Angiotensin Converting Enzyme Inhibitors (ACEI)

Article Author:
Linda Herman
Article Editor:
Khalid Bashir
Updated:
10/22/2019 7:22:07 PM
PubMed Link:
Angiotensin Converting Enzyme Inhibitors (ACEI)

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 are useful 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 a decrease in afterload, which improves heart failure.  Also, those with heart failure have less myocyte hypertrophy when using ACE inhibitors.  Also, the Heart outcomes Prevention Evaluation (HOPE) Study demonstrated better outcomes for those 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, researchers have studied several angiotensin-converting enzyme inhibitors. 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 begin on ACE inhibitors.  Other positive effects have been a drop in readmission for heart failure and a decrease in the incidence of re-infarction.[5][6]

There are suggestions that the ACE inhibitor is 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, the hypothesis is that ACE inhibitors interfere with the degradation of bradykinin, which is a peptide that causes vasodilation.[7]

Administration

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

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

Captopril –  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 – 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 to 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.  

There should be a dosage decrease 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 is preferable. The doses of the prodrugs can increase, though in those with some degree of poor hepatic function.[5]

Adverse Effects

About 1 to 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 reports of 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 ongoing phase III trial at this time.[10]

Life-threatening anaphylactoid reactions have occurred in patients receiving Hymenoptera venom desensitization treatment and also in patients receiving dialysis 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 requires monitoring 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 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 that can progress to hepatic necrosis and sometimes death. The clinician needs to discontinue the drug, and the patient managed appropriately.[15]

Contraindications

ACE inhibitors 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.

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

Monitoring

Renal function and electrolytes need to be checked regularly 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.[17] 

Since ACE inhibitors can affect the liver, AST and ALT also require monitoring.  

Toxicity

Excessive doses of ACE inhibitors are usually well-tolerated, but significantly large doses 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 becomes 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 medically 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 a choice if intravenous fluids are not successful. Also, vasopressors are an option for the treatment of hypotension.[18]

Enhancing Healthcare Team Outcomes

ACE inhibitors are one of the most widely used drugs for hypertension and heart failure, but their popularity does not mean they do not need the management of an interprofessional team. Besides the cardiologist, these drugs are widely prescribed by nurse practitioners, primary providers, and cardiac surgeons. While ACE inhibitors are relatively safe, a pharmacist should examine the patient's medication record to verify dosing and check for drug-drug interactions. Nursing can provide patient counsel, monitor for interactions and adverse events, and report any issues to the prescriber. It is important to monitor renal function and levels of electrolytes regularly. Because there are many ACE inhibitors available today, it is important to keep up with the guidelines and recommendations, and the pharmacist can help the prescriber in this area.[19][6][20] An interprofessional team approach will optimize ACE inhibitor therapy resulting in improved patient outcomes. [Level V]



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      Contributed by Linda L Herman

References

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