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Its also called as RAAS systemThereninangiotensin system(RAS) or thereninangiotensinaldosterone system(RAAS) is ahormone systemthat regulates blood pressureandfluid balance.The renin-angiotensin-aldosterone system (RAAS) plays an important role in regulatingblood volumeandsystemic vascular resistance, which together influencecardiac outputandarterial pressure.

Blood PressureRisesVasoconstriction

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A schematic portrayal of the homeostatic roles of the renin-angiotensin systemBlood VolumeRisesReninReleaseNa+ RetentionAldosteroneSecretionNa+ DepletionBlood VolumeFallsBlood PressureFallsAngiotensinFormation

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ANGIOTENSIN II

AlteredPeripheralResistanceAlteredRenalFunctionAlteredCardiovascularStructure

Rapid Pressor ResponseSlow Pressor ResponseVascular + CardiacHypertrophy + Remodeling

I. Direct vasoconstrictionII. Enhancement of peripheral noradrenergic neurotransmissionIII. Increased sympathetic discharge (CNS)IV. Catecholamine release from adrenal medullaI. Increased Na reabsorption by proximal tubuleII. Increased aldosterone releaseIII. Altered renal hemodynamics (vasoconstriction)+I. Stimulation of cell growthII. Hemodynamic changes A. Increased cardiac afterload + preload B. Increased vascular wall tension

AII has several very important functions:Constricts resistance vessels (viaAII [AT1] receptors) thereby increasingsystemic vascular resistanceandarterial pressureStimulates sodium transport (reabsorption) at several renal tubular sites, thereby increasing sodium and water retention by the bodyActs on the adrenal cortex to releasealdosterone, which in turn acts on the kidneys to increase sodium and fluid retention

Stimulates the release ofvasopressin(antidiuretic hormone, ADH) from the posterior pituitary, which increases fluid retention by the kidneysStimulates thirst centers within the brainFacilitatesnorepinephrinerelease fromsympathetic nerveendings and inhibits norepinephrine re-uptake by nerve endings, thereby enhancing sympathetic adrenergic functionStimulatescardiac hypertrophyand vascular hypertrophy

MECHANISM OF ACTION

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ACE inhibitors Captopril and other drugs in this class inhibit the converting enzyme peptidyl dipeptidase that hydrolyzes angiotensin I to angiotensin II and (under the name plasma kininase) inactivates bradykininEnalapril an oral prodrug that is converted by hydrolysis to a converting enzyme inhibitor, enalaprilat, with effects similar to those of captopril. Enalaprilat itself is available only for intravenous use, primarily for hypertensive emergencies. Lisinopril is a lysine derivative of enalaprilat. Benazepril, fosinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril are other long-acting members of the class. All are prodrugs, like enalapril, and are converted to the active agents by hydrolysis, primarily in the liver.

ACE inhibitors Angiotensin II inhibitors lower blood pressure principally by decreasing peripheral vascular resistance. Cardiac output and heart rate are not significantly changed. Unlike direct vasodilators, these agents do not result in reflex sympathetic activation and can be used safely in persons with ischemic heart disease. ACE inhibitors have a particularly useful role in treating patients with chronic kidney disease because they diminish proteinuria and stabilize renal function (even in the absence of lowering of blood pressure) but not in renal failure These benefits probably result from improved intrarenal hemodynamics, with decreased glomerular efferent arteriolar resistance and a resulting reduction of intraglomerular capillary pressure. ACE inhibitors have also proved to be extremely useful in the treatment of heart failure, and after myocardial infarction, and there is recent evidence that ACE inhibitors reduce the incidence of diabetes in patients with high cardiovascular risk.

Common Drugs

benazeprilcaptoprilenalaprilenalaprilatfosinoprillisinoprilperinodoprilquinaprilramipril

Adverse EffectsFirst-Dose HypotensionUsually occurs with initial dose.Worse in patients with severe hypertension, or are on diuretics, or are sodium or volume depleted.CoughPersistent, dry, irritating, nonproductive cough can develop with all ACE inhibitors. (Lehne, 2007, pg. 466)Due to rise in bradykinin which occurs due to inhibition of kinase II.Occurs in 5-10% of patients and is more common in women and the elderly.

Adverse Effects HyperkalemiaPotassium levels rise due to the inhibition of aldosterone, which causes potassium to be retained by the kidneys.Renal FailureCan cause renal insufficiency in people who have bilateral renal artery stenosis, because dropping the pressure in the renal arteries in these patients can cause glomerular filtration to fail.FetopathicIn the second and third trimesters a fetus can experience hypotension, hyperkalemia, skull hypoplasia, renal failure, and death.DysguesiaAngioedemaGranulocytopenia

CONTRAINDICATION

Drug InteractionsDiureticsCan cause an increased effect of medications especially with diuretics.Potassium sparing diureticsCause an increased risk of hyperkalemia due to the suppression of aldosterone.NSAIDSReduce antihypertensive effects of medication.

Indications For UseHypertension-used especially for malignant hypertension and hypertension secondary to renal arterial stenosis.Benefits of Using an ACE InhibitorDo not interfere with cardiovascular reflexesDo not interfere with patients who have asthma like beta-blockersDo not decrease potassium levels.Do not cause lethargy, weakness and sexual dysfunction.ACE inhibitors reduce the risk of cardiovascular mortality caused by hypertension.

Indications For UseHeart FailureBy decreasing arteriolar tone region blood flow to the heart improves. By decreasing afterload, cardiac output increases.Venous dilation increases causing a decrease in pulmonary congestion and peripheral edema.Dilates the vessels of the kidneys increasing renal flow and helps to excrete sodium and water. This helps to decrease edema and blood volume.Prevents pathologic changes in the heart that result from reducing the angiotensin II levels in the heart.

Indications For UseMyocardial Infarction (MI)Decreases the chance of heart failure after an MI.Should be given for 6 weeks post MI. If heart failure occurs it should be considered for permanent use.NephropathySlows renal disease of diabetic or nondiabetic originsDecreases glomerular filtration pressure.

Indications For UseType 2 DiabetesDecreases morbidity in high risk patients.Increased levels of angiotensin II have a correlation to type 2 diabetes.ACE inhibitors increase kinin levels, which increase production of prostaglandins and nitric oxide.Prostaglandins and nitric oxide improve muscular sensitivity to insulin. May preserve pancreatic function and prevent onset of diabetes especially with people who have hypertension.

QuestionsWhich of these patients would most likely be treated with an ACE inhibitor?A 38-year old women who has become hypertensive in the last trimester of her pregnancy.A 78-year old man who just had a heart attack and is in renal failure.A 60-year old man who is a diabetic and suffers from hypertension.A 72-year old female with a history of hypertenstion who comes to the ER in septic shock.

QuestionsWhich of these lab values would be a contraindication for taking an ACE inhibitor?Potassium 3.3Potassium 5.6BUN 10Creatinine 1.2