Angiotensins are peptides (substances smaller than proteins) that act as vasoconstricting agents (causing blood vessels to narrow). Narrowing the diameter of the blood vessels sends up the blood pressure. ACE (angiotensin converting enzyme) converts angiotensin to its activated form (called angiotensin II) enabling it to function. The ACE inhibitors are drugs that inhibit the formation of angiotensin II and are used for blood pressure control and congestive heart failure.The final mechanism of action is the relaxation of small peripheral vessels known as arterioles.
The Renin-Angiotensin-Aldosterone / Vasopressin System
This system is designed by nature to be activated in response to hypotension such as occurs with:
- salt deficiency
- loss of blood volume (as in acute bleeding)
- renal sympathetic nerve stimulation (an artificial condition induced in lab animals)
In these conditions the kidneys release the hormone Renin which changes another hormone Angiotensin I to Angiotensin II by activating Angiotensin Converting Enzyme (ACE). This conversion occurs in the blood as it circulates through the lungs. Angiotensin II then increases blood pressure by constricting the peripheral arterioles and to a lesser extent constricting the venous system. All of this is possible because of the presence of smooth muscle in the walls of the vascular system. Blocking ACE also increases the rate of metabolism.
ACE inhibitors block Angiotensin Converting Enzyme and thus slow the production of Angiotensin II, which in turn lowers arteriolar resistance and increases venous volume. the following effects derive from these conditions:
- an increase in cardiac output (by increasing the stroke volume of each contraction of the heart)
- lower resistance in the vessels of the kidneys – which leads to
- an increased excretion of sodium in the urine
Angiotensin II has the following effects:
- narrowing of blood vessels, which may lead to increased blood pressure and hypertension
- constriction of the exiting arterioles of the kidney causing increased perfusion pressure in the glomeruli.
- pressure on the left ventrical of the heart (an effect of high blood pressure) which may lead to ventricular hypertrophy and congestive heart failure
- 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 edema, increased blood volume and thus an increase in blood pressure.
- stimulation of the posterior pituitary to release vasopressin (aka anti-diuretic hormone (ADH) which also acts on the kidneys to increase water retention.
Inhibition of this system thus lowers blood pressure. Studies have shown that ACE inhibitors reduce the progress of diabetic nephropathy independently from blood pressure-lowering effect. This ACE inhibitors are used to help prevent 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) can be 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).
Thus the indications for ACE inhibitors include:
- Prevention of cardiovascular disorders
- Congestive heart failure
- Left ventricular dysfunction
- Prevention of nephropathy in diabetes mellitus
In several of these indications, ACE inhibitors are used first-line as several agents in the class have been clinically shown to be superior to other classes of drugs in the reduction of morbidity and mortality. ACE inhibitors are sometimes combined with diuretics (usually a thiazide) in the control of hypertension when an ACE inhibitor alone proves insufficient; and in chronic heart failure (usually furosemide) for improved symptomatic control. Thus there exists combination products combining an ACE inhibitor with a thiazide (usually hydrochlorothiazide) in a single tablet to allow easy administration by patients.
Common adverse drug reactions include: hypotension, cough, hyperkalemia, headache, dizziness, fatigue, nausea, renal impairment:
- A persistent dry cough is a relatively common adverse effect believed to be associated with the increases in bradykinin levels produced by ACE inhibitors. This occurs in about 8% of patients. Patients who experience this cough are often switched to angiotensin II receptor antagonists. Unlike the ACE inhibitors, they do not inhibit bradykinin metabolism or enhance prostaglandin synthesis. Angiotensin-II receptor antagonists are well tolerated. Cough occurs much less often with these agents than with angiotensin-converting enzyme inhibitors, and they do not adversely affect lipid profiles or cause rebound hypertension after discontinuation. Clinical trials indicate that angiotensin-II receptor antagonists are effective and safe in the treatment of hypertension. Their use in congestive heart failure and renal disease is under investigation.
- 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.
- Renal impairment is a significant adverse effect of all ACE inhibitors, and is associated with their effect on angiotensin II mediated homeostatic functions such as renal blood flow. Renal blood flow is affected by Angiotensin II because it vasoconstricts the efferent (exiting) arterioles of the glomeruli of the kidney, thereby increasing glomerular filtration rate (GFR). Hence, by reducing angiotensin II levels, ACE inhibitors 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 – the so-called “triple whammy” effect – such patients are at very high risk of developing renal failure.
- ACE inhibitors may cause hyperkalemia, because angiotensin II increases aldosterone release. Since aldosterone is responsible for increasing the excretion of potassium, ACE inhibitors ultimately cause retention of potassium.
- 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 slower than average.
Here is a list of ACE Inhibitors:
- Captopril (trade name Capoten) (the first ACE inhibitor)
- Enalapril (Vasotec/Renitec)
- Ramipril (Altace/Tritace/Ramace/Ramiwin)
- Quinapril (Accupril)
- Perindopril (Coversyl/Aceon)
- Lisinopril (Lisodur/Lopril/Novatec/Prinivil/Zestril)
- Benazepril (Lotensin)
- Fosinopril (Monopril)
Casokinins and lactokinins 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. The tripeptides Val-Pro-Pro and Ile-Pro-Pro produced by the probiotic Lactobacillus helveticus have been show to have ACE-inhibiting and antihypertensive functions.
ACE inhibitors have similar antihypertensive efficacy when equivalent doses are administered. The ACE inhibitors are contraindicated in patients with:
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)
ACE inhibitors should be used with caution in patients with:
- Impaired renal function
- Aortic valve stenosis or cardiac outflow obstruction
- Hypovolaemia or dehydration
- Hemodialysis with high flux polyacrylonitrile membranes
ACE inhibitors should be avoided in women who are likely to become pregnant.
Potassium supplementation should be used with caution and under medical supervision owing to the hyperkalemic effect of ACE inhibitors.
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. 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. 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. Patients with heart failure may benefit from the combination in terms of reducing morbidity and the incidence of congestive heart failure. The most compelling evidence has been found for the treatment of nephropathy. This combination therapy partially reversed the proteinuria and also exhibited a kidney protective effect in patients afflicted with diabetic nephropathy, and pediatric IgA nephropathy.