Diuretics and ACE inhibitors

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. 

Initiate diuretics and ACE inhibitors add digoxin, if symptoms persist add p blocker (when the patient is no longer overloaded with fluid)... 

Diuretics and ACE inhibitors provide significant benefits and can be used safely in the elderly, but smaller-than-usual initial doses might be needed, and dosage titrations should occur over a longer period to minimize the risk of hypotension. 

Congestive heart failure (CHF) For the treatment of mild to severe heart failure of ischemic or cardiomyopathic origin, in conjunction with digitalis, diuretics, and ACE inhibitors, to reduce the progression of disease. 

Lithium intoxication can be precipitated by the use of diuretics, particularly thiazides and metola-zone, and ACE inhibitors. NSAIDs can also precipitate lithium toxicity, mainly due to NSAID inhibition of prostaglandin-dependent renal excretion mechanisms. NSAIDs also impair renal function and cause sodium and water retention, effects which can predispose to interactions. Many case reports describe the antagonistic effects of NSAIDs on diuretics and antihypertensive drugs. The combination of triamterene and indomethacin appears particularly hazardous as it may result in acute renal failure. NSAIDs may also interfere with the beneficial effects of diuretics and ACE inhibitors in heart failure. It is not unusual to see patients whose heart failure has deteriorated in spite of increased doses of frusemide who are also concurrently taking an NSAID. 

Digoxin is indicated in patients with heart failure and atrial fibrillation. It is also most helpful in patients with a dilated heart and third heart sound. It is usually given only when diuretics and ACE inhibitors have failed to control symptoms. Only about 50% of patients with normal sinus rhythm (usually those with documented systolic dysfunction) will have relief of heart failure from digitalis. Better results are obtained in patients with atrial fibrillation. If the decision is made to use a cardiac glycoside, digoxin is the one chosen in most cases (and the only one available in the USA). When symptoms are mild, slow loading (digitalization) with 0.125-0.25 mg per day is safer and just as effective as the rapid method (0.5-0.75 mg every 8 hours for three doses, followed by 0.125-0.25 mg per day). 

Finally, the use of factorial designs, concluded by a response-surface analysis, is the latest approach used to select the most appropriate combination doses of two classes of drugs that allows complete pharmacological manipulation of the RAS, namely diuretics and ACE inhibitors (250, 251). 

NICE guidelines state that beta-blockers should be used in patients with heart failure due to left ventricular systolic dysfunction after a diuretic and ACE inhibitor regardless of whether symptoms persist or not. 

The combination of a potassium-sparing diuretic and ACE inhibitor can also cause severe hyponatraemia, more commonly indeed than life-threatening hyperkalaemia. 

Concurrent administration of potassium supplements, potassium-sparing diuretics, or salt substitutes can precipitate hyperkalemia in ACE inhibitor-treated patients, in whom aldosterone is suppressed (SED-14, 674). Regular monitoring of serum potassium is essential in these patients, because of the risk of hyperkalemia in patients given potassium (or potassium-sparing diuretics) and ACE inhibitors or angiotensin receptor antagonists. 

In contrast, published case reports and case series have provided more insight into the potential nephrotoxicity associated with COX-2-selective inhibitors. Taken together, these case reports suggest that COX-2 inhibitors, like non-selective NSAIDs, produce similar and consistent renal adverse effects in patients with one or more risk factors that induce prostaglandin-dependent renal function (that is patients with renal and cardiovascular disease and taking a number of culprit medications, such as diuretics and ACE inhibitors). Acute renal insufficiency, disturbances in volume status (edema, heart failure), metabolic acidosis, hyperkalemia, and hyponatremia have been commonly described. The duration of treatment with COX-2 inhibitors before the development of chnically recognized renal impairment ranged from a few days to 3-4 weeks. Withdrawal of COX-2 inhibitors and supportive therapy most often resulted in resolution of renal dysfunction, but in some patients hemodialysis was required (102,108-112). 

Hyperkalemia has been reported to increase the risk of dysrhythmias in patients taking disopyramide (39), and disopyramide should therefore be used with caution in patients who are taking drugs that can increase body potassium, such as potassium-sparing diuretics and ACE inhibitors. 

Blocker therapy is appropriate to further modify disease in systolic heart failure. In patients on a standard regimen of a diuretic and ACE inhibitor, /3-blockers have been shown to reduce morbidity and mortality.It is of paramount importance that /3-bIockers be dosed appropriately because of the risk of inducing an acute exacerbation of heart failure. They must be started in very low doses, doses much lower than those used to treat hypertension, and titrated slowly to high doses based on tolerability. 

The addition of aldosterone antagonists can rednce morbidity and mortality in systolic heart failure. Spironolactone has been studied in severe heart failure and has shown benefit in addition to diuretic and ACE inhibitor therapy. Eplerenone, the newest aldosterone antagonist, has been smdied in patients with symptomatic systolic heart failure within 3 to 14 days after an acute myocardial infarction in addition to a standard three-drug regimen. Collectively, both these agents should be considered in the specific heart failure population smdied but only in addition to diuretics, ACE/ARBs, and /8-blockers. 

Although many different drug classes are used in the management of hypertension, only three dasses of agents are known to prolong survival beta blockers, thiazide diuretics, and ACE inhibitors. 

Mild to moderate hypertension can often be controlled by a single drug (usually a thiazide or 3-htocker), but if this fails the traditional approach is to combine two drugs (c.g. diuretic and i-hlocker diuretic and ACE inhibitor) and add a third if necessary. 

Digoxin increases the force of cardiac contraction in the failing heart. Thi.s benefit has often Ireen doubted in patients with chronic heart failure in sinus rhythm, but recent clinical trials have shown that digoxin can reduce the symptoms of heart failure in patients who arc already receiving diuretics and ACE inhibitors. Digoxin is particulurly indicated in heart failure caused by atrial fibrillation (Chapter 17). 

Long-term administration of NSAIDs can result in renal papillary necrosis and other renal injury. Diclofenac should be used with caution in patients at greatest risk, including the elderly, those with impaired renal function, heart failure, liver dysfunction, and those taking diuretics and ACE inhibitors. 

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