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 black population with elevated blood pressure.
ACEi improves heart failure by decreasing afterload. Apart from decreasing the afterload, it also reduces cardiac myocyte hypertrophy. The Heart Outcomes Prevention Evaluation (HOPE) Study demonstrated better outcomes for those prescribed ACE inhibitors.
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.
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.
Current recommendations are the use of ACEi or ARB as first-line therapy for hypertension in patients with a history of diabetes. Also, the use of ACEi in diabetic hypertensive patients with no history of coronary heart disease has shown to decrease the incidence of myocardial infarction and improved heart function. 
Nephrotic Syndrome or Proteinuria
It has been shown that the use of ACEi reduces blood pressure and proteinuria in patients with kidney disease. The reduction in proteinuria is due to a reduction in the intraglomerular capillary pressure and blood pressure control.
Chronic Kidney Disease
ACEi or ARB are the first-line drugs in the management of chronic kidney disease (CKD) patients. The use of ACEI or ARB had a superior effect than no ACEI or ARB treatment on decreasing the proteinuria and slowing kidney disease progression. The efficacy of ACEI and ARB was comparable.
The use of ACEi or ARB is the mainstay of treatment in patients with glomerular diseases. It slows down the decline in glomerular filtration rate (GFR) and proteinuria.
The use of renin-angiotensin-aldosterone inhibitors prolongs graft survival in patients with posttransplant glomerulonephritis.
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 an 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.
Depending on the chemical structure, ACE inhibitors are classified into three groups:
1. Sulfhydryl-containing ACE inhibitor.
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.
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 prescribed orally, 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, a non-prodrug form is preferable in patients with underlying liver issues. 
About 1 to 10% will develop a dry, nonproductive paroxysmal cough and there is no treatment for the cough. Experimental studies have shown that the use of non-steroidal anti-inflammatory agents (NSAIDs) and intermediate-dose aspirin (500 mg) can help with ACEi induced cough 
Angioedema is the most significant adverse effect of ACEi. It can affect any part of the body, including intestine, but the most concerning is edema of the tongue, glottis and/or larynx causing airway obstruction. Angioedema has a higher rate of incidence in the African-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 the other agents. There is an ongoing phase III trial at this time.
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.
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. 
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.
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.
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.
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.
The combination therapy of ACEi and ARBs does not reduce the mortality in patients with heart failure when compared to monotherapy. In fact, the combination therapy can worsen renal indices and cause life-threatening hyperkalemia 
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, drop-in GFR or increasing creatinine the drug needs to be adjusted accordingly or discontinued. 
Excessive doses of ACE inhibitors are usually well-tolerated, but it can cause hypotension, drop-in GFR and electrolyte derangements. As the ACE inhibitors block aldosterone, they can cause 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 psychiatry.
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.
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 nephrologists and cardiologists, these drugs are widely prescribed by nurse practitioners and primary care providers. 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. An interprofessional team approach will optimize ACE inhibitor therapy resulting in improved patient outcomes. [Level V]
|||Page MR, The JNC 8 hypertension guidelines: an in-depth guide. The American journal of managed care. 2014 Jan; [PubMed PMID: 25618230]|
|||James PA,Oparil S,Carter BL,Cushman WC,Dennison-Himmelfarb C,Handler J,Lackland DT,LeFevre ML,MacKenzie TD,Ogedegbe O,Smith SC Jr,Svetkey LP,Taler SJ,Townsend RR,Wright JT Jr,Narva AS,Ortiz E, 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 Feb 5; [PubMed PMID: 24352797]|
|||Correction: Effects of an Angiotensin-Converting-Enzyme Inhibitor, Ramipril, on Cardiovascular Events in High-Risk Patients. The New England journal of medicine. 2000 May 4; [PubMed PMID: 10793171]|
|||Yusuf S,Sleight P,Pogue J,Bosch J,Davies R,Dagenais G, Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The New England journal of medicine. 2000 Jan 20; [PubMed PMID: 10639539]|
|||Williams B, Drug discovery in renin-angiotensin system intervention: past and future. Therapeutic advances in cardiovascular disease. 2016 Jun; [PubMed PMID: 27126389]|
|||Teng TK,Tromp J,Tay WT,Anand I,Ouwerkerk W,Chopra V,Wander GS,Yap JJ,MacDonald MR,Xu CF,Chia YM,Shimizu W,Richards AM,Voors A,Lam CS, Prescribing patterns of evidence-based heart failure pharmacotherapy and outcomes in the ASIAN-HF registry: a cohort study. The Lancet. Global health. 2018 Sep [PubMed PMID: 30103979]|
|||Zhang Y,Ding X,Hua B,Liu Q,Chen H,Zhao XQ,Li W,Li H, Real-world use of ACEI/ARB in diabetic hypertensive patients before the initial diagnosis of obstructive coronary artery disease: patient characteristics and long-term follow-up outcome. Journal of translational medicine. 2020 Apr 1; [PubMed PMID: 32238168]|
|||Heeg JE,de Jong PE,van der Hem GK,de Zeeuw D, Reduction of proteinuria by angiotensin converting enzyme inhibition. Kidney international. 1987 Jul; [PubMed PMID: 3041097]|
|||Silvariño R,Rios P,Baldovinos G,Chichet MA,Perg N,Sola L,Saona G,De Souza N,Lamadrid V,Gadola L, Is Chronic Kidney Disease Progression Influenced by the Type of Renin-Angiotensin-System Blocker Used? Nephron. 2019; [PubMed PMID: 31203280]|
|||Pazik J,Ostrowska J,Lewandowski Z,Mróz A,Perkowska-Ptasińska A,Baczkowska T,Durlik M, Renin-Angiotensin-Aldosterone system inhibitors and statins prolong graft survival in post-transplant glomerulonephritis. Annals of transplantation. 2008; [PubMed PMID: 19034222]|
|||Miller AJ,Arnold AC, The renin-angiotensin system in cardiovascular autonomic control: recent developments and clinical implications. Clinical autonomic research : official journal of the Clinical Autonomic Research Society. 2018 Nov 9 [PubMed PMID: 30413906]|
|||Pinargote P,Guillen D,Guarderas JC, ACE inhibitors: upper respiratory symptoms. BMJ case reports. 2014 Jul 17; [PubMed PMID: 25035451]|
|||Israili ZH,Hall WD, Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Annals of internal medicine. 1992 Aug 1; [PubMed PMID: 1616218]|
|||Tenenbaum A,Grossman E,Shemesh J,Fisman EZ,Nosrati I,Motro M, Intermediate but not low doses of aspirin can suppress angiotensin-converting enzyme inhibitor-induced cough. American journal of hypertension. 2000 Jul; [PubMed PMID: 10933569]|
|||Korzeniowska K,Cielewiczi A,Pawlaczyk M,Motowidlo K,Andrys-Wawrzyniak I,Jablecka A, ANGIOEDEMA AFTER ANGIOTENSIN-CONVERTING ENZYME INHIBITORS. Acta poloniae pharmaceutica. 2017 May; [PubMed PMID: 29513968]|
|||Tunon-de-Lara JM,Villanueva P,Marcos M,Taytard A, ACE inhibitors and anaphylactoid reactions during venom immunotherapy. Lancet (London, England). 1992 Oct 10; [PubMed PMID: 1357311]|
|||Rousaud Baron F,Garcia JM,Camps EM,Cubells TD,Comamala MR, ACE inhibitors and anaphylactoid reactions to high-flux membrane dialysis (AN69): clinical aspects. Nephron. 1992; [PubMed PMID: 1584327]|
|||Rosano GMC,Tamargo J,Kjeldsen KP,Lainscak M,Agewall S,Anker SD,Ceconi C,Coats AJS,Drexel H,Filippatos G,Kaski JC,Lund L,Niessner A,Ponikowski P,Savarese G,Schmidt TA,Seferovic P,Wassmann S,Walther T,Lewis BS, Expert consensus document on the management of hyperkalaemia in patients with cardiovascular disease treated with renin angiotensin aldosterone system inhibitors: coordinated by the Working Group on Cardiovascular Pharmacotherapy of the European Society of Cardiology. European heart journal. Cardiovascular pharmacotherapy. 2018 Jul 1; [PubMed PMID: 29726985]|
|||Perazella MA, Hyperkalemia and trimethoprim-sulfamethoxazole: a new problem emerges 25 years later. Connecticut medicine. 1997 Aug; [PubMed PMID: 9309892]|
|||Rahmat J,Gelfand RL,Gelfand MC,Winchester JF,Schreiner GE,Zimmerman HJ, Captopril-associated cholestatic jaundice. Annals of internal medicine. 1985 Jan; [PubMed PMID: 3881069]|
|||Quan A, Fetopathy associated with exposure to angiotensin converting enzyme inhibitors and angiotensin receptor antagonists. Early human development. 2006 Jan; [PubMed PMID: 16427219]|
|||Kuenzli A,Bucher HC,Anand I,Arutiunov G,Kum LC,McKelvie R,Afzal R,White M,Nordmann AJ, Meta-analysis of combined therapy with angiotensin receptor antagonists versus ACE inhibitors alone in patients with heart failure. PloS one. 2010 Apr 1; [PubMed PMID: 20376345]|
|||Lucas C,Christie GA,Waring WS, Rapid onset of haemodynamic effects after angiotensin converting enzyme-inhibitor overdose: implications for initial patient triage. Emergency medicine journal : EMJ. 2006 Nov; [PubMed PMID: 17057137]|
|||Lip GY,Ferner RE, Poisoning with anti-hypertensive drugs: angiotensin converting enzyme inhibitors. Journal of human hypertension. 1995 Sep; [PubMed PMID: 8551483]|
|||Pongpanich P,Pitakpaiboonkul P,Takkavatakarn K,Praditpornsilpa K,Eiam-Ong S,Susantitaphong P, The benefits of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers combined with calcium channel blockers on metabolic, renal, and cardiovascular outcomes in hypertensive patients: a meta-analysis. International urology and nephrology. 2018 Oct 15 [PubMed PMID: 30324578]|
|||Aziz F,Clark D,Garg N,Mandelbrot D,Djamali A, Hypertension guidelines: How do they apply to kidney transplant recipients. Transplantation reviews (Orlando, Fla.). 2018 Oct [PubMed PMID: 30293557]|