Hypertension: an overview of recommended treatment John Vann Jones PhD, FRCP

Drug review Hypertension Hypertension: an overview of recommended treatment John Vann Jones PhD, FRCP Skyline Imaging Ltd Professor Vann Jones provides an overview of the wide range of antihypertensive agents available and discusses the latest management guidelines. Further sources of information are provided in Resources. It is now about 40 years since the first trial of treatment of high blood pressure was published. Since then, we have had a succession of antihypertensive agents, some of which have stood the test of time, eg thiazides, and some of which have not, eg ganglion blocking agents. Others have fallen back to relative niche markets or become reserved for difficult cases, eg methyldopa. Today there are essentially six groups of drugs that are recommended as first- or second-line antihypertensives. As many hypertensive patients are not controlled on one agent (in the HOT study 1 it took up to five drugs to achieve target) it is also important to know what goes with what. In many cases, lower doses of two or more agents are better tolerated than larger doses of one. Another sound place to start is the concept of thinking of drug therapy in terms of a drug being compellingly indicated, possibly indicated, possibly contraindicated or compellingly contraindicated, which was introduced with the guidelines published in 1999 (see Table 1). 2 An example of a compelling contraindication, for instance, would be the use of ACE inhibitors in pregnancy or lactating mothers. 36 Prescriber 5 February 2007 www.escriber.com

In 2003 the British Hypertension Society (BHS) issued guidance on drug combinations using an A (ACE inhibitors or angiotensin-ii antagonists), B (beta-blockers), C (calcium-channel blockers) or D (diuretics) system. 3 Younger people respond better to A or B drugs while older people or Afro-Caribbeans respond better to C or D drugs. However, beta-blockers are no longer suggested as first-choice therapy for hypertension (see below). The guidance was therefore modified by dropping the B component (see Figure 1). This new guidance was issued jointly by the BHS and NICE in 2006 and recommended that younger people will therefore have an A drug, while older white patients or black patients will have a C or D drug as initial choice. 4 Thiazide diuretics Thiazide diuretics are still first-choice agents despite being introduced in 1958. On a global scale thiazides are the most important, being inexpensive and safe. 5 They can be used safely with all other antihypertensive agents. Thiazide diuretics, and related drugs such as chlortalidone, cause excretion of sodium, potassium and water by acting on the distal convoluted tubule. There is considerable evidence of their ability to prevent strokes but, as with all antihypertensives, these drugs appear relatively less effective at preventing coronary disease. There is little point in using other than small doses. Thiazides have their maximum effect at low dose and further increases only enhance side-effects without adding to the antihypertensive effect; in fact today s standard dose of bendroflumethiazide is 2.5mg while 10mg was used in the MRC trial of mild-to-moderate hypertension in 1985. 6 (see Table 2) The side-effects of thiazides are largely biochemical or metabolic. They cause sodium, potassium and magnesium loss while increasing cholesterol, triglycerides, blood glucose and uric acid. These effects, especially when high doses are used, may explain their relative Class of drug Compelling Possible Compelling Possible indications indications contraindications contraindications Diuretics heart failure diabetes gout dyslipidaemia elderly patients sexually active males systolic hypertension ACE inhibitors heart failure pregnancy left ventricular dysfunction bilateral renal artery after myocardial infarction stenosis hyperkalaemia Calcium-channel angina peripheral vascular heart block congestive cardiac blockers elderly patients disease failure systolic hypertension Alpha-blockers prostatic hypertrophy glucose intolerance orthostatic hypotension dyslipidaemia Angiotensin-II side-effects with other heart failure pregnancy antagonists drug classes, eg ACE bilateral renal artery inhibitor cough stenosis hyperkalaemia Beta-blockers angina heart failure asthma and chronic dyslipidaemia after myocardial infarction pregnancy obstructive pulmonary athletes and physically tachyarrhythmia disease active patients heart block peripheral vascular disease Table 1. Guidelines for selecting antihypertensive drug treatment 2 www.escriber.com Prescriber 5 February 2007 37

lack of success in preventing coronary disease. One finding from the MRC trial was that 10mg bendroflumethiazide produced impotence as frequently as propranolol. 6 younger (eg <55 years) and nonblack older (eg 55 years) or black Overall the guidelines suggest that compelling indications for thiazides are heart failure, elderly patients and systolic hypertension. A possible indication is diabetes and possible contraindications are hyperlipidaemia and sexually active males. The only compelling contraindication is gout (see Figure 2). step 1 step 2 A A + C or A + D C or D Calcium-channel blockers Calcium-channel blockers are effective antihypertensive agents. Verapamil, the oldest, and diltiazem form two separate groups of their own. They are chemically distinct from each other and also from all the other calcium-channel blockers that are dihydropyridines, eg nifedipine, felodipine and amlodipine. Verapamil and diltiazem share many properties with beta-blockers, eg blocking AV node transmission, and should be used carefully, if at all, with betablockers. Dihydropyridines do not resemble beta-blockers and can be safely and usefully combined with these agents. (see Table 3) Calcium-channel blockers block the movement of calcium ions through L-type calcium channels in smooth and cardiac muscle cells. This results in peripheral and coronary vasodilatation, reduced cardiac contractility and, if the AV node is involved (verapamil and diltiazem), bradycardia. Smooth muscle in the bowel is also affected resulting in gastrointestinal sideeffects (most notably constipation, especially with verapamil). The vasodilatation occurring with all calcium-channel blockers, but especially the dihydropyridines, can result in troublesome flushing and fluid retention, largely manifest as ankle swelling. This last effect can be very marked even on moderate doses of these drugs. A rare side-effect of dihydropyridines is gum hyperplasia. There is some debate about a possible increase in coronary heart disease with dihydropyridines. This has not been clearly substantiated and the BHS recommends that only the short-acting dihydropyridines, eg ordinary nifedipine not slow release, be avoided because of the variations in blood pressure and reflex tachycardia induced by these drugs. Long-acting step 3 step 4 resistant hypertension A: ACE inhibitor or angiotensin-ii antagonist C: calcium-channel blocker D: diuretic (thiazide) A + C + D add either alpha-blocker or spironolactone or other diuretic or beta-blocker Figure 1. BHS/NICE recommendations for managing hypertension 4 preparations, whether modified release or not, are recommended. Compelling indications for calcium-channel blockers are angina, the elderly 7 and systolic hypertension. A possible indication is peripheral vascular disease (but not in combination with a beta-blocker when peripheral ischaemia can be exacerbated) and possible contraindication congestive heart failure. The most compelling contraindication is heart block with diltiazem and verapamil. ACE inhibitors ACE inhibitors 8 block conversion of angiotensin I to angiotensin II, which is a potent vasoconstrictor and promotes the release of aldosterone. ACE inhibition results in vasodilatation and a reduction in circulating aldosterone levels. This can result in hyponatraemia but also potassium sparing, which can be clinically useful when these drugs are co-prescribed with potassiumlosing diuretics (usually thiazides in hypertension). www.escriber.com Prescriber 5 February 2007 39

VM act on distal convoluted tubule and cause excretion of sodium, potassium and water have maximum effect at low dose sodium, potassium and magnesium loss increased cholesterol, triglycerides, blood glucose and uric acid uricaemia impotence gynaecomastia Table 2. and side-effects of thiazide diuretics (see Table 4) ACE inhibitors also block the destruction of bradykinin, which itself has two important effects on the body. Bradykinin is a vasodilator and may therefore be partially responsible for the overall total vasodilatation with ACE inhibitors. However, when it accumulates it can cause cough the most clinically annoying of the ACE inhibitor side-effects. This is a class effect and will not generally improve with a change of ACE inhibitor. It is seen in 15-30 per cent of patients but is only totally intolerable in a few. Other side-effects include hypotension, which can be very marked and occurs especially with the first dose and in those with activation of the renin-angiotensin system, eg in heart failure or renovascular disease. Renal patients may also show further deterioration in renal function when ACE inhibitors are introduced. All patients should have their renal function monitored when ACE inhibitors are started. Rarer side-effects are altered taste, angioedema and skin reactions. ACE inhibitors may have a renal protective effect in diabetes. These patients often show an initial rise in creatinine but it plateaus out with longer-term gains in renal function, ie reduced rate of loss. It is important to monitor renal function closely in diabetic patients but also to hold one s nerve, not stopping the ACE inhibitor too soon. Because angiotensin may have a role in growth, ACE inhibitors are totally contraindicated in females who are trying to start a family, who are pregnant or who are breast-feeding. The same applies to angiotensin-ii antagonists (see below). The guidelines suggest compelling indications for the use of ACE inhibitors are heart failure, left ventricular dysfunction, recent myocardial infarction and in diabetic neuropathy. Compelling contraindications are pregnancy, bilateral renal artery stenosis and hyperkalaemia. Angiotensin-II antagonists Angiotensin-II antagonists are the newest of the firstchoice antihypertensive agents. Their use is growing rapidly, especially in ACE inhibitor-intolerant patients. They act by competing with angiotensin II at the angiotensin type I receptors. As a result, bradykinin does not accumulate as with ACE inhibitors and cough is not a feature. Indeed angiotensin-ii antagonists are remarkably well tolerated with a very low side-effect profile. (see Table 4) As with ACE inhibitors, blocking angiotensin II results in vasodilatation and a decrease in aldosterone levels. Renal function can also deteriorate and needs to be monitored and hypotension can occur. Hyperkalaemia can result, although potassium sparing, as with ACE inhibitors, can be clinically useful when diuretics are co-prescribed. 9 These drugs should not be used in females hoping to start a family, in pregnancy or when breast-feeding (see under ACE inhibitors). A possible indication is heart failure in patients who are ACE inhibitor intolerant, and compelling contraindications, as with ACE inhibitors, are pregnancy, renal artery stenosis and hyperkalaemia. Figure 2. Gout is the only compelling contraindication of thiazide diuretics Alpha-blockers Alpha-blockers are used largely as part of combination therapy. In practice they are mostly considered 40 Prescriber 5 February 2007 www.escriber.com

peripheral and coronary vasodilatation reduced cardiac contractility flushing, headache, fluid retention, palpitation, bradycardia, conduction abnormalities, nausea, constipation Table 3. and side-effects of calcium-channel blockers when calcium-channel blockers or ACE inhibitors are also inappropriate or unsuccessful. 10 They are probably the safest of the second-line add-on drugs, but in general have to be titrated upwards. It is important not to lose faith in them when lower doses seem to be ineffective since tachyphylaxis can be overcome by increasing the dose. They act by blocking the action of noradrenaline at postsynaptic alpha nerve endings in both arteries and veins, with vasodilatation resulting. Most modern alpha-blockers act selectively at alpha 1 nerve endings thus avoiding many of the side-effects of older alphablockers such as phenoxybenzamine and phentolamine, which are now used only in hospital mainly in patients with phaeochromocytoma. (see Table 5) Profound first-dose hypotension can result from alpha-blockade, especially with prazosin (Hypovase). Postural hypotension is also seen more with alphablockers than with the other antihypertensive agents. Noncardiac effects include an action on the bladder neck, and alpha-blockers can be used to treat benign prostatic hypertrophy, but conversely may cause urinary incontinence, especially in women. Indoramin, more so than the others, can result in sedation. In general, though, alpha-blockers are safe, well tolerated and can be safely added to other antihypertensive drugs or combinations. The guidelines suggest that prostatic hypertrophy is a compelling indication for alpha-blockers, and glucose intolerance and hyperlipidaemia possible indications. A possible contraindication is orthostatic hypotension. Beta-blockers Beta-blockers were introduced in the late 1960s, although the cardioselective agents did not arrive for another decade. 11 It is clear how they work in angina, but how they lower blood pressure is less certain. Betablocker therapy has, however, been downgraded from routine first-choice therapy under new guidelines from the BHS and NICE. 4 Recent analysis has shown that they are less effective at preventing stroke than the other first-choice drugs and may increase the risk of developing diabetes, especially if combined with a thiazide. Beta-blockers still have a role, however, and should be considered in women before the menopause, in those with increased sympathetic drive and in patients intolerant of the A drugs, ie ACE inhibitors or angiotensin-ii antagonists. See also compelling indications below. Beta-blockers are safe drugs. Their side-effects and contraindications are largely predictable on the basis of blockade of beta receptors. For example, the beta 2 receptors in the lungs cause bronchodilatation and hence, if blocked, bronchoconstriction results. In most people this is unimportant, but clearly matters in those with asthma. Likewise beta 2 receptors cause peripheral arterial vasodilatation, and if blocked vasoconstriction results. Beta-blockers are therefore relatively contraindicated in peripheral vascular disease. The division of beta-blockers into cardioselective (blocking largely beta 1 receptors in the heart) and noncardioselective (blocking all beta receptors) is relative: even the most cardioselective beta-blocker will have some blocking effect on beta 2 receptors. (see Table 6) The side-effects of beta-blockade include cold peripheries and a drop in heart rate and cardiac output with fatigue and loss of effort capacity. Less vasodilatation reduction in circulating aldosterone levels hyponatraemia, hyperkalaemia cough (ACE inhibitors) hypotension renal impairment altered taste (ACE inhibitors) angioedema (ACE inhibitors) skin reactions dizziness Table 4. and side-effects of ACE inhibitors and angiotensin-ii antagonists www.escriber.com Prescriber 5 February 2007 41

vasodilatation first-dose and postural hypotension urinary incontinence sedation Table 5. and side-effects of alpha-blockers predictable side-effects include nightmares and impotence. Compelling indications for beta-blockers are angina, recent myocardial infarction and in those with tachyarrhythmias. Possible indications include heart failure and pregnancy, while possible contraindications include hyperlipidaemia, athletic and physically active patients and in those with peripheral vascular disease. Compelling contraindications include asthma, chronic obstructive pulmonary disease with significant reversibility after beta-agonists, and heart block. Other oral antihypertensive agents Methyldopa This was at one time the world s best selling drug. It acts centrally as a false neurotransmitter. It is effective but sedation and loss of sexual function are problems, which to a certain extent can be overcome by using a moderate-sized dose last thing at night. Clonidine Clonidine stimulates central imidazoline receptors. It can cause marked hypertension when withdrawn suddenly and is now little used. decreased heart rate and reduced contractility cold peripheries reduction in heart rate, cardiac output fatigue Table 6. and side-effects of beta-blockers Moxonidine This is a relatively new centrally acting drug that also acts on imidazoline receptors. It is useful as an alternative in patients where other drugs have caused problems or as an add-on agent in difficult or refractory hypertension. Hydralazine Hydralazine acts on vascular smooth muscle largely at arteriolar level. The vasodilatation causes a reflex tachycardia and therefore it is best used with a betablocker. Hydralazine can also cause fluid retention so a diuretic is often also required; used together this combination can be very effective. In higher doses long term, hydralazine can cause a lupus-like syndrome. Doses over 100mg should be avoided. Minoxidil (Loniten) This is a potent vasodilator causing fluid retention and tachycardia like that seen with hydralazine. It is often used as a last resort but never in females: it causes excessive bodily hair growth that can be extremely pronounced and unsightly. Spironolactone Although not licensed for the management of hypertension in the UK, spironolactone is recommended in step 4 of the guidance (see Figure 1). It is a direct aldosterone antagonist that can cause painful gynaecomastia and in higher doses, if used with ACE inhibitors, hyperkalaemia. The dose should be kept to 25mg. Furosemide Furosemide is not usually regarded as an antihypertensive agent but can potentiate ACE inhibitors. It is useful as an alternative to thiazides if renal function is impaired (serum creatinine >160µmol per litre) and in refractory hypertension, when high doses ( 40mg twice daily) may be needed. Conclusion It will be apparent from the above descriptions that certain drugs sit more easily together than others, and hence the new ACD BHS/NICE advice. The majority of hypertensive patients need a combination of drugs to control their blood pressure, and common combinations are listed in Table 7. In general, drugs are additive in their effects. Since the late 1950s we have had a plethora of good and effective antihypertensive agents. Patients used to die of hypertensive heart failure but this, and the incidence of stroke, has been transformed by therapy. Less dramatic effects on coronary artery disease have been seen but it may be that the newer drugs and treatment given over a longer time course will bring 42 Prescriber 5 February 2007 www.escriber.com

the same degree of benefit as seen for all other hypertension end-points. References 1. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood pressure lowering and low dose aspirin in patients with hypertension: principal results of the hypertension optimal treatment (HOT) randomized trial. Lancet 1998;351:1755-62. 2. Ramsey LE, Williams B, Johnston GD, et al. BHS Guidelines. Guidelines for management of hypertension: report of the third working party of the British Hypertension Society. J Hum Hypertens 1999;13:569-92. 3.Brown MJ, Cruickshank JK, Dominiczak AF, et al. Better blood pressure control: how to combine drugs. J Hum Hypertens 2003;17:81-6. 4. National Institute for Health and Clinical Excellence. Hypertension: management of hypertension in adults in primary care. Clinical guideline 34 (partial update of NICE clinical guideline 18). 2006. 5. Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal results. BMJ 1985;291:97-104. 6. Hampton JR. Choosing the right beta-blocker. A guide to selection. Drugs 1994;48:549-68. 7. Tuomilehto J, Rastenyte D, Birkenhager WH, et al. Effects of calcium channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med 1999;340: 677-84. Resources Further reading Better blood pressure control: how to combine drugs. Brown MJ, Cruickshank JK, Dominiczak AF, et al. J Hum Hypertens 2003;17:81-6. BMJ collected resources: http://bmjjournals.com/ cgi/collection/hypertension. All articles published in the BMJ on hypertension since January 1998. Hypertension: management of hypertension in adults in primary care. National Institute for Health and Clinical Excellence. Clinical guideline 34 (partial update of NICE clinical guideline 18). NICE, 2006. Groups and organisations Blood Pressure Association, 60 Cranmer Terrace, London SW17 0QS. Tel: 020 8772 4994, fax: 020 8772 4999, website: www.bpassoc.org.uk. Provides literature about hypertension for patients and GPs. thiazides + ACE inhibitors (cancel potassium effects) thiazides + angiotensin-ii antagonists (cancel potassium effects) ACE inhibitors + calcium-channel blockers (any) alpha-blockers + all others beta-blockers + dihydropyridine calcium-channel blockers (cancel vasodilator tachycardia) Table 7. Useful combinations of antihypertensive agents 8. Hansson L, Lindholm LH, Niskanen L, et al. Effect of ACE inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: The Captopril Prevention Project (CAPP). J Hypertens 1990;8: 985-90. 9. McKay JH, Arcuri KE, Goldberg AI, et al. Losartan and low dose hydrochlorothiazide in patients with essential hypertension. A double-blind, placebo controlled trial of concomitant administration compared with individual components. Arch Intern Med 1996;156: 278-85. 10. Langdon CG, Packard RS. Doxazosin in hypertension: Results of a general practice study in 4809 patients. Br J Clin Pract 1994;48:293-8. 11. Ramsey LE. Thiazide diuretics in hypertension. Clin Exp Hypertens 1999;21:805-14. Professor Vann Jones was consultant cardiologist at the Royal Infirmary, Bristol British Hypertension Society. BHS Information Service: Jackie Howarth, BHS Administrative Officer, Clinical Sciences Building, Level 5, Leicester Royal Infirmary, PO Box 65, Leicester LE2 7LX. Tel: 07717 467 973; e-mail: bhs@le.ac.uk. Provides information on hypertension for health professionals. Has an annual conference, which concentrates on scientific issues, but the society aims to improve clinical practice. British Heart Foundation, 14 Fitzhardinge Street, London W1H 6DH. Tel: 020 7935 0185, website: www.bhf.org.uk. Charity providing information on all aspects of heart disease, including hypertension, for patients and health professionals. High Blood Pressure Foundation, Department of Medical Sciences, Western General Hospital, Edinburgh EH4 2XU. Tel: 0131 332 9211, fax: 0131 537 1012, website: www.hbpf.org.uk. Charity dedicated to improving the basic understanding and public awareness of high blood pressure. www.escriber.com Prescriber 5 February 2007 45