A 70 year-old Chinese man with a past history of mild hypertension and ischaemic heart disease presents with atrial fibrillation and congestive heart failure. Discuss the pharmacological management of this patient’s heart failure.

Outline:

·        Heart failure: diuretics, ACE inhibitors, digoxin.

·        Hypertension: thiazides.

·        Atrial fibrillation: digoxin, amiodarone, warfarin.

Suggested Answer:

Congestive heart failure is present when the heart cannot provide all organs with the blood supply appropriate to demand. The patient presents with a multitude of medical problems of which the one requiring immediate attention is heart failure after which appropriate measures should be taken to manage his hypertension, ischaemic heart disease and atrial fibrillation.

There are two main considerations in the treatment of patients with heart failure. Firstly, there is treatment for the failing pump itself and its major consequences, fluid retention and vasoconstriction. Equally important is the treatment of associated problems, some of which reflect the underlying cause of pump dysfunction (for example, angina pectoris) and some of which are secondary to heart failure (for example, arrhythmias). The objectives for treatment are to reduce mortality and morbidity. Unfortunately, despite vigorous treatment, most patients eventually succumb to the disease.

There is no more effective symptomatic treatment for heart failure than diuretics. Four main principles underlie their use in heart failure:  

1.         Use in moderation; avoid excessive doses of any single drug.

2.         Make use of synergism between different classes of drugs.

3.            Monitor blood chemistry to avoid uraemia, hyperkalaemia and hypernatraemia.

4.         Use in combination with an angiotensin-converting enzyme (ACE) inhibitor unless this is not tolerated.

Loop diuretics are usually used. The effective daily dose of frusemide is 40 mg (equivalent to 1 mg bumetanide), but reduced diuretic efficacy may lead to 80-120 mg daily being necessary. At this stage a second diuretic - either a thiazide such as bendrofluazide (5-10 mg daily) or metolazone (2-10 mg daily) - should usually be added. The thiazides are also effective in lowering the mild hypertension. Combination treatment is often required for only a few days. Careful monitoring of hydration status and blood chemistry is necessary during this time, usually requiring inpatient supervision.

The loop diuretics – frusemide, bumetanide, piretenide and ethacrynic acid act principally on the thick ascending limb of the loop of Henle by inhibiting active chloride ion transport, which thus prevents sodium ion reabsorption and lowers the osmotic gradient between cortex and medulla. The result is that large volumes of dilute urine are formed. As 25% of filtered sodium is reabsorbed at the loop of Henle, loop diuretics are the most efficacious diureics, causing 5-25% of filtered sodium to be excreted. They also have some renal vasodilator effect, reducing renal vascular resistance and increasing renal blood flow as well as decreasing peripheral vascular resistance which all leads to increased glomerular filtration rate and subsequently increased diuresis. Progressive increase in dose is matched by increasing diuresis. Indeed, they are so efficacious that overtreatment can readily dehydrate the patient. Loop diuretics remain effective at glomerular filtration rates below 10ml/min. They are readily absorbed from the gastrointestinal tract and greater than 90% bound to plasma proteins. They are rapidly secreted by the organic acid transport system at the proximal tubule.

The adverse effects of loop diuretics are a large part an extension of their therapeutic efficacy. Loop diuretics may produce profound diuresis resulting in fluid and electrolyte depletion. Fluid and electrolyte depletion are especially likely to occur when large doses are given and/or in patients with restricted sodium intake. Too vigorous diuresis, as evidenced by rapid and excessive weight loss, may induce orthostatic hypotension or acute hypotensive episodes, and the patient’s blood pressure should be closely monitored. Excessive dehydration is most likely to occur in geriatric patients and/or patients with chronic cardiac disease treated with prolonged sodium restriction or those receiving sympatholytic agents. The resultant hypovolemia may cause hemoconcentration, which could lead to circulatory collapse or thromboembolic episodes such as possibly fatal vascular thromboses and/or emboli. Pronounced reductions in plasma volume associated with rapid or excessive diuresis may also result in an abrupt fall in glomerular filtration rate and renal blood flow.

At the distal tubules, sodium is reabsorbed in exchange for potassium driven by a sodium-potassium pump at the basement membrane. Loop diuretics, by inhibiting the reabsorption of sodium at the loop of Henle cause more sodium to reach the distal tubule and so increase potassium excretion. Potassium depletion occurs frequently in patients with secondary hyperaldosteronism which may be associated with cirrhosis or nephrosis and is particularly important in cirrhotic, nephrotic, or digitalized patients. Hypokalemia and hypochloremia may result in metabolic alkalosis, especially in patients with other losses of potassium and chloride due to vomiting, diarrhea, GI drainage, excessive sweating, paracentesis, or potassium-losing renal diseases. In patients with cor pulmonale, alkalosis may cause compensatory respiratory depression. Loop diuretics may produce hyperglycemia and glycosuria, possibly as a result of hypokalemia, in patients with predisposition to diabetes. Loop diuretics also increase calcium and magnesium excretion. Hyperuricemia may result from frusemide administration and rarely gout has been precipitated; patients with a history of gout or elevated serum uric acid concentrations should be observed closely during therapy.

Other adverse effects of loop diuretics not found to have any correlation with its mechanism of action are as follows. Tinnitus, reversible or permanent hearing impairment, or reversible deafness have occurred, usually following rapid IV or IM administration of frusemide in doses greatly exceeding the usual therapeutic dose of 20—40 mg. Otic effects are most likely to occur in patients with severe impairment of renal function and/or in patients receiving other ototoxic drugs (e.g., aminoglycosides). Adverse GI effects include nausea, anorexia, oral and gastric irritation, vomiting, cramping, diarrhea, and constipation. Anemia, hemolytic anemia, leukopenia, neutropenia, and thrombocytopenia have occurred in patients receiving furosemide. Adverse dermatologic and/or hypersensitivity reactions include purpura, photosensitivity, rash, urticaria, pruritus, exfoliative dermatitis, erythema multiforme, interstitial nephritis, and necrotizing angiitis (vasculitis, cutaneous vasculitis).

The thiazides – chlorothiazide, hydrochlorothiazide, benzthiazide, bendrofluazide, cyclopenthiazide and the related chlorthalidone, xipamide, clopamide and metolazone act principally at the cortical diluting segment of the ascending limb, preventing sodium reabsorption by inhibiting a sodium-chloride co-transporter. This causes 5 – 10% of filtered sodium load to be excreted. As the distal tubule is responsible for diluting the urine before it enters the collecting tubules, thiazides limit the ability of the kidneys to produce a dilute urine. Increasing the dose beyond a small range produces no added diuresis. Such drugs tend to be ineffective once the glomerular filtration rate has fallen below 20 ml/min. Therefore, thiazides have a lower efficacy than loop diuretics. Thiazides lower blood pressure due to reduction in intravascular volume and peripheral vascular resistance. In chronic use they diminish the responsiveness of vascular smooth muscle to norepinephrine. Thiazides are generally well absorbed from the gut and most begin to act within an hour.

Like loop diuretics, the most frequent adverse effects of the thiazides are a result of their diuretic action which can lead to electrolyte imbalance, hypokalaemia, hyponatraemia and hypochloraemic alkalosis. Rashes, thrombocytopenia and agranulocytosis occur. Treatment with thiazides causes an increase in total serum cholesterol. Other less common side effects are anorexia, decreased sexual function, orthostatic hypotension, allergic dermatitis, gout, stomach upset, jaundice and pancreatitis.

All patients requiring chronic diuretic treatment for heart failure should also now receive an ACE inhibitor, in view of several studies such as the SOLVD studies showing improved survival even in mild failure. The primary action of these drugs is to inhibit the production of the hormone angiotensin II, a powerful vasoconstrictor which has direct and indirect renal effects. Secondly, they increase concentrations of the vasodilator bradykinin by inhibiting the enzyme responsible for its degradation. They also have important effects on the kidneys, electrolytes, and the electrical stability of the heart. When given with diuretics, angiotensin converting enzyme inhibitors improve the symptoms and signs of all grades of heart failure and improve exercise tolerance. Progression of heart failure from mild to severe is reduced, as is hospitalisation, and survival is improved in all grades of heart failure. Indeed, inhibition of angiotensin converting enzyme represents one of the most effective treatments for heart failure available.

Certain precautions should be taken before treatment is started. Potassium supplements and potassium sparing diuretics should be stopped, while other diuretics should be stopped temporarily 24 hours before the first dose of angiotensin converting enzyme inhibitor - they can be resumed the next day. The patient should sit or lie down for two to four hours after the first dose, depending on the drug used. A low dose should be given initially - for example, captopril 6.25 mg or enalapril 2.5 mg - and regular treatment can then usually be started at an intermediate dose - captopril 12.5 mg thrice daily or enalapril 2.5 mg twice daily. The patient should be reviewed after one or two weeks to check blood chemistry and test for symptomatic hypotension, and the drug dose should be modified accordingly. Provided the patient has not experienced significant hypotensive symptoms or a significant rise in serum creatinine or potassium concentration (>200 µmol/l or 5.0 mmol/l respectively), the dose of angiotensin converting enzyme inhibitor should be increased. Larger doses such as enalapril 10 mg twice daily or captopril 25-50 mg thrice daily are recommended as they have been shown to be beneficial in clinical trials.

Symptomatic hypotension occurred in only 2.2% of patients with moderate left ventricular dysfunction after treatment with enalapril. If hypotension does occur the patient may be dehydrated, in which case a treatment can often be restarted after correction of dehydration; obstructive valve disease might be present; or the patient could have diastolic rather than systolic left ventricular dysfunction. In trials of patients with mild and moderate heart failure only small changes in serum creatinine and urea concentration (8.8 µmol/l and 1.2 mmol/l respectively) occurred after treatment. Among patients with severe heart failure, many of whom had abnormal baseline blood chemistry, serum creatinine concentration was as likely to fall as it was to increase after starting enalapril treatment. As with symptomatic hypotension, renal dysfunction is often exacerbated by dehydration. Non-steroidal anti-inflammatory drugs may also cause renal dysfunction and should be avoided if possible in patients receiving angiotensin converting enzyme inhibitors. Only a small proportion of patients with mild and moderate heart failure develop hyperkalaemia, and this has rarely been a cause of study withdrawal in any of the large trials. Dehydration, non-steroidal anti-inflammatory drugs, and potassium sparing diuretics increase the risk of hyperkalaemia. Cough is common in patients with heart failure.

There has been recent re-evaluation of the role of digoxin in heart failure. Four large, double blind, randomised, placebo controlled trials and several smaller studies have shown digoxin to be of benefit in patients with in sinus rhythm. The size of this benefit is, however, probably smaller than that achieved with angiotensin converting enzyme inhibitors, which are to be preferred for their effect on prognosis. Digoxin, however, has been convincingly shown to be of benefit when given as well as an angiotensin converting enzyme inhibitor and diuretic.The indications for digoxin are therefore as an adjunct to diuretics and angiotensin converting enzyme inhibitors in patients who remain symptomatic and as an adjunct to diuretics in symptomatic patients who cannot tolerate an angiotensin converting enzyme inhibitor. Digoxin is, of course, indicated separately for the treatment of concomitant atrial fibrillation.

Digoxin is one of the cardiac glycosides obtained naturally from the plant foxglove. Digoxin inhibits membrane bound-ATPase directly and enhance vagal activity indirectly by complex peripheral and central mechanisms. The clinically important consequences are increased contractility and excitability of contracting cells and decreased generation and propagation of electric impulses from SA and AV nodes. Digoxin may be administered by mouth or i.v. It is eliminated 85% unchanged by the kidney and the remainder is metabolized by the liver. The half-life is 36h. Digoxin has many adverse effects, some of which can be fatal. Abnormal cardiac rhythms usually take the form of ectopic dysrhythmias and heart block. Gastrointestinal effects include anorexia, which usually precedes vomiting and is a warning sign that dosage is excessive. Diarrhoea may also occur. Visual effects include disturbances of color vision, photophobia and blurring. Gynaecomastia may occur in men and breast enlargement in women with long-term use. Mental effects include confusion, restlessness, agitation, nightmares and acute psychosis.

Cardiac dysrhythmias may develop due to depletion of body potassium from therapy with diuretics. Verapamil, nifedipine, quinidine and amiodarone raise steady-state plasma digoxin concentration and digoxin dosage should be reduced if these drugs are administered concurrently.

Other vasodilators such as hydralazine and isosorbide dinitrate improves symptoms, exercise tolerance and possibly survival in patients with congestive heart failure, but is seldom used in mainstream treatment. Other forms of treatments such as b-blockers, xamoterol and calcium channel blockers are controversial at present and should not be employed till further studies shed light on their therapeutic efficacy.

Between 10 percent and 50 percent of patients with heart failure have concomitant atrial fibrillation.

Four questions need to be asked before management is started:

1.         Is atrial fibrillation the cause or consequence of heart failure?

2.         Could the patient have mitral valve disease?

3.         Could the patient have thyrotoxicosis?

4.         Is atrial fibrillation part of sick sinus syndrome?

Control of ventricular rate is usually achieved with digoxin; if there is difficulty consider amiodarone but remember that plasma digoxin concentrations may rise. Thromboembolism should be prevented, and recent trials have shown substantial benefit of warfarin. Amiodarone prolongs the effective refractory period of myocardial cells, the AV node and of anomalous pathways. It also blocks b-adrenoceptors noncompetitively. Amiodarone is effective given orally. It is stored in fat and many other tissues with a half-life of 54 days. The drug is metabolized in the liver and eliminated via the biliary and intestinal tracts. Adverse cardiovascular effects include bradycardia, heart block and induction of ventricular dysrhythmias. Other effects are the development of corneal microdeposits which cause visual haloes and photophobia. Less commonly, pulmonary fibrosis and hepatitis occur. Interaction with digoxin and with warfarin increasing the effect of both these drugs. As they may administered at the same time to this patient, care must be taken to reduce the dosage accordingly and to monitor for any adverse drug interactions.