DIURETICS

Some thirty years ago the treatment of aedema in cardiac failure was revolu¬tionized by the organic mercurial diuretics. Efficient and powerful, they rapidly ousted older preparations and were hailed as the greatest advance in cardiac therapeutics since the introduction of digitalis by Withering. A similar revolu¬tion has occurred in the last few years with the introduction of oral diuretic drugs of comparable potency in which ease of administration amply counterbalance's their slightly less powerful action. The range of these is steadily extending.

The doctor thus has now at his disposal a number of powerful diuretics for the treatment of cardiac aedema. For their skilled use, and particularly for an understanding of their success or failure in any given case, it is necessary for him to have some knowledge of their mode of action and of the mechanisms under¬lying the causation of aedema.
Twenty years ago, aedema was considered a consequence of increased hydrostatic pressure at the venous end of the capillaries. Such increased pressure tends to force fluid out of the capillaries or hinder its reabsorption from the interstitial tissues and was accepted as a cause of aedema, particularly affecting dependent parts as in cardiac failure. This increased intravascular pressure is to some extent augmented by lowered plasma osmotic pressure in many patients with cardiac failure, in whom a low total plasma protein concen¬tration and particularly a low plasma albumin are common. It is now known that the cause of aedema is much more complex. Apparently the kidney plays a dominant role and retention of sodium, chloride and water plays an essential part. The low cardiac output in heart failure with impairment of renal blood supply, associated with a high pressure in the renal veins as part of the general increased venous pressure, seemed for a time the factor determining retention of water and electrolytes. Now, however, other fundamental aspects of renal^ physiology are known to be involved. It is accepted that the filtration theory of renal function is correct and that a large volume of nitrate pours through the glomeruli into the renal tubules each minute. Of this, some 97 per cent. is reabsorbed in the tubules, together with a considerable quantity of sodium, potassium, chloride and other ions. Clearly, since the litre or litre and a half of urine normally secreted in a day represents only some 3 per cent. of the glo-merular filtrate, any small change in the rate of reabsorption taking place in the tubules will have a dominant effect both on the volume of urine secreted and on the total quantity of fluid and electrolytes remaining in the body. It has become recognized that the primary defect in the genesis of oedema is increased reabsorp¬tion of sodium, of chloride and, as a secondary phenomenon, of water in the renal tubules. The adrenocortical hormones play an important role in controlling electrolyte and water reabsorption, and there is evidence that in oedematous states of diverse origin there is increased secretion in the body of the potent mineralocorticoid, aldosterone. This steroid has a specific effect on renal tubular function, promoting reabsorption of sodium and chloSde and loss of potassium. There has been also increased understanding of the mechanisms by which reabsorption of various anions and cations occurs, and in particular the role of carbonic anhydrase in promoting reabsorption of sodium chloride has become clear. The newer diuretics have been studied in considerable detail in relation to those aspects of renal physiology, and in using them attention must be paid not only to their potent action in promoting increased loss of water but to their effects upon individual electrolytes, including sodium, potassium, chloride and bicarbonate. Further, the recognition of the role of aldosterone in promoting oedema has led to the discovery of specific antagonists to this steroid— the spironolactones—now established therapeutic agents.
Mercurial diuretics act by interfering with the mechanisms for absorption of sodium and/or chloride in the proximal tubule. This may not be the whole story, since potassium secretion can also be affected and this is primarily a function of the distal tubules. The action of the mercurials is profoundly influenced by the acid base balance and the enhanced activity of these diuretics when acidosis is induced with ammonium chloride is utilized in therapeutics. Mercurial diuretics lose their effect under two main circumstances : first, when congestive failure is severe and there is marked reduction in renal blood flow with a fall in glomerular filtration rate ; and secondly, when there is hypochlo-rasmic alkalosis associated with hyponatrsemia. The importance of these factors in the management of the patient with so-called resistant oedema is discussed below.
Organic Mercurial Diuretics.—The most popular organic mercurial diuretic is mersalyl B.P., dispensed in ampoules of 2 ml. containing 10 per cent. of the sodium salt of mersalyl acid with 5 per cent. of theophylline in water. It should be administered by deep intramuscular injection; it is active when given intravenously, but by this route it can cause severe, even fatal, reactions; it should never be injected subcutaneously because it then causes intense irritation and may produce sloughing. Commonly a test dose of 0-5 ml. is given initially followed next day by the full 2 ml. injection. The drug may be given on alter¬nate days or every third day. The action can be enhanced by previous adminis¬tration of ammonium chloride 3 g. (30 gr.) in tablets given orally two hours before the injection. Its action commences within an hour or two and persists for eight to twelve hours. The drug should, therefore, be given in the morning since if administered late in the day the patient's sleep may be disturbed. The effect of mersalyl on the water-logged patient may be dramatic : a diuresis of 2 or 3 litres is common, larger diureses up to 4 or 5 litres are sometimes observed and on occasion a dramatic fluid loss of up to 8 to 10 litres has been recorded after a single injection. In a few patients the effect persists into the second day, ' but usually the urinary output on the day following administration falls to below
the oliguric level which obtained before the mersalyl was given.
Mersalyl is relatively non-toxic. It can on occasion produce side reactions, notably skin rashes which may inconvenience the patient and may preclude further injections. More serious is the potential poisonous action of mercury on • the kidney, fortunately a rare occurrence but liable to appear if the drug is given to a patient with active renal inflammation, such as acute glomerulonephritis. In cardiac failure toxic reactions may occur if repeated doses of mersalyl are given without a diuretic response ; then the mercury tends to accumulate in the body and a mercurial nephrosis may result. Its other side-effects are related to its action and consist in salt depletion, which is discussed in detail below.
Attempts have been made to find a substitute for mersalyl suitable for sub¬cutaneous injection. While some preparations have proved moderately success¬ful, their use has been superseded by the advent of the newer oral diuretics. •
Acetazolamide.—This is a carbonic anhydrase inhibitor. It acts on the renal tubules to increase excretion of sodium and bicarbonate and also of potassium but not chloride. It thus produces an alkaline urine and a metabolic acidosis. Its action is self-limiting since, with the elimination of bicarbonate, the substrate, on which the carbonic anhydrase inhibitor acts, diminishes. Its
action is too transient and it is not a useful diuretic.
Thiazide Group.—A group of oral diuretics of major therapeutic impor¬tance is the thiazides of which chlorothiazide was the first member to be intro¬duced, followed by a succession of modifications which are substantially more potent than the parent substance. These include hydrochlorothiazide, hydro-flumethiazide and a number of substituted forms such as bendrofluazide. The actions of all these drugs are similar and they differ primarily in their effective dosage, hydrochlorothiazide and hydroflumethiazide (50 mg. dose) being some ten times as potent on a weight to weight basis as chlorothiazide (0-5 g. dose), while bendrofluazide (2-5 mg. dose) is 200 times as potent. Their primary action is on sodium and chloride excretions, which are greatly increased. The effects on potassium and bicarbonate ions are less marked. The increased excretion of water is secondary to the salt loss. These drugs do not lose their effectiveness with continued administration as happens with carbonic anhydrase inhibitors, and their action is rapid. Their principal disadvantage is the production of potassium deficiency—an effect which results from their pharmacological action and hence is not truly toxic. Toxic effects, such as skin rashes and gastro-intestinal irritation, are uncommon. One side-effect is their tendency to cause a rise in the blood uric acid. This may rarely be associated with a clinical attack of gout, and the drugs have been known to precipitate an acute attack in individuals with no previous history of the disorder. The risk is increased in the subjects of gross polycythasmia, as e.g. in cyanotic congenital heart disease.
This tendency may preclude their use in some patients.
Equivalent doses of those drugs are : chlorothiazide 0-5 g. twice daily,
hydrochlorothiazide, hydroflumethiazide 50 mg. twice daily and bendrofluazide 5 mg. once daily, for three consecutive days in each week. During this period it is wise to administer effervescent potassium tablets two or three times a day to balance potassium loss. This may be very serious in a patient already depleted of that element and particularly in one who is fully digitalized.
The drug firms were quick to recognize the value of such potassium supple¬ments, and there are many preparations on the market incorporating one or other thiazide with a potassium salt. These are widely prescribed, but it should be realized that such fixed-proportion " package-deal " tablets allow no latitude for individual patient's needs, and further and more seriously, these enteric-coated tablets loaded with a salt have led to numerous instances of damage (haemorrhage or perforation) to the small intestine.
Other Oral Diuretics.—A variety of other oral diuretic drugs is now available, and the number steadily increases. Three only will be cited here.
Chlorthalidone is a powerful diuretic of the sulphamyi type. Given in a dose of 0-4 g. twice or thrice weekly it has an effect comparable to the thiazide drugs.
Triamterene is chemically unrelated to the sulphamyi group and differs in its action in that, while promoting excretion of water and sodium, it conserves potassium. A potent diuretic in its own right, its most important role is as an adjuvant to the thiazides. Given with the latter it is claimed to eliminate the need for potassium supplements, and a combined preparation (triamterene) is available. The average daily dose of triamterene is 0-15 g., in three divided doses.
Frusemide is not a thiazide but incorporates the potent sulphamoyl group. 'It is a powerful diuretic with a prompt short-lived action. Given orally, it acts within an hour : given intravenously in 30 minutes. The action is over in four to five hours but is intense, so that some caution in administration must be observed. A diuresis of over six litres has followed administration of 0-2 g., and such sudden loss of water and dissolved electrolytes may be hazardous. The oral dosage in severe heart failure should be of the order of 80 to 240 mg., the intravenous dose 20 to 60 mg. This latter is for patients in acute left ventricular failure, in whom the speedy brief action of the drug is of especial value. Fruse¬mide does not cause disproportionate potassium, loss, but with massive diuresis hypokalaemia is a possible sequel to be foreseen and prevented by preliminary potassium loading.
Any of these drugs is worthy of trial in a case of, resistant heart failure, when mercurials and thiazides have failed. Whether any (e.g. frusemide) will evntually replace the thiazides as the drug of choice is uncertain.