David Levy, MD, FRCP
Thiazide diuretics have been the mainstay of antihypertensive treatment since the first potent thiazide was introduced in 1957, and have often been the agents against which other drug classes have been compared in important clinical trials . They are especially useful in low-renin (salt-sensitive) states, for example older people, and black or obese patients. Resistant hypertension (see below), common in these groups, is frequently due to inadequate diuretic therapy. Despite half a century of use, disagreement continues about their optimum dosing and whether blood pressure lowering effects and cardiovascular benefits are common to all agents in the class. There is continuing controversy about their potential metabolic disadvantages – concern about these, together with their low pharmaceutical profile, prevents their being used in many patients – but there is no evidence that these in any way blunt their cardiovascular benefits, even in people with diabetes (Box 11.7). They are as effective in reducing coronary events as any other class of antihypertensive agents, but in ALLHAT were more effective in reducing heart failure and stroke than lisinopril or amlodipine.
Loop diuretics (furosemide, bumetanide, torsemide) have a shorter duration of action than the thiazides, and in patients with normal or moderately impaired renal function (eGFR > 30–40 mL/min), thiazides are more effective antihypertensives. In advanced renal impairment, where reduced eGFR limits the amount of sodium reaching the distal tubules, the site of action of the thiazides, loop diuretics are often needed for other indications (peripheral oedema, heart failure or nephrotic syndrome), but are more effective in blood pressure reduction.
Comparing the effectiveness of the thiazides is very difficult (Table 11.6). Chlorthalidone (a thiazide-like agent) has been the drug used in most major clinical trials, but hydrochlorothiazide is almost universally used in fixed-dose combinations. Bendroflumethiazide is widely used in the UK, but is not available as monotherapy in the USA. Indapamide (another thiazide-like agent) is the only drug that is widely used in both monotherapy and fixed-dose combinations. There is reasonable evidence that the very long half-life of chlorthalidone makes it a more effective 24-hour agent than the shorter-acting hydrochlorothiazide or bendroflumethiazide, and this may account for its remarkable cardiovascular benefits in large-scale studies; it may be effective if doses are occasionally missed, or even if taken on alternate days.
Potassium-sparing diuretics (British National Formulary, sections 2.2.3 and 2.2.4)
The potassium-sparing agents, weak diuretics that cause very little natriuresis on their own and which act on the collecting ducts of the renal tubule, should be more widely used, both in thiazide-treated patients and in resistant hypertension (see below). They also reduce urinary magnesium loss, often associated with hypokalemia and difficulty in restoring normokalemia. Amiloride is most often used in the UK, but triamterene and spironolactone are also suitable. Fixed-dose combinations of thiazides and potassium-sparing agents used to be widely promoted, but because of the potassium-retaining effects of the angiotensin-blocking agents and the recognition of type 4 renal tubular acidosis in diabetes with its associated tendency to hyperkalemia, they are less used in diabetes. However, maintaining adequate serum potassium levels is important, because of the risk of symptoms and arrhythmias with hypokalemia, but also because there is good epidemiological and clinical trial evi- dence that hypokalemia is associated with increased risks of ischemic events, and there is an association between hypokalemia and hyperglycemia. Co-amilozide (e.g. amiloride 2.5 mg and hydrochlorothiazide 25 mg) is a typical example of the combination, but many others are
Alpha-blocking agents (British National Formulary, section 2.5.4)
The alpha-blockers are overall metabolically neutral, with perhaps minor beneficial effects on the lipid profile. They are useful in men with symptomatic benign prostatic hypertrophy. The major drug in this class is doxazosin. Used in ALLHAT up to 4 mg daily, it was a less effective anti-hypertensive agent than chlorthalidone, and was inferior to it in reducing cardiovascular events and episodes of heart failure. However, modified- release doxazosin up to 8 mg daily was a highly effective agent when added as a non-blinded third agent in ASCOT-BPLA (mean fall in blood pressure 12/7 mmHg). Dizziness, headache, fatigue and oedema were the commonest side-effects in ASCOT, resulting in withdrawal of 8% of patients. Use only the modified-release form, starting at 4 mg daily.
Centrally acting agents (British National Formulary, 2.5.2)
Prazosin and clonidine are obsolete, and methyldopa is used only in pregnancy. Moxonidine is the best tolerated of the centrally acting agents, but still has limiting central side-effects, especially dry mouth and headache. It may reduce microalbuminuria in type 1 diabetes through inhibition of afferent renal sympathetic nerves. Dose is 200–600 µg daily.
Defined (in people with diabetes) as blood pressure above 130/80 mmHg, despite good adherence to treatment with three antihypertensive agents of different classes, including a diuretic. Given the difficulty of achieving this target in any hypertensive diabetic person, a more practical blood pressure definition might be that defining the goal in non-diabetic people (i.e. >140/90 mmHg). The definitions are arbitrary, but are important in drawing attention to a large group of people who require extra thought about the possibility of secondary or reversible causes of hypertension, and serious consideration of their therapeutic regimen (Box 11.8). The prevalence of resistant hypertension is not known, even in non-diabetic populations, but may be as high as 10–20%. Poor control of SBP is characteristic, and worsens with increasing age. Acknowledge the existence of true refractory hypertension – blood pressure that is never near target despite compliance with multiple medications – in patients often showing combinations of these characteristics.
Approach to patients with resistant hypertension
Assess drug adherence and drug-related causes
Although strictly a cause of ‘pseudoresistance’ rather than true treatment resistance, it is so common and so difficult to quantify that it qualifies as an important real-life factor. In clinical trials, almost 50% of participants stop taking their medication within the first year; of those continuing with treatment, another 50% had a ‘drug holiday’ lasting three or more days at least once a year . Regular medication reviews, actively involving patients and their carers, are important. Make every attempt to simplify treatment, using once-daily fixed-dose combinations wherever possible, even if you were taught to despise them. Dose slippage or failure to increase doses to recommended levels is common, and results from many factors. Home monitoring of blood pressure improves adherence in resistant hypertension.
Although non-blood pressure medication is unlikely itself to be a cause of resistant hypertension, bear in mind the drugs that antagonize existing antihypertensives (e.g. NSAIDs) and those that worsen blood pressure (e.g. sympathomimetics, glucocorticoids).
Consider secondary causes of hypertension
Obstructive sleep apnea
Strongly associated with all degrees of hypertension, but particularly when it is severe; up to 80% of treatment-resistant hypertensive subjects have objective evidence of sleep apnoea. It is particularly prevalent and severe in men. OSA and hypertension are probably linked through sympathetic nervous system activation, resulting in increased cardiac output, peripheral resistance, and salt and water retention. This link is supported by the finding that spironolactone may reduce OSA in people with resistant hypertension. Awareness of the link between OSA and poorly controlled hypertension is clearly important. Administering a simple questionnaire would be practical in the routine setting, for exam- ple the Epworth Sleepiness Score assesses the severity of daytime somno- lence using eight simple questions (score ?: 10: ‘sleepy’; score ?: 18: ‘very sleepy’) (sleepapnoeanz.org.nz/epworth_scale.html).
The presence of even a moderate degree of CKD (e.g. serum creatinine > 130 µmol/L, 1.5 mg/dL) was associated with failure to achieve target blood pressure in ALLHAT. Seeking and stenting renal artery stenosis in severe or treatment-resistant hypertensive people used to be an important radiology subspecialty, but medical treatment is probably now the best approach; it is not clear which agents are best in this situation.
Cushing’s syndrome is usually listed as a cause of resistant hypertension, and it is, but the clinical diagnosis is likely to be evident in a severely hypertensive person, although poorly controlled diabetes rather than poorly controlled hypertension is more likely to be associated with clinically inapparent Cushing’s syndrome. Pheochromocytoma is associated with sustained rather than paroxysmal hypertension in about 50% of cases. Always think of this diagnosis in resistant hypertension. Plasma metanephrines are thought to be the best screening test, but they are not generally available, and triplicated 24-hour urinary free catecholamine measurements are the simplest initial tests.
The spectrum of hyperaldosteronism now extends from the uncommon aldosterone-secreting Conn adenoma of the adrenal, presenting with resistant hypertension and significant hypokalemia, to normokalemic hyperaldosteronism with no discrete adrenal lesion. There may be considerable overlap with the highly prevalent low-renin state. Depending on the diagnostic methods used, about 20% of patients with resistant hypertension may have underlying primary aldosteronism. Again, the link with obesity and sympathetic nervous system activation and its consequences is strong, but not yet confirmed causally. Until renin levels are routinely available, recognizing that hyperaldosteronism is common and is likely to respond to specific agents should help achieve target blood pressure. Complex and time-consuming protocols are no longer needed for initial evaluation, and a random measurement of the aldosterone/ renin ratio will be reliable in patients even on treatment, other than those taking potassium-sparing diuretics, especially spironolactone .
Assess diurnal blood pressure and white-coat effect
Patients with resistant hypertension should have ABPM. The white-coat effect is as frequent in treatment-resistant patients as it is in other groups, and is likely to carry the same increased risk of adverse cardiovascular events (in patients already at high risk) as has now been established in untreated people with the white-coat phenomenon. Consistently elevated clinic blood pressure readings should be factored into management unless ABPM measurements are strictly normal.
Management Lifestyle intervention
The many lifestyle factors already described should be reinforced. In particular, resistant hypertension is often associated with high dietary salt intake. Aerobic exercise is important, and there may be substantial reductions in blood pressure with possibly some legacy effect after the exercise programme has finished in patients with very severe hypertension on triple therapy.
The greatest benefit in patients already taking three agents, including a diuretic, derives from optimizing the diuretic regimen, as many have inappropriate volume expansion. If there is poorly controlled hypertension without a diuretic, then initially introduce a diuretic and maximize its dose. In those already taking a thiazide, maximize the dose, or perhaps, in view of the strong evidence (see above), replace the existing thiazide with chlorthalidone 25–50 mg daily. Ensure that any fixed-dose combina- tion with an angiotensin blocker contains the 25-mg dose of hydrochlorothiazide, or consider increasing bendroflumethiazide to 5 mg daily. After stabilizing a patient on therapy in this way, an ABPM test would be wise. If still poorly controlled, then in view of the high prevalence of hyperaldosteronism in this group, consider adding the aldosterone antagonist spironolactone 25 mg daily, with careful monitoring of renal function and potassium levels (expect K+ concentration to rise by about 0.5 mmol/L). Responses may be dramatic: for example, addition of this dose of spironolactone as a fourth agent in ASCOT-BPLA further reduced blood pressure by a mean of 22/10 mmHg. Because of its anti-androgenic action, spironolactone is absolutely contraindicated in women of childbearing age, and breast tenderness with or without gynecomastia is common in men.
Amiloride, which acts as an indirect aldosterone antagonist, is better tolerated, and may be more effective in lowering blood pressure than spironolactone. Start at 5 mg daily, increasing gradually to 20 mg daily or more. Monitor renal function and serum potassium frequently; K+ concentration will rise, possibly by up to 0.8 mmol/L.
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David Levy, MD, FRCP, Consultant Physician, Gillian Hanson Centre, Whipps Cross University Hospital; Honorary Senior Lecturer
Queen Mary University of London London, UK
This edition first published 2011, © 2011 by David Levy. 1st edition 1998 (Greenwich Medical Media/Cambridge University Press) 2nd edition 2006 (Altman Publications)