Clinica Cayanga Medical Resources

Musculoskeletal

Structure
Fibre atrophy, changes in the distribution frequency of type IIa and IIb fibres, reduced mitochondrial density, volume, and number of cristae have all been described in skeletal muscle in moderate or severe heart failure. There is also a substantial reduction in muscle bulk, sometimes amounting to cachexia, but it is not possible to be sure of a specific skeletal myopathy of heart failure. Even so, these changes probably reflect a deficiency of oxygen delivery rather than the effects of primary reduction in the amount of exercise performed.

Function
In chronic heart failure there is a reduction in the strength of both small and large muscle groups, probably because of inherent defects in the quality of the muscle itself. There is also early fatiguability resulting in reduced physical activity, which leads to further muscle wasting and dysfunction.

Metabolism
Abnormalities of skeletal muscle metabolism in heart failure include early depletion of phosphocreatine, early acidification, accumulations of inorganic phosphate, reductions in the rate of resynthesis of phosphocreatine and of rate of removal of adenosine diphosphate. These changes are not the result of impaired blood flow, but probably reflect changes in oxidative enzymes in skeletal muscle.

Autonomic and neuroendocrine systems
Activation of the neuroendocrine system helps to support the circulation but in the long term is harmful. Adverse consequences include hypoperfusion of organs, myocardial toxicity, increased susceptibility to ventricular arrhythmias and progression of the underlying disease, be it ischaemia or cardiomyopathy.

The renin–angiotensin–aldosterone system
In untreated heart failure there is a mild activation of the systemic renin system, augmented by the use of diuretics. In addition, there is probably activation of the local systems in heart, kidney, brain, and blood vessel walls. The beneficial effects of inhibition show how important these systems may be. In the kidney, increased local angiotensin II may contribute to reductions in renal blood flow and glomerular filtration rate (GFR), especially on exercise. In very severe failure, angiotensin-mediated efferent arteriolar constriction maintains transcapillary hydraulic pressure (and therefore filtration) when overall perfusion pressure is unduly low.

The autonomic nervous system
There is activation of the sympathetic nervous system early in heart failure and a concomitant reduction in resting vagal tone. There is no clearly understood mechanism for this, particularly in mild cases.
Investigation of sympathovagal balance is limited by the lack of precise and quantifiable methods, but analysis of variations of heart rate variability shows promise in this context. The pattern in heart failure is very abnormal with a dramatic reduction in total heart rate variability and a selective loss of the higher frequency rhythm characteristic of respiratory sinus arrhythmia, and a relative preservation of low and very low frequency rhythms. This pattern is associated with high risk for the development of unstable ventricular arrhythmias and cardiac sudden death. Plasma noradrenaline levels correlate both with the degree of left ventricular failure, and with prognosis.

b-Receptor function
Chronic sympathetic activation leads to a depletion in myocardial catecholamine stores and a downregulation of b-1 receptors on the myocardium. There is also a decoupling of receptors from the post-receptor response, all of which lead to a loss of myocardial response to increased sympathetic drive. Clinically this manifests as chronotropic incompetence, loss of response to sympathomimetic stimulation and impaired exercise tolerance.

The natriuretic peptide systems
These peptides are natriuretic and also relax peripheral vasculature. Their release is increased in chronic heart failure associated with cardiac enlargement, but the significance of the increased plasma levels is uncertain; their natriuretic effects appear blunted in heart failure. There is increasing interest in the ability of elevated natriuretic peptide levels to become a biochemical marker of left ventricular systolic dysfunction.

The vasopressin system
Vasopressin concentrations are increased in chronic heart failure to levels that induce marked effects. Its actions are a combination of arteriolar vasoconstriction as well as renal water retention.
The kidney—oedema in heart failure
Oedema in heart failure is the consequence of retention of salt and water by the kidneys which behave in a way that resembles their response to haemorrhage. Yet blood volume is expanded rather than reduced leading to the concept of reduced ‘effective' blood volume. Where this ‘ineffectiveness' might be sensed is not certain, but candidates are arterial baroceptors and the low pressure receptors in atrial, ventricular, and juxtapulmonary capillaries. Those on the arterial side are more likely to be responsible, sensing in some way inadequate filling of the arterial tree by the sick heart. This concept of reduced ‘effective' blood volume is also invoked to explain renal salt and water retention when cardiac output is much increased—as in hyperthyroidism, arteriovenous fistula, anaemia, or beriberi—so-called ‘high output cardiac failure'.
Increased sympathetic tone, activation systemically and locally of the renin-angiotensin system could all plausibly be involved to explain the renal inability to excrete sodium and water normally, but, sodium retention in particular is likely to result from the summation of many influences on the kidney.
How does the kidney retain sodium in heart failure?
In moderate or severe heart failure, there is striking reduction in renal blood flow with relative preservation of GFR particularly during exercise. These haemodynamic changes, probably mediated by increased efferent arteriolar tone favour sodium reabsorption by increasing oncotic and reducing hydrostatic pressures in the peritubular capillaries. The effects of ‘loop' diuretics suggest that there must also be increased sodium reabsorption in the loop of Henle and/or distal nephron mediated by factors which are unknown. Animal studies support an intrarenal redistribution of blood flow with juxtamedullary sodium-retaining nephrons better perfused than cortical nephrons, but there remains considerable doubt as to whether this occurs in humans.

Venous pressure and oedema
Cardiac oedema was once attributed to a primary rise in central venous pressure leading to a parallel increase in tissue capillary pressure and via Starling forces to increased filtration and decreased reabsorption of fluid, resulting in oedema and a reduction in plasma volume. This concept is untenable. In many patients sodium retention clearly precedes any rise in central venous pressure. At no stage in the development of clinical or experimental heart failure has blood volume been shown to be reduced. A reduction in lymphatic fluid return because of an increased central venous pressure is certainly a possible factor, but oedema must ultimately result from primary renal retention of salt and water.

Renal dysfunction
Low arterial pressure and the effects of the circulating and intrarenal neurohormonal systems described above contribute to impair renal excretory function in heart failure. Mild increases in blood urea, with lesser ones of plasma creatinine are common and overenthusiastic diuretic therapy can provoke significant renal failure. In very severe heart failure, when glomerular filtration is dependent on angiotensin-mediated efferent arteriolar tone, angiotensin-converting enzyme (ACE) inhibitors can induce significant oliguria or even anuria, readily reversed when the drug is withdrawn.

Electrolyte disturbances
These occur largely as a result of diuretic therapy, favouring hyponatraemia, hypokalaemia, alkalosis, and magnesium depletion.
Other organ systems

The liver
Hepatic congestion is due to venous engorgement of the liver and can result in an increase in size, local tenderness, and minor derangements in liver function. In severe cases nausea and right hypochondrial discomfort develop, and rarely jaundice. Impaired albumin and clotting factor production (important for those taking warfarin), and malabsorption may result.
 

Gastrointestinal tract
Intestinal mucosal oedema can contribute to malabsorption and a higher rate of intestinal angiodysplasia can lead to recurrent blood loss, another problem for patients who require anticoagulation.
 

Salt and water retention—diuretics

Conservative measures
The value of bed rest and moderate sodium restriction has been known for years, but these simple approaches have been neglected since the advent of potent diuretics. Supine bed rest enhances venous return, increases cardiac output and the secretion of atrial natriuretic peptide and increases the proportion of the output reaching the kidneys, thus facilitating natriuresis and diuresis and enhancing the efficacy of diuretic therapy. In the stabilized patient, however, there is evidence of the benefit of regular physical exercise improving symptoms and exercise tolerance. Strict sodium restriction to an intake of 20–30 mmol/day is an unpleasant treatment, found impractical or unacceptable by most patients, but more modest restriction may reduce the need for drugs and thus reduce risks of toxicity.
Fluid restriction (intake confined to 500–1000 ml/24 h) was once commonly prescribed for heart failure and there are still good reasons for this approach in advanced failure, as a number of factors combine to reduce the ability of the kidneys to excrete free water.

 

Diuretics
By increasing urinary excretion of salt and water, diuretics reduce cardiac preload and thereby relieve congestion. Most, with the exception of spironolactone, influence renal tubular reabsorptive mechanisms in relation to their concentration in the tubular fluid which they reach largely by the organic ion transport mechanisms in the proximal convoluted tubule. Because of strong protein binding, loop agents and thiazides do not enter tubular fluid by glomerular filtration in significant amounts. The efficacy of a diuretic in individual cases depends therefore not only on inherent potency and site of action, but also critically on renal perfusion and tubular function as well as the antinatriuretic neurohumoral factors associated with heart failure. In the presence of heavy proteinuria, protein binding of diuretics in tubular fluid may also limit their efficacy.

Thiazide diuretics
The hazards of extreme hypovolaemia, and of serious electrolyte disturbance are less with thiazides. In maximal doses, these agents are capable of inhibiting reabsorption of some 5 per cent of the filtered load of sodium, quite enough for many patients with cardiac oedema. The dose–response curve of thiazides is flat, with little difference between small and large doses. Most thiazides affect urinary salt excretion for some 8–10 h but some, like chlorthalidone, last for as long as 24–36 h.

Potassium supplements
All thiazides tend to increase urinary potassium losses to a degree dependent on tubular flow rate, the delivery of sodium to the distal nephron, and the extent of secondary aldosteronism present. Chloruresis and potassium loss both tend to produce alkalosis, which further inhibits renal potassium conservation. The rate at which potassium may be lost is, therefore, variable and the need to provide supplements or not, equally variable. There is no doubt that severe potassium depletion can be provoked by thiazide treatment, especially by chlorthalidone, and that such depletion can potentiate cardiotoxic effects of digitalis analogues. When in doubt the wisest course is to prescribe supplements, or to combine treatment with one of the distally acting agents which promote potassium retention. Preparations providing thiazide diuretics and potassium in the same tablet are often prescribed, but the amounts of potassium incorporated may not suffice to prevent hypokalaemia; separate preparations of the diuretic and of potassium supplements are preferable.

Potassium-sparing diuretics
Spironolactone, amiloride, and triamterene all act on the distal nephron, promoting modest increases in sodium excretion and significant inhibition of potassium secretion. Spironolactone is a true antagonist of aldosterone. Effective doses range from 25 to 400 mg daily and depend on the degree of aldosteronism present. Side-effects of nausea and abdominal discomfort complicate higher dosage and prolonged use is commonly complicated by the development of gynaecomastia. The onset of action is delayed for a full 24–72 h. There is recent evidence of particular benefit from low dose (25–50 mg) spironolactone in severe (grade IV) heart failure.
Triamterene and amiloride block luminal sodium channels directly. Triamterene is rather less potent and less well tolerated than amiloride, which is as effective in conserving potassium and excreting sodium as is spironolactone, but free of the side-effect of gynaecomastia. Effective doses range between 5 and 20 mg daily.
The addition of any of these agents to thiazides or ‘loop' diuretics augments sodium excretion and reduces potassium loss, but to a variable degree depending on haemodynamic factors and the activity of the renin–aldosterone system. It is not safe to assume potassium homeostasis without regular checks of plasma levels, particularly in the first 1–2 weeks after their introduction.

Loop' diuretics
Loop agents all act principally by inhibiting sodium chloride cotransport in the ascending limb of the loop of Henle, which is critical to the mechanisms of urinary concentration and dilution. They are all extremely potent, and promote a considerably greater excretion of chloride than of sodium. They tend to increase urinary potassium losses in an amount dependent on the extent of secondary hyperaldosteronism present and the degree of alkalosis induced by chloride deficiency or any pre-existing potassium depletion.
These drugs are potentially dangerous particularly in the elderly. Their remarkable potency results in a risk of extreme hypovolaemia, postural hypotension, circulatory failure, and uraemia when they are given without proper supervision, particularly to patients whose disease could well be controlled by less drastic agents. Weight loss from diuretic therapy should be achieved ideally at a rate not exceeding 1–2 kg/day. These caveats apart, ‘loop' diuretics properly prescribed provide a major advance in the care of patients whose oedema cannot be controlled by less powerful drugs. Given by mouth, all begin to induce natriuresis and diuresis within 1–2 h and have a peak effect at about 4 h, which is complete at about 6 h. The relatively short period of action can be used to tailor treatment for individual patients. The threshold dose required to produce a natriuresis in any given case may be increased for a number of reasons, including slow gastrointestinal absorption, reduced renal perfusion, impaired secretory function of the proximal tubule, as well as the sodium-retaining consequences of increased activity of the renin–angiotensin system and other neurohumoral mechanisms. In this situation, larger individual doses are required as a first step, with increased frequency of administration as the second.

Resistant oedema
Combinations of loop agents, thiazides, and distal acting drugs may fail to control fluid retention, particularly when cardiac failure coexists with impaired renal function. In such cases, metolazone has been shown to be remarkably effective when combined with a loop agent. Indeed its addition may produce an excessive natriuresis and it is often wise to begin with a small dose, e.g. 2.5–5 mg on alternate days, increasing if necessary to a maximum dose of 20 mg/day.
In extreme cases ACE inhibitors may cause an acute fall in GFR, oliguria, and uraemia secondary to inhibition of angiotensin-mediated efferent arteriolar tone.
When fluid retention persists despite therapy, there is a need to decide whether to increase the dose of ACE inhibitor or of a diuretic first. Cold extremities and a rise in blood urea above 20 mmol/litre (BUN over 60 mg/100 ml) indicates predominance of poor cardiac output, best treated by an increase in ACE inhibition, together with a reduction in diuretic dose. When blood urea concentrations are below some 12–18 mmol/l (BUN 36–54 mg/100 ml) and the extremities are warm, it may be more effective to increase the dose of diuretic first.
In cases with delayed, or inadequate absorption of loop agents due to intestinal oedema, higher blood levels can be achieved by the use of bolus doses given intramuscularly or intravenously. More effective and more comfortable for the patient is a slow infusion given by a low pump delivering the total 24-h dose in 100 ml or less of 5 per cent dextrose.

Contraindications and complications during diuretic therapy
There are some cardiac conditions in which removal of fluid from the circulation is quite inappropriate, despite clear evidence of an elevation in central venous pressure. These include constrictive pericarditis, pericardial tamponade, right ventricular infarction, pulmonary embolism, or mitral valve disease when cardiac output is severely compromised.
Prolonged treatment with loop agents or thiazides induce hyperuricaemia and may cause gout. Hyperglycaemia can be provoked by thiazides particularly, and the risk appears greatest in the elderly. Hypercalcaemia is increasingly recognized as a consequence of thiazide treatment. Hyponatraemia represents more of a problem and, hypomagnesaemia is often not sufficiently recognized.
 

Diuretic-induced hyponatraemia
This complication is never, or almost never, due to sodium depletion, but almost always due to a relative water overload. A number of factors contribute. Increased tubular reabsorption of sodium in the proximal tubule results in less sodium and chloride delivered to the diluting sites. Excretion free water is thereby decreased. It is decreased further by the use of diuretics which inhibit electrolyte transport at these diluting sites. In addition, patients with cardiac insufficiency are often thirsty. Finally, plasma levels of antidiuretic hormone are increased in severe heart failure. Mild hyponatraemia needs no treatment, although it is a sign of a guarded prognosis. More severe hyponatraemia accompanied by symptoms requires treatment. If diuretics cannot be reduced, the addition of an ACE inhibitor may increase cardiac performance and renal perfusion, but on occasion hyponatraemia follows ACE inhibition. Water restriction is then only moderately effective and is rarely tolerated by patients. Demethylchlortetracycline has been tried in this situation but usually without great benefit.
 

Magnesium depletion
Both ‘loop' diuretics and thiazides can provoke magnesium depletion. Symptoms and signs are rare but can include depression, muscle weakness, refractory hypokalaemia, hypertension, and ventricular or atrial dysrhythmias resistant to treatment. Treatment with magnesium glycerophosphate is quite well accepted in doses of 3–6 g daily providing 12–24 mmol of magnesium per 24 h. Other possible preparations include magnesium hydroxide which gives approximately 20 mmol in 15 ml but at the risk of diarrhoea and less efficient absorption.
 

Acute pulmonary oedema
Apart from morphine, the most effective treatment is intravenous injections of ‘loop' diuretics. Frusemide 20–40 mg increases urinary salt and water excretion within 2 min, reaching a peak at 5–10 min and complete within 25 or 35 min. There is some evidence that the beneficial effects can be attributed not only to natriuresis and diuresis but also to falls in left atrial pressure the result of dilatation of venous capacitance vessels.
 

Digitalis—maintenance therapy: indications and regimens
Maintenance therapy may be indicated for the management of heart failure due to systolic ventricular dysfunction. Much debate has centred around the value of digitalis long-term use in patients in sinus rhythm. The situation has been clarified by 14 studies using digoxin. Significant benefits included one or more of the following: subjective measures, heart failure scores, haemodynamic measures, exercise capacity, and frequency of hospital admission. One of the trials showed that the benefits of digoxin were additive to those of ACE inhibitors. A subsequent randomized study showed that withdrawal of it in patients treated with diuretics and ACE inhibitors led to worsening heart failure. Against the evidence of benefit must be set the possibility of harm. Some consider that cardiac glycosides should be used with particular caution in patients with severe coronary heart disease because the threshold to ventricular fibrillation may be lowered. Evidence is inconclusive that digitalis is an independent risk factor for death, but it cannot be pronounced innocent in this regard. The case at present is ‘not proven'. The DIG study, involving over 7500 patients found no significant effect of digoxin on mortality, although there was a reduction in the rate of admission to hospital.
Assessment of ventricular rate during exercise should be made before deciding the dose to control atrial fibrillation, but in the presence of good renal function up to 250 µg digoxin twice daily may be required. Higher doses are very rarely needed. More commonly, smaller doses are dictated by impaired renal function or by unwanted effects. For most patients with sinus rhythm and good renal function, a dose of digoxin of 250 µg daily is usually appropriate but, with impaired renal function, smaller doses are necessary. Digitoxin may be better in this situation because accumulation is less likely. The usual dose is 100 µg daily or rarely 200 µg daily. Lower doses should be given in the presence of impaired liver function.
 

Measurement of plasma concentrations
Blood samples should be drawn when plasma concentrations after oral dosage have passed the absorption peak and fallen to a plateau, which then decays at a rate corresponding to the elimination half-life of the drug. In practice this requires sampling after an interval of about 8 h from the last oral dose. Exercise affects interpretation of results, by increasing the binding of digoxin to skeletal muscle. Plasma concentrations after a period of rest can be increased by as much as 75 per cent compared with those during exercise. Pregnancy and renal impairment can produce falsely elevated plasma glycoside concentrations in some assays.
Therapeutic plasma concentrations of digoxin are in the range of 1–2 µg/litre. Those for digitoxin are approximately 10–15 times higher, due chiefly to greater protein binding.
 

Digitalis toxicity
There is considerable variation in the plasma and tissue concentrations at which toxicity occurs. Serious toxicity is unusual with plasma concentrations below 2 µg/litre, and are likely to be present with concentrations more than 3 µg/litre. Between these figures some patients have a satisfactory therapeutic response while others have troublesome adverse effects.
The extracardiac toxic effects include fatigue with profound muscular weakness, severe visual disturbances, nausea and anorexia, abdominal pain, vomiting, diarrhoea, headache, restlessness, and agitation.
In the absence of heart disease or very large overdose, the cardiac manifestations are usually relatively benign. First-, second-, and third-degree atrioventricular block may occur, but severe bradycardia or long pauses are unlikely because the rate of subsidiary junctional pacemakers tends to be accelerated by the glycosides. In patients with heart disease the manifestations are usually more serious. While almost any rhythm disturbance can occur, the following may be regarded as characteristic: frequent ventricular extrasystoles, junctional and ventricular rhythms or tachycardias; atrial tachycardias with varying degrees of atrioventricular block, bradycardia due to sinoatrial block; an unduly slow ventricular response in atrial fibrillation, progressive regularization of ventricular response in atrial fibrillation due to the emergence of accelerated junctional beats, and ventricular fibrillation. Some digitalis-induced arrhythmias are very complex and difficult to analyse. With very high plasma levels, asystole may occur. This may be associated with refractory hyperkalaemia.
 

Treatment of digitalis toxicity
In most patients it is sufficient to withhold the drug, and especially in the presence of hypokalaemia, to give potassium. Potassium may be contraindicated when atrioventricular block is present because the conduction defect may be exacerbated. Atropine and pervenous pacing have an occasional role in the management of bradyarrhythmias.
A specific antidote (Digibind, Ovine) is valuable because of the risk to life in severe toxicity. The antibody fragments rapidly bind intravascular and interstitial digoxin. Their small size permits rapid diffusion into the interstitial space where binding of free digoxin sets up a concentration gradient leading to the egress of tissue stores of the glycoside. An initial clinical response can usually be expected within 60 min, and complete reversal of toxicity within about 4 h. If renal function is normal, the bound digoxin is excreted with a half-life of approximately 16 h. The dose is based on body weight and plasma digoxin concentration for patients toxic from excessive maintenance therapy or on the amount ingested after a single dose. Allergic reactions have occurred in less than 1 per cent of patients. Recrudescence of toxicity is rare, but caution is needed if renal failure is severe enough to prolong greatly the elimination of the digoxin–antibody complex, which may eventually release free digoxin.
Lidocaine or phenytoin may be effective for serious arrhythmias, even if they are of supraventricular origin. b-adrenoceptor-blocking agents are useful for ectopic ventricular arrhythmias but may precipitate heart failure or bradyarrhythmias in susceptible patients. Electrical cardioversion may precipitate ventricular fibrillation and should be considered only for the most pressing indications. The lowest effective energy should be used. Dialysis and haemoperfusion are ineffective for both digoxin and digitoxin toxicity because the large tissue stores equilibrate relatively slowly with the much lower concentrations in plasma.

b-Blockers
Recent controlled trials (undertaken largely in relatively young men) have shown major benefit from the use of selective b-blockers (bisoprolol, metoprolol, carvedilol) in stable mild and moderate heart failure due to left ventricular systolic dysfunction. Overall mortality was reduced by some 30 per cent and that due to sudden death by 44 per cent. Initial doses should be small (e.g. metoprolol 5 mg) and increased only slowly over weeks or months. The position with regard to symptomless heart failure, diastolic heart failure, heart failure in the elderly, and severe heart failure (grade IV) is uncertain and these drugs should be avoided in these groups until further evidence is available.

Vasodilators
In most cases of heart failure, balanced vasodilatation with agents that reduce both preload and afterload leads to the greatest haemodynamic improvement and clinical benefit. A simple classification based on whether the major site of action is on arteries or veins is widely adopted (Table 2). The way in which reduction in venous (preload) or arterial (afterload) tone or both affect the cardiac output.

Nitroprusside
Nitroprusside is a balanced vasodilator which can only be given intravenously and whose rapid onset and offset of action renders it only suitable, but eminently so, for the acute situation; close haemodynamic monitoring both of systemic arterial and right heart pressures are essential during its use. As light degrades the parent compound, the delivery system must be shielded. The dose ranges from 10 µg/kg per min up to 30 µg/kg per min depending on response. A typical indication for its use would be a patient with low cardiac output and high filling pressures due to poor systolic left ventricular function resulting from dilated cardiomyopathy, acute myocardial infarction, chronic coronary heart disease, acute or chronic aortic or mitral incompetence, or acute ventricular septal defect following acute myocardial infarction. Two main problems complicate its use. Hypotension is best avoided by starting at a very low dose and by close continuous monitoring of systemic arterial and pulmonary capillary wedge pressures. Second, toxic metabolites of cyanide or cyanate accumulate in patients with liver or renal dysfunction. These problems make many prefer nitrates which are safer, and as effective.

Nitrates
Glyceryl trinitrate is prepared in intravenous, sublingual, and transcutaneous formulations, while the mainstays of oral therapy are isosorbide mono- or dinitrate. They all cause vascular smooth muscle relaxation, particularly in veins, by increasing intracellular cyclic guanine monophosphate. Though some decrease in arteriolar tone also occurs, this effect is seen predominantly in the capacitance and pulmonary vessels resulting, acutely, in a reduction in preload. Frequently repeated doses of nitrate lead to the development of tolerance.

Hydralazine
This drug is an arteriolar smooth muscle relaxant. Its acute haemodynamic profile, but these effects do not translate into long-term benefit in controlled trials. The contribution of hydralazine with isosorbide dinitrate is more effective and is now the only way in which hydralazine is used in heart failure. The value of the combination was shown in the two Veterans Heart Failure trials (V-HeFTI and II). But ACE inhibitors are superior in controlling symptoms, in exercise capacity and in reducing mortality. Moreover, some one-third of patients cannot tolerate the combination because of headache, palpitation, or nasal congestion. Overall, hydralazine plus isosorbide is a second line approach, although a trial has shown benefit from adding this combination to ACE inhibition. Doses of hydralazine begin at 37.5 mg four times a day, and of isosorbide 20 mg four times daily, increasing to a maximum tolerated dose averaging 400 and 150 mg/day respectively.

Calcium channel blockers
These agents are arteriolar vasodilators acting by decreasing the slow inward calcium current that promotes arterial smooth muscle contraction. The main concern in their use in heart failure is that they also decrease calcium availability within cardiac myocytes, which decreases contractility. Interest in heart failure is therefore centred on those agents with relatively greater effects on the peripheral vascular calcium channels, such as nifedipine, felodipine, and amlodipine. There are few long-term studies on their value in heart failure but several reports have shown that nifedipine may lead to deterioration, probably reflecting its negative inotropic effects and, in some cases, the ill effects of secondary reflex neuroendocrine activation.

Angiotensin-converting enzymes inhibitors
ACE inhibitors are superior to other vasodilators. Their effects depend mainly on the inhibition of conversion of angiotensin I to II, both systemically and locally, although their action in inhibiting destruction of bradykinin may also be important.
The major benefits of their use probably derives from arterial and venous dilatation, reducing cardiac filling pressures, wall stress, chamber size, and myocardial hypertrophy and increasing left ventricular ejection fraction. Adverse effects are few. In advanced renal failure, any tendency towards hyperkalaemia may be aggravated and in very severe heart failure with low renal perfusion pressure, inhibition of angiotensin-mediated efferent arteriolar vasoconstriction may so reduce glomerular transcapillary hydraulic pressure as to cause acute but reversible renal failure.

Clinical efficacy
Heart failure is a progressive disorder and deterioration depends, at least in part, on a vicious cycle of increasing neurohumoral activation leading to increased vascular resistance and escalating cardiac work and dysfunction. ACE inhibitors and b-blockers are well placed to disturb this cycle and a number of studies have confirmed that the former reduce the rate of progression of heart failure and delay the onset of symptoms in patients with asymptomatic left ventricular dysfunction. They also reduce mortality in all grades of heart failure, including that after myocardial infarction.

Place in management
The effects of ACE inhibitors on survival, disease progression and the development of myocardial infarction make them mandatory treatment in all grades of symptomatic heart failure, although certain precautions should be taken before treatment is started. In most studies they have been combined with diuretics and, when used alone have proved inadequate. In mild to moderate left ventricular function they are now also combined with b-blockers.
Treatment can be begun in most patients with mild or moderate heart failure without admission to hospital, but in those with severe heart failure on high doses of diuretics admission is essential.
A low dose should be given initially (e.g. 2–6.25 mg captopril, 2.5 mg enalapril). The patient should remain seated or supine until the peak haemodynamic effect of the drug has been observed (1–2 h with captopril, 2–6 h with other ACE inhibitors). Head-down tilt of the bed and intravenous saline will usually correct symptomatic hypotension. Once treatment has been successfully introduced, the dose can be increased to achieve maximum symptomatic benefit, though this may be delayed for weeks or months.
 

Adverse effects

First dose hypotension
A precipitous fall in blood pressure, occasionally accompanied by a bradycardia can occur in response to the first dose of an ACE inhibitor. This is usually only seen in volume depleted patients, and those on large doses of diuretic. In patients at risk a small test dose of a short-acting inhibitor is advisable, e.g. captopril 2 mg or perhaps 6.25 mg, with close observation of the blood pressure response over the subsequent 1–2 h. Correction of fluid-volume status may permit subsequent uncomplicated reintroduction of ACE inhibitors in patients who have shown this phenomenon. It is also important to ensure that significant pulmonary or obstructive valve disease has not been missed and that the patient does not have an unusual type of heart muscle disease causing diastolic dysfunction, for example, amyloid.
 

Renal dysfunction
Small increases in plasma creatinine (i.e. £ 10 per cent increase) are common when ACE inhibitions are used to treat advanced heart failure, but serious renal dysfunction is rare. Even so, frequent monitoring of blood urea, serum creatinine and urine output are essential when ACE inhibitors are introduced in patients with severe left ventricular dysfunction.

Hyperkalaemia
Modest hyperkalaemia (plasma potassium 4.6–5.8 mmol/l) is to be expected when ACE inhibitors are given to patients whose GFR is less than 20–30 ml/min. Volume depletion and extrarenal uraemia increase the likelihood of hyperkalaemia and co-prescription of a non-steroidal anti-inflammatory or potassium-conserving diuretic much increases the risk.

Cough
There is a small but significant increase in its incidence during ACE inhibitor therapy but, in trials, this has not led to more withdrawals in the actively treated patients. Cough should not be attributed immediately to ACE inhibition, and pulmonary congestion or airways obstruction must be excluded; even if it is due to the ACE inhibitor, the patient may be able to tolerate it and in some it may, on occasion, resolve spontaneously.

Other adverse effects
Taste disturbance, skin rash, proteinuria, and leucopenia have been rare in recent trials. Angio-oedema is another rare but troublesome complication.

Catecholamines
Haemodynamic profiles and usage of catecholamines
In contrast to the use of b-blockers in stable mild to moderate heart failure catecholamines can be used intravenously to provide short-term circulatory support in acute severe failure. They enhance the inotropic state of the heart, although both salbutamol and low-dose dopamine have the useful actions of peripheral, splanchnic, or renal vasodilatation and noradrenaline may cause vasoconstriction.
Any increase in the inotropic state of the heart, also increases myocardial oxygen consumption to a greater or lesser extent. An increase in heart rate will further augment oxygen demand as will the development of tachyarrhythmias. Catecholamine usage in an individual patient requires careful consideration of the balance between augmented short-term cardiac performance and longer-term adverse effects on myocardial oxygen demands.

Adrenergic pharmacology
Classification of adrenergic receptors into a and b subtypes has been considerably refined (Table 4) and now includes a-1, a-2, b-1, b-2, and dopamine receptor subtypes. In chronic heart failure, cardiac efferent sympathetic activity is increased coupled with impairment of neuronal reuptake further increasing intrasynaptic noradrenaline concentration. However, tolerance to the action of both endogenous and exogenous catecholamines arises through b-adrenoceptor downregulation.
Noradrenaline, adrenaline, and dopamine and their synthetic derivatives interact with the six adrenoceptor subtypes according to their specificity and affinity for these receptors. Human ventricular muscle contains predominantly b-1-adrenoceptor subtypes in close proximity to the adrenergic synapse, mediating an inotropic response. The sinoatrial node, however, may respond preferentially to b-2-adrenoceptors distributed throughout the specialized tissue and responsive to circulating catecholamines (adrenaline/noradrenaline) as well as neuronally released noradrenaline.

Dopamine
Effects are dose-dependent; the renal and mesenteric circulation, and to a lesser extent the coronary and cerebrovascular vessels dilate at low-dose (Table 6). The most important clinical effect is on the kidney with increased renal blood flow, glomerular filtration, and natriuresis. This action is especially useful in the management of persistent heart failure associated with reversible reduction in myocardial contractility or with impaired diuretic responsiveness as a result of renal artery vasoconstriction. Dopaminergic vasodilatation is antagonized by phenothiazines and by butyrophenones. Higher doses activate b-1-adrenoceptors leading to an increase in myocardial contractility and heart rate and an increase in myocardial oxygen demand. Yet they may augment coronary perfusion pressure. High-dose dopamine infusion leads to dominant a-1-adrenoceptor actions and peripheral vasoconstriction.

Noradrenaline
The main actions of noradrenaline are a-receptor-mediated vasoconstriction and b-1-adrenoceptor-mediated enhancement of contractility. Arteriolar vasoconstriction significantly increases blood pressure and cardiac output usually decreases. Heart rate usually falls because of baroreceptor mediated vagal stimulation and sympathetic withdrawal (as a result of elevated blood pressure) of b-1-adrenoceptor stimulation. Vasoconstriction is most intense in muscle, skin, liver, and kidney. Actions on the myocardium result from increased afterload, increased preload, and increased contractility. Myocardial oxygen demand will increase. Noradrenaline is useful in the short term to improve cerebral and coronary perfusions in shock, during resuscitation and may be used to counteract hypotension as a result of vasodilator therapy. It has little role in the longer term when adverse effects on oxygen demand are likely to be hazardous.

Adrenaline
Action on a- and b-adrenoceptors (most notably the b-1-adrenoceptors) in the heart augments cardiac contractility and increases heart rate, automaticity, and conduction. Vasoconstriction and increase in blood pressure are less pronounced than with noradrenaline. At low dose, systemic vascular resistance may fall while at higher doses vasoconstriction is evident. Myocardial oxygen demand is substantially and progressively increased and tachycardia and cardiac arrhythmias may limit usefulness particularly with acute circulatory failure. The main use is in short-term acute inotropic support, for example during cardiopulmonary resuscitation.

Isoprenaline
Isoprenaline has powerful b-adrenoceptor stimulatory actions, producing increases in heart rate, inotropic state and atrioventricular conduction and automaticity. Peripheral vascular and pulmonary vascular resistance fall from b-2-adrenoceptor stimulation. Systolic blood pressure may rise from cardiac effects, although diastolic pressure normally falls. Myocardial oxygen consumption increases greatly and arrhythmias and myocardial ischaemia frequently limit dose.
Isoprenaline is most frequently used for its chronotropic action as a short-term intravenous infusion in patients with symptomatic bradycardia, for example heart block. The infusion rate may be adjusted to achieve a heart rate alleviating acute symptoms, pending longer-term management such as cardiac pacing. Rarely, oral medication (30–60 mg 6-hourly) is necessary if other chronotropic measures are not available.

Dobutamine
This drug has some b-1-adrenoceptor selectivity and hence has less effect on the sinus node and on heart rate. Enhancement of left ventricular contractile activity provides a useful short-term role for it in shock states with primary or secondary ventricular disease. Effects on heart rate and arrhythmogenesis, however, are not infrequently limiting.

Salbutamol
This b-2-adrenoceptor agonist causes peripheral vasodilatation and hence afterload reduction. Increases in heart rate limit clinical usefulness and alternative vasodilator agents are usually to be preferred.

Dopexamine
Dopexamine is a dopamine analogue acting on b-2-adrenoceptors and some dopamine receptors. The combined effects of renal, hepatic, and splanchnic vasodilatation with peripheral vasodilatation offer a haemodynamic profile that may be of value, although increases in heart rate, as with dobutamine, can restrict its use.

Phosphodiesterase inhibitors
Emoximone and milrinone are selective phosphodiesterase inhibitors with primary myocardial effects. These drugs increase cardiac contractility, promote ventricular relaxation and cause modest peripheral vasodilatation. Improvements in myocardial performance are short lived, and both atrial and ventricular arrhythmias may be increased.