Potassium depletion. Diuretics, which act at sites 1, 2 and 3 (Fig. 26.1), cause more sodium to reach the sodium-potassium exchange site in the distal tubule (site 4) and so increase potassium excretion. This subject warrants discussion since hypokalemia may cause cardiac arrhythmia in patients at risk (for instance patients receiving digoxin). The safe lower limit for serum potassium concentration in such patients is normally quoted as 3.5mmol/l. Whether or not diuretic therapy causes significant lowering of serum potassium depends both on the drug and on the circumstances in which it is used.
• The loop diuretics cause a smaller fall in serum potassium than do the thiazides, for equivalent diuretic effect, but have a greater capacity for diuresis, i.e. higher efficacy especially in large dose, and so are associated with greater decline in potassium. If diuresis is brisk and continuous, clinically important potassium depletion is likely to occur.
• Low dietary intake of potassium predisposes to hypokalaemia; the risk is particularly notable in the elderly, many of whom ingest less than 50 mmol per day (the dietary normal is 80 mmol).
• Hypokalaemia may be aggravated by other drugs, e.g. P2-adrenoceptor agonists, theophylline, corticosteroids, amphotericin.
• Hypokalaemia during diuretic therapy is also more likely in hyperaldosteronism, whether primary or more commonly secondary to severe liver disease, congestive cardiac failure or nephrotic syndrome.
• Potassium loss occurs with diarrhoea, vomiting or small bowel fistula, and may be aggravated by diuretic therapy.
• When a thiazide diuretic is used for hypertension, there is probably no case for routine prescription of a potassium supplement if no predisposing factors are present (see Ch. 24).
Potassium depletion can be minimised or corrected by:
• Maintaining a good dietary potassium intake (fruits, fruit juices, vegetables)
• Combining a potassium-depleting with a potassium-sparing drug
• Intermittent use of potassium-losing drugs, i.e. drug holidays
• Potassium supplements: KC1 is preferred because chloride is the principal anion excreted along with sodium when high efficacy diuretics are used. Potassium-sparing diuretics generally defend serum potassium more effectively than potassium supplements. Formulations of the latter include: potassium chloride sustained-release tabs (Slow-K tabs) containing 8 mmol each of potassium and chloride; potassium chloride effervescent tabs (Sando-K tabs) containing 12 mmol of potassium and 8 mmol of chloride. All forms of potassium are irritant to the gastrointestinal tract and in the oesophagus may even cause ulceration. The elderly, in particular, should be warned never to take such tablets dry but always with a large cupful of liquid and sitting upright or standing.
Hyperkalaemia may occur especially if a potassium-sparing diuretic is given to a patient with impaired renal function. Angiotensin-coverting enzyme (ACE) inhibitors and angiotensin II receptor antagonists can also cause modest elevation of plasma potassium. They may cause dangerous hyperkalaemia if combined with KC1 supplements or other potassium-sparing drugs, in the presence of impaired renal function. With suitable monitoring, however, the combination can be used safely, as well illustrated by the RALES trial (see p. 517, and footnote 3). Ciclosporin, tacrolimus, indometacin and possibly other NSAIDs may cause hyperkalaemia with the potassium-sparing diuretics.
Hypovolaemia can result from overtreatment. Acute loss of excessive fluid leads to postural hypotension and dizziness. A more insidious state of chronic hypovolaemia can develop especially in the elderly. After initial benefit, the patient becomes sleepy and lethargic. Blood urea concentration rises and sodium concentration may be low. Renal failure may result.
Urinary retention. Sudden vigorous diuresis can cause acute retention of urine in the presence of bladder neck obstruction, e.g. due to prostatic enlargement.
Hyponatraemia may result if sodium loss occurs in patients who drink a large quantity of water when taking a diuretic. Other mechanisms are probably involved, including enhancement of antidiuretic hormone release. Such patients have reduced total body sodium and extracellular fluid and are oedema-free. Discontinuing the diuretic and restricting water intake are effective. The condition should be distinguished from hyponatraemia with oedema which develops in some patients with congestive
Depends on the severity and the following measures are appropriate:
• Any potassium-sparing diuretic should be discontinued.
• A cation-exchange resin, e.g. polystyrene sulphonate resin (Resonium A, Calcium Resonium.see later) can be used orally (more effective than rectally) to remove body potassium via the gut.
• Potassium may be moved rapidly from plasma into cells by giving:
(1) Sodium bicarbonate. 50 ml of 8.4% solution through a central line, and repeated in a few minutes if characteristic £CG changes persist.
(2) Glucose, 50 ml of 50% solution, plus 10 units of soluble insulin by i.v. infusion.
(3) Nebulised fj,-agonist, salbutamol 5-10 mg. is effective in stimulating the pumping of potassium into skeletal muscle.
• In the presence of ECG changes, calcium gluconate, 10 ml of the 10% solution, should be given i.v. and repeated if necessary in a few minutes; it has no effect on the serum potassium but opposes the myocardial effect of an elevated serum potassium. Calcium may potentiate digoxln and should be used cautiously, if at all. in a patient taking this drug. Sodium bicarbonate and calcium salt must not be mixed in a syringe or reservoir becuse calcium precipitates.
• Dialysis may be needed in refractory cases and is highly effective-
cardiac failure, cirrhosis or nephrotic syndrome. Here salt and water intake should be restricted because extracellular fluid volume is expanded.
The combination of a potassium-sparing diuretic and ACE inhibitor can also cause severe hyponatraemia, more commonly indeed than life-threatening hyperkalemia.
Urate retention with hyperuricaemia and, sometimes, clinical gout occurs with the high and moderate efficacy diuretics, but the effect is unimportant or negligible with the low efficacy diuretics. Two mechanisms appear to be responsible. First, diuretics cause volume depletion, reduction in glomerular filtration and increased aborption of almost all solutes in the proximal tubule including urate. Second, diuretics and uric acid are organic acids and compete for the transport mechanism which carries such substances from the blood into the tubular fluid. Diuretic-induced hyperuricaemia can be prevented by allopurinol or probenecid (which also antagonises diuretic efficacy by reducing their transport into the urine).
Magnesium deficiency. Loop and thiazide diuretics cause significant urinary loss of magnesium; potassium-sparing diuretics probably also cause magnesium retention. Magnesium deficiency brought about by diuretics seems rarely to be severe enough to induce the classic picture of neuromuscular irritability and tetany but cardiac arrhythmias, mainly of ventricular origin, do occur and respond to repletion of magnesium (8 mmol of Mg++ is given as 4 ml of 50% magnesium sulphate infused i.v. over 10-15 min followed by up to 72 mmol infused over the next 24 h).
Carbohydrate intolerance is caused by those diuretics which produce prolonged hypokalaemia, i.e. the loop and thiazide type. It appears that intracellular potassium is necessary for the formation of insulin, and glucose intolerance is probably due to insulin deficiency. Insulin requirements thus increase in established diabetics and the disease may become mainifest in latent diabetics. The effect is generally reversible over several months.
Calcium homeostasis. Renal calcium loss is increased by the loop diuretics; in the short term this is not a serious disadvantage and indeed frusemide may be used in the management of hypercalcaemia after rehydration has been achieved. In the long term hypocalcaemia may be harmful especially in elderly patients who tend in any case to be in negative calcium balance. Thiazides, by contrast, decrease renal excertion of calcium and this property may influence the choice of diuretic in a potentially calcium deficient or osteoporotic individual, for thiazide use is associated with reduced risk of hip fracture in the elderly. The hypocalciuric effect of the thiazides has also been used effectively in patients with idiopathic hypercalciuria, the commonest metabolic cause of renal stones.
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