Osmotic diuretics such as mannitol are non-resorbable solutes which retain water in the tubular fluid (Site 1, Fig. 27.1). Their effect is to increase water rather than sodium loss, and this is reflected in their special use acutely to reduce intracranial or intraocular pressure and not states associated with sodium overload.

Loop of Henle

The tubular fluid now passes into the loop of Henle where 25% of the filtered sodium is reabsorbed. There are two populations of nephron: those with short loops that are confined to the cortex, and the juxtamedullary nephrons whose long loops penetrate deep into the medulla and are concerned principally with water conservation;¹ the following discussion refers to the latter.

The physiological changes are best understood by considering first the ascending limb. In the thick segment (Site 2, Fig. 27.1), sodium and chloride ions are transported from the tubular fluid into the interstitial fluid by the three-ion co-transporter system (i.e. Na⁺/K⁺/2Cl⁻ called NKCC2) driven by the sodium pump. The co-transport of these ions is dependent on potassium returning to the lumen through the rectifying outer medullary potassium (ROMK) channel; otherwise potassium would be rate limiting. As the tubule epithelium is ‘tight’ here, i.e. impermeable to water, the tubular fluid becomes dilute, the interstitium becomes hypertonic, and fluid in the adjacent descending limb, which is permeable to water, becomes more concentrated as it approaches the tip of the loop, because the hypertonic interstitial fluid sucks water out of this limb of the tubule. The ‘hairpin’ structure of the loop thus confers on it the property of a countercurrent multiplier, i.e. by active transport of ions a small change in osmolality laterally across the tubular epithelium is converted into a steep vertical osmotic gradient.

The high osmotic pressure in the medullary interstitium is sustained by the descending and ascending vasa recta, long blood vessels of capillary thickness that lie close to the loops of Henle and act as countercurrent exchangers, for the incoming blood receives sodium from the outgoing blood.²Furosemide, bumetanide, piretanide, torasemide and ethacrynic acid act principally at Site 2 by inhibiting the three-ion transporter, thus preventing sodium ion reabsorption and lowering the osmotic gradient between cortex and medulla; this results in the formation of large volumes of dilute urine. Hence, these drugs are called ‘loop’ diuretics.

Distal convoluted tubule

The ascending limb of the loop then re-enters the renal cortex where its morphology changes into the thin-walled distal convoluted tubule (Site 3, Fig. 27.1). Here uptake is still driven by the sodium pump but sodium and chloride are taken up through a different transporter, the Na–Cl co-transporter, called NCC (formerly NCCT). Both ions are rapidly removed from the interstitium because cortical blood flow is high and there are no vasa recta present; the epithelium is also tight at Site 3 and consequently the urine becomes more dilute. Thiazides act principally at this region of the cortical diluting segment by blocking the NCC transporter.

Collecting duct

In the collecting duct (Site 4), sodium ions are exchanged for potassium and hydrogen ions. The sodium ions enter through the epithelial Na channel (called ENaC), which is stimulated by aldosterone. The aldosterone (mineralocorticoid) receptor is inhibited by the competitive receptor antagonist spironolactone, whereas the sodium channel is inhibited by amiloride and triamterene. All three of these diuretics are potassium sparing because potassium is normally secreted through the potassium channel, ROMK (see Fig. 27.1), down the potential gradient created by sodium reabsorption.

All other diuretics, acting proximal to Site 4, cause potassium loss, because they dump sodium into the collecting duct. Removal of this sodium through ENaC increases the potential gradient for potassium secretion through ROMK. The potassium-sparing diuretics are normally considered weak diuretics because Site 4 is normally responsible for ‘only’ 2–3% of sodium reabsorption, and they usually cause less sodium loss than thiazides or loop diuretics. Nevertheless, patients with genetic abnormalities of ENaC show salt wasting or retention to a degree that significantly affects their blood pressure, depending on whether the mutation causes, respectively, loss or gain of channel activity. Although ENaC clearly does not have the capacity to compensate for large sodium losses, e.g. during loop diuretic usage, it is the main site of physiological control (via aldosterone) over sodium loss.

The collecting duct then travels back through the medulla to reach the papilla; in doing so it passes through a gradient of increasing osmotic pressure which draws water out of tubular fluid. This final concentration of urine is under the influence of antidiuretic hormone (ADH) whose action is to increase water permeability by increasing the expression of specific water channels (or aquaporins); in its absence water remains in the collecting duct. Ethanol causes diuresis by inhibiting the release of ADH from the posterior pituitary gland.

Diuresis may also be achieved by extrarenal mechanisms, by raising the cardiac output and increasing renal blood flow, e.g. with dobutamine and dopamine.

Classification

The maximum efficacy in removing salt and water that any drug can achieve is dependent on its site of action, and it is appropriate to rank diuretics according to their natriuretic capacity, as set out below. The percentages refer to the highest fractional excretion of filtered sodium under carefully controlled conditions and should not be taken to represent the average fractional sodium loss during clinical use.

High efficacy

Furosemide

and the other ‘loop’ diuretics can cause up to 25% of filtered sodium to be excreted. Their action impairs the powerful urine-concentrating mechanism of the loop of Henle and confers higher efficacy compared with drugs that act in the relatively hypotonic cortex (see below). Progressive increase in dose is matched by increasing diuresis, i.e. they have a high ‘ceiling’ of effect. In fact, they are so effective that over-treatment can readily dehydrate the patient. Loop diuretics remain effective at a glomerular filtration rate (GFR) below 10 mL/min (normal 120 mL/min).

Moderate efficacy

The thiazide family,

including bendroflumethiazide and the related chlortalidone, clopamide, indapamide, mefruside, metolazone and xipamide, cause 5–10% of filtered sodium load to be excreted. Increasing the dose produces relatively little added diuresis compared to loop diuretics, i.e. they have a low ‘ceiling’ of effect. Such drugs cease to be effective once the GFR has fallen below 20 mL/min (except metolazone).

Low efficacy

Triamterene, amiloride and spironolactone

cause 2–3% of the filtered sodium to be excreted. They are potassium sparing and combine usefully with more efficacious diuretics to prevent the potassium loss, which other diuretics cause.

Osmotic diuretics,

e.g. mannitol, also fall into this category.

Individual diuretics

High-efficacy (loop) diuretics

Moderate-efficacy diuretics

(See also Hypertension, Ch. 24.)

Thiazides

Thiazides depress salt reabsorption in the distal convoluted tubule (at Site 3), i.e. upstream of the region of sodium–potassium exchange at Site 4. Hence these drugs have the important effect of raising potassium excretion. Thiazides lower blood pressure, initially due to a reduction in intravascular volume but chronically by a reduction in peripheral vascular resistance. The latter is accompanied by diminished responsiveness of vascular smooth muscle to noradrenaline/norepinephrine; they may also have a direct action on vascular smooth muscle membranes, acting on an as yet unidentified ion channel.

Uses

Thiazides are given for mild cardiac failure and mild hypertension, or for more severe degrees of hypertension, in combination with other drugs.

Pharmacokinetics

Thiazides are generally well absorbed orally and most begin to act within an hour. Differences among the numerous derivatives lie principally in duration of action. The relatively water-soluble, e.g. cyclopenthiazide, chlorothiazide, hydrochlorothiazide, are most rapidly eliminated, their peak effect occurring within 4–6 h and passing off by 10–12 h. They are excreted unchanged in the urine and active secretion by the proximal renal tubule contributes to their high renal clearance and t_½ of less than 4 h.

The relatively lipid-soluble members of the group, e.g. polythiazide, hydroflumethiazide, distribute more widely into body tissues and act for > 24 h, which can be problematic if the drug is used for diuresis, but there is no evidence this property makes them more effective at controlling hypertension. With the exception of metolazone, thiazides are not effective when renal function is moderately impaired (GFR < 20 mL/min), because they are not filtered in sufficient concentration to inhibit the NCC.

Adverse effects

in general are discussed below. Rashes (sometimes photosensitive), thrombocytopenia and agranulocytosis occur. Thiazide-type drugs increase total plasma cholesterol concentration, but in long-term use this is less than 5%, even at high doses. The questions about the appropriateness of thiazides for mild hypertension, of which ischaemic heart disease is a common complication, are laid to rest by their proven success in randomised outcome comparisons (see Ch. 24).

Bendroflumethiazide

is a satisfactory member for routine use. For a diuretic effect the oral dose is 5–10 mg, which usually lasts less than 12 h, so that it should be given in the morning. As an antihypertensive, 2.5 mg is commonly prescribed. However, this dose does not achieve maximal blood pressure reduction in patients with salt-dependent hypertension (which includes most patients receiving a blocker of the renin–angiotensin system), and has not been shown to prevent strokes or heart attacks. New guidance is likely to recommend some return to higher doses – and/or greater use of the thiazide-like diuretics (below), with or without co-prescribed K⁺-sparing diuretic. Important potassium depletion is uncommon, but plasma potassium concentration should be checked in potentially vulnerable groups such as the elderly (see Ch. 25). If marked hypokalaemia occurs hyperaldosteronism should be excluded.

Hydrochlorothiazide is a satisfactory alternative. Other members of the group include benzthiazide, chlorothiazide, cyclopenthiazide, hydroflumethiazide and polythiazide.

Diuretics related to the thiazides

Several compounds, although not strictly thiazides, share structural similarities with them and probably act at the same site on the nephron; they therefore exhibit moderate therapeutic efficacy. Overall, these substances have a longer duration of action, are used for oedema and hypertension, and their profile of adverse effects is similar to that of the thiazides. They are listed below.

Chlortalidone acts for 48–72 h after a single oral dose.

Indapamide is structurally related to chlortalidone but lowers blood pressure at subdiuretic doses, perhaps by altering calcium flux in vascular smooth muscle. It has less apparent effect on potassium, glucose or uric acid excretion (see below).

Metolazone is effective when renal function is impaired. It potentiates the diuresis produced by furosemide and the combination can be effective in resistant oedema, although the risk of hypokalaemia is very high.

Xipamide is structurally related to chlortalidone and to furosemide. It induces a diuresis for about 12 h that is brisker than with thiazides; this may trouble the elderly.

Low-efficacy diuretics

Spironolactone

(Aldactone) is structurally similar to aldosterone and competitively inhibits its action in the distal tubule (Site 4; exchange of potassium for sodium); excessive secretion of aldosterone contributes to fluid retention in hepatic cirrhosis, nephrotic syndrome, congestive heart failure (see specific use in Ch. 25) and primary hypersecretion (Conn’s syndrome). Spironolactone is also useful in the treatment of resistant hypertension, where increased aldosterone sensitivity is increasingly recognised as a contributory factor.

Spironolactone itself has a short t_½ (1.6 h), being extensively metabolised, and its prolonged diuretic effect is due to the most significant active product, canrenone (t_½ 17 h). Spironolactone is relatively ineffective when used alone but is more efficient when combined with a drug that reduces sodium reabsorption proximally in the tubule, i.e. a loop diuretic. Spironolactone (and amiloride and triamterene; see below) usefully reduces the potassium loss caused by loop diuretics, but its combination with another potassium-sparing diuretic must be avoided as hyperkalaemia will result. Dangerous potassium retention is particularly likely if spironolactone is given to patients with impaired renal function. It is given orally in one or more doses totalling 100–200 mg/day. Maximum diuresis may not occur for up to 4 days. If after 5 days the response is inadequate, the dose may be increased to 300–400 mg/day. Lower doses (0.5–1 mg/kg) are required to treat hypertension.

Adverse effects. Oestrogenic effects are the major limitation to its long-term use. They are dose dependent, but in the Randomized Aldactone Evaluation Study (RALES)³ (see Ch. 25) even 25 mg/day caused breast tenderness or enlargement in 10% of men. Women may also report breast discomfort or menstrual irregularities, including amenorrhoea. Minor gastrointestinal upset also occurs and there is increased risk of gastroduodenal ulcer and bleeding. These are reversible on stopping the drug. Spironolactone is reported to be carcinogenic in rodents, but many years of clinical experience suggest that it is safe in humans. Nevertheless, the UK licence for its use in essential hypertension was withdrawn (i.e. possible use long term in a patient group that includes the relatively young), but is retained for other indications.

Eplerenone

is a spironolactone analogue licensed for use in heart failure that appears to be free of the oestrogenic effects; probably because of its lower affinity for the oestrogen receptor. It is useful in patients who need an aldosterone-receptor blocking agent, but are intolerant of the endocrine effects of spironolactone.

Amiloride

blocks the ENaC sodium channels in the distal tubule. This action complements that of the thiazides with which it is frequently combined to increase sodium loss and limit potassium loss. One such combination, co-amilozide (Moduretic; amiloride 2.5–5 mg plus hydrochlorothiazide 25–50 mg) is used for hypertension or oedema. The maximum effect of amiloride occurs about 6 h after an oral dose, with a duration of action greater than 24 h (t_½ 21 h). The oral dose is 5–20 mg daily.

Triamterene

(Dytac) is a potassium-sparing diuretic with an action and use similar to that of amiloride. The diuretic effect extends over 10 h. Gastrointestinal upsets occur. Reversible, non-oliguric renal failure may occur when triamterene is used with indometacin (and presumably other NSAIDs). It may also give the urine a blue coloration.

Indications for diuretics

• Oedema states associated with sodium overload, e.g. cardiac, renal or hepatic disease, and also without sodium overload, e.g. acute pulmonary oedema following myocardial infarction. Note that oedema may also be localised, e.g. angioedema over the face and neck or around the ankles with some calcium channel blockers, or due to low plasma albumin, or immobility in the elderly; in none of these circumstances is a diuretic indicated.

• Hypertension, by reducing intravascular volume and probably by other mechanisms too, e.g. reduction of sensitivity to noradrenergic vasoconstriction.

• Hypercalcaemia. Furosemide reduces calcium reabsorption in the ascending limb of the loop of Henle, which action may be utilised in the emergency reduction of raised plasma calcium levels in addition to rehydration and other measures.

• Idiopathic hypercalciuria, a common cause of renal stone disease, may be reduced by thiazide diuretics.

• The syndrome of inappropriate secretion of antidiuretic hormone secretion (SIADH) may be treated with furosemide if there is a dangerous degree of volume overload (see also p. 423).

• Nephrogenic diabetes insipidus, paradoxically, may respond to diuretics which, by contracting vascular volume, increase salt and water reabsorption in the proximal tubule, and thus reduce urine volume.

Therapy

Congestive cardiac failure

The main account appears in Chapter 25, where the emphasis is now on early use of angiotensin-converting enzyme (ACE) inhibitors and β-adrenoceptor antagonists that are specifically diuretic sparing. But oral diuretics are easily given repeatedly, and lack of supervision can result in insidious over-treatment. Relief at disappearance of the congestive features can mask exacerbation of the low-output symptoms of heart failure, such as tiredness and postural dizziness due to reduced blood volume. A rising blood urea level is usually evidence of reduced glomerular blood flow consequent on a fall in cardiac output, but does not distinguish whether the cause of the reduced output is over-diuresis or worsening of the heart failure itself. The simplest guide to the success or failure of diuretic regimens is to monitor body-weight, which the patient can do equipped with just bathroom scales. Fluid intake and output charts are more demanding of nursing time, and often less accurate.

Acute pulmonary oedema: left ventricular failure

(See p. 425.)

Renal oedema

The chief therapeutic aims are to reduce dietary sodium intake and to prevent excessive sodium retention using diuretic drugs. Reduction of sodium reabsorption in the renal tubule by diuretics is most effective where glomerular filtration has not been seriously reduced by disease. Furosemide and bumetanide are effective even when the filtration rate is very low; furosemide may usefully be combined with metolazone but the resulting profound diuresis requires careful monitoring. Secondary hyperaldosteronism complicates the nephrotic syndrome because albumin loss causes plasma colloid pressure to fall, and the resulting diversion of intravascular volume to the interstitium activates the renin–angiotensin–aldosterone system; spironolactone may then be added usefully to potentiate a loop diuretic and to conserve potassium, loss of which can be severe.

Hepatic ascites

(See also p. 550.)

Ascites and oedema are due to portal venous hypertension together with decreased plasma colloid osmotic pressure causing hyperaldosteronism as with nephrotic oedema (above). Furthermore, diversion of renal blood flow from the cortex to the medulla favours sodium retention. In addition to dietary sodium restriction, spironolactone is the preferred diuretic to produce a gradual diuresis; too vigorous depletion of sodium with added potassium loss and hypochloraemic alkalosis may worsen hepatic encephalopathy. Abdominal paracentesis can be very effective if combined with human albumin infusion to prevent further aggravating hypoproteinaemia.

Adverse effects characteristic of diuretics

Potassium depletion

Diuretics that act at Sites 1, 2 and 3 (see Fig. 27.1) 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 because hypokalaemia may cause cardiac arrhythmia in patients at risk (e.g. receiving digoxin). The safe lower limit for plasma potassium concentration is normally quoted as 3.5 mmol/L. Whether or not diuretic therapy causes significant lowering of serum potassium levels depends both on the drug and on the circumstances in which it is used:

• The loop diuretics produce a smaller fall in serum potassium concentration 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 levels. 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. β₂-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. 25).

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: KCl is preferred because chloride is the principal anion excreted along with sodium when high-efficacy diuretics are used. Potassium-sparing diuretics generally defend plasma potassium more effectively than potassium supplements. 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. ACE inhibitors and angiotensin II receptor antagonists can also cause a modest increase in plasma potassium levels. They may cause dangerous hyperkalaemia if combined with KCl supplements or other potassium-sparing drugs, in the presence of impaired renal function. These may not be obvious, for example, to the patient who is using an unprescribed ‘low sodium’ salt substitute to reduce their salt (NaCl) intake.⁴ However, with suitable monitoring the combination can be used safely, as was well illustrated by the RALES trial.⁵ Ciclosporin, tacrolimus, indometacin and possibly other NSAIDs may cause hyperkalaemia with the potassium-sparing diuretics.

Treatment of hyperkalaemia

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 below) can be used orally (more effective than rectally), to remove body potassium by the gut.

• Potassium may be moved rapidly from plasma into cells by giving:

sodium bicarbonate, 50 mL 8.4% solution through a central line, and repeated in a few minutes if characteristic ECG changes persist

glucose, 50 mL 50% solution, plus 10 units soluble insulin by i.v. infusion

nebulised β₂-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 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 a raised serum potassium level. Calcium may potentiate digoxin 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 because calcium precipitates.

• Dialysis may be needed in refractory cases and is highly effective.

Hypovolaemia

can result from over-treatment. 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 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 than life-threatening hyperkalaemia.

Urate retention

with hyperuricaemia and, sometimes, clinical gout occurs with thiazides and loop diuretics. The effect is unimportant or negligible with the low-efficacy diuretics, e.g. amiloride and spironolactone. Two mechanisms appear to be responsible. First, diuretics cause volume depletion, reduction in glomerular filtration and increased absorption of almost all solutes in the proximal tubule, including urate. Second, diuretics and uric acid are organic acids and compete for the transport mechanism that pumps 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 is rarely 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 (2 g or 8 mmol of Mg^2 + is given as 4 mL 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 that produce prolonged hypokalaemia, i.e. the loop and thiazide type. This may affect the depolarisation and entry of calcium into islet cells which is necessary to stimulate formation and release of insulin, so glucose intolerance is probably due to secondary insulin deficiency. Insulin requirements thus increase in established diabetics and the disease may become manifest 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 furosemide 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 excretion of calcium and this property may influence the choice of diuretic in a potentially calcium-deficient or osteoporotic individual, as thiazide use is associated with a 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.

Interactions

Loop diuretics (especially as intravenous boluses) potentiate ototoxicity of aminoglycosides and nephrotoxicity of some cephalosporins. NSAIDs tend to cause sodium retention, which counteracts the effect of diuretics; the mechanism may involve inhibition of renal prostaglandin formation. Diuretic treatment of a patient taking lithium can precipitate toxicity from this drug (the increased sodium loss is accompanied by reduced lithium excretion). Other drugs that may induce hyperkalaemia, hypokalaemia, hyponatraemia or glucose intolerance with diuretics are described above.

Abuse of diuretics

Psychological abnormality sometimes takes the form of abuse of diuretics and/or purgatives. The subject usually desires to slim to become more attractive, or may have anorexia nervosa. There can be severe depletion of sodium and potassium, with renal tubular damage due to chronic hypokalaemia.

Osmotic diuretics

Osmotic diuretics are small molecular weight substances that are filtered by the glomerulus but not reabsorbed by the renal tubule, and thus increase the osmolarity of the tubular fluid. Thus they prevent reabsorption of water (and also, by more complex mechanisms, of sodium) principally in the proximal convoluted tubule and probably also the loop of Henle. The result is that urine volume increases according to the load of osmotic diuretic.

Mannitol,

a polyhydric alcohol (mol. wt. 452), is used most commonly; it is given intravenously. In addition to its effect on the kidney, mannitol encourages the movement of water from inside cells to the extracellular fluid, which is thus transiently expanded before diuresis occurs. These properties define its uses, which are for rapid reduction of intracranial or intraocular pressure, and to maintain urine flow to prevent renal tubular necrosis. Because it increases circulatory volume, mannitol is contraindicated in congestive cardiac failure and pulmonary oedema.

Methylxanthines

The general properties of the methylxanthines (theophylline, caffeine) are discussed elsewhere (see p. 155). Their mild diuretic action probably depends in part on smooth muscle relaxation in the afferent arteriolar bed increasing renal blood flow, and in part on a direct inhibitory effect on salt reabsorption in the proximal tubule. Their uses in medicine depend on other properties.

Carbonic anhydrase inhibitors

The enzyme carbonic anhydrase facilitates the reaction between carbon dioxide and water to form carbonic acid (H₂CO₃), which then breaks down to hydrogen (H⁺) and bicarbonate () ions. This process is fundamental to the production of either acid or alkaline secretions, and high concentrations of carbonic anhydrase are present in the gastric mucosa, pancreas, eye and kidney. Because the number of H⁺ ions available to exchange with Na⁺ in the proximal tubule is reduced, sodium loss and diuresis occur. But reabsorption from the tubule is also reduced, and its loss in the urine leads within days to metabolic acidosis, which attenuates the diuretic response to carbonic anhydrase inhibition. Consequently, inhibitors of carbonic anhydrase are obsolete as diuretics, but still have specific uses. Acetazolamide is the most widely used carbonic anhydrase inhibitor.

Reduction of intraocular pressure

This action is not due to diuresis (thiazides actually raise intraocular pressure slightly). The formation of aqueous humour is an active process requiring a supply of bicarbonate ions which depends on carbonic anhydrase. Inhibition of carbonic anhydrase reduces the formation of aqueous humour and lowers intraocular pressure. This is a local action and is not affected by the development of acid–base changes elsewhere in the body, i.e. tolerance does not develop. In patients with acute glaucoma, acetazolamide can be taken either orally or intravenously. Acetazolamide is not recommended for long-term use because of the risk of hypokalaemia and acidosis, but brinzolamide or dorzolamide are effective as eye drops, well tolerated, and thus suitable for chronic use in glaucoma.

High-altitude (mountain) sickness

may affect unacclimatised people at altitudes over 3000 metres, especially after rapid ascent; symptoms range from nausea, lassitude and headache to pulmonary and cerebral oedema. The initiating cause is hypoxia: at high altitude, the normal hyperventilatory response to falling oxygen tension is inhibited because alkalosis is also induced. Acetazolamide induces metabolic acidosis, increases respiratory drive, notably at night when apnoetic attacks may occur, and thus helps to maintain arterial oxygen tension. The usual dose is 125–250 mg twice daily, given orally on the day before the ascent and continued for 2 days after reaching the intended altitude; 250 mg twice daily is used to treat established high-altitude sickness, combined with a return to a lower altitude. (Note that this is an unlicensed indication in the UK.) As an alternative or in addition to acetazolamide, dexamethasone may be used: 2 mg 6-hourly for prevention, and 4 mg 6-hourly for treatment.

The drug has two other uses. In periodic paralysis, where sudden falls in plasma K⁺ concentration occur due to its exchange with Na⁺ in cells, the rise in plasma H⁺ caused by acetazolamide provides an alternative cation to K⁺ for exchange with Na⁺. Acetazolamide may be used occasionally as a second-line drug for tonic–clonic and partial epileptic seizures.

Adverse effects

High doses of acetazolamide may cause drowsiness and fever, rashes (it is a sulfonamide-type drug) and paraesthesiae may occur (from the acidosis). Blood disorders have been reported. Renal calculi may develop, because the urine calcium is in less soluble form, owing to low citrate content of the urine, a consequence of metabolic acidosis.

Dichlorphenamide is a similar, but a more potent, inhibitor of carbonic anhydrase.

Cation-exchange resins

Cation-exchange resins are used to treat hyperkalaemia by accelerating potassium loss through the gut, especially in the context of poor urine output or before dialysis (the most effective means of treating hyperkalaemia). The resins consist of aggregations of big insoluble molecules carrying fixed negative charges, which loosely bind positively charged ions (cations); these readily exchange with cations in the fluid environment to an extent that depends on their affinity for the resin and their concentration.

Resins loaded with sodium or calcium exchange these cations preferentially with potassium cations in the intestine (about 1 mmol potassium per g resin); the freed cations (calcium or sodium) are absorbed and the resin plus bound potassium is passed in the faeces. The resin does not merely prevent absorption of ingested potassium, but it also takes up the potassium normally secreted into the intestine and ordinarily reabsorbed.

In hyperkalaemia, oral administration or retention enemas of a polystyrene sulphonate resin may be used. A sodium-phase resin (Resonium A) should obviously not be used in patients with renal or cardiac failure as sodium overload may result. A calcium-phase resin (Calcium Resonium) may cause hypercalcaemia and should be avoided in predisposed patients, e.g. those with multiple myeloma, metastatic carcinoma, hyperparathyroidism and sarcoidosis. Orally they are very unpalatable, and as enemas patients rarely manage to retain them for as long as necessary (at least 9 h) to exchange potassium at all available sites on the resin.

Alteration of urine pH

Alteration of urine pH by drugs is sometimes desirable. The most common reason is in the treatment of poisoning (a fuller account is given on p. 126). A summary of the main indications appears below.

Alkalinisation of urine:

• increases the elimination of salicylate, phenobarbital and chlorophenoxy herbicides, e.g. 2,4-D, MCPA

• treats crystal nephropathy by increasing drug solubility, e.g. of methotrexate, sulphonamides and triamterene. NB indinavir requires acidification

• reduces irritation of an inflamed urinary tract

• discourages the growth of certain organisms, e.g. Escherichia coli.

The urine can be made alkaline by sodium bicarbonate i.v., or by potassium citrate by mouth. Sodium overload may exacerbate cardiac failure, and sodium or potassium excess are dangerous when renal function is impaired.

Acidification of urine:

• is used as a test for renal tubular acidosis

• increases elimination of amfetamine, methylene dioxymethamfetamine (MDMA or ‘Ecstasy’), dexfenfluramine, quinine and phencyclidine, although it is very rarely needed.

Oral NH₄ Cl, taken with food to avoid vomiting, acidifies the urine. It should not be given to patients with impaired renal or hepatic function. Other means include arginine hydrochloride, ascorbic acid and calcium chloride by mouth.

Drugs and the kidney

Adverse effects

The kidneys comprise only 0.5% of body-weight, yet they receive 25% of the cardiac output. It is hardly surprising that drugs can damage the kidney and that disease of the kidney affects responses to drugs.

Drug-induced renal disease

Drugs and other chemicals damage the kidney by:

1. Direct biochemical effect. Substances that cause such toxicity include:

• heavy metals, e.g. mercury, gold, iron, lead

• antimicrobials, e.g. aminoglycosides, amphotericin, cephalosporins

• iodinated radiological contrast media, e.g. agents for visualising the biliary tract

• analgesics, e.g. NSAID combinations and paracetamol (actually its metabolite, NABQI, in overdose, see p. 282)

• solvents, e.g. carbon tetrachloride, ethylene glycol.

2. Indirect biochemical effect:

• cytotoxic drugs and uricosurics may cause urate to be precipitated in the tubule

• calciferol may cause renal calcification by inducing hypercalcaemia

• diuretic and laxative abuse can cause tubular damage secondary to potassium and sodium depletion

• anticoagulants may cause haemorrhage into the kidney.

3. Immunological effect. A wide range of drugs produces a wide range of injuries:

• drugs include phenytoin, gold, penicillins, hydralazine, isoniazid, rifampicin, penicillamine, probenecid, sulphonamides

• injuries include arteritis, glomerulitis, interstitial nephritis, systemic lupus erythematosus.

A drug may cause damage by more than one of the above mechanisms, e.g. gold. The sites and pathological types of injury are as follows:

Glomerular damage

The large surface area of the glomerular capillaries renders them susceptible to damage from circulating immune complexes; glomerulonephritis, proteinuria and nephrotic syndrome may result, e.g. following treatment with penicillamine when the patient has made an immune response to the drug. The degree of renal impairment is best reflected in the creatinine clearance, which measures the GFR because creatinine is eliminated entirely by this process.

Tubule damage

By concentrating 180 L glomerular filtrate into 1.5 L urine each day, renal tubule cells are exposed to much greater amounts of solutes and environmental toxins than are other cells in the body. The proximal tubule, through which most water is reabsorbed, experiences the greatest concentration and so suffers most drug-induced injury. Specialised transport processes concentrate acids, e.g. salicylate (aspirin), cephalosporins and bases, e.g. aminoglycosides, in renal tubular cells. Heavy metals and radiographic contrast media also cause damage at this site. Proximal tubular toxicity is manifested by leakage of glucose, phosphate, bicarbonate and amino acids into the urine.

The counter-current multiplier and exchange systems of urine concentration (see p. 453) cause some drugs to accumulate in the renal medulla. Analgesic nephropathy is often first evident at this site, partly because of high tissue concentration and partly, it is believed, because of ischaemia through inhibition of locally produced vasodilator prostaglandins by NSAIDs. The distal tubule is the site of lithium-induced nephrotoxicity; damage to the medulla and distal nephron is manifested by failure to concentrate the urine after fluid deprivation and by failure to acidify urine after ingestion of ammonium chloride.

Tubule obstruction

Given certain physicochemical conditions, crystals can deposit within the tubular lumen. Methotrexate, for example, is relatively insoluble at low pH and can precipitate in the distal nephron when the urine is acid, typically in high dose for chemotherapy. Similarly the uric acid produced by the metabolism of nucleic acids released during rapid tumour cell lysis can cause a fatal urate nephropathy. This was a particular problem with the introduction of chemotherapy for leukaemias until the introduction of allopurinol, which is now routinely given before the start of chemotherapy to block xanthine oxidase so that the much more soluble uric acid precursor, hypoxanthine, is excreted instead. A recent and highly effective alternative to allopurinol for high-risk patients is recombinant uric acid oxidase (Rasburicase), which catalyses conversion of uric acid to the more soluble allantoin. Crystal nephropathy is also reported with agents as diverse as indinavir, orlistat, ciprofloxacin, aciclovir, sulfadiazine and triamterene.

Prescribing in renal disease

Drugs may:

• exacerbate renal disease (see above)

• be ineffective, e.g. thiazide diuretics in moderate or severe renal failure; uricosurics

• be potentiated by accumulation due to failure of renal excretion.

Clearly, the first option is to seek an alternative drug that does not depend on renal elimination. Problems of safety arise for patients with impaired renal function who must be treated with a drug that is potentially toxic and that is wholly or largely eliminated by the kidney.

A knowledge of, or at least access to, sources of pharmacokinetic data is essential for safe therapy for such patients, e.g. manufacturers’ data, formularies and specialist journals.

The profound influence of impaired renal function on the elimination of some drugs is illustrated in Table 27.1.

Table 27.1 Drug t_½ (h) in normal and severely impaired renal function

	Normal	Severe renal impairment^a
Captopril	2	25
Amoxicillin	2	14
Gentamicin	2.5	> 50
Atenolol	6	100
Digoxin	36	90

a Glomerular filtration rate < 5 mL/min (normal value is 120 mL/min). These values illustrate the major effect of impaired renal function on the elimination of certain drugs. Depending on the circumstances, alternative drugs must be found or special care exercised when prescribing drugs that depend significantly on the kidney for elimination.

The t_½ of other drugs, where activity is terminated by metabolism, is unaltered by renal impairment, but many such drugs produce pharmacologically active metabolites that are more water soluble than the parent drug, rely on the kidney for their elimination, and accumulate in renal failure, e.g. acebutolol, diazepam, warfarin, pethidine.

The majority of drugs fall into an intermediate class and are partly metabolised and partly eliminated unchanged by the kidney.

Administering the correct dose to a patient with renal disease must therefore take into account both the extent to which the drug normally relies on renal elimination and the degree of renal impairment; the best guide to the latter is the creatinine clearance and not the serum creatinine level itself,⁶ which can be notoriously misleading in the elderly and at extremes of body mass.

Dose adjustment for patients with renal impairment

• Adjustment of the initial dose (or where necessary the priming or loading dose, see p. 96) is generally unnecessary, as the volume into which the drug has to distribute should be the same in the uraemic as in the healthy subject. There are exceptions to this rule of thumb; for example, the volume of distribution of digoxin is contracted in uraemic patients due to altered tissue binding of the drug.

• Adjustment of the maintenance dose involves either reducing each dose given or lengthening the time between doses.

• Special caution is needed when the patient is hypoproteinaemic and the drug is usually extensively plasma protein bound, or in advanced renal disease when accumulated metabolic products may compete for protein binding sites. Careful observation is required in the early stages of dosing until response to the drug can be gauged.

General rules

1. Drugs that are completely or largely excreted by the kidney, or drugs that produce active, renally eliminated metabolites: give a normal or, if there is special cause for caution (see above), a slightly reduced initial dose, and lower the maintenance dose or lengthen the dose interval in proportion to the reduction in creatinine clearance.

2. Drugs that are completely or largely metabolised to inactive products: give normal doses. When the note of special caution (see above) applies, a modest reduction of initial dose and the maintenance dose rate are justified while drug effects are assessed.

3. Drugs that are partly eliminated by the kidney and partly metabolised: give a normal initial dose and modify the maintenance dose or dose interval in the light of what is known about the patient’s renal function and the drug, its dependence on renal elimination and its inherent toxicity.

Recall that the time to reach steady-state blood concentration (see p. 83) is dependent only on drug t_½, and a drug reaches 97% of its ultimate steady-state concentration in 5 × t_½. Thus, if t_½ is prolonged by renal impairment, so also will be the time to reach steady state.

Schemes for modifying drug dosage for patients with renal disease diminish but do not remove their increased risk of adverse effects; such patients should be observed particularly carefully throughout a course of drug therapy. Where the service is available, dosing should be monitored by drug plasma concentration measurements.

Nephrolithiasis

Calcareous stones result from hypercalciuria, hyperoxaluria and hypocitraturia. Hypercalciuria and hyperoxaluria render urine supersaturated in respect of calcium salts; citrate makes calcium oxalate more soluble and inhibits its precipitation from solution.

Non-calcareous stones occur most commonly in the presence of urea-splitting organisms, which create conditions in which magnesium ammonium phosphate (struvite) stones form. Urate stones form when urine is unusually acid (pH < 5.5).

Pharmacological aspects of micturition

Some physiology

The detrusor, whose smooth muscle fibres comprise the body of the bladder, is innervated mainly by parasympathetic nerves, which are excitatory and cause the muscle to contract. The internal sphincter, a concentration of smooth muscle at the bladder neck, is well developed only in the male and its principal function is to prevent retrograde flow of semen during ejaculation. It is rich in α₁ adrenoceptors, activation of which causes contraction. There is an abundant supply of oestrogen receptors in the distal two-thirds of the female urethral epithelium, which degenerates after the menopause causing loss of urinary control.

When the detrusor relaxes and the sphincters close, urine is stored; this is achieved by central inhibition of parasympathetic tone accompanied by a reflex increase in α-adrenergic activity. Voiding requires contraction of the detrusor, accompanied by relaxation of the sphincters. These acts are coordinated by a micturition centre, probably in the pons.

Functional abnormalities

The main abnormalities that require treatment are:

• Unstable bladder or detrusor instability, characterised by uninhibited, unstable contractions of the detrusor which may be of unknown aetiology or secondary to an upper motor neurone lesion or bladder neck obstruction.

• Decreased bladder activity or hypotonicity due to a lower motor neurone lesion or over-distension of the bladder, or both.

• Urethral sphincter dysfunction which is due to various causes including weakness of the muscles and ligaments around the bladder neck, descent of the urethrovesical junction and periurethral fibrosis; the result is stress incontinence.

• Atrophic change affecting the distal urethra in females.

Drugs that may be used to alleviate abnormal micturition

Antimuscarinic

drugs such as oxybutynin and flavoxate are used to treat urinary frequency; they increase bladder capacity by diminishing unstable detrusor contractions. Both drugs may cause dry mouth and blurred vision, and may precipitate glaucoma. Oxybutynin has a high level of unwanted effects; the dose needs to be carefully assessed, particularly in the elderly. Flavoxate has less marked side-effects but is also less effective. Propiverine, tolterodine and trospium are also antimuscarinic drugs used for urinary frequency, urgency and incontinence. Propantheline was formerly used widely in urinary incontinence but had a low response rate and a high incidence of adverse effects; it is now used mainly for adult enuresis. The need for continuing antimuscarinic drug therapy should be reviewed after 6 months.

Tricyclic antidepressants

Imipramine, amitriptyline and nortriptyline are effective, especially for nocturnal but also for daytime incontinence. Their parasympathetic blocking (antimuscarinic) action is probably in part responsible, but imipramine may also benefit by altering the patient’s sleep profile.

Oestrogens,

either applied locally to the vagina or taken by mouth, may benefit urinary incontinence due to atrophy of the urethral epithelium in post-menopausal women.

Parasympathomimetic

drugs, e.g. bethanechol, carbachol and distigmine, may be used to stimulate the detrusor when the bladder is hypotonic, e.g. due to an upper motor neurone lesion. Distigmine, which is an anticholinesterase, is preferred but, as its effect is not sustained, intermittent catheterisation is also needed when the hypotonia is chronic.

Benign prostatic hyperplasia (BPH)

One of the commonest problems in men older than 50 years, BPH was for a long time helped only by surgical intervention. The prostate gland is a mixture of capsular and stromal tissue, rich in α₁ adrenoceptors, and glandular tissue under the influence of androgens. Both these, the α receptors and androgens, are targets for drug therapy. Because the bladder itself has few α receptors, it is possible to use selective α₁-blockade without affecting bladder contraction.

α-Adrenoceptor antagonists

Prazosin, alfuzosin, indoramin, terazosin and doxazosin are all α-adrenoceptor blockers with selectivity for the α₁ subtype. They cause significant increases (compared to placebo) in objective measures such as maximal urine flow rate, and drugs also improve semi-objective symptom scores. In normotensive men, falls in blood pressure are generally negligible; in hypertensive patients, the decline in pressure can be regarded as an added bonus (provided concurrent treatment is adjusted). These drugs can cause dizziness and asthenia, even in the absence of marked changes in blood pressure. Nasal stuffiness can be a problem – especially in patients who resort to α-agonists (e.g. pseudoephedrine) for rhinitis.

These adverse events are avoided by using tamsulosin, which selectively blocks the α_1A subclass ⁷ of adrenoceptors and is therefore less likely to affect blood pressure, provided the single 400-microgram daily dose of tamsulosin is not exceeded.

Finasteride

An alternative drug for such prostatic symptoms is the type II 5α-reductase inhibitor, finasteride, which inhibits conversion of testosterone to its more potent metabolite, dihydrotestosterone. Finasteride does not affect serum testosterone, or most non-prostatic responses to testosterone. It reduces prostatic volume by about 20% and increases urinary flow rates by a similar degree. These changes translate into modest clinical benefits, which are generally inferior to those of an α₁ antagonist.

Finasteride (t_½ 6 h) is taken as a single 5-mg tablet each day. The improvement in urine flow appears over 6 months (as the prostate shrinks in size), and in 5–10% of patients may be at the cost of some loss of libido. The serum concentration of prostate-specific antigen is approximately halved. Although this may reflect a real reduction in risk of prostatic cancer, in patients receiving finasteride it is safer to regard values of the antigen in the upper half of the usual range as abnormal. Lower doses of finasteride have also been used successfully to halt the development of baldness.⁸Dutasteride is an alternative 5α-reductase inhibitor.

Other antiandrogens, such as the gonadorelin agonists, are used in the treatment of prostatic cancer, but the need for parenteral administration makes them less suitable for BPH.

Erectile dysfunction

Erectile dysfunction (ED), the inability to achieve or maintain a penile erection sufficient to permit satisfactory sexual intercourse, is estimated to affect over 100 million men worldwide, with a prevalence of 39% in those aged 40 years.⁹

Its numerous causes include cardiovascular disease, diabetes mellitus and other endocrine disorders, alcohol and substance abuse, and psychological factors (14%). Although the evidence is not conclusive, drug therapy is thought to underlie 25% of cases, reputedly from antidepressants (selective serotonin-reuptake inhibitors (SSRIs) and tricyclics), phenothiazines, cyproterone acetate, fibrates, levodopa, histamine H₂-receptor blockers, phenytoin, carbamazepine, allopurinol, indometacin and, possibly, β-adrenoceptor blockers and thiazide diuretics.

Sexual arousal releases from the endothelial cells of penile blood vessels neurotransmitters that relax the smooth muscle of the arteries, arterioles and trabeculae of its erectile tissue, greatly increasing penile blood flow and facilitating rapid filling of the sinusoids and expansion of the corpora cavernosa. The venous plexus that drains the penis thus becomes compressed between the engorged sinusoids and the surrounding and firm tunica albuginea, causing the near-total cessation of venous outflow. The penis becomes erect, with an intracavernous pressure of 100 mmHg. The principal neurotransmitter is nitric oxide, which acts by raising intracellular concentrations of cyclic guanosine monophosphate (cGMP) to relax vascular smooth muscle. The isoenzyme phosphodiesterase type 5 (PDE5) is selectively active in penile smooth muscle and terminates the action of cGMP by converting it to the inactive non-cyclic GMP.

Sildenafil

(Viagra) is a highly selective inhibitor of PDE5 (70-fold more so than isoenzymes 1, 2, 3 and 4 of PDE), prolonging the action of cGMP, and thus the vasodilator and erectile response to normal sexual stimulation. Its emergence as an agent for erectile dysfunction is an example of serendipity in drug development. Sildenafil was originally being developed for another indication but when the clinical trials ended the volunteers declined to return surplus tablets for they had discovered that the drug conferred unexpected benefits on their sexual lives. Its development for erectile dysfunction followed.

Sildenafil is well absorbed orally, reaches a peak in the blood after 30–120 min and has a t_½ of 4 h. The drug should be taken 1 h before intercourse in an initial dose of 50 mg (25 mg in the elderly); thereafter 25–100 mg may be taken according to response, with a maximum of one 100-mg dose per 24 h. Food may delay the onset and offset of effect. Sildenafil is effective in 80% of patients with erectile dysfunction.

Adverse effects are short lived, dose related, and comprise headache, flushing, nasal congestion and dyspepsia. High doses can inhibit PDE6, which is needed for phototransduction in the retina, and some patients report a transient blue coloration to their vision.¹⁰ Some patients experience non-arteritic anterior ischaemic optic neuropathy (NAION), consisting of blurred vision and/or visual field loss generally within 24 h of taking sildenafil. Priapism¹¹ has been reported.

Interactions. Sildenafil is contraindicated in patients who are taking organic nitrates, for their metabolism is blocked and severe and acute hypotension result. Patients with recent stroke or myocardial infarction, or whose blood pressure is known to be less than 90/50 mmHg, should not use it. Sildenafil is a substrate for the P450 isoenzyme CYP 3A4 (and to a lesser extent CYP2C9 which gives scope for drug–drug interactions. The metabolic inhibitors erythromycin, saquinavir and ritonavir (protease inhibitors used for AIDS), and cimetidine produce substantial rises in the plasma level of sildenafil. More selective PDE5 inhibitors now available include vardenafil, which has a kinetic profile similar to that of sildenafil, and taladafil which has a very long t_½ (17 h). This latter could be viewed as a mixed blessing in erectile dysfunction, but is important for the use of this drug class in pulmonary hypertension.

Alprostadil

is a stable form of prostaglandin E₁, a powerful vasodilator (see p. 401), and is effective for psychogenic and neuropathic erectile dysfunction. Alprostadil increases arterial inflow and reduces venous outflow by contracting the corporal smooth muscle that occludes draining venules. It can be administered either as a urethral suppository (0.125–1 mg) or injected directly into the dorsolateral aspect of the proximal third of the penis (so-called intracavernosal injection). The duration and grade of erection are dose related. The patient package insert from the manufacturer provides some helpful drawings. The dose (5–20 micrograms) is titrated initially in the doctor’s surgery, aiming for an erection lasting for not more than 1 h. Painful erection is the commonest adverse effect.

Papaverine,

an alkaloid (originally extracted from opium but devoid of narcotic properties ¹²), is also a non-specific phosphodiesterase inhibitor. It is effective (up to 80%) for psychogenic and neurogenic erectile dysfunction by intracavernosal self-injection shortly before intercourse (efficacy may be increased by also administering the α-adrenoceptor blocker phentolamine),¹³ although its use has waned with the availability of orally active selective PDE5 inhibitors such as sildenafil. Papaverine used in this way can cause priapism requiring aspiration of the corpora cavernosa and injection of an α-adrenoceptor agonist, e.g. metaraminol.

Summary

• The actions of drugs on the kidney are of an importance disproportionate to the low prevalence of kidney disorders.

• The kidney is the main site of loss, or potential loss, of all body substances. It is among the functions of drugs to help reduce losses of desirable substances and increase losses of undesired substances.

• The kidney is also at increased risk of toxicity from foreign substances because of the high concentrations these can achieve in the renal medulla.

• Diuretics are among the most commonly used drugs, perhaps because the evolutionary advantages of sodium retention have left an ageing population without salt-losing mechanisms of matching efficiency.

• Loop diuretics, acting on the ascending loop of Henle, are the most effective, and are used mainly to treat the oedema states. Potassium is lost as well as sodium.

• Thiazides, acting on the cortical diluting segment of the tubule, have lower natriuretic efficacy, but slightly greater antihypertensive efficacy than loop diuretics. Potassium loss is rarely a significant problem with thiazides, and thiazides reduce loss of calcium.

• Potassium retention with hyperkalaemia can occur with potassium-sparing diuretics, which block sodium transport in the last part of the distal tubule, either directly (e.g. amiloride) or by blocking aldosterone receptors (spironolactone).

• Drugs have little ability to alter the filtering function of the kidney when this is reduced by nephron loss.

• Prostatic enlargement is the main disease of the lower urinary tract; drugs can be used to postpone, or avoid, surgery. The symptoms of benign prostatic hyperplasia are partially relieved either by α₁-adrenoceptor blockade or by inhibiting synthesis of dihydrotestosterone in the prostate.

• Drugs are effective for the relief of erectile dysfunction, notably sildenafil, a highly specific phosphodiesterase inhibitor.

Guide to further reading