FDA approved uses:
ACE inhibitors show efficacy in treatment due to the overall reduction of mortality in multiple patient disease states. There is evidence of mortality benefit in patients with hypertension, heart failure, Acute MI, and diabetes mellitus.
Non-FDA approved uses:
ACE inhibitors may delay the progression of nephropathy and reduce the risks of cardiovascular events in hypertensive patients with diabetes mellitus type I and type II. The addition of an ACE inhibitor has shown a significant reduction in serum creatinine in both hypertensive patients and normotensive patients with albuminuria. Therapy has shown a significant decrease in the progression of diabetic nephropathy.
ACE is involved in the renin-angiotensin-aldosterone system (RAAS; media item 1) and stimulates the conversion of angiotensin I to angiotensin II. ACE inhibitors are competitive inhibitors of ACE, which prevents the conversion of angiotensin I to angiotensin II. Angiotensin II acts as a potent vasoconstrictor that, when inhibited, can reduce blood pressure by dilating vessels and decreasing aldosterone secretion.
It is essential to understand the role of the RAS hormonal system in depth to appreciate the therapeutic effects of ACE inhibitors and understand why this is a target for hypertensive therapy. Initially, afferent arteriole juxtaglomerular cells synthesize prorenin, which is actively cleaved to renin. Angiotensinogen produced from the liver is then cleaved by renin to form angiotensin I. The angiotensin I molecule is converted to angiotensin II by ACE. Angiotensin II is the molecule that has significant actions on various systems. Initially, Angiotensin II induces vasoconstriction, which ultimately increases systemic blood pressure. Even further, Angiotensin II stimulates the adrenal cortex and the pituitary to produce Aldosterone and Anti-diuretic hormone (ADH), respectively. Aldosterone induces sodium reabsorption and, in turn, water reabsorption through internal mineralocorticoid receptor activity ; ADH increases the synthesis of aquaporin-2 channels in the collecting duct inducing selective reabsorption of water.
ACE inhibitors are most commonly oral agents, but intravenous forms are available. Medications most commonly end with the suffix -pril. Examples include lisinopril, ramipril, and captopril.
Most Common Adverse Reactions
Commonly, patients on ACE inhibitors have reported dry cough between the one week of initiation up to six months, with some sources citing up to one year after initiation. Discontinuing therapy usually resolves the cough 1 to 4 days after but can be prolonged up to a month. The concern for dry cough with therapy initiation is a decrease in medication adherence. Additionally, there is an increased propensity to develop bronchospasm in these patients. ACE metabolizes bradykinin and other local molecules. Inhibiting ACE in the lung increases the concentration of kinins, causing bronchial irritation. After discontinuation of ACE inhibitor therapy, an angiotensin receptor blocker (ARB) can initiate as an alternate therapy. ARB’s have a lower incidence of cough recurrence compared to reinitiating ACE inhibitor therapy. If cough recurs on ARB therapy, switch to a different drug class entirely.
One percent to 10%: flushing, orthostatic effect, chest pain, altered sense of smell, fatigue, headache, alopecia, diaphoresis, erythema, pruritus, skin photosensitivity, Steven-Johnson Syndrome, toxic epidermal necrolysis, urticaria, diabetes mellitus, gout, SIADH, constipation, diarrhea, dysgeusia, flatulence, pancreatitis, xerostomia, impotence, bone marrow suppression, hemolytic anemia, leukopenia, neutropenia, thrombocytopenia, common cold, weakness, blurred vision, diplopia, photophobia, vision loss, tinnitus, cough.
Hypotension can cause intolerance to therapy leading to discontinuation in a small population of patients, which is more common in patients with increased renin baseline concentrations. Allowing repletion of fluids and discontinuing diuretic medication before therapy can minimize hypotensive episodes.
A slight reduction of glomerular filtration rate (GFR) is common when initiating therapy. GFR reduction can become severe in certain settings and co-morbidities. Patients with diseases affecting renal perfusion can cause further reduction of GFR to a severe level warranting discontinuation. Some co-morbidities can include heart failure, chronic kidney disease, and bilateral renal artery stenosis.
Hyperkalemia from ACE inhibitors is a direct result of the mechanism of action. The blockade of angiotensin II prevents the downstream secretion of aldosterone. Aldosterone causes reabsorption of sodium and, subsequently, water. Consequently, protons and potassium get secreted into the urine. Without the secretion of potassium through aldosterone, potassium can easily increase in patients on ACE inhibitors. Co-morbidities that decrease kidney function or medications that cause potassium retention increases the risk of hyperkalemia.
Angioedema is a rare but potentially life-threatening side effect of ACE inhibitor use. The side effect is a swelling of the face, lips, and upper airway in an episodic nature. The inflammation creates difficulty in the patient’s ability to maintain an airway; therefore, endotracheal intubation is necessary to secure the airway. The mechanism of angioedema is thought to be through an extensive accumulation of bradykinins in select individuals. Bradykinin induces prominent vasodilation and plasma extravasation into the local tissue. The primary treatment of ACE inhibitor-induced angioedema is the discontinuation of ACE inhibitor therapy. It is also suggested to avoid ACE inhibitor therapy in individuals with hereditary angioedema or a history of angioedema episodes.
Less than 1%: Acute renal failure, anaphylactoid reactions, angioedema, anuria, arthralgia, arthritis, asthma, ataxia, azotemia, bronchitis, bronchospasm, cardiac arrest, cardiac arrhythmia, cerebrovascular accident, chills, confusion, cutaneous pseudolymphoma, dehydration, drowsiness, dyspepsia, dyspnea, dysuria, eosinophilia, eosinophilic pneumonitis, epistaxis, facial edema, fever, gastritis, hallucination, heartburn, hemoptysis, hepatic necrosis, hepatitis, herpes zoster, hypersomnia, hypervolemia, hypoglycemia, hyponatremia, increased erythrocyte sedimentation rate, insomnia, intestinal angioedema, irritability, laryngitis, leukocytosis, malaise, malignant neoplasm of lung, mastalgia, memory impairment, mood changes, muscle spasm, musculoskeletal pain, myalgia, myocardial infarction, oliguria, orthopnea, orthostatic hypotension, palpitations, paresthesia, paroxysmal nocturnal dyspnea, pemphigus, peripheral edema, peripheral neuropathy, pharyngitis, pleural effusion, pneumonia, positive ANA titer, psoriasis, pulmonary embolism, pulmonary infarct, pulmonary infiltrates, pyelonephritis, rhinitis, rhinorrhea, sinusitis, skin infection, skin lesion, skin rash, sore throat, systemic lupus erythematosus, transient ischemic attacks, tremor, uremia, urinary tract infection, vasculitis, vertigo, viral infection, visual hallucination, weight gain, weight loss, wheezing.
The use of drugs that inhibit the renin-angiotensin system correlates with teratogenic effects such as oligohydramnios, decreased fetal renal function, anuria, renal failure, skull hypoplasia, and death.
The proposed mechanism behind oligohydramnios is evident at the level of the fetal kidney. The low-pressure hemodynamics of the fetus becomes easily disrupted with a decreased amount of angiotensin II. Fetal renal pressure becomes lower, reducing the ability to maintain GFR, leading to oligohydramnios and anuria.
ACE inhibitors are contraindicated in a patient with a history of hypersensitivity to any ACE inhibitor or component of the formulation, angioedema related to previous treatment with ACE inhibitor, idiopathic or hereditary angioedema, or current use of aliskiren in a patient with diabetes mellitus. Also, consider drugs with cross-reactivity with ACE inhibitors.
ACE inhibitors are not recommended in pregnant patients and require discontinuation as soon as pregnancy is detected.
Use with great caution in the following situations:
Typical parameters to monitor are BUN, serum creatinine, renal function, WBC, and potassium. If a patient has collagen vascular disease and/or renal impairment, periodically monitor complete blood count with differential to evaluate kidney erythropoietin production. In patients with hypotensive effects within 1 to 3 hours of initial dose or with increased dosages or preexisting hepatic impairment, consider baseline hepatic function tests. A white and red blood cell counts are necessary to evaluate for rare side effects of anemia, neutropenia, agranulocytosis, and thrombocytopenia.
When used at therapeutic doses, the risk of toxicity is rare. Toxicity is more likely when the drug is used in combination or at supratherapeutic doses.
When combining ACE inhibitors with other antihypertensive drugs, they have the potential to increase side effects like hyperkalemia, hypotension, and renal failure. One should pay more attention when the patient is given an ACE inhibitor and is already on a potassium-sparing diuretic, NSAIDs, cyclosporine, and anticoagulants.
All the presently available ACE inhibitors have similar antihypertensive effects at equivalent doses. The only ACE inhibitor that is different is captopril. This agent has a short duration of action and is more likely to induce side effects. It is the only ACE inhibitor to penetrate the blood-brain barrier and potentially cause confusion and lethargy.
Clinicians widely use ACE inhibitors in medicine for the treatment of hypertension, heart failure, and patients with chronic kidney disease. While effective, healthcare workers (nurse practitioners, physicians, and pharmacists) who prescribe these agents should be aware of their side effects and limitations. Patients also need to be monitored for their renal function and electrolyte concentrations regularly. Finally, the healthcare worker should be aware that these agents can produce a chronic dry cough, and the clinician should try another class of antihypertensive medication.
Even though ACE inhibitors are among the oldest drug classes available, there is a threat that familiarity can lead to carelessness. That is why, like any other drug, these agents require the oversight and coordination of an interprofessional team. Pharmacists need to verify that dosing is appropriate, and check for drug interactions. Nursing will monitor and for female patients, emphasize that if they think they are pregnant or trying to get pregnant, that therapy will need to change to accommodate that. Nursing will also be taking blood pressure at every visit, and charting so the prescriber can determine if dosing or other changes may be for hypertensive control. The clinician must remain informed by these findings from the other members of the interprofessional healthcare team, so he can take corrective action if necessary. Communication and collaboration among healthcare team members will make ACE inhibitor therapy more effective, leading to better patient outcomes. [Level V]
|||Whelton PK,Carey RM,Aronow WS,Casey DE Jr,Collins KJ,Dennison Himmelfarb C,DePalma SM,Gidding S,Jamerson KA,Jones DW,MacLaughlin EJ,Muntner P,Ovbiagele B,Smith SC Jr,Spencer CC,Stafford RS,Taler SJ,Thomas RJ,Williams KA Sr,Williamson JD,Wright JT Jr, 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension (Dallas, Tex. : 1979). 2018 Jun; [PubMed PMID: 29133356]|
|||Knežević T,Gellineo L,Jelaković A,Premužić V,Dika Ž,Laganović M,Jelaković B, Treatment of hypertension induced albuminuria. Current pharmaceutical design. 2018 Nov 26 [PubMed PMID: 30479206]|
|||Hradec J, Pharmacological therapy for chronic heart failure. Vnitrni lekarstvi. 2018 Fall [PubMed PMID: 30441998]|
|||Leru PM,Anton VF,Bumbea H, Nine year follow-up of a rare case of angioedema due to acquired C1-inhibitor deficiency with late onset and good response to attenuated androgen. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology. 2018 [PubMed PMID: 30386386]|
|||Viberti G,Mogensen CE,Groop LC,Pauls JF, Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. European Microalbuminuria Captopril Study Group. JAMA. 1994 Jan 26; [PubMed PMID: 8295285]|
|||Lewis EJ,Hunsicker LG,Bain RP,Rohde RD, The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. The New England journal of medicine. 1993 Nov 11; [PubMed PMID: 8413456]|
|||Chen YJ,Li LJ,Tang WL,Song JY,Qiu R,Li Q,Xue H,Wright JM, First-line drugs inhibiting the renin angiotensin system versus other first-line antihypertensive drug classes for hypertension. The Cochrane database of systematic reviews. 2018 Nov 14 [PubMed PMID: 30480768]|
|||Patel S,Rauf A,Khan H,Abu-Izneid T, Renin-angiotensin-aldosterone (RAAS): The ubiquitous system for homeostasis and pathologies. Biomedicine [PubMed PMID: 28772209]|
|||Silva P,Brown RS,Epstein FH, Adaptation to potassium. Kidney international. 1977 Jun; [PubMed PMID: 327141]|
|||Yee AH,Burns JD,Wijdicks EF, Cerebral salt wasting: pathophysiology, diagnosis, and treatment. Neurosurgery clinics of North America. 2010 Apr; [PubMed PMID: 20380974]|
|||Yeo WW,Chadwick IG,Kraskiewicz M,Jackson PR,Ramsay LE, Resolution of ACE inhibitor cough: changes in subjective cough and responses to inhaled capsaicin, intradermal bradykinin and substance-P. British journal of clinical pharmacology. 1995 Nov; [PubMed PMID: 8703645]|
|||Lunde H,Hedner T,Samuelsson O,Lötvall J,Andrén L,Lindholm L,Wiholm BE, Dyspnoea, asthma, and bronchospasm in relation to treatment with angiotensin converting enzyme inhibitors. BMJ (Clinical research ed.). 1994 Jan 1; [PubMed PMID: 8298346]|
|||Malini PL,Strocchi E,Zanardi M,Milani M,Ambrosioni E, Thromboxane antagonism and cough induced by angiotensin-converting-enzyme inhibitor. Lancet (London, England). 1997 Jul 5; [PubMed PMID: 9217714]|
|||Matchar DB,McCrory DC,Orlando LA,Patel MR,Patel UD,Patwardhan MB,Powers B,Samsa GP,Gray RN, Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension. Annals of internal medicine. 2008 Jan 1; [PubMed PMID: 17984484]|
|||Sachs B,Meier T,Nöthen MM,Stieber C,Stingl J, [Drug-induced angioedema : Focus on bradykinin]. Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete. 2018 Apr [PubMed PMID: 29392343]|
|||Kostis JB,Shelton B,Gosselin G,Goulet C,Hood WB Jr,Kohn RM,Kubo SH,Schron E,Weiss MB,Willis PW 3rd,Young JB,Probstfield J, Adverse effects of enalapril in the Studies of Left Ventricular Dysfunction (SOLVD). SOLVD Investigators. American heart journal. 1996 Feb; [PubMed PMID: 8579032]|
|||Bakris GL,Weir MR, Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Archives of internal medicine. 2000 Mar 13; [PubMed PMID: 10724055]|
|||Kifor I,Moore TJ,Fallo F,Sperling E,Chiou CY,Menachery A,Williams GH, Potassium-stimulated angiotensin release from superfused adrenal capsules and enzymatically dispersed cells of the zona glomerulosa. Endocrinology. 1991 Aug; [PubMed PMID: 1855477]|
|||Gubler MC,Antignac C, Renin-angiotensin system in kidney development: renal tubular dysgenesis. Kidney international. 2010 Mar; [PubMed PMID: 19924102]|
|||Wilkins B,Hullikunte S,Simmonds M,Sasse A,Larsen PD,Harding SA, Improving the Prescribing Gap For Guideline Recommended Medications Post Myocardial Infarction. Heart, lung [PubMed PMID: 29523466]|
|||Shaikh A, A Practical Approach to Hypertension Management in Diabetes. Diabetes therapy : research, treatment and education of diabetes and related disorders. 2017 Oct [PubMed PMID: 28929319]|
|||Alzahrani T,Tiu J,Panjrath G,Solomon A, The effect of angiotensin-converting enzyme inhibitors on clinical outcomes in patients with ischemic cardiomyopathy and midrange ejection fraction: a post hoc subgroup analysis from the PEACE trial. Therapeutic advances in cardiovascular disease. 2018 Nov 15 [PubMed PMID: 30442080]|
|||Brar S,Ye F,James MT,Hemmelgarn B,Klarenbach S,Pannu N, Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With Outcomes After Acute Kidney Injury. JAMA internal medicine. 2018 Oct 27 [PubMed PMID: 30422153]|
|||Saglimbene V,Palmer SC,Ruospo M,Natale P,Maione A,Nicolucci A,Vecchio M,Tognoni G,Craig JC,Pellegrini F,Lucisano G,Hegbrant J,Ariano R,Lamacchia O,Sasso A,Morano S,Filardi T,De Cosmo S,Pugliese G,Procaccini DA,Gesualdo L,Palasciano G,Johnson DW,Tonelli M,Strippoli GFM, The Long-Term Impact of Renin-Angiotensin System (RAS) Inhibition on Cardiorenal Outcomes (LIRICO): A Randomized, Controlled Trial. Journal of the American Society of Nephrology : JASN. 2018 Nov 12 [PubMed PMID: 30420421]|