Cardiac failure inhibitors

Angiotensin converting enzyme (ACE) plays a central role in cardiovascular hemostasis. Its major function is the generation of angiotensin (ANG) II from ANGI and the degradation of bradykinin. Both peptides have profound impact on the cardiovascular system and beyond. ACE inhibitors are used to decrease blood pressure in hypertensive patients, to improve cardiac function, and to reduce work load of the heart in patients with cardiac failure. 

In some patients with hypertension and in all patients with cardiac failure, the renin-angiotensin system is activated to an undesired degree, burdening the heart. The consequences of diminished ANG II generation by ACE inhibitors are multiple. In patients with hypertension, blood pressure is reduced as a result... 

ACE inhibitors are approved for the treatment of hypertension and cardiac failure [5]. For cardiac failure, many studies have demonstrated increased survival rates independently of the initial degree of failure. They effectively decrease work load of the heart as well as cardiac hypertrophy and relieve the patients symptoms. In contrast to previous assumptions, ACE inhibitors do not inhibit aldosterone production on a long-term scale sufficiently. Correspondingly, additional inhibition of aldosterone effects significantly reduces cardiac failure and increases survival even further in patients already receiving diuretics and ACE inhibitors. This can be achieved by coadministration of spironolactone, which inhibits binding of aldosterone to its receptor. 

The substrate specificity of ACE is low. ACE cleaves a variety of pairs of amino acids from the carboxy-terminal part of several peptide substrates. The conversion of ANGI to ANGII and the degradation of bradykinin to inactive fragments are considered the most important functions of ACE. Both peptides have profound impact on the cardiovascular system and beyond. ACE is thus an important target for ACE inhibitors. These compounds are frequently and efficiently used in the treatment of hypertension and cardiac failure. 

Vasodilators are a group of dtugs, which relax the smooth muscle cells of the blood vessels and lead to an increased local tissue blood flow, a reduced arterial pressure and a reduced central venous pressure. Vasodilators reduce the cardiac pre-load as well as after-load and thereby reduce cardiac work. They are used in a variety of conditions including hypertension, cardiac failure and treatment/prevention of angina pectoris. Major groups are Ca2+-channel blockers (e.g. dihydropyridines), NO-donators (e.g. organic nitrates), K+-channel openers (minoxidil), phosphodiesterase inhibitors (e.g. sildenafil), Rho-kinase inhibitors (e.g. Y27632) or substances with unknown mechanism of action (e.g. hydralazine). Inhibitors of the... 

Undesired effects. The magnitude of the antihypertensive effect of ACE inhibitors depends on the functional state of the RAA system. When the latter has been activated by loss of electrolytes and water (resulting from treatment with diuretic drugs), cardiac failure, or renal arterial stenosis, administration of ACE inhibitors may initially cause an excessive fall in blood pressure. In renal arterial stenosis, the RAA system may be needed for maintaining renal function and ACE inhibitors may precipitate renal failure. Dry cough is a fairly frequent side effect, possibly caused by reduced inactivation of kinins in the bronchial mucosa. Rarely, disturbances of taste sensation, exanthema, neutropenia, proteinuria, and angioneurotic edema may occur. In most cases, ACE inhibitors are well tolerated and effective. Newer analogues include lisinopril, perindo-pril, ramipril, quinapril, fosinopril, benazepril, cilazapril, and trandolapril. 

Digoxin remains the mainstay of treatment for patients with chronic myocardial failure. Other drugs with inotropic and/or vasodilator properties, including the catecholamines and phosphodiesterase III (PDE) inhibitors, are used in the treatment of acute cardiac failure. The inotropic actions of most of these drugs result from a direct or indirect elevation of [Ca2-i-]i (intracellular Ca2+ concentration). This acts as a trigger for a process which leads to increased contractile state and cardiac contraction (Figures 8.3 and 8.4). Myofilament calcium sensitisers increase the sensitivity of contractile proteins to calcium. Some newer drugs, such as vesnarinone, have multiple mechanisms of action. 

This class of drug is very well tolerated in clinical trials their side effect profiles are indistinguishable or even better than placebo. Unlike the ACE inhibitors they do not produce cough, and are a valuable alternative for the 10-15% of patients who discontinue their ACE inhibitor for this reason. ATj receptor antagonists are used to treat hypertension but any role in cardiac failure or after myocardial infarction (as have ACE inhibitors) remains to be established. 

Cardiac failure (See also chapter 25). There is now dear evidence from prospective trials that P-blockade is beneficial in terms of mortality for patients with aU grades of moderate heart failure. Data support the use of both nonselective (carvedilol, a-blocker as well) and Pj-selective (metoprolol and bisoprolol) agents. The survival benefit exceeds that provided by ACE inhibitors over placebo. The negative inotropic effects can still be significant, so the starting dose is low (e.g. bisoprolol 1.25 mg p.o. or carvedilol 3.625 mg b.d.) and may be tolerated only with additional anti-failure therapy e.g. diuretic. 

Other important steps in secondary prevention include ACE inhibitors and statins in selected p.iticnts with cardiac failure and hypercholesterolaemia. respectively,... 

A test dose should be given to patients who are in cardiac failure (or who are already taking a diuretic for another reason, e.g. hypertension). Maintenance of blood pressure in such individuals may depend greatly on an activated renin-angiotensin-aldosterone system and a standard dose of an ACE inhibitor can cause a catastrophic fall in blood pressure. Except for captopril, most ACE inhibitors (including enalapril) are prodrugs, which are inactive for several hours after dosing. This has favoured the use of captopril... 

The phosphodiesterase inhibitors, enoximone and milrinone have positive inotropic effect due to selective myocardial enzyme inhibition and may be used for short-term treatment of severe congestive cardiac failure. Evidence from longer term use indicates that these drugs reduce survival. 

The best antitussive of all is removal of the cause of the cough itself, e.g. treatment of underlying conditions such as asthma, postnasal drip or gastro-oesphageal reflux. In patients with hypertension or cardiac failure, a common cause of a dry cough is treatment with an ACE inhibitor. 

Inhibition of the renin-angiotensin system by ACE inhibitors has proved efficacious in the treatment of hypertension, cardiac failure, myocardial infarction, in secondary prevention after myocardial infarction, and for kidney protection in diabetic and non-diabetic nephropathy. The development of specific antagonists to subtype 1 of the angiotensin II receptor (ATi) has provided a new tool for inhibiting the renin-angiotensin system. 

On the premise that phosphodiesterase inhibitors also inhibit the production of cytokines, milrinone has been used in the treatment of nine patients with the systemic inflammatory response sjmdrome and compared with seven patients with congestive heart failure (4). In both groups mikinone significantly altered cardiac index, pulmonary capillary wedge pressure, and left ventricular stroke work index. In the patients with cardiac failure it also reduced systemic vascular resistance index, and the dose of adrenaline had to be increased substantially during milrinone infusion to counteract vasodilatation. 

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