ACE inhibitor

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"ACEI" redirects here. For other uses, see acei (disambiguation).
Not to be confused with Acetylcholinesterase inhibitor.
Angiotensin-converting-enzyme inhibitor
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Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of high blood pressure and heart failure.[1][2] 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

vasodilator.[1][3] This combination is synergistic in lowering blood pressure.[1][3]
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 use

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 often the first drug choice, particularly when diabetes is present,

systemic sclerosis (hardening of tissues, as scleroderma renal crisis). In those with stable coronary artery disease, but no heart failure, benefits are similar to other usual treatments.[9]

In 2012, there was a meta-analysis published in the BMJ that described the protective role of ACE inhibitors in reducing the risk of pneumonia when compared to angiotensin II receptor blocker (ARBs).[10] 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.[11]

Other

ACE inhibitors may also be used to help decrease excessive water consumption in people with

psychogenic polydipsia.[12][13] 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;[14] the same effect has been demonstrated in other ACE inhibitors.[15]

Additionally ACE-I are commonly used after renal transplant to manage post-transplant

erythrocytosis, a condition characterised by a persistently high hematocrit greater than 51% which often develops 8–24 months after successful transplantation,[16] as ACE-I have been shown to decrease erythropoietin production.[17]

Adverse effects

Common side effects include: low blood pressure,

fatigue, nausea, and kidney impairment.[18][19]

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.

renal function should be closely monitored over the first few days after initiation of treatment with ACE inhibitor in patients with decreased renal perfusion.[19] A moderate reduction in renal function, no greater than 30% rise in serum creatinine
, that is stabilized after a week of treatment is deemed acceptable as part of the therapeutic effect, providing the residual renal function is sufficient.

Reduced GFR is especially a problem if the patient is concomitantly taking an

NSAID and a diuretic.[21] When the three drugs are taken together, the risk of developing renal failure is significantly increased.[22]

High blood potassium is another possible complication of treatment with an ACE inhibitor due to its effect on aldosterone. Suppression of angiotensin II leads to a decrease in aldosterone levels. Since aldosterone is responsible for increasing the excretion of potassium, ACE inhibitors can cause retention of potassium. Some people, however, can continue to lose potassium while on an ACE inhibitor.[23] 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.[19]

Another possible adverse effect specific for ACE inhibitors, but not for other RAAS blockers, is an increase in bradykinin level.[19]

A persistent dry cough is a relatively common adverse effect believed to be associated with the increases in bradykinin levels produced by ACE inhibitors, although the role of bradykinin in producing these symptoms has been disputed.

angiotensin II receptor antagonists
.

Some (0.7%)[21] develop angioedema due to increased bradykinin levels.[26] A genetic predisposition may exist.[27]

A severe rare allergic reaction can affect the bowel wall and secondarily cause abdominal pain.[28]

Blood

Hematologic effects, such as neutropenia, agranulocytosis and other blood dyscrasias, have occurred during therapy with ACE inhibitors, especially in people with additional risk factors.[29]

Pregnancy

In pregnant women, ACE inhibitors taken during all the trimesters have been reported to cause

intrauterine growth retardation, pulmonary hypoplasia, patent ductus arteriosus, and incomplete ossification of the skull.[19][30] Overall, about half of newborns exposed to ACE inhibitors are adversely affected, leading to birth defects.[31][21]

ACE inhibitors are

congenital malformations, particularly affecting the cardiovascular and central nervous systems.[32]

Overdose

Symptoms and Treatment: There are few reports of ACE inhibitor overdose in the literature. The most likely manifestations are hypotension, which may be severe,

renal impairment with metabolic acidosis. 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.[33]

Contraindications and precautions

The ACE inhibitors are contraindicated in people with:

ACE inhibitors should be used with caution in people with:

A combination of ACE inhibitor with other drugs may increase effects of these drugs, but also the risk of adverse effects.

potassium supplements
.

Potassium supplementation should be used with caution and under medical supervision owing to the hyperkalemic effect of ACE inhibitors.[36]

Concomitant use with

cyclooxygenase inhibitors tends to decrease ACE inhibitor's hypotensive effect.[37][21]

Mechanism of action

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.[38][39]

Renin–angiotensin–aldosterone system

Main article: Renin–angiotensin system
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.

Renin activates a circulating liver derived

vasoconstrictor.[41]

Effects

ACE inhibitors block the conversion of angiotensin I (ATI) to angiotensin II (ATII).[42] They thereby lower arteriolar resistance and increase venous capacity; decrease cardiac output, cardiac index, stroke work, and volume; lower resistance in blood vessels in the kidneys; and lead to increased natriuresis (excretion of sodium in the urine). Renin increases in concentration in the blood as a result of negative feedback of conversion of ATI to ATII. ATI increases for the same reason; ATII and aldosterone decrease. Bradykinin increases because of less inactivation by ACE.

Under normal conditions, angiotensin II has these effects:

  • 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
    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][43] which prevents aldosterone release from the adrenal cortex.[43] This allows the kidney to excrete sodium ions along with obligate water, and retain potassium ions. This decreases blood volume, leading to decreased blood pressure.[43]

renal failure
.

ACE inhibitors have been shown to be effective for indications other than hypertension[45] even in patients with normal blood pressure.[46] 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,[47] 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.).

ACE inhibitors have also been shown to cause a central enhancement of parasympathetic nervous system activity in healthy volunteers and patients with heart failure.[48][49] This action may reduce the prevalence of malignant cardiac arrhythmias, and the reduction in sudden death reported in large clinical trials.[50] 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

The ACE inhibitor enalapril has also been shown to reduce cardiac cachexia in patients with chronic heart failure.[51] Cachexia is a poor prognostic sign in patients with chronic heart failure.[52] ACE inhibitors are under early investigation for the treatment of frailty and muscle wasting (sarcopenia) in elderly patients without heart failure.[53]

Examples

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).[54][55]

ACE inhibitors are easily identifiable by their common suffix, '-pril'. ACE inhibitors can be divided into three groups based on their molecular structure of the

carboxyl) to the active center of ACE:[56]

Sulfhydryl-containing agents

These agents appear to show

skin eruptions.[56]

Dicarboxylate-containing agents

This is the largest group, including:

Phosphonate-containing agents

Naturally occurring

  • A comprehensive resource on anti-hypertensive peptides is available in form of a database. It contains around 1700 unique antihypertensive peptides[57]
  • Arfalasin (HOE 409) is angiotensin antagonist.[58]

Dairy products

Comparative information

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 the only ACE inhibitor capable of passing through the blood–brain barrier, although the significance of this characteristic has not been shown to have any positive clinical effects.

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.[63]

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.[64]

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.[65]

Equivalent doses in hypertension

The ACE inhibitors have different strengths with different starting dosages. Dosage should be adjusted according to the clinical response.[66][67][68]

ACE inhibitors dosages for hypertension
Dosage
Note:
tid = three times a day, d = daily
Drug dosages from Drug Lookup, Epocrates Online
.
Name Equivalent daily dose Start Usual Maximum
Benazepril 10 mg 10 mg 20–40 mg 80 mg
Captopril 50 mg (25 mg bid) 12.5–25 mg bid-tid 25–50 mg bid-tid 150 mg/d
Enalapril 5 mg 5 mg 10–40 mg 40 mg
Fosinopril 10 mg 10 mg 20–40 mg 80 mg
Lisinopril 10 mg 10 mg 10–40 mg 80 mg
Moexipril 7.5 mg 7.5 mg 7.5–30 mg 30 mg
Perindopril 4 mg 4 mg 4–8 mg 16 mg
Quinapril 10 mg 10 mg 20–80 mg 80 mg
Ramipril 2.5 mg 2.5 mg 2.5–20 mg 20 mg
Trandolapril 2 mg 1 mg 2–4 mg 8 mg

Combination with angiotensin II receptor antagonists

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.

The combination therapy of angiotensin II receptor antagonists with ACE inhibitors may be superior to either agent alone. This combination may increase levels of bradykinin while blocking the generation of angiotensin II and its activity at the AT1 receptor. This 'dual blockade' may be more effective than using an ACE inhibitor alone, because angiotensin II can be generated via non-ACE-dependent pathways. Preliminary studies suggest this combination of pharmacologic agents may be advantageous in the treatment of

nephropathy.[70][71] However, the more recent ONTARGET study showed no benefit of combining the agents and more adverse events.[72] While statistically significant results have been obtained for its role in treating hypertension, clinical significance may be lacking.[73] There are warnings about the combination of ACE inhibitors with ARBs.[74]

Patients with heart failure may benefit from the combination in terms of reducing

morbidity and ventricular remodeling.[75][76]

The most compelling evidence for the treatment of nephropathy has been found: This combination therapy partially reversed the proteinuria and also exhibited a renoprotective effect in patients with diabetic nephropathy,[70] and pediatric IgA nephropathy.[77]

History

Main article:
ACE inhibitors drug design

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.[81]

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.[82] In 1970, Ng and Vane, using BPF provided by Ferreira, showed the conversion is inhibited during its passage through the pulmonary circulation.[83]

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 analogues 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.[84]

Captopril was approved by the United States Food and Drug Administration in 1981.[85] The first nonsulfhydryl-containing ACE inhibitor, enalapril, was approved four years later.[86] At least 8 other ACE inhibitors have since been marketed.[87]

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.[88] 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.[89] Since the first lactotripeptides discovery, more than 20 human clinical trials have been conducted in many different countries.[61]

Note

  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.[43]

See also

References

  1. ^
    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).
  2. ISBN 978-1-4160-6231-8
    . Angiotensin-converting enzyme inhibitors ACE inhibitors have been demonstrated to reduce sudden cardiac death in some studies of persons with CHF.24,56
  3. ^
    S2CID 263490929
    . ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II, thereby producing vasodilation and lowering BP. Because the hydrolysis of bradykinin is also inhibited by these drugs, cough (7% to 12%) can occur.
  4. 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. 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. ^ "Type 2 diabetes in adults: management". www.nice.org.uk. National Institute for Health and Care Excellence (NICE). May 2017. Retrieved October 25, 2018.
  9. PMID 28104622
    .
  10. PMID 22786934
    .
  11. PMID 22786934
    .
  12. ^ "Psychogenic polydipsia – Management – Emerging treatments". British Medical Journal. May 5, 2016. Archived from the original on August 27, 2021. Retrieved October 28, 2016.
  13. S2CID 27207760
    .
  14. PMID 9509495
    .
  15. S2CID 39998447
    .
  16. PMID 12631334
    .
  17. S2CID 24893488
    .
  18. ^
    ISBN 0-9757919-2-3.[page needed
    ]
  19. ^
    S2CID 207488068
    .
  20. ^
    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.
  21. ^
    S2CID 263490929
    . Angioedema (0.7%) can also occur via pathobiology that remains obscure, and its occurrence can be life-threatening. ...their efficacy is reduced by dietary or other sources of sodium, and renal function may be further threatened if given with NSAIDs.
  22. S2CID 37558579
    .
  23. PMID 10979053
    .
  24. PMID 11265121
    .
  25. S2CID 46779755
    .
  26. PMID 25058867
    .
  27. S2CID 13866090
    .
  28. PMID 23485983
    .
  29. ^ FDA Prescribing information, http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20%28General%20Monographs-%20A%29/ACE%20INHIBITORS.html
  30. PMID 9520613
    .
  31. PMID 22753220
    .
  32. PMID 16760444
    .
  33. ^ "ACE Inhibitors". RxMed.com. Retrieved 2018-09-20.
  34. ^ "ACE I". cvpharmacology.
  35. ^ a b "ACEI contraindications". Open Anesthesia.
  36. PMID 11044229
    .
  37. S2CID 220688413
    . Coadministration of nonsteroidal anti-inflammatory drugs (NSAIDs [cyclooxygenase inhibitors]) can reduce the hypotensive effects of ACE inhibitors. ACE inhibitors can inhibit 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.
  38. PMID 16959581
    .
  39. S2CID 829514
    .
  40. ^ Human Physiology, Silverthorn (Pearson Benjamin Cummings 2004)[page needed]
  41. PMID 10619573
    .
  42. ^ Ogbru O. "ACE Inhibitors (Angiotensin Converting Enzyme Inhibitors)". MedicineNet.com. MedicineNet, Inc. Archived from the original on 26 March 2010. Retrieved 2010-03-20.
  43. ^
    ISBN 978-0-323-03961-1
    . Despite the lack of long-term suppression in plasma angiotensin II levels, they maintain their BP-lowering effect without the development of tolerance. Importantly, ACE inhibitors do not interfere with cognitive function or cardiovascular reflexes.
  44. PMID 10780101
    .
  45. PMID 12182524
    . Retrieved 20 February 2019.
  46. S2CID 12855742
    .
  47. PMID 15459003
    .
  48. PMID 2987341
    .
  49. PMID 11785658.[verification needed
    ]
  50. PMID 8436747
    .
  51. S2CID 31118266
    .
  52. S2CID 27285694
    .
  53. PMID 21475695
    .
  54. ^ "Angiotensin-Converting Enzyme (ACE) Inhibitors". Cleveland Clinic. Retrieved 2022-11-05.
  55. ^ "Lisinopril". go.drugbank.com. Retrieved 2022-11-05.
  56. ^
    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.
  57. PMID 25392419
    .
  58. ^ "US4013791A - Peptides having an antihypertensive effect". Google Patents. 1975-12-03. Retrieved 2020-03-21.
  59. PMID 15051858
    .
  60. S2CID 18513821
    .
  61. ^
    PMID 19061526
    .
  62. PMID 12957917
    .
  63. ^ "Debate: Do ACE Inhibitors Have Unique Properties, Beyond Their Antihypertensive Effect?"
  64. S2CID 5770772
    .
  65. PMID 22511654
    .
  66. ^ What are the dose comparisons of all ACE inhibitors used in hypertension? Archived 2015-04-02 at the Wayback Machine TripAnswers, Trip, May 25, 2007. Accessed 2009-11-21
  67. ^ Common Medication Conversions (Equivalents): Ace Inhibitors Archived 2015-03-17 at the Wayback Machine. GlobalRPh.com. Accessed 2009-11-22.
  68. ^ Treating High Blood Pressure and Heart Disease: the ACE Inhibitors. Consumer Reports Health Best Buy Drugs. June 2009.
  69. PMID 14975535
    .
  70. ^
    PMID 15853685
    .
  71. PMID 16105846
    .
  72. PMID 18378520. Archived
    (PDF) from the original on 2022-10-09.
  73. S2CID 25509704
    .
  74. ^ Shelley Wood (11 April 2014). "EMA: Don't Combine ARBs, ACE Inhibitors, and Direct Renin Inhibitors". www.medscape.com.
  75. S2CID 40739892
    .
  76. PMID 15967846
    .
  77. PMID 16047643
    .
  78. PMID 23257181
    .
  79. LCCN 2012940771
    .
  80. PMID 14302350
    .
  81. S2CID 4289093
    .
  82. S2CID 4174541
    .
  83. S2CID 4200012
    .
  84. S2CID 30766421
    .
  85. ^ "Drugs@FDA: FDA-Approved Drugs". www.accessdata.fda.gov. Retrieved 2023-09-29.
  86. ^ "Drugs@FDA: FDA-Approved Drugs". www.accessdata.fda.gov. Retrieved 2023-09-29.
  87. PMID 12182524
    .
  88. PMID 8901799
    .
  89. PMID 7673515
    .

External links

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