ACE inhibitors

ACE inhibitors or angiotensin-converting enzyme inhibitors, are a group of pharmaceuticals that are used primarily in treatment of hypertension and congestive heart failure.]
mechanism of action

Primarily angiotensin converting enzyme inhibitors reduce the activity of the renin-angiotensin-aldosterone system.

The renin-angiotensin-aldosterone system (RAAS)

Renin-angiotensin-aldosterone system

One mechanism for maintaining the blood pressure is the release of a protein called renin from cells in the kidney (specifically: the juxtaglomerular apparatus). This produces another protein called angiotensin which signals the adrenal gland to produce a hormone called aldosterone. This system is activated in response to a fall in blood pressure (hypotension) as well as markers of problems with the salt-water balance of the body, such as decreased sodium concentration in a part of the kidney known as the distal tubule, decreased blood volume and stimulation of the kidney by the sympathetic nervous system . In such a situation, the kidneys release renin which acts as an enzyme and cuts off all but the first 10 amino-acid residues of angiotensinogen (a protein made in the liver, and which circulates in the blood). These 10 residues are then known as angiotensin I. Angiotensin I is then converted to angiotensin II by angiotensin converting enzyme (ACE) which removes a further 2 residues and is found in the pulmonary circulation as well as in the endothelium of many blood vessels. The system in general aims to increase blood pressure by increasing the amount of salt and water the body retains, although angiotensin is also very good at causing the blood vessels to tighten (a potent vasoconstrictor).

Effects

ACE inhibitors block the conversion of angiotensin I to angiotensin II. They therefore 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).

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
stimulation of 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.
stimulation of the posterior pituitary to release 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. 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.).

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

The ACE inhibitor enalapril has also been shown to reduce cardiac cachexia in patients with chronic heart failure. Cachexia is a poor prognostic sign in patients with chronic heart failure. ACE-inhibitors are now used to reverse frailty and muscle wasting in elderly patients without heart failure.[citation needed]

Adverse effects

Common adverse drug reactions include: hypotension, cough, hyperkalemia, headache, dizziness, fatigue, nausea and renal impairment. There is also some evidence to suggest that ACE inhibitors might increase inflammation-related pain.]

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.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.[]

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.

In pregnant women, ACE inhibitors taken during the first trimester have been reported to cause major 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.[]
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Contraindications and precautions

The ACE inhibitors are contraindicated in patients with:
Previous angioedema associated with ACE inhibitor therapy
Renal artery stenosis (bilateral, or unilateral with a solitary functioning kidney)
Hypersensitivity to ACE inhibitors

ACE inhibitors should be used with caution in patients with:
Impaired renal function
Aortic valve stenosis or cardiac outflow obstruction
Hypovolemia or dehydration
Hemodialysis with high flux polyacrylonitrile membranes

ACE inhibitors are ADEC Pregnancy category D, and should be avoided in women who are likely to become pregnant.[8] In the U.S., ACE inhibitors are required to be labeled 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.]

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