Jump to content

ACE inhibitor: Difference between revisions

From Wikipedia, the free encyclopedia
Browse history interactively
← Previous editNext edit →
Content deleted Content added
VisualWikitext
m →‎Blood Brain Barrier Crossing ACE Inhibitors & Dementia Reduction: retitle Blood Brain Barrier Crossing ACE Inhibitors & Dementia, Blood Pressure, RAAS
Addition of reference to Lactotripeptides and addition to history
Line 67: Line 67:
===Naturally occurring===
===Naturally occurring===


[[Casokinin]]s and [[lactokinin]]s are breakdown products of [[casein]] and [[whey]] that occur naturally after ingestion of [[milk]] products, especially [[cultured milk]]. Their role in blood pressure control is uncertain.<ref name="FitzGerald2004">FitzGerald RJ, Murray BA, Walsh DJ. [http://jn.nutrition.org/cgi/content/full/134/4/980S Hypotensive peptides from milk proteins.] J Nutr 2004;134:980S-8S. PMID 15051858.</ref> The [[tripeptide]]s Val-Pro-Pro and Ile-Pro-Pro produced by the [[probiotic]] ''[[Lactobacillus helveticus]]'' have been shown to have ACE-inhibiting and antihypertensive functions.<ref>Aihara K, Kajimoto O, Hirata H, Takahashi R, Nakamura Y. [http://www.jacn.org/cgi/content/full/24/4/257 Effect of powdered fermented milk with Lactobacillus helveticus on subjects with high-normal blood pressure or mild hypertension.] J Am Coll Nutr. 2005 Aug;24(4):257-65 PMID 16093403.</ref>
* [[Casokinin]]s and [[lactokinin]]s are breakdown products of [[casein]] and [[whey]] that occur naturally after ingestion of [[milk]] products, especially [[cultured milk]]. Their role in blood pressure control is uncertain.<ref name="FitzGerald2004">FitzGerald RJ, Murray BA, Walsh DJ. [http://jn.nutrition.org/cgi/content/full/134/4/980S Hypotensive peptides from milk proteins.] J Nutr 2004;134:980S-8S. PMID 15051858.</ref>
* 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.<ref>Aihara K, Kajimoto O, Hirata H, Takahashi R, Nakamura Y. [http://www.jacn.org/cgi/content/full/24/4/257 Effect of powdered fermented milk with Lactobacillus helveticus on subjects with high-normal blood pressure or mild hypertension.] J Am Coll Nutr. 2005 Aug;24(4):257-65 PMID 16093403.</ref> <ref>Boelsma E; Kloek J [http://www.ncbi.nlm.nih.gov/pubmed/19061526 Lactotripeptides and antihypertensive effects: a critical review.] 2009 Mar;101(6):776-86.</ref>


==Comparative information==
==Comparative information==
Line 117: Line 118:


Captopril was approved by the United States [[Food and Drug Administration]] in 1981. The first non-sulfhydryl-containing (ACE) inhibitor enalapril was marketed two years later. Since then, at least twelve other ACE inhibitors have been marketed.
Captopril was approved by the United States [[Food and Drug Administration]] in 1981. The first non-sulfhydryl-containing (ACE) inhibitor enalapril was marketed two years later. Since then, at least twelve other ACE inhibitors have been marketed.


In 1991, Japanese scientists created the first ever milk-based ACE inhibitor in the form of a fermented milk drink, using specific cultures to liberate the IPP from the dairy protein. Interestingly, Val-Pro-Pro 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]]. Shortly after this, in 1996, the first human study confirmed the blood pressure lowering effect of IPP in fermented milk.<ref>Y. Hata, et al., "A Placebo-Controlled Study of the Effect of Sour Milk on Blood Pressure in Hypertensive Subjects," Am. J. Clin. Nutr. 64, 767-771 (1996)</ref> Although twice the amount of VPP is needed to achieve the same ACE inhibiting activity as the originally discovered IPP, it is assumed that VPP also adds to the total blood pressure lowering effect. <ref>Y. Nakamur: [http://www.ncbi.nlm.nih.gov/pubmed/7673515?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Purification and Characterization of Angiotensin I-Converting Enzyme Inhibitors from Sour Milk.] J. Dairy Sci. 78, 777-783 (1995). </ref> <ref> Nakamura, et al.: [http://www.ncbi.nlm.nih.gov/pubmed/7673515?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Antihypertensive Effect of Sour Milk and Peptides Isolated from it that are Inhibitors to Angiotensin I-Converting Enzyme.] J. Dairy Sci. 78, 1253-1257 (1995).</ref>
Since the first [[lactotripeptides]] discovery, more than 20 human clinical trials have been conducted in many different countries.<ref name="ncbi.nlm.nih.gov">Boelsma E; Kloek J [http://www.ncbi.nlm.nih.gov/pubmed/19061526 Lactotripeptides and antihypertensive effects: a critical review.] 2009 Mar;101(6):776-86.</ref>


== See also ==
== See also ==

Revision as of 10:19, 20 October 2009

Captopril, the first ACE inhibitor

ACE inhibitors, or inhibitors of angiotensin-converting enzyme (ACE), are a group of pharmaceuticals that are used primarily in treatment of hypertension and congestive heart failure, in some cases as the drugs of first choice.

Clinical use

The renin-angiotensin-aldosterone system (RAAS)

Main article: Renin-angiotensin system

This system is activated in response to hypotension, decreased sodium concentration in the distal tubule, decreased blood volume and renal sympathetic nerve stimulation. In such a situation, the kidneys release renin which cleaves the liver-derived angiotensinogen into angiotensin I. Angiotensin I is then converted to angiotensin II via the ACE in the pulmonary circulation as well as in the endothelium of blood vessels in many parts of the body.[1] The system in general aims to increase blood pressure. ACE inhibitors causes a central enhancement of parasympathetic activity, in healthy volunteers and patients with heart failure.[2][3] This action may reduce the prevalence of malignant cardiac arrhythmias, and the reduction in sudden death reported in large clinical trials. Enalapril has also been shown to reduce cardiac cachexia in patients chronic heart failure.[4] Cachexia is a poor prognostic sign in patients with chronic heart failure.[5] ACE-inhibitors are now used to reverse frailty and muscle wasting in elderly patients without heart failure.

Effects

ACE inhibitors lower arteriolar resistance and increase venous capacity; increase cardiac output and cardiac index, stroke work and volume, lower renovascular resistance, and lead to increased natriuresis (excretion of sodium in the urine). ACE inhibitors therefore block the conversion of angiotensin I to angiotensin II.

Normally, angiotensin II will have the following effects:

  • vasoconstriction (narrowing of blood vessels), which may lead to increased blood pressure and hypertension
– constriction of the efferent arterioles of the kidney, leading to increased perfusion pressure in the glomeruli.
  • Ventricular remodeling of the heart, which may lead to ventricular hypertrophy and CHF
  • stimulate the adrenal cortex to release aldosterone, a hormone that acts on kidney tubules to retain sodium and chloride ions and excrete potassium. Sodium is a "water-holding" molecule, so water is also retained, which leads to increased blood volume, hence an increase in blood pressure.
  • stimulate the posterior pituitary into releasing vasopressin (also known as anti-diuretic hormone (ADH)) which also acts on the kidneys to increase water retention.
  • decrease renal protein kinase C

With ACE inhibitor use, the effects of angiotensin II are prevented, leading to decreased blood pressure.

Epidemiological and clinical studies have shown that ACE inhibitors reduce the progress of diabetic nephropathy independently from their blood pressure-lowering effect[6]. This action of ACE inhibitors is utilised in the prevention of diabetic renal failure.

ACE inhibitors have been shown to be effective for indications other than hypertension even in patients with normal blood pressure. The use of a maximum dose of ACE inhibitors in such patients (including for prevention of diabetic nephropathy, congestive heart failure, prophylaxis of cardiovascular events) is justified because it improves clinical outcomes, independent 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).

Adverse effects

Common adverse drug reactions include: hypotension, cough, hyperkalemia, headache, dizziness, fatigue, nausea and renal impairment.[7]

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 remains disputed by some authors.[8] Patients who experience this cough are often switched to angiotensin II receptor antagonists.

Rash and taste disturbances, infrequent with most ACE inhibitors, are more prevalent in captopril and is attributed to its sulfhydryl moiety. This has led to decreased use of captopril in clinical setting, although it is still used in scintigraphy of the kidney.

Renal impairment is a significant adverse effect of all ACE inhibitors. The reason for this is still unknown. Some suggest that it is associated with their effect on angiotensin II-mediated homeostatic functions such as renal blood flow. Renal blood flow may be affected by angiotensin II because it vasoconstricts the efferent arterioles of the glomeruli of the kidney, thereby increasing glomerular filtration rate (GFR). Hence, by reducing angiotensin II levels, ACE inhibitors may reduce GFR, a marker of renal function. Specifically, ACE inhibitors can induce or exacerbate renal impairment in patients with renal artery stenosis. This is especially a problem if the patient is also concomitantly taking an NSAID and a diuretic. When the three drugs are taken together, there is a very high risk of developing renal failure.[9]

ACE inhibitors may cause hyperkalemia. Suppression of angiotensin II leads to a decrease in aldosterone levels. Since aldosterone is responsible for increasing the excretion of potassium, ACE inhibitors ultimately cause retention of potassium.

A severe allergic reaction can occur that rarely can affect the bowel wall and secondarily cause abdominal pain. This "anaphylactic" reaction is very rare as well.

Some patients develop angioedema due to increased bradykinin levels. There appears to be a genetic predisposition towards this adverse effect in patients who degrade bradykinin more slowly than average.[10]

Examples

ACE inhibitors can be divided into three groups based on their molecular structure:

Sulfhydryl-containing agents

Dicarboxylate-containing agents

This is the largest group, including:

Phosphonate-containing agents

  • Fosinopril (Monopril) is the only member of this group

Naturally occurring

Comparative information

Comparatively, all ACE inhibitors have similar antihypertensive efficacy when equivalent doses are administered. The main point-of-difference lies with captopril, the first ACE inhibitor, which has a shorter duration of action and increased incidence of certain adverse effects.

Certain agents in the ACE inhibitor class have been proven, in large clinical studies, to reduce mortality post-myocardial infarction, prevent development of heart failure, etc. The ACE inhibitor most prominently recognized for these qualities is ramipril (Altace). Because ramipril has been shown to reduce mortality rates even among patient groups not suffering from hypertension, there are some (mostly drug reps) who believe that ramipril's benefits may extend beyond those of the general abilities it holds in common with other members of the ACE inhibitor class.[citation needed]

Blood Brain Barrier Crossing ACE Inhibitors & Dementia, Blood Pressure, RAAS

Contraindications and precautions

The ACE inhibitors are contraindicated in patients with:

ACE inhibitors should be used with caution in patients with:

ACE inhibitors are ADEC Pregnancy category D, and should be avoided in women who are likely to become pregnant.[7] In the U.S., ACE inhibitors are required to be labelled with a "black box" warning concerning the risk of birth defects when taking during the second and third trimester. It has also been found that use of ACE inhibitors in the first trimester is also associated with a risk of major congenital malformations, particularly affecting the cardiovascular and central nervous systems.[14]

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

Angiotensin II receptor antagonists

ACE inhibitors share many common characteristics with another class of cardiovascular drugs called 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 there are other conversion pathways, and 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.

Use in combination

While counterintuitive at first glance, 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 that this combination of pharmacologic agents may be advantageous in the treatment of essential hypertension, chronic heart failure, and nephropathy.[15][16] However, more studies are needed to confirm these highly preliminary results. While statistically significant results have been obtained for its role in treating hypertension, clinical significance may be lacking.[17]

Patients with heart failure may benefit from the combination in terms of reducing morbidity and ventricular remodeling.[18][19]

The most compelling evidence has been found for the treatment of nephropathy: this combination therapy partially reversed the proteinuria and also exhibited a renoprotective effect in patients afflicted with diabetic nephropathy,[15] and pediatric IgA nephropathy.[20]

History

Main article: ACE inhibitors drug design

The first step in the development of (ACE) inhibitors was the discovery of angiotensin converting enzyme (ACE) in plasma by Leonard T. Skeggs and his colleagues in 1956. Brazilian scientist Sergio Ferreira reported in 1965 of a 'bradykinin potentiating factor (BPFs) present in the venom of bothrops jararaca, a South American pit viper.( Brit J Pharmacol & Chemother 1965). Dr SH Ferreira then proceeded to John Vanes laboratory as a Post-Doc with his already isolated BPFs. 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 that the plasma (ACE) was too slow to account for the conversion of angiotensin I to angiotensin II in vivo. Subsequent investigation showed that rapid conversion occurs during its passage through the pulmonary circulation.[21]

Bradykinin is rapidly inactivated in the circulating blood and it disappears completely in a single passage through the pulmonary circulation. Angiotensin I also disappears in the pulmonary circulation due to 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.[22] In 1970, Ng and Vane using bradykinin potentiating factor (BPF) provided by Sérgio Henrique Ferreira showed that the conversion of angiotensin I to angiotensin II was inhibited during its passage through the pulmonary circulation.[23]

Bradykinin potentiating factor (BPF) is derived from the venom of the pit viper (Bothrops jararaca). It is a family of peptides and its 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, due to 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.

Captopril was approved by the United States Food and Drug Administration in 1981. The first non-sulfhydryl-containing (ACE) inhibitor enalapril was marketed two years later. Since then, at least twelve other ACE inhibitors have been marketed.


In 1991, Japanese scientists created the first ever milk-based ACE inhibitor in the form of a fermented milk drink, using specific cultures to liberate the IPP from the dairy protein. Interestingly, Val-Pro-Pro 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. Shortly after this, in 1996, the first human study confirmed the blood pressure lowering effect of IPP in fermented milk.[24] Although twice the amount of VPP is needed to achieve the same ACE inhibiting activity as the originally discovered IPP, it is assumed that VPP also adds to the total blood pressure lowering effect. [25] [26] Since the first lactotripeptides discovery, more than 20 human clinical trials have been conducted in many different countries.[27]

See also

References

  1. ^ Human Physiology, Silverthorn (Pearson Benjamin Cummings 2004)
  2. ^ Ajayi, AA (1985). "Acute and Chronic Effects of the Converting Enzyme Inhibitors Enalapril and Lisinopril on Reflex Control of Heart Rate in Normotensive Man". J hypertension. 3: 47–53. doi:10.1097/00004872-198502000-00008. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  3. ^ Adigun, AQ (2001). Cell Mol Biol. 47: 1063–7. {{cite journal}}: Missing or empty |title= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  4. ^ Adigun, AQ (2001). "The effects of enalapril-digoxin-diuretic combination therapy on nutritional and anthropometric indices in chronic congestive heart failure: preliminary findings in cardiac cachexia". Eur J Heart Fail. 3: 359–63. doi:10.1016/S1388-9842(00)00146-X. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  5. ^ Anker, S (1997). "Wasting as independent risk factor for mortality in chronic heart failure". Lancet. 349: 1050–3. doi:10.1016/S0140-6736(96)07015-8. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  6. ^ Hoogwerf BJ, Young JB.Cleve Clin J Med. 2000 Apr;67(4):287-93.The HOPE study - effect of Rampipril on cardiovascular risk in those with know atherosclerosis or diabetes http://www.ncbi.nlm.nih.gov/pubmed/10780101
  7. ^ a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3.
  8. ^ Okumura H, Nishimura E, Kariya S, et al. Angiotensin-converting enzyme (ACE) 阻害薬誘発性の咳嗽発現とACE遺伝子型,血漿中ブラジキニン,サブスタンスP及びACE阻害薬濃度との関連性 [No relation between angiotensin-converting enzyme (ACE) inhibitor-induced cough and ACE gene polymorphism, plasma bradykinin, substance P and ACE inhibitor concentration in Japanese patients]. Yakugaku Zasshi 2001;121(3):253-7. Japanese. PMID 11265121
  9. ^ Thomas MC. Diuretics, ACE inhibitors and NSAIDs - the triple whammy. Med J Aust 2000;172(4):184–185. PMID 10772593
  10. ^ Molinaro G, Cugno M, Perez M, et al. Angiotensin-converting enzyme inhibitor-associated angioedema is characterized by a slower degradation of des-arginine(9)-bradykinin. J Pharmacol Exp Ther 2002;303:232-7. PMID 12235256.
  11. ^ FitzGerald RJ, Murray BA, Walsh DJ. Hypotensive peptides from milk proteins. J Nutr 2004;134:980S-8S. PMID 15051858.
  12. ^ Aihara K, Kajimoto O, Hirata H, Takahashi R, Nakamura Y. Effect of powdered fermented milk with Lactobacillus helveticus on subjects with high-normal blood pressure or mild hypertension. J Am Coll Nutr. 2005 Aug;24(4):257-65 PMID 16093403.
  13. ^ Boelsma E; Kloek J Lactotripeptides and antihypertensive effects: a critical review. 2009 Mar;101(6):776-86.
  14. ^ Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006;354(23):2443-51. PMID 16760444
  15. ^ a b Luno J, Praga M, de Vinuesa SG. The reno-protective effect of the dual blockade of the renin angiotensin system (RAS). Curr Pharm Des 2005;11(10):1291-300. PMID 15853685
  16. ^ van de Wal RM, van Veldhuisen DJ, van Gilst WH, Voors AA. Addition of an angiotensin receptor blocker to full-dose ACE-inhibition: controversial or common sense? Eur Heart J 2005;26(22):2361-7. PMID 16105846
  17. ^ Finnegan PM, Gleason BL. Combination ACE inhibitors and angiotensin II receptor blockers for hypertension. Ann Pharmacother 2003;37(6):886-9. PMID 12773079
  18. ^ Krum H, Carson P, Farsang C, et al. Effect of valsartan added to background ACE inhibitor therapy in patients with heart failure: results from Val-HeFT. Eur J Heart Fail 2004;6(7):937-45. PMID 15556056
  19. ^ Solomon SD, Skali H, Anavekar NS, et al. Changes in ventricular size and function in patients treated with valsartan, captopril, or both after myocardial infarction. Circulation 2005;111(25):3411-9. PMID 15967846
  20. ^ Yang Y, Ohta K, Shimizu M, et al. Treatment with low-dose angiotensin-converting enzyme inhibitor (ACEI) plus angiotensin II receptor blocker (ARB) in pediatric patients with IgA nephropathy. Clin Nephrol 2005;64(1):35-40. PMID 16047643
  21. ^ K.K.F.Ng and J.R.Vane: Conversion of angiotensin I to angiotensin II. Nature 1967, 216, 762-766
  22. ^ K.K.F.Ng and J.R.Vane: Fate of angiotensin I in the circulation. Nature 1968, 218, 144-150.
  23. ^ K.K.F.Ng and J.R.Vane: Some properties of angiotensin converting enzyme in the lung in vivo. Nature 1970, 225, 1142-1144.
  24. ^ Y. Hata, et al., "A Placebo-Controlled Study of the Effect of Sour Milk on Blood Pressure in Hypertensive Subjects," Am. J. Clin. Nutr. 64, 767-771 (1996)
  25. ^ Y. Nakamur: Purification and Characterization of Angiotensin I-Converting Enzyme Inhibitors from Sour Milk. J. Dairy Sci. 78, 777-783 (1995).
  26. ^ Nakamura, et al.: Antihypertensive Effect of Sour Milk and Peptides Isolated from it that are Inhibitors to Angiotensin I-Converting Enzyme. J. Dairy Sci. 78, 1253-1257 (1995).
  27. ^ Boelsma E; Kloek J Lactotripeptides and antihypertensive effects: a critical review. 2009 Mar;101(6):776-86.

Template:Link FA Template:Link FA

Retrieved from "https://en.wikipedia.org/w/index.php?title=ACE_inhibitor&oldid=320977364"