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ACE inhibitor

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Angiotensin-converting-enzyme inhibitor
Drug class
Captopril, the first synthetic ACE inhibitor
Class identifiers
UseHypertension
ATC codeC09A
Biological targetAngiotensin-converting enzyme
Clinical data
Drugs.comDrug Classes
Consumer ReportsBest Buy Drugs
WebMDMedicineNet  RxList
External links
MeSHD000806
Legal status
In Wikidata

Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of cardiovascular and kidney diseases.[1] This class of medicine works by causing relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart.

ACE inhibitors inhibit the activity of angiotensin-converting enzyme, an important component of the renin–angiotensin system which converts angiotensin I to angiotensin II,[2] and hydrolyzes bradykinin.[3] Therefore, ACE inhibitors decrease the formation of angiotensin II, a vasoconstrictor, and increase the level of bradykinin, a peptide vasodilator.[3][2] This combination is synergistic in lowering blood pressure.[3][2]

As a result of inhibiting the ACE enzyme in the bradykinin system, the ACE inhibitor drugs allow for increased levels of bradykinin which would normally be degraded. Bradykinin produces prostaglandin. This mechanism can explain the two most common side effects seen with ACE Inhibitors: angioedema and cough.

Frequently prescribed ACE inhibitors include benazepril, zofenopril, perindopril, trandolapril, captopril, enalapril, lisinopril, and ramipril.

Medical uses

[edit]

ACE inhibitors were initially approved for the treatment of hypertension and can be used alone or in combination with other anti-hypertensive medications. Later, they were found useful for other cardiovascular and kidney diseases[4] including:

In treating high blood pressure, ACE inhibitors are a first-line initial drug choice.[8] Age, frailty, and race can influence treatment choices and it is common to need more than one drug to obtain the desired improvement.[1]

All ACE inhibitors but enalapril, which can be given intravenously, are administered orally.[1] Each one has different strengths with different starting dosages. Dosage should be adjusted according to the clinical response.[9][10] Most ACE inhibitors can be dosed once daily with the exception of captopril.[1] ACE inhibitors possess many common characteristics with another class of cardiovascular drugs, angiotensin II receptor antagonists, which are often used when patients are intolerant of the adverse effects produced by ACE inhibitors. ACE inhibitors do not completely prevent the formation of angiotensin II, as blockage is dose-dependent, so angiotensin II receptor antagonists may be useful because they act to prevent the action of angiotensin II at the AT1 receptor, leaving AT2 receptor unblocked; the latter may have consequences needing further study.[citation needed] There are fixed-dose combination drugs, such as ACE inhibitor and thiazide combinations.

ACE inhibitors have also been used in chronic kidney failure and kidney involvement in systemic sclerosis (hardening of tissues, as scleroderma renal crisis).[11] In those with stable coronary artery disease, but no heart failure, benefits are similar to other usual treatments.[12]

In 2012, a meta-analysis published in the BMJ described the protective role of ACE inhibitors in reducing the risk of pneumonia when compared to angiotensin II receptor blocker (ARBs).[13] The authors found a decreased risk in patients with previous stroke (54% risk reduction), with heart failure (37% risk reduction), and of Asian descent (43% risk reduction vs 54% risk reduction in non-Asian population). However, no reduced pneumonia-related mortality was observed.[13]

ACE inhibitors have been shown to be effective for indications other than hypertension[14] even in patients with normal blood pressure.[15] The use of a maximum dose of ACE inhibitors in such patients (including for prevention of diabetic nephropathy, congestive heart failure, and prophylaxis of cardiovascular events) is justified,[16] because it improves clinical outcomes independently of the blood pressure-lowering effect of ACE inhibitors. Such therapy, of course, requires careful and gradual titration of the dose to prevent the effects of rapidly decreasing blood pressure (dizziness, fainting, etc.).[17][1]

ACE inhibitors may also be used to help decrease excessive water consumption in people with schizophrenia resulting in psychogenic polydipsia.[18][19] A double-blind, placebo-controlled trial showed that when used for this purpose, enalapril led to decreased consumption (determined by urine output and osmolality) in 60% of people;[20] the same effect has been demonstrated in other ACE inhibitors.[21]

Use of ACE inhibitors in kidney transplant patients may have little to no benefits.[22]

Specific populations

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Pregnancy

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In pregnant women, ACE inhibitors taken during all the trimesters have been reported to cause congenital malformations, stillbirths, and neonatal deaths. Commonly reported fetal abnormalities include hypotension, renal dysplasia, anuria/oliguria, oligohydramnios, intrauterine growth retardation, pulmonary hypoplasia, patent ductus arteriosus, and incomplete ossification of the skull.[23][24] Overall, about half of newborns exposed to ACE inhibitors are adversely affected, leading to birth defects.[25][2]

ACE inhibitors are ADEC pregnancy category D and should be avoided in women who are likely to become pregnant.[26] In the U.S., ACE inhibitors must be labeled with a boxed warning concerning the risk of birth defects when taken during the second and third trimester. Their use in the first trimester is also associated with a risk of major congenital malformations, particularly affecting the cardiovascular and central nervous systems.[27][1]

Breastfeeding

[edit]

ACE inhibitors may be used with caution during breastfeeding due to evidence showing small amounts being present in breastmilk. Enalapril is most commonly prescribed and has the most data published. The medications are considered safe for the mother.[1]

In children

[edit]

Common ACE inhibitors used in pediatrics for hypertension include captopril, enalapril, and lisinopril and are used in patients older than six years old.[1]

In the elderly

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ACE inhibitors are strongly advised not to be started in elderly patients presenting with dehydration. Potassium and creatinine must be monitored during course of treatment.[1]

Contraindications

[edit]

The ACE inhibitors are contraindicated in people with:

ACE inhibitors should be used with caution in people with hemodialysis with high-flux polyacrylonitrile membranes.[citation needed]

Interactions

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A combination of ACE inhibitor with other drugs may increase effects of these drugs, but also the risk of adverse effects.[23] Commonly reported adverse effects of drug combination with ACE inhibitor are acute renal failure, hypotension, and hyperkalemia. Drugs interacting with ACE inhibitor should be prescribed with caution. Special attention should be given to combinations of ACE inhibitor with diuretics (especially potassium-sparing diuretics), NSAIDs, anticoagulants, cyclosporine, DPP-4 inhibitors, and potassium supplements

Angiotensin II receptor antagonists (ARBs) should not be used with ACE inhibitors.[31] Dual RAAS inhibitor therapy (ACE inhbitors, ARBs, direct renin inhibitors, or mineralocorticoid receptor antagonists) has been found to significantly increase the risk of developing kidney damage and hyperkalemia.[32]

Potassium supplementation should be used with caution and under medical supervision owing to the hyperkalemic effect of ACE inhibitors.[33]

Concomitant use with cyclooxygenase inhibitors tends to decrease ACE inhibitor's hypotensive effect.[34][2]

Adverse effects

[edit]

Common side effects include low blood pressure, cough, hyperkalemia, headache, dizziness, fatigue, nausea, and kidney impairment.[26][23][1]

The main adverse effects of ACE inhibition can be understood from their pharmacological action. The other reported adverse effects are liver problems and effects on the fetus.[23] Kidney problems may occur with all ACE inhibitors that directly follows from their mechanism of action. However, the decrease may be significant in conditions of pre-existing decreased renal perfusions, such as renal artery stenosis, heart failure, polycystic kidney disease, or volume depletion.[1] In these patients, the maintenance of GFR depends on angiotensin-II-dependent efferent vasomotor tone.[35] Therefore, renal function should be closely monitored over the first few days after initiation of treatment with ACE inhibitor in patients with decreased renal perfusion.[23][1] Generally, a moderate reduction in renal function (no greater than 30% rise in serum creatinine which stabilizes within 2–4 weeks) is considered acceptable as part of the therapeutic effect.[36][37][1]

Reduced GFR is especially a problem if the patient is concomitantly taking an NSAID and a diuretic.[2] When the three drugs are taken together, the risk of developing renal failure is significantly increased.[38]

Hyperkalemia, or high blood potassium, is a common adverse effect of treatment in 2% to 6% of patients.[1] Suppression of angiotensin II leads to a decrease in aldosterone levels.[1] Since aldosterone is responsible for increasing the excretion of potassium, ACE inhibitors can cause retention of potassium.[1] Some people, however, can continue to lose potassium while on an ACE inhibitor.[39] Hyperkalemia may decrease the velocity of impulse conduction in the nerves and muscles, including cardiac tissues. This leads to cardiac dysfunction and neuromuscular consequences, such as muscle weakness, paresthesia, nausea, diarrhea, and others. Close monitoring of potassium levels is required in patients receiving treatment with ACE inhibitors who are at risk of hyperkalemia.[23][1]

Another possible adverse effect specific for ACE inhibitors, but not for other RAAS blockers, is an increase in bradykinin level. Additional research on this topic is required.[23][1]

A persistent dry cough is a common adverse effect produced by ACE inhibitors in 10% to 20% of patients.[40][1] People who experience coughing are often switched to angiotensin II receptor antagonists.[40][1]

Between 0.1% and 0.7% of patients develop angioedema or swelling.[41][1] A genetic predisposition may exist.[42][1]

Blood

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Hematologic effects, such as neutropenia, agranulocytosis and other blood dyscrasias, have occurred during therapy with ACE inhibitors, especially in people with additional risk factors.[43]

Overdose

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There are few reports of ACE inhibitor overdose, toxicity is more likely with the addition of other hypertensive drugs or higher than recommended doses.[1] The most likely manifestations are hypotension, which may be severe, hyperkalemia, hyponatremia and renal impairment with metabolic acidosis.[1] Related symptoms of hypotension are treated with naloxone.[1] Treatment should be mainly symptomatic and supportive, with volume expansion using normal saline to correct hypotension and improve renal function, and gastric lavage followed by activated charcoal and a cathartic to prevent further absorption of the drug. Captopril, enalapril, lisinopril and perindopril are known to be removable by hemodialysis.[44]

Pharmacology

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Mechanism of action

[edit]

ACE inhibitors reduce the activity of the renin–angiotensin–aldosterone system (RAAS) as the primary etiologic (causal) event in the development of hypertension in people with diabetes mellitus, as part of the insulin-resistance syndrome or as a manifestation of renal disease.[45][46]

Renin–angiotensin–aldosterone system

[edit]
Renin–angiotensin–aldosterone system

The renin–angiotensin–aldosterone system is a major blood pressure regulating mechanism. Markers of electrolyte and water imbalance in the body such as hypotension, low distal tubule sodium concentration, decreased blood volume and high sympathetic tone trigger the release of the enzyme renin from the cells of juxtaglomerular apparatus in the kidney.[47]

Renin activates a circulating liver derived prohormone angiotensinogen by proteolytic cleavage of all but its first ten amino acid residues known as angiotensin I. ACE (angiotensin converting enzyme) then removes a further two residues, converting angiotensin I into angiotensin II. ACE is found in the pulmonary circulation and in the endothelium of many blood vessels.[48] The system increases blood pressure by increasing the amount of salt and water the body retains. Angiotensin II is also a potent vasoconstrictor.[49]

Effects

[edit]

ACE inhibitors block the conversion of angiotensin I (ATI) to angiotensin II (ATII).[50][1] Arteriolar resistance is lowered, venous capacity is increased; cardiac output, cardiac index, stroke work, and volume is lowered; resistance in renal blood vessels is lowered; and lead to increased natriuresis (excretion of sodium in the urine).[51][52] Bradykinin levels increase because angiotensin-converting enzyme also degrades bradykinin, and its inhibition reduces bradykinin inactivation.[53][54]

Under normal conditions, angiotensin II has these effects:[54]

  • Vasoconstriction (narrowing of blood vessels) and vascular smooth muscle hypertrophy (enlargement) induced by ATII may lead to increased blood pressure and hypertension. Further, constriction of the efferent arterioles of the kidney leads to increased perfusion pressure in the glomeruli.
  • It contributes to ventricular remodeling and ventricular hypertrophy of the heart through stimulation of the proto-oncogenes c-fos, c-jun, c-myc, transforming growth factor beta (TGF-B), through fibrogenesis and apoptosis (programmed cell death).
  • Stimulation by ATII of the adrenal cortex to release aldosterone, a hormone that acts on kidney tubules, causes sodium and chloride ions retention and potassium excretion. Sodium is a "water-holding" ion, so water is also retained, which leads to increased blood volume, hence an increase in blood pressure.
  • Stimulation of the posterior pituitary to release vasopressin (antidiuretic hormone, ADH) also acts on the kidneys to increase water retention. If ADH production is excessive in heart failure, Na+ level in the plasma may fall (hyponatremia), and this is a sign of increased risk of death in heart failure patients.
  • A decrease renal protein kinase C

During the course of ACE inhibitor use, the production of ATII is decreased,[note 1][55] which prevents aldosterone release from the adrenal cortex.[55] This allows the kidney to excrete sodium ions along with water, and retain potassium ions. This decreases blood volume, leading to decreased blood pressure.[55]

Epidemiological and clinical studies have shown ACE inhibitors reduce the progress of diabetic nephropathy independently from their blood pressure-lowering effect.[56] This action of ACE inhibitors is used in the prevention of diabetic renal failure.[57]

ACE inhibitors have also been shown to cause a central enhancement of parasympathetic nervous system activity in healthy volunteers and patients with heart failure.[58][59] This action may reduce the prevalence of malignant cardiac arrhythmias, and the reduction in sudden death reported in large clinical trials.[60] ACE Inhibitors also reduce plasma norepinephrine levels, and its resulting vasoconstriction effects, in heart failure patients, thus breaking the vicious circles of sympathetic and renin angiotensin system activation, which sustains the downward spiral in cardiac function in congestive heart failure.[citation needed]

The ACE inhibitor enalapril has also been shown to reduce cardiac cachexia in patients with chronic heart failure.[61] Cachexia is a poor prognostic sign in patients with chronic heart failure.[62] ACE inhibitors are under early investigation for the treatment of frailty and muscle wasting (sarcopenia) in elderly patients without heart failure.[63]

History

[edit]

ACE in plasma was discovered by Leonard T. Skeggs, Norman Shumway, and their colleagues in 1956,[64] but at that time there was no known physiological basis for its use in heart failure treatment. That changed in 1962, when the physiological rationale for using vasodilators to reduce afterload in heart failure was established by American cardiologist Edmund Sonnenblick through force-velocity studies of isolated cardiac muscle.[65] These studies demonstrated that the resistance against which the ventricle contracts directly determines its performance—providing the theoretical justification for afterload reduction as a therapeutic strategy that ACE inhibitors would later exploit.

Around this time, it was also noted that those who worked in banana plantations in South-western Brazil collapsed after being bitten by a pit viper, leading to a search for a blood pressure lowering component in its venom.[66] Brazilian scientist Sérgio Henrique Ferreira reported a bradykinin-potentiating factor (BPF) present in the venom of Bothrops jararaca, a South American pit viper, in 1965.[67] Ferreira then went to John Vane's laboratory as a postdoctoral fellow with his already-isolated BPF. The conversion of the inactive angiotensin I to the potent angiotensin II was thought to take place in the plasma. However, in 1967, Kevin K. F. Ng and John R. Vane showed plasma ACE is too slow to account for the conversion of angiotensin I to angiotensin II in vivo. Subsequent investigation showed rapid conversion occurs during its passage through the pulmonary circulation.[68]

Bradykinin is rapidly inactivated in the circulating blood, and it disappears completely in a single pass through the pulmonary circulation. Angiotensin I also disappears in the pulmonary circulation because of its conversion to angiotensin II. Furthermore, angiotensin II passes through the lungs without any loss. The inactivation of bradykinin and the conversion of angiotensin I to angiotensin II in the lungs was thought to be caused by the same enzyme.[69] In 1970, Ng and Vane, using BPF provided by Ferreira, showed the conversion is inhibited during its passage through the pulmonary circulation.[70]

BPFs are members of a family of peptides whose potentiating action is linked to inhibition of bradykinin by ACE. Molecular analysis of BPF yielded a nonapeptide BPF teprotide (SQ 20,881), which showed the greatest ACE inhibition potency and hypotensive effect in vivo. Teprotide had limited clinical value as a result of its peptide nature and lack of activity when given orally. In the early 1970s, knowledge of the structure-activity relationship required for inhibition of ACE was growing. David Cushman, Miguel Ondetti and colleagues used peptide analogs to study the structure of ACE, using carboxypeptidase A as a model. Their discoveries led to the development of captopril, the first orally-active ACE inhibitor, in 1975.[71]

Captopril was approved by the United States Food and Drug Administration in 1981.[72] The first nonsulfhydryl-containing ACE inhibitor, enalapril, was approved four years later.[73] At least 8 other ACE inhibitors have since been marketed.[74]

In 1991, Japanese scientists created the first milk-based ACE inhibitor, in the form of a fermented milk drink, using specific cultures to liberate the tripeptide isoleucine-proline-proline (IPP) from the dairy protein. Valine-proline-proline (VPP) is also liberated in this process—another milk tripeptide with a very similar chemical structure to IPP. Together, these peptides are now often referred to as lactotripeptides. In 1996, the first human study confirmed the blood pressure-lowering effect of IPP in fermented milk.[75] Although twice the amount of VPP is needed to achieve the same ACE-inhibiting activity as the originally discovered IPP, VPP also is assumed to add to the total blood pressure lowering effect.[76] Since the first lactotripeptides discovery, more than 20 human clinical trials have been conducted in many different countries.[77]

Agents

[edit]

Currently, there are 10 ACE inhibitors approved for use in the United States by the FDA: captopril (1981), enalapril (1985), lisinopril (1987), benazepril (1991), fosinopril (1991), quinapril (1991), ramipril (1991), perindopril (1993), moexipril (1995) and trandolapril (1996).[78]

ACE inhibitors are easily identifiable by their common suffix, '-pril'.[1] ACE inhibitors can be divided into three groups based on their molecular structure[1] of the enzyme binding sites (sulfhydryl, phosphinyl, carboxyl) to the active center of ACE:[79]

Sulfhydryl-containing agents

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These agents appear to show antioxidative properties but may be involved in adverse events such as skin eruptions.[79]

Dicarboxylate-containing agents

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This is the largest group, including:[citation needed]

Phosphonate-containing agents

[edit]

Naturally occurring

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ACE inhibitor peptides can be derived from natural sources such as algae, fruit, seeds, dairy and animal products.[80] A comprehensive resource on anti-hypertensive peptides is available in the form of a database. It contains around 1700 unique antihypertensive peptides.[81] Arfalasin (HOE 409) is an angiotensin antagonist.[82][needs context]

Dairy products

[edit]

Casokinins and lactokinins, breakdown products of casein and whey, occur naturally after ingestion of milk products, especially cultured milk. Their role in blood pressure control is uncertain.[83] The lactotripeptides Val-Pro-Pro and Ile-Pro-Pro produced by the probiotic Lactobacillus helveticus or derived from casein have been shown to have ACE-inhibiting and antihypertensive functions.[84][77] In one study, L. helveticus PR4 was isolated from Italian cheeses.[85]

Comparative information

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All ACE inhibitors have similar antihypertensive efficacy when equivalent doses are administered. The main differences lie with captopril, the first ACE inhibitor. Captopril has a shorter duration of action and an increased incidence of adverse effects. It is also capable of passing through the blood–brain barrier.[86][87]

In a large clinical study, one of the agents in the ACE inhibitor class, ramipril (Altace), demonstrated an ability to reduce the mortality rates of patients with a myocardial infarction and to slow the subsequent development of heart failure. This finding was made after it was discovered that regular use of ramipril reduced mortality rates even in test subjects who did not have hypertension.[88]

Some believe ramipril's additional benefits may be shared by some or all drugs in the ACE-inhibitor class. However, ramipril currently remains the only ACE inhibitor for which such effects are actually evidence-based.[89]

A meta-analysis confirmed that ACE inhibitors are effective and certainly the first-line choice in hypertension treatment. This meta-analysis was based on 20 trials and a cohort of 158,998 patients, of whom 91% were hypertensive. ACE inhibitors were used as the active treatment in seven trials (n=76,615) and angiotensin receptor blocker (ARB) in 13 trials (n=82,383). ACE inhibitors were associated with a statistically significant 10% mortality reduction: (HR 0.90; 95% CI, 0.84–0.97; P=0.004). In contrast, no significant mortality reduction was observed with ARB treatment (HR 0.99; 95% CI, 0.94–1.04; P=0.683). Analysis of mortality reduction by different ACE inhibitors showed that perindopril-based regimens are associated with a statistically significant 13% all-cause mortality reduction. Taking into account the broad spectrum of the hypertensive population, one might expect that an effective treatment with ACE inhibitors, in particular with perindopril, would result in an important gain of lives saved.[90]

Note

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  1. ↑ ACE inhibitors don't appear to permanently reduce ATII plasma level after cessation of taking it. In short, ACE inhibitors don't cure high ATII plasma levels.[55]

See also

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References

[edit]
  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 Singh B, Cusick AS, Goyal A, Patel P (May 4, 2025). "ACE Inhibitors". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 28613646. Archived from the original on January 23, 2026. Retrieved July 30, 2026.
  2. 1 2 3 4 5 6 Byrd JB, Ram CV, Lerma EV (2019). "Pharmacologic treatment of hypertension". Nephrology Secrets. Elsevier. pp. 477–482. doi:10.1016/b978-0-323-47871-7.00078-2. ISBN 978-0-323-47871-7. S2CID 263490929.
  3. 1 2 3 Kaplan's Essentials of Cardiac Anesthesia. Elsevier. 2018. doi:10.1016/c2012-0-06151-0. ISBN 978-0-323-49798-5. Mechanisms of Action:ACE inhibitors act by inhibiting one of several proteases responsible for cleaving the decapeptide Ang I to form the octapeptide Ang II. Because ACE is also the enzyme that degrades bradykinin, ACE inhibitors increase circulating and tissue levels of bradykinin (Fig. 8.4).
  4. ↑ Jackson EK (2006). "Chapter 30. Renin and Angiotensin". In Brunton LL, Lazo JS, Parker K (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. ISBN 978-0-07-142280-2.
  5. ↑ "Myocardial Infarction". The Lecturio Medical Concept Library. Retrieved 27 August 2021.
  6. ↑ "Congestive Heart Failure". The Lecturio Medical Concept Library. 7 August 2020. Retrieved 27 August 2021.
  7. ↑ Kester M, Karpa KD, Vrana KE (2012). "Cardiovascular System". Elsevier's Integrated Review Pharmacology. Elsevier. pp. 125–151. doi:10.1016/b978-0-323-07445-2.00008-2. ISBN 978-0-323-07445-2. ACE inhibitors also slow progression of kidney disease in patients with diabetic nephropathies. Renal benefits are probably a result of improved renal hemodynamics from decreased glomerular arteriolar resistance.
  8. ↑ Johnson AE, Jackson CD, Alexander JT (April 28, 2026). "Management of Hypertension in Adults". Journal of the American Medical Association. 335 (16): 1440–1440. doi:10.1001/jama.2026.1132. ISSN 0098-7484. Retrieved July 29, 2026.
  9. ↑ Common Medication Conversions (Equivalents): Ace Inhibitors Archived 2015-03-17 at the Wayback Machine. GlobalRPh.com. Accessed 2009-11-22.
  10. ↑ Treating High Blood Pressure and Heart Disease: the ACE Inhibitors. Consumer Reports Health Best Buy Drugs. June 2009.
  11. ↑ Xiong A, Cao Y, Xiang Q, Song Z, Zhang Y, Zhou S, et al. (June 2022). "Angiotensin‐converting enzyme inhibitors prior to scleroderma renal crisis in systemic sclerosis: A systematic review and meta‐analysis". Journal of Clinical Pharmacy and Therapeutics. 47 (6). Wiley-Blackwell: 722–731. doi:10.1111/jcpt.13621. ISSN 0269-4727.
  12. ↑ Bangalore S, Fakheri R, Wandel S, Toklu B, Wandel J, Messerli FH (January 2017). "Renin angiotensin system inhibitors for patients with stable coronary artery disease without heart failure: systematic review and meta-analysis of randomized trials". BMJ. 356: j4. doi:10.1136/bmj.j4. PMC 5244819. PMID 28104622.
  13. 1 2 Caldeira D, Alarcão J, Vaz-Carneiro A, Costa J (July 2012). "Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis". BMJ. 345 (jul11 1) e4260. doi:10.1136/bmj.e4260. PMC 3394697. PMID 22786934.
  14. ↑ Bicket DP (August 2002). "Using ACE inhibitors appropriately". American Family Physician. 66 (3): 461–468. PMID 12182524. Retrieved 20 February 2019.
  15. ↑ Jerums G, Allen TJ, Campbell DJ, Cooper ME, Gilbert RE, Hammond JJ, et al. (November 2004). "Long-term renoprotection by perindopril or nifedipine in non-hypertensive patients with Type 2 diabetes and microalbuminuria". Diabetic Medicine. 21 (11): 1192–1199. doi:10.1111/j.1464-5491.2004.01316.x. PMID 15498085. S2CID 12855742.
  16. ↑ Strippoli GF, Craig M, Deeks JJ, Schena FP, Craig JC (October 2004). "Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review". BMJ. 329 (7470): 828. doi:10.1136/bmj.38237.585000.7C. PMC 521570. PMID 15459003.
  17. ↑ White E, PharmD (2022-12-06). "ACE Inhibitors: Class & Utilization Review". The Cardiology Advisor. Retrieved 2026-01-05.
  18. ↑ "Psychogenic polydipsia – Management – Emerging treatments". BMJ. May 5, 2016. Archived from the original on August 27, 2021. Retrieved October 28, 2016.
  19. ↑ Dundas B, Harris M, Narasimhan M (June 2007). "Psychogenic polydipsia review: etiology, differential, and treatment". Current Psychiatry Reports. 9 (3): 236–241. doi:10.1007/s11920-007-0025-7. PMID 17521521. S2CID 27207760.
  20. ↑ Greendyke RM, Bernhardt AJ, Tasbas HE, Lewandowski KS (April 1998). "Polydipsia in chronic psychiatric patients: therapeutic trials of clonidine and enalapril". Neuropsychopharmacology. 18 (4): 272–281. doi:10.1016/S0893-133X(97)00159-0. PMID 9509495.
  21. ↑ Sebastian CS, Bernardin AS (April 1990). "Comparison of enalapril and captopril in the management of self-induced water intoxication". Biological Psychiatry. 27 (7): 787–790. doi:10.1016/0006-3223(90)90594-r. PMID 2183881. S2CID 39998447.
  22. ↑ Natale P, Mooi PK, Green SC, Cross NB, Cooper TE, Webster AC, et al. (July 31, 2024). Cochrane Kidney and Transplant Group (ed.). "Antihypertensive treatment for kidney transplant recipients". Cochrane Database of Systematic Reviews. 2024 (8). doi:10.1002/14651858.CD003598.pub3. PMC 11290053. PMID 39082471. Retrieved July 29, 2026.
  23. 1 2 3 4 5 6 7 Sidorenkov G, Navis G (October 2014). "Safety of ACE inhibitor therapies in patients with chronic kidney disease". Expert Opinion on Drug Safety. 13 (10): 1383–1395. doi:10.1517/14740338.2014.951328. PMID 25148900. S2CID 207488068.
  24. ↑ Sørensen AM, Christensen S, Jonassen TE, Andersen D, Petersen JS (March 1998). "[Teratogenic effects of ACE-inhibitors and angiotensin II receptor antagonists]". Ugeskrift for Laeger (in Danish). 160 (10): 1460–1464. PMID 9520613.
  25. ↑ Bullo M, Tschumi S, Bucher BS, Bianchetti MG, Simonetti GD (August 2012). "Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists: a systematic review". Hypertension. 60 (2): 444–450. doi:10.1161/HYPERTENSIONAHA.112.196352. PMID 22753220.
  26. 1 2 Rossi S (2006). Australian Medicines Handbook. Adelaide: Australian Medicines Handbook. ISBN 0-9757919-2-3. [page needed]
  27. ↑ Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, et al. (June 2006). "Major congenital malformations after first-trimester exposure to ACE inhibitors". The New England Journal of Medicine. 354 (23): 2443–2451. doi:10.1056/NEJMoa055202. PMID 16760444.
  28. ↑ "Ace Inhibitors", MotherToBaby | Fact Sheets, Brentwood (TN): Organization of Teratology Information Specialists (OTIS), 1994, PMID 35951780, retrieved 2026-02-16
  29. ↑ "ACE I". cvpharmacology.
  30. 1 2 "ACEI contraindications". Open Anesthesia.
  31. ↑ "Recommendations | Hypertension in adults: diagnosis and management | Guidance | NICE". www.nice.org.uk. August 28, 2019. Retrieved 2026-07-29.
  32. ↑ Whitlock R, Leon SJ, Manacsa H, Askin N, Rigatto C, Fatoba ST, et al. (October 31, 2023). "The association between dual RAAS inhibition and risk of acute kidney injury and hyperkalemia in patients with diabetic kidney disease: a systematic review and meta-analysis". Nephrology, Dialysis, Transplantation. 38 (11): 2503–2516. doi:10.1093/ndt/gfad101. ISSN 1460-2385. PMC 10615629. PMID 37309038. Archived from the original on June 18, 2025. Retrieved August 2, 2026.
  33. ↑ Bakris GL, Siomos M, Richardson D, Janssen I, Bolton WK, Hebert L, et al. (November 2000). "ACE inhibition or angiotensin receptor blockade: impact on potassium in renal failure. VAL-K Study Group". Kidney International. 58 (5): 2084–2092. doi:10.1111/j.1523-1755.2000.00381.x. PMID 11044229.
  34. ↑ Sear JW (2019). "Antihypertensive Drugs and Vasodilators". Pharmacology and Physiology for Anesthesia. Elsevier. pp. 535–555. doi:10.1016/b978-0-323-48110-6.00026-0. ISBN 978-0-323-48110-6. S2CID 220688413. Coadministration of nonsteroidal anti-inflammatory drugs (NSAIDs [cyclooxygenase inhibitors]) can reduce the hypotensive effects of ACE inhibitors. ACE inhibitors can reduce the excretion of lithium and can result in lithium toxicity. Because these drugs do not affect the breakdown of kinins (as is seen with the ACE inhibitors), patients do not develop episodes of coughing and rarely develop angioneurotic edema.
  35. ↑ Tucker BM, Perazella MA (2019). "Medications: 3. What are the major adverse effects on the kidney of ACE inhibitors and ARBs?". Nephrology Secrets. Elsevier. pp. 78–83. doi:10.1016/b978-0-323-47871-7.00019-8. ISBN 978-0-323-47871-7. S2CID 239423283. due to inhibition of angiotensin II production by ACE inhibitors or competitive antagonism of the angiotensin II receptor by ARBs... results in loss of angiotensin II–induced efferent arteriolar tone, leading to a drop in glomerular filtration fraction and GFR. The efferent arteriolal vasodilation reduces intraglomerular hypertension (and pressure-related injury) and maintains perfusion (and oxygenation) of the peritubular capillaries.
  36. ↑ Bakris GL, Weir MR (March 2000). "Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern?". Archives of Internal Medicine. 160 (5): 685–693. doi:10.1001/archinte.160.5.685. PMID 10724055.
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  56. ↑ Hoogwerf BJ, Young JB (April 2000). "The HOPE study. Ramipril lowered cardiovascular risk, but vitamin E did not". Cleveland Clinic Journal of Medicine. 67 (4): 287–293. doi:10.3949/ccjm.67.4.287 (inactive 14 July 2025). PMID 10780101.{{cite journal}}: CS1 maint: DOI inactive as of July 2025 (link)
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  71. ↑ Cushman DW, Ondetti MA (April 1991). "History of the design of captopril and related inhibitors of angiotensin converting enzyme". Hypertension. 17 (4): 589–592. doi:10.1161/01.HYP.17.4.589. PMID 2013486. S2CID 30766421.
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  74. ↑ Bicket DP (August 2002). "Using ACE inhibitors appropriately". American Family Physician. 66 (3): 461–468. PMID 12182524.
  75. ↑ Hata Y, Yamamoto M, Ohni M, Nakajima K, Nakamura Y, Takano T (November 1996). "A placebo-controlled study of the effect of sour milk on blood pressure in hypertensive subjects". The American Journal of Clinical Nutrition. 64 (5): 767–771. doi:10.1093/ajcn/64.5.767. PMID 8901799.
  76. ↑ Nakamura Y, Yamamoto N, Sakai K, Takano T (June 1995). "Antihypertensive effect of sour milk and peptides isolated from it that are inhibitors to angiotensin I-converting enzyme". Journal of Dairy Science. 78 (6): 1253–1257. doi:10.3168/jds.S0022-0302(95)76745-5. PMID 7673515.
  77. 1 2 Boelsma E, Kloek J (March 2009). "Lactotripeptides and antihypertensive effects: a critical review". The British Journal of Nutrition. 101 (6): 776–786. doi:10.1017/S0007114508137722. PMID 19061526.
  78. ↑ "Lisinopril". go.drugbank.com. Retrieved 2022-11-05.
  79. 1 2 3 4 Shibata S, Fujita T (2018). "Renin Angiotensin Aldosterone System Blockers". Hypertension: A Companion to Braunwald's Heart Disease. Elsevier. pp. 230–241. doi:10.1016/b978-0-323-42973-3.00024-x. ISBN 978-0-323-42973-3. ACE inhibitors are classified according to the chemical structure of the site of binding (sulfhydryl, phosphinyl, carboxyl) to the active center of ACE.
  80. ↑ de Amorim AP, Alessandra Santana Moura Y, Mirella Soares de Souza K, Porto AL, Bezerra RP (August 2023). "Encapsulation of peptides inhibitors of the angiotensin-converting enzyme: A systematic review". Materials Today Communications. 36. doi:10.1016/j.mtcomm.2023.106850. ISSN 2352-4928 – via ScienceDirect.
  81. ↑ Kumar R, Chaudhary K, Sharma M, Nagpal G, Chauhan JS, Singh S, et al. (January 2015). "AHTPDB: a comprehensive platform for analysis and presentation of antihypertensive peptides". Nucleic Acids Research. 43 (Database issue): D956–D962. doi:10.1093/nar/gku1141. PMC 4383949. PMID 25392419.
  82. ↑ "US4013791A - Peptides having an antihypertensive effect". Google Patents. 1975-12-03. Retrieved 2020-03-21.
  83. ↑ FitzGerald RJ, Murray BA, Walsh DJ (April 2004). "Hypotensive peptides from milk proteins". The Journal of Nutrition. 134 (4): 980S–988S. doi:10.1093/jn/134.4.980S. PMID 15051858.
  84. ↑ Aihara K, Kajimoto O, Hirata H, Takahashi R, Nakamura Y (August 2005). "Effect of powdered fermented milk with Lactobacillus helveticus on subjects with high-normal blood pressure or mild hypertension". Journal of the American College of Nutrition. 24 (4): 257–265. doi:10.1080/07315724.2005.10719473. PMID 16093403. S2CID 18513821.
  85. ↑ Minervini F, Algaron F, Rizzello CG, Fox PF, Monnet V, Gobbetti M (September 2003). "Angiotensin I-converting-enzyme-inhibitory and antibacterial peptides from Lactobacillus helveticus PR4 proteinase-hydrolyzed caseins of milk from six species". Applied and Environmental Microbiology. 69 (9): 5297–5305. Bibcode:2003ApEnM..69.5297M. doi:10.1128/AEM.69.9.5297-5305.2003. PMC 194939. PMID 12957917.
  86. ↑ Ho JK, Moriarty F, Manly JJ, Larson EB, Evans DA, Rajan KB, et al. (September 2021). "Blood-Brain Barrier Crossing Renin-Angiotensin Drugs and Cognition in the Elderly: A Meta-Analysis". Hypertension. 78 (3): 629–643. doi:10.1161/HYPERTENSIONAHA.121.17049. PMC 9009861. PMID 34148364.
  87. ↑ Glodzik L, Santisteban MM (September 2021). "Blood-Brain Barrier Crossing Renin-Angiotensin System Drugs: Considerations for Dementia and Cognitive Decline". Hypertension. 78 (3): 644–646. doi:10.1161/HYPERTENSIONAHA.121.17595. PMC 9125564. PMID 34379433.
  88. ↑ "Controversies in Cardiology II". Medscape.
  89. ↑ Ball SG, et al. (The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators) (October 1993). "Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators". Lancet. 342 (8875): 821–828. doi:10.1016/0140-6736(93)92693-N. PMID 8104270. S2CID 5770772.
  90. ↑ van Vark LC, Bertrand M, Akkerhuis KM, Brugts JJ, Fox K, Mourad JJ, et al. (August 2012). "Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients". European Heart Journal. 33 (16): 2088–2097. doi:10.1093/eurheartj/ehs075. PMC 3418510. PMID 22511654.
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