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CLINICAL USE Indications for ACE inhibitors include:
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 often combined with Diuretic s in the control of hypertension (usually a Thiazide ), when an ACE inhibitor alone proves insufficient; and in chronic heart failure (usually Furosemide ) for improved symptomatic control. Thus there exists, on the market, combination products combining an ACE inhibitor with a thiazide (usually Hydrochlorothiazide ) in a single tablet to allow easy administration by patients. MECHANISM OF ACTION They work by modulating the Renin-angiotensin-aldosterone (RAS or RAAS) system. By inhibiting angiotensin converting enzyme, ACE inhibitors significantly (but not completely) block the conversion of Angiotensin I to Angiotensin II . Decreased plasma angiotensin II levels result in a reduction of vasoconstriction and a reduction of Aldosterone secretion. The decreased Aldosterone secretion results in a subsequent decrease in sodium and water retention. As a complementary action, ACE inhibitors also reduce the degradation of Bradykinin . Thus ACE inhibitors work to lower blood pressure by decreasing the formation of a potent vasoconstrictor (angiotensin II), decreasing the secretion of a hormone that ultimately increases blood volume (aldosterone) and decreasing the degradation of a potent vasodilator (bradykinin). EFFECTS OF ACE INHIBITORS ACE inhibitors lower Arteriolar resistance and increase venous capacitance; increase Cardiac Output and Cardiac Index , stroke work and Volume , lower renovascular resistance, and lead to increased Natriuresis (excretion of Sodium in the Urine ). 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 patient suffering from the effects of rapidly decreasing their blood pressure (dizziness, fainting, ''etc''). ADVERSE EFFECTS Common adverse drug reactions include: Hypotension , Cough , Hyperkalaemia , Headache , Dizziness , Fatigue , Nausea , renal impairment (Rossi, 2004). A persistent dry cough is a relatively common adverse effect believed to be associated with the increases in Bradykinin levels produced by ACE inhibitors. Patients who experience this cough are often switched to Angiotensin II Receptor Antagonist s. 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, and is associated with their effect on angiotensin II-mediated Homeostatic functions such as renal bloodflow. 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 (Thomas, 2000). Some patients develop Angioedema due to increased bradykinin levels. There appears to be a genetic predisposition towards this side-effect in patients who degrade bradykinin slower than average (Molinaro 2002). EXAMPLES OF ACE INHIBITORS ACE inhibitors can be divided into three groups based on their molecular structure: Sulfhydryl-containing ACE inhibitors
Dicarboxylate-containing ACE inhibitors This is the largest group, including:
Phosphonate-containing ACE inhibitors
Naturally occurring Casokinin s and Lactokinin s are breakdown products of Casein and Whey that occur naturally after ingestion of Milk products, especially Sour Milk . Their role in blood pressure control is uncertain. (FitzGerald ''et al'', 2004) 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 (see the captopril article for more detail). Certain agents in the ACE inhibitor class have been proven, in large clinical studies, to reduce mortality post- Myocardial Infarct , prevent development of heart failure, ''etc''. While these effects are likely to be class-effects, good Evidence-based Medicine practice would direct the use of those agents with established clinical efficacy (see AMH 2004, or other sources for more details on specific agents). 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. (Rossi, 2005) Potassium supplementation should be used with caution and under medical supervision owing to the Hyperkalaemic effect of ACE inhibitors. ANGIOTENSIN II RECEPTOR ANTAGONISTS ACE inhibitors share many common characteristics with another class of cardiovascular drugs called Angiotensin II Receptor Antagonist s, 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. Use in combination with ACE inhibitors 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 . (van de Wal et al., 2005) 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. (Finnegan & Gleason, 2003) Patients with heart failure may benefit from the combination in terms of reducing Morbidity and Ventricular Remodeling . (Krum et al., 2004; Solomon et al., 2005) 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 , (Luno et al., 2005) and pediatric IgA Nephropathy . (Yang et al., 2005) REFERENCES
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