitors are one of the most widely used antihypertensive , and they are a first-line choice for treating primary hypertension according to the Eighth National Committee guideline for the management of high blood pressure in the general non-black population and in patients 18 years or older who have chronic . The angiotensin converting enzyme inhibitors are also often used to treat hypertension associated with specific clinical conditions, , and their use is considered standard care for patients who have recently had an ST segment elevation myocardial infarction.

ACE Inhibitors And The Renin-Angiotensin System

The antihypertensive effect of the angiotensin-converting enzyme (ACE) inhibitors is mediated through the renin-angiotensin system (RAS), one of many homeostatic mechanisms the body uses to regulate blood pressure. The RAS also regulates fluid, potassium, and sodium balances. The RAS is very complex, and it has other physiological effects aside from blood pressure control, but this discussion will focus on the RAS and hypertension.

The effect of the RAS on blood pressure is complex, but the basic process is highlighted below.

• Decreased renal blood flow, volume depletion, decrease in serum sodium, and sympathetic stimulation cause the kidneys to convert pre- renin to renin. Renin is an enzyme that converts angiotensinogen, a compound that is synthesized by the liver, to angiotensin I. • Angiotensin I (no direct biological actions and a precursor) is then changed to angiotensin II by ACE.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 5 • Angiotensin II binds to specific receptors, and it increases blood pressure by its action as a potent vasoconstrictor, increasing the secretion of the hormone , and aldosterone increases renal tubular reabsorption of sodium and water, and stimulating the sympathetic .

The net result is an increase in blood pressure, and the RAS is the primary way long-term control of blood pressure is attained.

The ACE inhibitors inhibit the activity of ACE. This decreases the production of angiotensin II, increases the activity of renin, and decreases the secretion of aldosterone. The net effect is a lowered blood pressure.

The RAS can also be manipulated to lower blood pressure by preventing angiotensin II from binding to the angiotensin I and angiotensin II receptors. These are G protein-coupled receptor for which angiotensin II is a ligand, and the angiotensin receptors blockers (ARBs) like prevent ligand binding to the receptor and thus diminish the vasoconstrictive action of angiotensin II. The ACE inhibitors and the ARBs both lower blood pressure by their effects on the RAS by but different methods.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 6 Pharmacological Profile Of Ace Inhibitors

Angiotensin-converting enzyme inhibitors are available as tablets and a solution for injection. ACE inhibitors are also available combined with a or with a . The ACE inhibitors currently available in the United States are listed in Table 1. The generic name is followed by the trade name.

Table 1: ACE Inhibitors

Benazepril (Lotensin) Captopril (Capoten) (Vasotec) (Monopril) Lisinopril (Prinivil, Zestril) (Univasc)

Perindopril (Aceon) (Accupril) (Altace) Mavik)

Pharmacological Category

Angiotensin-Converting Enzyme (ACE) Inhibitor, antihypertensive.

Uses

There are slight differences in the prescribing information for the ACE inhibitors, but they are not significant. The four primary uses for ACE inhibitors are: 1) Treatment of hypertension, 2) Treatment of , symptomatic, reduced ejection fraction, 3) Improving left ventricular function and decreasing mortality after acute myocardial infarction, and 4) Treatment of diabetic nephropathy.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 7 US

Drugs that act on the RAS can cause injury, fetal toxicity, and death to a developing fetus. Discontinue an ACE inhibitor as soon as it is known the patient is pregnant.

Contraindications

The potential for allergic cross-reactivity between ACE inhibitors is unclear, so administration of one ACE inhibitor to patient who has had an allergic reaction to another is inadvisable.

Patients With Diabetes Mellitus and Taking

The concomitant use of an ACE inhibitor and aliskiren in patients who have diabetes mellitus is contraindicated. Aliskiren itself has the potential to cause , hypotension, and renal impairment, this risk is increased if the patient is given an ACE inhibitor,1,2 and hypotension, hyperkalemia, and renal impairment are potential adverse effects of the ACE inhibitors.

Hereditary or Idiopathic Angioedema

The use of ACE inhibitors in patients who have these conditions can cause an attack of angioedema. ACE inhibitor-induced angioedema is discussed later. Co-administration of an ACE inhibitor with or within 36 hours of administration of a inhibitor like puts patients at risk for angioedema.3

Warnings

If a patient has any of the medical conditions listed below or is at risk for them, clinicians should use ACE inhibitors cautiously and carefully monitor the patient for adverse effects. In addition, some of the adverse effects of

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 8 the ACE inhibitors (cough, cholestatic jaundice, hematologic abnormalities) are listed as warnings because these may cause significant harm, may be less well known, or can be prevented by close follow-up.

Aortic Stenosis

The ACE inhibitors reduce afterload and in the context of aortic stenosis, this could result in decreased coronary perfusion, ischemia, and hypotension. Because of this, aortic stenosis is listed in ACE inhibitor prescribing information as a warning and clinicians are advised to use these drugs cautiously if a patient has aortic stenosis. Recent literature reviews have questioned the magnitude of this risk.4,5

Cardiovascular Disease

Treatment of cardiovascular diseases is a primary use of ACE inhibitors. Hypotension is a common adverse effect of the ACE inhibitors and in patient who or ischemic heart disease, hypotension could cause a myocardial infarction (MI) or a stroke.

Collagen Vascular Disease

Hematologic abnormalities like agranulocytosis and neutropenia can happen if a patient who has a collagen vascular disease, i.e., systemic lupus erythematous, is given an ACE inhibitor.6,7 This risk is increased if the patient also has renal impairment.6,7

Cholestatic Jaundice

There have been reports (rare) of serious hepatotoxicity and cholestatic jaundice caused by ACE inhibitors.8

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Cough is a common adverse effect of ACE inhibitors,7,9,10 and this adverse effect is more common in women7,9 and people of Chinese descent.7 It typically begins one to two weeks after beginning the drug, but the onset can take several months. The cough should subside within several days of discontinuing an ACE inhibitor, but it may linger for a few weeks.7 If the ACE inhibitor is discontinued and then re-started, the incidence of cough increases considerably.5 Clinicians should remember that cough can be caused by an infectious and/or pulmonary problem and that for patients who have heart failure, cough may be a sign of pulmonary congestion.

Hematologic Effects

The ACE inhibitors can cause anemia, agranulocytosis, neutropenia, and thrombocytopenia.11-13 These adverse effects are much more likely to occur in patients who have a collagen vascular disease, for example, systemic lupus erythematous, or who have renal failure.

Hyperkalemia

The ACE inhibitors decrease urinary excretion of potassium and a mild degree of hyperkalemia is not uncommon in patients taking an ACE inhibitor.14 The risk for hyperkalemia during administration of an ACE inhibitor is higher for patients who are elderly and for patients who have diabetes, renal impairment, or who are taking a potassium sparing diuretic like , a potassium supplement, or a non-steroidal anti- inflammatory.7

The issue of ACE inhibitors and hyperkalemia is further complicated by their effect on the kidneys.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 10 Hypertrophic Cardiomyopathy with Outflow Tract Obstruction

Hypertrophic cardiomyopathy (HCM) is a genetic disease that causes the myocardium to become thick and hypertrophied. Hypertrophic cardiomyopathy itself reduces the amount of blood that the ventricle can hold. In HCM with outflow tract obstruction the mitral valve is affected, and the and abnormal movement of the mitral valve during systole decreases . Because the ACE inhibitors reduce afterload, there is concern that they could exacerbate HCM with outflow tract obstruction.

Renal Impairment

The relationship of the ACE inhibitors and renal function is complicated. The ACE inhibitors decrease renal perfusion and they blunt the body’s autoregulatory ability to increase glomerular filtration rate (GFR) when needed.7,15,16 Because of these effects, a slight change in GFR and a small increase in serum are not unusual soon after a patient begins taking an ACE inhibitor,7 but for most patients, serious renal damage or impairment does not happen.7

The ACE inhibitors are typically prescribed for patients who are at risk for renal impairment and/or who may have a level of compromised renal function that has not been detected - patients who are elderly, patients taking non-steroidal anti-inflammatories, or patients who have , diabetes mellitus, heart failure, renal stenosis, acute volume depletion.7,15 These patients should be closely monitored for changes in GFR and serum creatinine because for them, changes in renal function are not uncommon, less well tolerated, and can have serious consequences.15 The standard of care is to discontinue therapy with ACE inhibitors if hyperkalemia

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 11 cannot be controlled or if the serum creatinine increases ≥ 30%,7,15 but the safety of this approach has been questioned.15

Adverse Reactions

Adverse effects of ACE inhibitors include (but are not limited to) angioedema, cough, hypotension, hyperkalemia, and serum creatinine increase.

Dose Adjustment, Hepatic Impairment

ACE inhibitor prescribing information does not recommend for adjusting doses for patients who have hepatic impairment. However, there have been reports (rare) of serious hepatotoxicity and cholestatic jaundice caused by ACE inhibitors, so the risk of their use in patients who have hepatic impairment and the need for a lower than normal dose depending on patient circumstances and comorbidities.

Dose Adjustment, Renal Impairment

ACE inhibitor doses should be decreased if a patient has renal impairment. The appropriate dosing adjustment can be determined by measuring serum creatinine, creatinine clearance, or GFR; check the prescribing information for the specific ACE inhibitor for directions as to which to use.

Example:

The prescribing information for states that if creatinine clearance is ≥ 30 mL/minute/1.73 m2, no dosing adjustment is needed; if the creatinine clearance is < 30 mL/minute/1.73 m2, the initial dose should be 5 mg and the maximum daily dose should be 40 mg; typically, these are 10 mg and 40 mg respectively.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 12 Example:

The prescribing information for enalapril states that is the serum creatinine is > 1.6 mg/dL, the initial dose should be 2.5 mg rather than 5 mg.

Use in Pregnancy

The ACE inhibitors are contraindicated for use during the second and third trimester (see the U.S., Boxed warning).17 ACE inhibitor use should be discontinued as soon as it is discovered the patient is pregnant. Several literature reviews have concluded that use of an ACE inhibitor during the first trimester is not associated with an increased risk for fetal malformations.

Breastfeeding

There is little information about the risks and safety of ACE inhibitors while breastfeeding.19 The prescribing information for the ACE inhibitors states that small amounts of the pro-drug and the active form are present in breast ; the risk-benefit of continuing or stopping therapy with an ACE inhibitor should be considered for each nursing woman, and if breastfeeding is continued, the child’s weight should be monitored for the first four weeks.

LACTMED, a database that is administered by the U.S. National Library of Medicine, states that because ACE inhibitors are found in in low levels “... amounts ingested by the infant are small and would not be expected to cause any adverse effects in breastfed infants.” However, the LACTMED database also notes that for fosinopril, lisinopril, moexipril, ramipril, and trandolapril “...no information is available on the use of this drug during breastfeeding, (and) an alternate drug may be preferred, especially while nursing a newborn or preterm infant.”20

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 13 Drug-drug Interactions

The ACE inhibitors interact with many commonly used medications; check a reliable source for updated information on important ACE-inhibitor-drug interactions.

Dietary Considerations

The recommendations regarding the ACE inhibitors and food vary from drug to drug; check an up-to-date source of drug information if you have questions about the interaction between food and an ACE inhibitor.

• Captopril: Take on an empty stomach, one-two hours after or before meals. • Enalapril: Limit potassium and sodium intake. • Fosinopril: Potassium supplements should be taken only with the approval of and supervision by a physician. • Lisinopril and Trandolapril: Use potassium salt substitutes carefully if the patient had diabetes or renal impairment or if he/she is taking a potassium-sparing diuretic or a potassium supplement. • Moexipril: Taken on an empty stomach one hour before meals. • : Do not take with food.

Pharmacodynamics

Except for captopril and lisinopril, the ACE inhibitors are pro-drugs, changed in the liver to a pharmacologically active metabolite. The onset of action of the ACE inhibitors is typically within an hour, and the peak effect on blood pressure will be seen (depending on the drug) from one to six hours after ingestion. The ACE inhibitors are mostly given once a day, but some can be taken two-three times a day.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 14 Monitoring During Therapy

Monitor blood pressure, BUN, creatinine, blood pressure, serum potassium and when appropriate, a complete blood count (CBC).

Ace Inhibitors For Hypertension

The ACE inhibitors are one of the four first-choice drugs for treating hypertension, the others being ARBs, calcium channel blockers, and thiazide . Hypertension is a very common disease that affects approximately 75 million Americans – roughly 1 in 3 adults. The ACE inhibitors are widely prescribed for the treatment of primary hypertension, and they have distinct, specific advantages for treating hypertensive patients who have chronic kidney disease, diabetes mellitus, heart failure, and myocardial infarction.

Primary Hypertension

When choosing an antihypertensive for a patient who has primary hypertension, the clinician must consider a drug’s effectiveness at lowering blood pressure, its effectiveness at preventing the complications of hypertension, the adverse effect profile of the drug, and whether the antihypertensive is suitable for the patient. The ACE inhibitors are a first-line drug for treating primary hypertension,21-23 and there are several reasons why they are often the initial choice.21-23

1. The ACE inhibitors are as effective in reducing blood pressure to the desired level and preventing the cardiovascular complications of hypertension like MI and stroke as the other first-line anti- hypertensives, the ARBs, calcium channel blockers, and thiazide diuretics.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 15 2. The risk for adverse effects from beta-blockers (which are often a second or third-line choice), calcium channel blockers, and thiazide diuretics increases as the dose is increased. This does not happen with the ACE inhibitors and as blood pressure control may require dose titration, this is a significant consideration. In addition, the ACE inhibitors are usually well tolerated. 3. Patients who are < 50 years of age have a better response to ACE inhibitors. 4. The ACE inhibitors are the anti-hypertensive of choice for patients who have heart failure and reduced ejection fraction, for patients who have hypertension and chronic kidney disease, and for patients who have recently had an MI, and for many patients who have type 1 or . The use of ACE inhibitors for these patient populations will be discussed separately. 5. Monotherapy is acceptable for patients who have mild hypertension. But many patients require two or more drugs to control blood pressure, and an ACE-inhibitor-calcium channel blocker combination is considered the first-line choice for combination therapy.22,24,25 This approach has the added advantage of adding a calcium channel blocker to a drug that is (likely) already being used.

African Americans and the elderly do not respond well to ACE inhibitors, and ACE inhibitors should not be the first-choice drug in patients who have hypertension and atrial fibrillation and need heart rate control.22,23,26,27 Because African Americans do not respond well to ACE inhibitors, higher doses are needed if these drugs are used in this patient population. These effects may be because to some degree, primary hypertension in African Americans is caused by different pathophysiologic mechanisms, i.e., a greater sensitivity to dietary sodium and increased peripheral resistance.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 16 However, African Americans who have hypertension have an elevated risk for developing kidney disease and for a more rapid and severe progression of renal damage, and ACE inhibitors, alone or in combination with another anti-hypertensive like a calcium channel blocker can be beneficial to African Americans who have hypertension and chronic kidney disease.22,27

Comorbid Hypertension/Chronic Kidney Disease

Hypertension is a common in patients who have chronic kidney disease (CKD)28 and as renal damage progresses, so does the incidence of hypertension.28 Untreated hypertension can result in a further loss of kidney function and end-stage renal disease (ESRD) and it increases the risk for developing cardiovascular disease so blood pressure control, even in patients who have a mild degree of hypertension, is very important.

The ACE inhibitors are a first-line medication for treating hypertension in patients who have chronic kidney disease with >500 mg/day, 23,28-30 regardless of the age or the race of the patient,23 and the ACE inhibitors have been proven to slow the progression of CKD and prevent complications.28-30

The tone of the functions of the kidneys is to excrete and reabsorb serum protein, and the urinary protein level can be used to assess renal function. The urinary protein level should be < 150 mg/day, and a urinary protein level above that point is called proteinuria. Proteinuria is common in CKD because of damage to the glomeruli and for a patient who has CKD, the higher the level of urinary protein the more rapid the progression of kidney damage.28 The ACE inhibitors reduce proteinuria and this effect has been correlated with a decrease in the progression of kidney damage.28

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 17 Ace Inhibitors For Heart Failure With Reduced Ejection Fraction

The primary goals when treating a patient who has heart failure with reduced ejection fraction are to improve cardiac function and quality of life while reducing the risk of morbidity and mortality. Lifestyle changes are an important part of the treatment regimen, but many patients who have heart failure will require pharmacologic therapy.

The ACE inhibitors are the first-line choice for treating patients who have symptomatic heart failure and/or heart failure with reduced ejection fraction.31-35 In this patient population the ACE inhibitors have been proven to: 1) reduce the rate of hospitalization, 2) reduce the occurrence of cardiovascular events, 3) reduce the severity of symptoms, 4) reduce morbidity and mortality associated with heart failure, and 5) to have a relatively minimal risk for serious adverse effects.

The therapeutic mechanism of action of the ACE inhibitors is primarily is mediated through the RAS, which is affected in patients who have heart failure, and there is evidence that the AC inhibitors have many other complex actions which can have a positive effect on the myocardium.31,36 There is no evidence one ACE inhibitor is superior to another for treating a patient who has symptomatic heart failure/heart failure with reduced ejection fraction.31

Standard therapy is to use a low dose of an ACE inhibitor as the first drug and then if needed, a beta-blocker can be added to the treatment regimen31,32,34,35 because for this patient population, ACE inhibitors and the beta-blockers are complementary.34,36 Some authorities recommend that the two drugs be started together,34,35 others feel that an ACE inhibitor should be given first and then followed by a beta-blocker.31,35 Neither approach has

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 18 been clinically compared; the latter approach is used in the United States,37 and it was derived from clinical trials.

One of the advantages of beginning treatment with an ACE inhibitor is that the hemodynamic effects of the ACE inhibitors are seen very quickly, the hemodynamic effects of the beta-blockers are comparatively delayed, and during initiation of therapy with a beta-blocker cardiac function can temporarily become worse.35 A low dose of an ACE inhibitor is given; the dose is increased until the patient is receiving a moderate dose (i.e., begin with 5 mg/day of lisinopril, and advance to 15-20 mg/day), the beta-blocker is started and when beta blockade has been attained, the ACE inhibitor dosing can be titrated upward as needed.35

The ACE inhibitors should be used cautiously for patients who have heart failure with reduced ejection fraction if the patient has renal impairment. While therapy with an ACE inhibitor is being started and during titration, blood pressure, serum potassium, and renal function should be carefully monitored.

Ace Inhibitors In ST Segment Elevation Myocardial Infarction

Prescribing ACE inhibitors for patient who have had a STEMI is standard, routine care.38,39 The latest American College of College and the American Heart Association guidelines for treating patients who have a STEMI stated:

“An angiotensin-converting should be administered within the first 24 hours to all patients with STEMI with anterior location, HF, or ejection fraction less than or equal to 0.40, unless contraindicated.” Also, “Angiotensin-converting enzyme inhibitors are

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 19 reasonable for all patients with STEMI and no contraindications to their use.”

Many randomized trials have shown that the ACE inhibitors have many benefits for patients who have had an acute STEMI. These benefits are listed below,39-42 and they are present when the ACE inhibitor is started within 24 hours of a STEMI or within 16 days.39

• Long-term improvement of left ventricular ejection fraction • Increased rate of survival in high-risk patients • Increase rate of survival in all patients • A reduction in the rate of MI recurrence, 10.8% as opposed to 13.2% • A possible decrease in the incidences of atrial fibrillation, sudden ventricular arrhythmias

After a STEMI the myocardium begins to remodel. Remodeling is defined as changes in the structure of the heart and post MI, the myocardium become dilated, hypertrophied, and scarred. One of the benefits of ACE inhibitors for post-MI patients, and likely part of the reason the ACE inhibitors increase the survival rate for these patients, is that these drugs decrease the pathological remodeling that is caused by an MI.43,44

Prescribing an ACE inhibitor for a patient who has had a STEMI should be done using the basic principles of use for these drugs. They should not be used in patients who are hypotensive, hyperkalemic, or have significant renal impairment; there is no proven advantage of one ACE inhibitor compared to the others, and; use the lowest effective starting dose and slowly increase the dose while observing for hypotension, hyperkalemia, and changes in renal function.39 After starting therapy with an ACE inhibitor for a post-STEMI patient there is no pressing need to stop using the drug unless

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 20 there are unmanageable adverse effects, and long-term use is considered to be beneficial.39

Diabetic Nephropathy And ACE Inhibitor Use

Diabetic nephropathy is a common complication of type 1 and type 2 diabetes that is characterized by persistent albuminuria (> 300 mg/day), elevated blood pressure, and a progressive decline in glomerular filtration rate (GFR). It is a disease that can cause serious complications like diabetic retinopathy and end-stage renal disease (ESRD) and early identification and treatment for this disease are critically important. One of the primary therapies for treating patients who have diabetic nephropathy is blood pressure control with an ACE inhibitor.45-47

Treatment with ACE inhibitors has been proven to decrease the progression of diabetic nephropathy and decrease protein excretion.46-48 ACE inhibitors have a comparatively low risk of adverse effects, and they may slow the development of diabetic retinopathy. There is also evidence that they increase insulin sensitivity.48

Although it is not completely understood how the ACE inhibitors improve outcomes in this disease and there are doubts about the true limits of the safety and effectiveness of ACE inhibitors as a treatment for diabetic nephropathy,49,50 the American Diabetes Association (ADA) in their 2016 and 2018 Standards of Medical Care in Diabetes noted: “Either an ACE inhibitor or an angiotensin receptor blocker is recommended for the treatment of nonpregnant patients with diabetes and modestly elevated urinary albumin excretion (30 mg – 299 mg/day) and is strongly recommended for those with urinary albumin excretion > 300 mg/day and/or estimated glomerular filtration rate <60 mL/min/1.73 m2.” 45,50

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 21 The ACE inhibitors are a first-line therapy for treating patients who have diabetic nephropathy, but their use in these patients requires care because patients who have diabetes are at risk for (AKI) In addition, the ACE inhibitors can reduce renal blood flow and GFR, their use may slightly increase the risk for AKI in vulnerable patients,50 and hypoglycemia is an adverse effect, albeit rare, of the ACE inhibitors.7,51,52

ACE Inhibitor-Induced Angioedema

Angiotensin-converting enzymes inhibitor-induced angioedema is an uncommon, potentially serious complication of the ACE inhibitors. The term angioedema is descriptive of both the underlying cause and the clinical presentation; angioedema is a vascular reaction in the deep dermis, subcutaneous, or submucosal tissues that causes localized edema.

Angiotensin-converting enzyme inhibitor-induced angioedema is caused by localized . The ACE inhibitors block normal activity of ACE and angiotensin II, both of which have a role is the inactivation and breakdown of . Bradykinin is an inflammatory mediator. It increases capillary permeability and it increases blood flow to infected and/or inflamed areas of the body by causing vasodilation and the ACE inhibitors, by their effect on ACE and angiotensin II, increase circulating levels of bradykinin and this results in vasodilation. The likely explanation for this pathophysiologic mechanism is genetic variants in enzymes that degrade bradykinin when ACE and angiotensin II are prevented from doing so by ACE inhibitors.53-55

Angiotensin-converting enzyme inhibitor-induced angioedema is an uncommon adverse effect but angioedema itself is a relatively common pathology, and there are multiple causes. Angioedema can also be caused by a histamine mediated hypersensitivity reaction to drugs, food, and insect

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 22 stings; there are rare hereditary and acquired forms of angioedema that are bradykinin-mediated but do not involve use of an ACE inhibitor, and other drugs like NSAIDS, angiotensin receptor blockers (ARBs), and can cause angioedema by other pathologic mechansims.54,56

Statistics and Clinical Presentation

Angioedema is a clinical condition that is commonly seen in emergency rooms,54 and many of these cases are caused by ACE inhibitors.53,54 The incidence of ACE inhibitor-induced has been estimated to be 0.1% - 0.7%.54,57 ACE inhibitor-induced angioedema can happen any time.54,55 Many cases begin in the first days and weeks after a patient starts taking an ACE inhibitor. However, ACE inhibitor-induced angioedema has occurred many years after therapy with the drug was begun, 54,55 and it can happen after an ACE inhibitor therapy with the drug has been stopped.55 Factors that have been reported to increase the risk for developing ACE inhibitor-induced angioedema are listed in Table 2.54,55 The risk of developing ACE inhibitor- induced angioedema is not related to any specific drug of this class or to the dose.54

Table 2: Risk Factors for ACE Inhibitor-Induced Angioedema

African American ethnicity Age > 65 years

Aspirin or other NSAID use CAD Female gender

Heart failure History of angioedema History of angioedema related to NSAID use Seasonal allergies Smoking Use of a dipeptidyl peptidase 4 inhibitor, i.e., sitagliptin

Renal transplant use of mammalian target of rapamycin inhibitors

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The edema is localized, non-pitting, and the patient will not have a rash or urticaria. It affects non-dependent areas, usually the face, lips, tongue, and upper airway. The intestine and the lower airway structures can also become edematous.54,58 The edema develops relatively quickly, minutes to hours, and it subsides and is usually gone in 24-72 hours but resolution may take longer.54,55

Some patients will have recurring episodes, especially if he/she does not stop taking the drug, and the subsequent attacks may happen more often and become increasingly more severe.54 ACE inhibitor-induced angioedema is uncomfortable and frightening and although it is seldom dangerous, death caused by laryngeal and tongue edema and airway obstruction has occurred.59

It is not clear if someone who has had ACE inhibitor-induced angioedema should avoid the ARBs. The risk for developing angioedema from an ARB is less than that of an ACE inhibitor, and the cross reactivity between these drugs has been reported to be low.55 The ARBS are first-line therapy for many common diseases, for example, hypertension, so if their use is indicated, the clinician and the patient must decide if the benefits of an ARB outweigh the risk of developing drug-related angioedema.

Treatment of Angioedema

Angiotensin-converting enzyme inhibitor-induced angioedema is a clinical diagnosis; there are no tests that can confirm its presence. Discontinuing the ACE inhibitor, supportive care, and airway management are the primary treatments for ACE inhibitor-induced angioedema.54 and antihistamines have been used but because of the mechanism of action of

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 24 ACE inhibitor-induced angioedema it is very unlikely they would help.54,55,60,61

Off-label use of products like fresh frozen plasma, bradykinin antagonists, inhibitors of kallikrein (an enzyme that degrades bradykinin) and other drugs have been used successfully (and with some failures) as treatments for ACE inhibitor-induced angioedema, but their use for this would have to be considered experimental.62

ACE Inhibitor Overdose

Drug ingestions done with an intent to cause self-harm and accidental pediatric exposures to medications are often unwitnessed and laboratory confirmation of an ACE inhibitor ingestion, for example, blood measurement of the drug, is not practical. The documented clinical experience with ACE inhibitor overdoses and pediatric exposures consists of a relatively small number of case reports and several retrospective reviews and case series.

Substantial amounts of ACE inhibitors have been well tolerated (i.e., 7.5 g of captopril, which has a maximum daily dose 200 mg),63 and adults and children, assuming the ingestion was accidental, can be safely observed at home if the ingestion was less than twice the standard daily dose.64

Clinical Presentation

Hypotension is the primary sign of ACE inhibitor overdose and for most cases, it is the only sign of overdose64-66 but serious effects like AKI, anion gap acidosis, syncope, and rhabdomyolysis have been reported to be caused by a lisinopril overdose.67 The onset of hypotension is typically seen several hours after the ingestion and if hypotension develops, it should be within six hours.68

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 25 Treatment

Treatment should begin with an evaluation of the patient’s airway, breathing, and circulation (ABCs). A complete history of the events of the overdose should be obtained. Find out what medical problems the patient has and what medications he/she is currently taking.

Give the patient a dose of activated charcoal if: 1) a toxic dose of an ACE inhibitor was ingested, or the dose is not known, 2) the ingestion occurred ≤ one hour before presentation, 3) the patient is awake and alert, 4) there is no reason to suspect that the patient’s level of consciousness will quickly deteriorate, and if 5) he/she has a normal gag reflex and a functioning gastrointestinal (GI) tract.

Measure serum acetaminophen and salicylate; other laboratory tests and diagnostic procedures can be done if needed.

Hypotension should be treated with intravenous (IV) fluids and if needed, vasopressors.69 There are case reports of naloxone reversing hypotension caused by ACE inhibitor overdose, but there are case reports in which naloxone was unsuccessful.70,71 Hypotension caused by an ACE inhibitor can be easily managed with IV fluids but unless there is a contraindication to its use, there is essentially no harm in giving a hypotensive patient a dose of naloxone.

Summary

The ACE inhibitors are widely prescribed for the treatment of primary hypertension, and they have distinct, specific advantages for treating hypertensive patients who have chronic kidney disease, diabetes mellitus,

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 26 heart failure, and myocardial infarction. The four primary (labeled) uses for the ACE inhibitors are treatment of hypertension, heart failure, diabetic nephropathy, and there is improvement of left ventricular function and decreased mortality after acute myocardial infarction.

Contraindication and adverse effects of ACE inhibitors for certain patients, including during pregnancy and risk to a fetus, have been discussed. Prior to beginning ACE inhibitor treatment, the patient’s blood pressure, serum potassium, and renal function should be evaluated, and then periodically monitored after therapy has started. Some patients, such as those with diabetes or renal impairment, are more susceptible to the adverse effects of ACE inhibitors so they require closer observation. The risk of ACE inhibitor treatment for patients who have hepatic impairment and the need for a dosing adjustment should be made on a case-by-case basis. The dose of an ACE inhibitor should be reduced if a patient has renal impairment.

Treatment of an ACE inhibitor overdose or accidental exposure to an amount that may cause hypotension would include the standard care for any overdose.

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nursece4less.com nursece4less.com nursece4less.com nursece4less.com 27 1. The renin-angiotensin system (RAS) regulates blood pressure by, among other things,

a. causing the kidneys to convert pre-renin to renin. b. synthesizing renin to angiotensin I in the kidneys. c. increasing renal blood flow. d. increasing serum sodium.

2. ______binds to specific receptors, and it increases blood pressure by its action as a potent vasoconstrictor.

a. Angiotensin I b. Renin c. Angiotensin II d. Sodium

3. The angiotensin converting enzyme (ACE) inhibitors have the net effect of

a. decreasing the activity of renin. b. lowering blood pressure. c. increasing the vasoconstrictive action of angiotensin II. d. increasing serum sodium levels in the body.

4. True or False: The ACE inhibitors and the angiotensin receptors blockers (ARBs) both lower blood pressure by their effects on the RAS using the same methods.

a. True b. False

5. Treatment of ______is a primary use of ACE inhibitors.

a. hypotension b. aortic stenosis c. cholestatic jaundice d. cardiovascular diseases

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 28 6. In patients who have hepatic impairment, dosing recommendations for ACE inhibitors provide for

a. dose adjustment based on a patient circumstances and comorbidities. b. prescribing a different ACE inhibitor. c. discontinuing the use of the drug completely. d. adjusting the dose in all cases.

7. Cough is a common adverse effect of ACE inhibitors, and this adverse effect is more common in

a. men. b. Caucasians. c. women. d. adolescents.

8. Angiotensin-converting enzyme inhibitors may be used cautiously in pregnant women during the

a. first trimester. b. second trimester. c. third trimester. d. All of the above

9. Mothers who are nursing and who are taking ACE inhibitors should know that

a. ACE inhibitors are not found in breast milk. b. there are well-known risks with taking ACE inhibitors while breastfeeding. c. ACE inhibitors are found in breast milk in low levels. d. ACE inhibitors cause adverse effects in breastfed infants.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 29 10. True or False: Patients who are < 50 years of age have a better response to ACE inhibitors.

a. True b. False

11. The ACE inhibitors reduce proteinuria in patients and this effect has been correlated with

a. a decrease in the progression of kidney damage. b. an accelerated rate of kidney damage. c. rhabdomyolysis. d. severe renal impairment.

12. Which of the following ACE inhibitors is superior for treating a patient who has symptomatic heart failure/heart failure with reduced ejection fraction?

a. Captopril b. Enalapril c. Fosinopril d. None of the above

13. The ACE inhibitors are a first-line therapy for treating patients who have

a. hypoglycemia. b. acute kidney injury. c. diabetic nephropathy. d. diabetes complicated with hypotension.

14. ______is the primary sign of ACE inhibitor overdose and for most cases, it is the only sign of overdose.

a. acute kidney injury b. Hypotension c. Anion gap acidosis d. Rhabdomyolysis

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 30 15. Except for ______, the ACE inhibitors are pro-drugs, changed in the liver to a pharmacologically active metabolite.

a. perindopril b. captopril and lisinopril c. enalapril d. fosinopril and moexipril

CORRECT ANSWERS:

1. The renin-angiotensin system (RAS) regulates blood pressure by, among other things,

a. causing the kidneys to convert pre-renin to renin.

“Decreased renal blood flow, volume depletion, decrease in serum sodium, and sympathetic stimulation cause the kidneys to convert pre-renin to renin. Renin is an enzyme that converts angiotensinogen, a compound that is synthesized by the liver, to angiotensin I.”

2. ______binds to specific receptors, and it increases blood pressure by its action as a potent vasoconstrictor.

c. Angiotensin II

“Angiotensin II binds to specific receptors, and it increases blood pressure by its action as a potent vasoconstrictor.”

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 31 3. The angiotensin converting enzyme (ACE) inhibitors have the net effect of

b. lowering blood pressure.

“The ACE inhibitors inhibit the activity of ACE. This decreases the production of angiotensin II, increases the activity of renin, and decreases the secretion of aldosterone. The net effect is a lowered blood pressure.”

4. True or False: The ACE inhibitors and the angiotensin receptors blockers (ARBs) both lower blood pressure by their effects on the RAS using the same methods.

b. False

“The ACE inhibitors and the ARBs both lower blood pressure by their effects on the RAS by but different methods.”

5. Treatment of ______is a primary use of ACE inhibitors.

d. cardiovascular diseases

“Treatment of cardiovascular diseases is a primary use of ACE inhibitors.”

6. In patients who have hepatic impairment, dosing recommendations for ACE inhibitors provide for

a. dose adjustment based on a patient circumstances and comorbidities.

“… there have been reports (rare) of serious hepatotoxicity and cholestatic jaundice caused by ACE inhibitors, so the risk of their use in patients who have hepatic impairment and the need for a lower than normal dose depending on patient circumstances and comorbidities.”

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 32 7. Cough is a common adverse effect of ACE inhibitors, and this adverse effect is more common in

c. women.

“Cough is a common adverse effect of ACE inhibitors, and this adverse effect is more common in women and people of Chinese descent.”

8. Angiotensin-converting enzyme inhibitors may be used cautiously in pregnant women during the

a. first trimester.

“Angiotensin-converting enzyme inhibitor use should be discontinued as soon as it is discovered the patient is pregnant... Drugs that act on the RAS can cause injury, fetal toxicity, and death to a developing fetus. Discontinue an ACE inhibitor as soon as it is known the patient is pregnant.”

9. Mothers who are nursing and who are taking ACE inhibitors should know that

c. ACE inhibitors are found in breast milk in low levels.

“ACE inhibitors are found in breast milk in low levels.... amounts ingested by the infant are small and would not be expected to cause any adverse effects in breastfed infants.”

10. True or False: Patients who are < 50 years of age have a better response to ACE inhibitors.

a. True

“Patients who are < 50 years of age have a better response to ACE inhibitors.”

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 33 11. The ACE inhibitors reduce proteinuria in patients and this effect has been correlated with

a. a decrease in the progression of kidney damage.

“The ACE inhibitors reduce proteinuria and this effect has been correlated with a decrease in the progression of kidney damage.”

12. Which of the following ACE inhibitors is superior for treating a patient who has symptomatic heart failure/heart failure with reduced ejection fraction?

a. Captopril b. Enalapril c. Fosinopril d. None of the above [correct answer]

“There is no evidence one ACE inhibitor is superior to another for treating a patient who has symptomatic heart failure/heart failure with reduced ejection fraction.”

13. The ACE inhibitors are a first-line therapy for treating patients who have

c. diabetic nephropathy.

“The ACE inhibitors are a first-line therapy for treating patients who have diabetic nephropathy...”

14. ______is the primary sign of ACE inhibitor overdose and for most cases, it is the only sign of overdose.

b. Hypotension

“Hypotension is the primary sign of ACE inhibitor overdose and for most cases, it is the only sign of overdose ...”

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 34 15. Except for ______, the ACE inhibitors are pro-drugs, changed in the liver to a pharmacologically active metabolite.

b. captopril and Lisinopril

“Except for captopril and lisinopril, the ACE inhibitors are pro-drugs, changed in the liver to a pharmacologically active metabolite.”

References

The References below include published works and in-text citations of published works that are intended as helpful material for your further reading.

1. Zheng SL, Roddick AJ, Ayis S. (2017). Effects of aliskiren on mortality, cardiovascular outcomes and adverse events in patients with diabetes and cardiovascular disease or risk: A systematic review and meta- analysis of 13,395 patients. Diab Vasc Dis Res. 2017;14(5):400-406. 2. Harel Z, Gilbert C, Wald R, et al. (2012). The effect of combination treatment with aliskiren and blockers of the renin-angiotensin system on hyperkalaemia and acute kidney injury: systematic review and meta-analysis. BMJ. 2012 Jan 9;344: e42. doi: 10.1136/bmj.e42. 3. Owens RE and Oliphant CS. (2017). Angioedema spotlight: A closer examination of sacubitril/valsartan safety results. J Am Board Fam Med. 2017;30(4):556-557. 4. Andersson C. and Abdulla J. (2017). Is the use of renin-angiotensin system inhibitors in patients with aortic valve stenosis safe and of prognostic benefit? A systematic review and meta-analysis. Eur Heart J Cardiovasc Pharmacother. 2017;3(1):21-27. 5. Bull S, Loudon M, Francis JM, et al. (2015). A prospective, double- blind, randomized controlled trial of the angiotensin-converting enzyme inhibitor Ramipril In Aortic Stenosis (RIAS trial). Eur Heart J Cardiovasc Imaging. 2015;16(8):834-841. 6. Hashmi HR, Jabbour R, Schreiber Z, Khaja M. (2016). Benazepril- induced agranulocytosis: A case report and review of the literature. Am J Case Rep. 2016;17:425-428.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 35 7. Townsend RR. (2017). Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. UpToDate. October 3, 2017. Retrieved online from https://www.uptodate.com/contents/major-side-effects-of- angiotensin-converting-enzyme-inhibitors-and-angiotensin-ii-receptor- blockers. 8. Forner D, Kulai T, Arnason T, E Gruchy S, MacLeod M. (2017). Ramipril-associated cholestasis in the setting of recurrent drug- induced liver injury. Gastroenterol Hepatol Bed Bench. 2017;10(2):143-146. 9. Vukadinović D, Nikolovska Vukadinović A, Lavall D, Laufs U, Wagenpfeil S, Böhm M. (2018). Rate of cough during treatment with angiotensin converting enzyme inhibitors: A meta-analysis of randomized placebo- controlled trials. Clin Pharmacol Ther. 2018 Jan 13. doi: 10.1002/cpt.1018. [Epub ahead of print] 10. Alharbi FF, Kholod AAV, Souverein PC, et al. (2017). The impact of age and sex on the reporting of cough and angioedema with renin- angiotensin system inhibitors: a case/noncase study in VigiBase. Fundam Clin Pharmacol. 2017;31(6):676-684. 11. Trimble MA, Sketch MH Jr, Mehta RH. (2007). Hemolytic anemia: a rare but potentially serious adverse effect of captopril. Herz. 2007; 32(1):62-64. 12. Hashmi HR, Jabbour R, Schreiber Z, Khaja M. (2016). Benazepril- induced agranulocytosis: A case report and review of the literature. Am J Case Rep. 2016; 17:425-428. 13. Moussa Z, Schiano T, Spatoliatore G, Salman S. (1992). Neutropenia induced by low-dose captopril. N Y State J Med. 1992;92(5):219-220. 14. Tamargo J, Caballero R, Delpón E. (2018). New therapeutic approaches for the treatment of hyperkalemia in patients treated with renin-angiotensin-aldosterone system inhibitors. Cardiovasc Drugs Ther. 2018 Jan 25. doi: 10.1007/s10557-017-6767-5. [Epub ahead of print] 15. Schmidt M, Mansfield KE, Bhaskaran K, et al. (2017). Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study. BMJ. 2017 Mar 9;356:j791. doi: 10.1136/bmj.j791. 16. Beldhuis IE, Streng KW, Ter Maaten JM, et al. (2017). Renin- angiotensin system inhibition, worsening renal function, and outcome in heart failure patients with reduced and preserved ejection fraction: A meta-analysis of published study data. Circ Heart Fail. 2017 Feb;10(2). pii: e003588. doi: 10.1161/CIRCHEARTFAILURE.116.003588.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 36 17. Bateman BT, Patorno E, Desai RJ, et al. (2017). Angiotensin- converting enzyme inhibitors and the risk of congenital malformations. Obstet Gynecol. 2017;129(1):174-184. 18. Podymow T, Joseph G. (2015). Preconception and pregnancy management of women with diabetic nephropathy on angiotensin converting enzyme inhibitors. Clin Nephrol. 2015;83(2):73-99. 19. Beardmore KS, Morris JM, Gallery ED. (2002). Excretion of antihypertensive medication into human breast milk: a systematic review. Hypertens Pregnancy. 2002;21(1):85-95. 20. U.S. National Library of Medicine. Toxnet: Toxicology Data Network. LACTMED. Retrieved online February 6, 2018 from https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm. 21. Mann J FE. Hilgers K. (2016). Renin-angiotensin system inhibition in the treatment of hypertension. UpToDate. July 5, 2016. Retrieved online from https://www.uptodate.com/contents/renin-angiotensin- system-inhibition-in-the-treatment-of-hypertension#!. 22. Mann J FE. (2017). Choice of drug therapy in primary (essential) hypertension. UpToDate. December 18, 2017. Retrieved online from https://www.uptodate.com/contents/choice-of-drug-therapy-in- primary-essential-hypertension#!. 23. James PA, Oparil S, Cater BL, et al. (2014). 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults. Report from the Panel Members Appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520. 24. Jamerson, K., et al. (2008). Benazepril plus or hydrocholorothiazide for hypertension in high-risk patients. N Engl Med 2008;359(23):2417-2428 25. Bakris, GL, et al. (2013). Comparison of benazepril plus amlodipine or in high-risk patients with hypertension and coronary artery disease. Am J Cardiol. 2013;112(2):255-259. 26. Bangalore S, Ogedegbe G, Gyamfi J, et al. (2015). Outcomes with angiotensin-converting enzyme inhibitors vs other antihypertensive agents in hypertensive blacks. Am J Med. 2015;128(11):1195-1203. 27. Egan BM. (2017). Treatment of hypertension in blacks. UpToDate. January 30, 2017. Retrieved online from https://www.uptodate.com/contents/treatment-of-hypertension-in- blacks#!. 28. Mann J FE. (2016). Overview of hypertension in acute and chronic kidney disease. UpToDate. July 28, 2016. Retrieved online from https://www.uptodate.com/contents/overview-of-hypertension-in- acute-and-chronic-kidney-disease. 29. Vejakama P, Ingsathit A, McKay GJ, et al. (2017). Treatment effects of renin-angiotensin aldosterone system blockade on and

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 37 mortality in chronic kidney disease patients. BMC Nephrol. 2017 Nov 29;18(1):342. doi: 10.1186/s12882-017-0753-9. 30. Verbeke F, Lindley E, Van Bortel L, et al. (2014). A European Renal Best Practice (ERBP) position statement on the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for the management of blood pressure in non–dialysis-dependent chronic kidney disease: an endorsement with some caveats for real-life application. Nephrol Dial Transplant. 2014;29(3):490–496. 31. Colucci WS. (2018). Use of angiotensin converting enzyme inhibitors in heart failure with reduced ejection fraction. UpToDate. January 30, 2018. Retrieved online from https://www.uptodate.com/contents/use- of-angiotensin-converting-enzyme-inhibitors-in-heart-failure-with- reduced-ejection-fraction#!. 32. Yancy CW, Jessup M, Bozkurt B, et al. (2017). 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6): e137–e161. 33. Tai C, Gan T, Zou L, et al. (2017). Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on cardiovascular events in patients with heart failure: a meta-analysis of randomized controlled trials. BMC Cardiovasc Disord. 2017 Oct 5;17(1):257. doi: 10.1186/s12872-017-0686-z. 34. Ponikowski P, Voors A, Anker D, et al. (2016). 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891-975. 35. Gottlieb S. (2017). Pharmacologic therapy of heart failure with reduced ejection fraction. UpToDate. April 28, 2017. Retrieved online from https://www.uptodate.com/contents/pharmacologic-therapy-of-heart- failure-with-reduced-ejection-fraction?source=see_link. 36. Colucci W. (2016). Angiotensin converting enzyme inhibitors and receptor blockers in heart failure: Mechanisms of action. UpToDate. December 22, 2016. Retrieved online from https://www.uptodate.com/contents/angiotensin-converting-enzyme- inhibitors-and-receptor-blockers-in-heart-failure-mechanisms-of-action 37. Yancy CW, et al. (2013). 2013 ACC/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16): e147-e239.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 38 38. O’Gara PT, Kushner FG, Ascheim DD, et al. (2013). 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction: Executive Summary. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in Collaboration with the American College of Emergency Physicians and Society for Cardiovascular Angiography and Interventions. Circulation. 2013;127(4):529-555. 39. Reeder GS. (2016). Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use. UpToDate. April 6, 2016. Retrieved online from https://www.uptodate.com/contents/angiotensin-converting-enzyme- inhibitors-and-receptor-blockers-in-acute-myocardial-infarction- recommendations-for-use. 40. Vantrimpont P, Rouleau JL, Wun CC, et al. (1997). Additive beneficial effects of beta-blockers to angiotensin-converting enzyme inhibitors in the Survival and Ventricular Enlargement (SAVE) Study. SAVE Investigators. J Am Coll Cardiol. 1997; 29(2):229-236. 41. Park H, Kim HK, Jeong MH, et al. (2017). Clinical impacts of inhibition of renin-angiotensin system in patients with acute ST-segment elevation myocardial infarction who underwent successful late percutaneous coronary intervention. J Cardiol. 2017;69(1):216-221. 42. Batra G, Lindhagen L, Andell P, et al. (2017). Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are associated with improved outcome but do not prevent new-onset atrial fibrillation after acute myocardial infarction. J Am Heart Assoc. 2017 Mar 20;6(3). pii: e005165. doi: 10.1161/JAHA.116.005165. 43. Düsing R. (2016). Pharmacological interventions into the renin- angiotensin system with ACE inhibitors and angiotensin II receptor antagonists: effects beyond blood pressure lowering. Ther Adv Cardiovasc Dis. 2016;(3):151-161. 44. Reeder GS. (2017). Angiotensin converting enzyme inhibitors in acute myocardial infarction: Mechanisms of action. UpToDate. May 10, 2017. Retrieved online from https://www.uptodate.com/contents/angiotensin-converting-enzyme- inhibitors-in-acute-myocardial-infarction-mechanisms-of- action?source=see_link. 45. American Diabetes Association (2016). Microvascular Complications and Foot Care. Diabetes Care. 2016; 39(Suppl. 1): S72-S80. 46. Hsu FY, Lin FJ, Ou HT, Huang SH, Wang CC. (2017). Renoprotective effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in diabetic patients with proteinuria. Kidney Blood Press Res. 2017;42(2):358-368. 47. Bakris GL. (2017). Treatment of diabetic nephropathy. UpToDate. October 31, 2017. Retrieved online from

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 39 https://www.uptodate.com/contents/treatment-of-diabetic- nephropathy#!. 48. Bakris GL. (2017). Treatment of hypertension in patients with diabetes mellitus. UpToDate. Nov 27, 2017. Retrieved online from https://www.uptodate.com/contents/treatment-of-hypertension-in- patients-with-diabetes-mellitus#!. 49. Elrggal ME, Ahmed SM, El Nahas M. (2016). Renin-angiotensin- aldosterone system blockade in diabetic kidney disease: A critical and contrarian point of view. Saudi J Kidney Dis Transpl. 2016;27(6):1103- 1113. 50. American Diabetes Association. Microvascular Complications and Foot Care: Standards of Medical Care in Diabetes —2018. Diabetes Care. 2018; 41(Supplement 1): S105-S118. 51. Jarred G, Kennedy RL. (2010). Therapeutic perspective: starting an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker in a diabetic patient. Ther Adv Endocrinol Metab. 2010;1(1):23-28. 52. Morris AD, Boyle DI, McMahon AD, et al. (1997) ACE inhibitor use is associated with hospitalization for severe hypoglycemia in patients with diabetes. DARTS/MEMO Collaboration. Diabetes Audit and Research in Tayside, Scotland. Medicines Monitoring Unit. Diabetes Care 1997; 20(9):1363-1367. 53. Guyer AC, Banerji A. (2017). ACE inhibitor-induced angioedema. UpToDate. October 5, 2017. Retrieved online from https://www.uptodate.com/contents/ace-inhibitor-induced- angioedema. 54. Bernstein JA, Cremonesi P, Hoffmann TK, Hollingsworth J. (2017). Angioedema in the emergency department: a practical guide to differential diagnosis and management. Int J Emerg Med. 2017 Dec;10(1):15. doi: 10.1186/s12245-017-0141-z. Epub 2017. 55. Brown T, Gonzalez J, Monteleone C. (2017). Angiotensin-converting enzyme inhibitor-induced angioedema: A review of the literature. J Clin Hypertens (Greenwich). 2017 Dec;19(12):1377-1382. 56. Stone C Jr, Brown NJ. (2017). Angiotensin-converting enzyme inhibitor and other drug-associated angioedema. Immunol Allergy Clin North Am. 2017;37(3):483-495. 57. Banerji A, Blumenthal KG, Lai KH, Zhou L. (2017). of ACE inhibitor angioedema utilizing a large electronic health record. J Allergy Clin Immunol Pract. 2017;5(3):744-749. 58. Myslinski J, Heiser A, Kinney A. (2017). Hypovolemic shock caused by angiotensin-converting enzyme inhibitor-induced Visceral angioedema: A case series and a simple method to diagnose this complication in the emergency department. Emerg Med. 2017 Dec 18. pii: S0736-

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 40 4679(17)31175-7. doi: 10.1016/j.jemermed.2017.12.009. [Epub ahead of print] 59. Stauber T, Confino-Cohen R, Goldberg A. (2014). Life-threatening angioedema induced by angiotensin-converting enzyme inhibitors: characteristics and risk factors. Am J Rhinol Allergy. 2014; 28(1):54- 58. 60. Riha HM, Summers BB, Rivera JV, Van Berkel MA. (2017). Novel therapies for angiotensin-converting enzyme inhibitor-induced angioedema: A systematic review of current evidence. J Emerg Med. 2017;53(5):662-679. 61. Scalese MJ, Reinaker TS. (2016). Pharmacologic management of angioedema induced by angiotensin-converting enzyme inhibitors. Am J Health Syst Pharm. 2016;73(12):873-879. 62. Lawlor CM, Ananth A, Barton BM, Flowers TC, McCoul ED. (2018). Pharmacotherapy for angiotensin-converting enzyme inhibitor-induced angioedema: A systematic review. Otolaryngol Head Neck Surg. 2018 ;158(2):232-239. 63. Lechleitner P, Dzien A, Haring C, Glossmann H. (1990). Uneventful self- poisoning with a very high dose of captopril. Toxicology. 1990; 64(3):325-329. 64. Balit CR, Gilmore SP, Isbister GK. (2007). Unintentional paediatric ingestions of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists. J Paediatr Child Health. 2007;43(10):686-8. 65. Lewis JC, Alsop JA. (2013). A 13-year review of lisinopril ingestions in children less than 6 years of age. Clin Toxicol (Phila). 2013;51(9):864- 870. 66. Forrester MB. (2007). Adult lisinopril ingestions reported to Texas poison control centers, 1998 - 2005. Hum Exp Toxicol. 2007;26(6):483-489. 67. Belay TW, Nusair AR. (2013). Apparent lisinopril overdose requiring . Am J Health Syst Pharm. 2013;70(14):1226-1229. 68. Lucas C, Christie GA, Waring WS. (2006). Rapid onset of haemodynamic effects after angiotensin converting enzyme- inhibitor overdose: implications for initial patient triage. Emerg Med J. 2006;23(11):854-857. 69. DeRoos FJ. (2011) Other anti-hypertensives. In: Nelson LS, Lewin NA, Howland MA, Hoffman RS, Goldfrank LR, Flomenbaum NE, eds. Goldfrank’s Toxicologic Emergencies, 9th ed. New York, NY: McGraw- Hill;914-924. 70. Varon J, Duncan SR. (1991). Naloxone reversal of hypotension due to captopril overdose. Ann Emerg Med. 1991;20(10):1125-1127. 71. Barr CS, Payne R, Newton RW. (1991). Profound prolonged hypotension following captopril overdose. Postgrad Med J. 1991;67(792):953-954.

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