Angiotensin Converting Enzyme Inhibitors (ACEI)


Article Author:
Linda Herman


Article Editor:
Khalid Bashir


Editors In Chief:
Timothy Craig
Yoon Kim
Robert Hostoffer


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
2/14/2019 7:44:28 AM

Indications

Hypertension

In 2014, the Eighth Joint National Commission (JNC8) published evidence-based guidelines for the treatment of high blood pressure in adults which recommended that ACE inhibitors are one of four drug classes recommended for initial therapy for adults with elevated blood pressure.  The other three classes of drugs are calcium channel blockers, thiazide diuretics, and angiotensin receptor blockers which can be used as initial therapy for the general nonblack population.  Only thiazide and calcium channel blockers are recommended as initial therapy for the general block population with elevated blood pressure.[1][2]

Heart Failure

It is the decrease in afterload which improves heart failure.  Also, those with heart failure have less myocyte hypertrophy when ACE inhibitors are used.  Also, the Heart outcomes Prevention Evaluation (HOPE) Study demonstrated better outcomes for those that were prescribed ACE inhibitors.[3][4]

Asymptomatic Left Ventricular Dysfunction

Has been shown to decrease the incidence of overt heart failure.

Post Myocardial Infarction

In 2000, The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators published a landmark study demonstrating significantly reduced rates of death, myocardial infarction, and stroke in high-risk patients assigned to receive the ACE inhibitor, ramipril.[4]

Since the HOPE Study, several angiotensin converting enzyme inhibitors have been studied.  Most of the patients in those studies had an ST-elevation MI.  Most patients had not received a PCI but had received fibrinolytic therapy or no reperfusion, so data on the benefit with the addition of ACE inhibitors in patients receiving PCI is limited.  The research continued to demonstrate decreased mortality for patients with low left ventricular ejection fraction, heart failure or anterior myocardial infarctions that are begun on ACE inhibitors.  Other positive effects have been decreasing in readmission for heart failure and decrease in the incidence of re-infarction.[5][6]

It is suggested that the ACE Inhibitor be given with a diuretic.

Mechanism of Action

Angiotensin II causes direct vasoconstriction of precapillary arterioles and postcapillary venules, inhibits the reuptake of norepinephrine, stimulates the release of catecholamines from the adrenal medulla, reduces urinary excretion of sodium and water, stimulates synthesis and release of aldosterone, and stimulates hypertrophy of both vascular smooth muscle cells and cardiac myocytes. 

The exact mechanism of ACE inhibitors is not fully known. They do interfere with the renin-angiotensin-aldosterone system but their effect is not directly related to renin levels in the blood.  ACE inhibitors, as the name implies, blocks angiotensin converting enzyme that converts angiotensin I to angiotensin II.  Decreased production of angiotensin II enhances natriuresis, lowers blood pressure, and prevents remodeling of smooth muscle and cardiac myocytes. Lowered arterial and venous pressure reduces preload and afterload.  Also, it is hypothesized that ACE inhibitors interfere with the degradation of bradykinin which is a peptide which causes vasodilation. [7]

Administration

ACE inhibitors available are grouped into three main groups depending on their chemical structure:

1. Sulfhydryl-containing ACE inhibitor of which there is only 1. 

Captopril (Capoten) –  Hypertension therapy is 25 mg either BID or TID with a maximum of 450 mg.

Heart Failure therapy is 6.25 mg TID with a maximum of 450 mg.

2. Dicarboxylic-containing ACE inhibitors: see table

3. Phosphorus-containing ACE inhibitor of which there is only one. 

Fosinopril (Monopril) – Hypertension therapy dosing is 10 mg increasing to a maximum dose of 80 mg. May split into two equal doses during the day to control blood pressure. Heart failure therapy is 5 - 10 mg daily to a maximum dose of 40 mg.

General information about dosing: 

All of the ACE inhibitors are PO except for enalapril which can be given intravenously. The dosage is 1.25 mg every 6 hours.  It can be increased to 5 mg every 6 hours.  

The dosage should be decreased in patients with heart failure, salt-depleted patients, and/or renal impairment. 

Lisinopril and captopril are the only ACE inhibitors that do not have to be activated in the body to be effective. All the other ACE inhibitors are prodrugs and require activation.  Most reach peak serum levels within 1 hour after ingestion.  Since most of the activation occurs in the liver, when a patient has a severe hepatic failure, a non-prodrug form should be used.  The doses of the prodrugs can be increased though in those with some degree of poor hepatic function.[5]

Adverse Effects

About 1 -10% will develop a dry, nonproductive paroxysmal cough. The patient must then decide if they can tolerate a cough and continue the medication.  There is no treatment for a cough.[8][9]

Angioedema is the most significant.  It can be of any part of the body including intestine, but the most concerning is edema of the tongue, glottis and/or larynx causing airway obstruction.  There have been reported fatal cases.  Angioedema has a higher rate of incidence in the Afro-American population. When airway compromise is present, the treatment is always securing the airway with an endotracheal tube that allows ventilation until the edema resolves.  Multiple treatments have been tried such as diphenhydramine, methylprednisolone, and epinephrine.  Also, fresh frozen plasma and the newer agents, bradykinin blocking agents have been tried.  There are case reports that these bradykinin blocking agents might improve the angioedema but no literature exists proving that they are better than previous treatment.  There is an on-going Phase III trial at this time.[10]

Life-threatening anaphylactoid reactions have occurred in patients receiving Hymenoptera venom desensitization treatment and also in patients being dialyzed with high-flux membranes.  Treatment includes diphenhydramine, epinephrine and blood pressure support with fluids and catecholamines.[11][12]

These drugs have been known to cause renal failure.  Those with heart failure who depend on the renin-angiotensin-aldosterone system may develop changes in renal function with the use of ACE inhibitors.  Also, about 1/5 of patients with renal artery stenosis develop increases in blood urea nitrogen and creatinine.  Any patient who already has a renal insufficiency is susceptible to a worsening of renal function.  The renal function needs to be monitored during treatment for susceptible groups. [13]

As with any medication that lowers blood pressure, hypotension is an adverse reaction.  Those at risk for this side effect: heart failure with a systolic blood pressure below 100 mmHg, ischemic heart disease, cerebrovascular disease, hyponatremia, high dose diuretic therapy, renal dialysis, or severe volume and/or sodium depletion.

ACE inhibitors may cause hyperkalemia.  Those at risk for this side effect: prior history of renal impairment and/or diabetes, simultaneous use of potassium-sparing diuretics and/or potassium supplements.  Treatment depends upon the level of potassium, EKG changes, and whether the patient still has kidney function and produces urine.[13]

There has been one report of increased sudden death in patients taking ACE inhibitors and Co-trimoxazole simultaneously.  The mechanism is believed to be hyperkalemia.[14]

Cholestatic jaundice or hepatitis is another serious adverse effect which can progress to hepatic necrosis and sometimes death.  The drug needs to be discontinued, and the patient managed in the appropriate way.[15]

Contraindications

They are contraindicated in patients with a history of angioedema or hypersensitivity related to treatment with an ACE inhibitor and those with hereditary or idiopathic angioedema. 

Should not be given to patients that are already taking a direct renin inhibitor such as aliskiren (tekturna).

Should not be given in pregnancy. It is a Category D in Pregnancy because it is known to cause skull hypoplasia, anuria, hypotension, renal failure, lung hypoplasia, skeletal deformations, oligohydramnios, and death.[16]

Monitoring

[17]Renal function and electrolytes need to be checked on a regular basis due to the effects of the drug on the renin-angiotensin-aldosterone system.  Those with increasing potassium, BUN and creatinine need to have the drug discontinued. 

Since ACE inhibitors can have an effect on the liver, AST and ALT should also be monitored.  

Toxicity

ACE inhibitors overdoses are usually well tolerated, but significantly large dose can cause hypotension which is prolonged. Also, ACE inhibitors block aldosterone which enhances potassium excretion of the body.  When Aldosterone is blocked, potassium can accumulate, and sodium excretion is enhanced. Both lead to hyperkalemia and hyponatremia.

If the patient presents within 1 hour of ingestion and is awake and able to protect their airway, activated charcoal can be given. If they remain asymptomatic for 6 hours of observation, they can be considered medical stable for either discharge or referral to a mental health center depending on the circumstances of the overdose.

For those with hypotension, fluids should be the first line of therapy. There is no antidote for ACE inhibitor poisoning.  Naloxone has been used in captopril overdoses in the past with some success and can be tried if intravenous fluids are not successful. Also, vasopressors can be used for treatment of the hypotension.[18]

Enhancing Healthcare Team Outcomes

ACE inhibitors are one of the most widely used drugs for hypertension and heart failure. Besides the cardiologist, these drugs are widely prescribed by nurse practitioners, primary providers and cardiac surgeons. The ACE inhibitors are relatively safe, however, it is important to monitor renal function and levels of electrolytes on a regular basis. Because there are many ACE inhibitors available today, it is important to keep up with the guidelines and recommendations.[19][6][20]


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    Contributed by Linda L Herman
Attributed To: Contributed by Linda L Herman

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Angiotensin Converting Enzyme Inhibitors (ACEI) - Questions

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Which antihypertensive medication can cause a dry cough?



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What is the most beneficial effect of angiotensin-converting enzyme inhibitors when used for congestive heart failure?



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Which antihypertensive agents lead to an increase in the levels of bradykinin by blocking its breakdown?



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Which class of antihypertensive drugs has been linked to angioedema?



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What medication is the best choice for treatment for a 65-year-old patient with hypertension, congestive heart failure, hyperlipidemia, and type 2 diabetes mellitus?



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Which antihypertensive agent may cause hyperkalemia and require monitoring of potassium?



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Which class of drugs has been shown to reduce morbidity and mortality in patients with congestive heart failure and a reduced ejection fraction?



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By which mechanism do angiotensin-converting enzyme inhibitors cause vasodilatation?



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Which of the following statements about angiotensin-converting enzyme (ACE) inhibitors is not correct?



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Which peptide has been thought to cause vasodilatation in patients taking angiotensin-converting enzyme inhibitors?



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Which of the following statements is correct concerning the use of angiotensin-converting enzyme (ACE) inhibitors?



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What is the mechanism of action of enalapril?



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A friend is hypertensive and has been on an angiotensin-converting enzyme (ACE) inhibitor for years. She calls to report her pregnancy. Why should she be encouraged to call her physician as soon as possible?



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What is the mechanism of action when angiotensin-converting enzyme inhibitors (ACE-I) are used to treat heart failure in a 71-year-old?



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Which medication is contraindicated in pregnant women?



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A 72-year-old female complains of a chronic dry cough of 6 months duration. She has a history of ischemic cardiomyopathy on simvastatin, aspirin, lisinopril, furosemide, and metoprolol. She denies nasal symptoms, reflux symptoms, fever, chills, or weight loss. Vital signs: 128/88 - 86 - 16- afebrile. Exam shows normal ENT, cardiovascular, pulmonary, and abdominal exams. Chest x-ray shows cardiomegaly but no other abnormalities. Select the most appropriate next step.



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Which of the following medications can be the etiology of chronic cough?



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Which outcome was not decreased by ramipril in the Heart Outcomes Prevention Evaluation study?



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Which of the following is a contraindication for the initiation of an angiotensin-converting enzyme inhibitor in patients with unstable angina?



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Which angiotensin-converting enzyme inhibitor would be most appropriate in a patient with severe liver disease?



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Which of the following patient groups benefit most from receiving angiotensin-converting enzyme inhibitors?



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ACE inhibitors can cause which of the following electrolyte disturbances because of decreased aldosterone production and decreased excretion?



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Why are angiotensin-converting enzyme inhibitors (ACE-I) are used in heart failure?



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Which is the best antihypertensive medication in a diabetic patient?



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Angiotensin-converting enzyme (ACE) inhibitors are least likely to be prescribed for which condition?



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Which of the following types of drugs reduce blood pressure by causing a decrease in aldosterone secretion?



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A 58-year-old female presents to the emergency department with edema of the tongue. She has difficulty swallowing but her airway is intact, and the pulse oximeter is 96%. She has a history of diabetes mellitus and hypertension. Vital signs are blood pressure 150/90 mmHg, pulse 76 bpm, respirations 12, and she is afebrile. Which of the following mediations is most likely responsible for her presentation?



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Which drug has a similar effect as captopril?



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Which of the following are the most common adverse effects of angiotensin-converting enzyme (ACE) inhibitors? Select all that apply.



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Angiotensin Converting Enzyme Inhibitors (ACEI) - References

References

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