The kidney is a complex organ maintaining fluid, electrolyte and acid–base balance. It also serves an endocrine function by secreting renin and erythropoietin.
The kidney is a complex organ maintaining fluid, electrolyte and acid–base balance. It also serves an endocrine function by secreting renin and erythropoietin. Diuretics are drugs that act on the kidney (see Figure 22.1) to increase urine production and can be divided into the following groups:
Carbonic anhydrase inhibitors.
Figure 22.1 Main sites of action of the diuretics.
Bendroflumethiazide, Chlorothiazide, Metolazone
Thiazides (which are chemically related to the sulfonamides) are widely used in the treatment of mild heart failure and hypertension, alone or in combination with other drugs. They have also been used in diabetes insipidus where they act by a complex (not fully understood) mechanism, initially causing a diuresis by decreasing Na+ and water reabsorption in the distal convoluted tubule which in turn reduces glomerular filtration, thereby enhancing Na+ and water absorption in the proximal tubule. In addition, they have been used in renal tubular acidosis. The main difference among the drugs is their rate of absorption from the gut due to differences in lipid solubility and rate of onset and duration of action due to differences in handling by the renal tubule.
Mechanism of Action
Thiazides are moderately potent and act mainly on the early segment of the distal tubule by inhibiting Na+ and Cl− reabsorption. This leads to increased Na+ and Cl− excretion and therefore increased water excretion. The increased Na+ load reaching the distal tubule stimulates an exchange with K+ and H+ so that thiazides tend to precipitate a hypokalaemic, hypochloraemic alkalosis. Thiazides also reduce carbonic anhydrase activity resulting in an increased bicarbonate excretion; however, this effect is small and of little clinical significance.
Metolazone has very powerful synergistic effects when combined with a loop diuretic and is useful in cases of severe oedema.
Cardiovascular – thiazides appear to produce their antihypertensive effect by a reduction in plasma volume and systemic vascular resistance, which is maximally achieved at low dose.
Renal – they reduce renal blood flow and may cause a reduction in glomerular filtration rate.
Biochemical – their actions on the kidney lead to various biochemical imbalances. Hypokalaemia may provoke dangerous arrhythmias in those patients taking digoxin concurrently, although oral K+ supplements usually maintain plasma levels within normal limits. Combination with a K+ sparing diuretic may help to control plasma K+. Hypercalcaemia may result from reduced renal Ca2+ excretion. Thiazides may also precipitate a hypochloraemic alkalosis, hyponatraemia and hypomagnesaemia. Thiazides and uric acid are secreted by the same mechanism within the renal tubules. This competition leads to reduced uric acid excretion and a rise in plasma levels, which may precipitate gout.
Metabolic – reduced glycogenesis and insulin secretion coupled with enhanced glycogenolysis tends to raise plasma glucose levels. These effects are most noticeable in diabetic patients. Thiazides increase plasma cholesterol and triglyceride levels.
Haematological – various blood dyscrasias are occasionally seen and include aplastic and haemolytic anaemia, leucopenia, agranulocytosis and thrombocytopenia.
Miscellaneous – impotence, rash and photosensitivity occur rarely. Bendroflumethiazide may precipitate pancreatitis.
Interactions – the hypokalaemia produced by thiazides may prolong the duration of action of non-depolarising muscle relaxants. Non-steroidal anti-inflammatory drugs antagonise the effects of thiazides.