ANTI- HYPERTENSIVE AGENTS

CLINICAL ANTI- HYPERTENSIVE AGENTS Jacqueline van Schoor, MPharm, BSc (Hons) Amayeza Info Centre Hypertension represents a major public health concern. It affects about a billion people worldwide and is the most common treatable risk factor for cardiovascular disease in patients over the age of 50 years. A clear relationship exists between elevated blood pressure (BP) and the various manifestations of cardiovascular disease. See Expand your Portfolio on page 65 The new target Although blood pressure reduction is undoubtedly beneficial, it is important to emphasise at the outset that the concept of single risk factor intervention has been challenged by the recognition that the real target is cardiovascular disease risk. From an evidence-based perspective, the new target is cardiovascular risk and not its individual components. The importance of lifestyle in hypertension Despite the availability of a myriad of effective antihypertensive agents, a healthy lifestyle remains the cornerstone of the management of hypertension. A healthy lifestyle: Decreases blood pressure Improves antihypertensive medicine efficacy Reduces cardiovascular risk The risk of cardiovascular disease can be reduced by increasing consumption of fresh fruits and vegetables, fish and fish oils, as well as by moderate intensity physical activity and a low to moderate alcohol intake. The effects of various lifestyle interventions in reducing systolic blood pressure (SBP) are shown in Table 1. Table 1: The effects of lifestyle interventions on SBP reduction (Adapted from South African Hypertension guideline 2006) Intervention Reduce weight Reduce salt intake Restrict alcohol consumption Increase fruit and vegetable consumption Physical activity Stop tobacco use Recommendation Maintain normal body weight (Body Mass Index 18.5 24.9 kg/m 2 ) Reduce salt intake to 6 g or less per day (equivalent to 2.4 g sodium) Limit consumption to 2 standard * drinks per day in men and 1 standard drink a day in women Do not drink alcohol every day Increase fruit, vegetables, legumes to 5 or more helpings a day Exercise for at least 30 minutes on most days of the week (minimum 150 minutes/ week) Approximate SBP reduction 5 20 mm Hg/10 kg weight loss 2 8 mm Hg 2 4 mm Hg Reduces stroke by up to 26% 4 9 mm Hg * A standard drink contains approx. 10 g ethanol (e.g. 25 ml spirits/liqueur, 125 ml wine, 340 ml beer, 60 ml sherry). 22 SA Pharmaceutical Journal April 2008

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CLINICAL When should antihypertensive therapy be initiated in the patient with hypertension? Pharmacotherapy for hypertension should be commenced: In patients at low added risk despite a period of 6-12 months of lifestyle modification and observation. In patients at moderate added risk despite a period of 3-6 months of lifestyle modification and observation. In patients at high or very high added risk. See Figure 1 and Tables 2 and 3 for risk stratification of patients. The treatment of hypertension is based on the above risk stratification of the patient as assessed using Tables 2 and 3. See Figure 1. Table 2: Major risk factors for cardiovascular disease, target-organ damage and associated clinical conditions (Adapted from SA Hypertension guideline 2006) Major risk factors Levels of systolic and diastolic blood pressure Dyslipidaemia Total cholesterol > 6.5 mmol/l OR LDL > 4 mmol/l OR HDL < 1 mmol/l for men and < 1.2 mmol/l for women Diabetes mellitus Men > 55 years Women > 65 years Smoking Family history of early onset of CVD Men < 55 years Women < 65 years Waist circumference Men 102 cm and women 88 cm Target-organ damage Left ventricular hypertrophy Microalbuminuria: albumin / creatinine ratio 3-30 mg/mmol Slightly elevated creatinine Men 115-133 umol/l Women 107-124 umol/l Associated clinical conditions Coronary heart disease Chronic kidney disease Albumin/creatinine ratio > 30 mg/mmol Stroke or transient ischaemic attack Advanced retinopathy haemorrhages OR exudates OR papilloedema Peripheral arterial disease Table 3: Stratification of risk (Adapted from SA Hypertension guideline 2006) BP (mm Hg) Normal High-normal Stage 1 Mild HT Stage 2 Moderate HT Stage 3 Severe HT SBP 120-129 or DBP 80-84 SBP 130-139 or DBP 85-89 SBP 140-159 or DBP 90-99 SBP 160-179 or DBP 100-109 SBP > 180 or DBP > 110 Other risk factors No other major risk factors Average risk Average risk Low added risk Moderate added risk High added risk 1-2 major risk factors Low added risk Low added risk Moderate added risk Moderate added risk 3 major risk factors or TOD or DM Moderate added risk High added risk High added risk High added risk Associated clinical conditions High added risk KEY: TOD = Target-organ damage; DM = Diabetes mellitus Figure 1: Risk stratification of patients LOW ADDED RISK MODERATE ADDED RISK HIGH/VERY HIGH ADDED RISK LIFESTYLE MODIFICATION AS APPROPRIATE Monitor BP and other risk factors for 6 12 months Monitor BP and other risk factors for 3 6 months SBP 140 or DBP 90 SBP < 140 or DBP < 90 SBP < 140 or DBP < 90 SBP 140 or DBP 90 CONTINUE TO MONITOR BEGIN DRUG TREATMENT 24 SA Pharmaceutical Journal April 2008

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CLINICAL What is the target BP level that the patient with hypertension should aim for? Target blood pressure levels for patients with hypertension depend on the patient s risk factors, the presence of target-organ damage and the presence of associated clinical conditions. See Table 2. Which antihypertensive should be selected? Recent studies have led to a reconsideration of the medicines of choice for the management of uncomplicated hypertension. There are three important classes of antihypertensive agents for the management of hypertension in patients with uncomplicated hypertension: Diuretics thiazide and thiazide-like Angiotensin-converting enzyme inhibitors (ACE-Is) and Calcium channel blockers The treatment of uncomplicated hypertension as recommended by the South African Hypertension guideline 2006, is as follows: Step 1 Initiate therapy with low-dose hydrochlorothiazide (12.5 mg up to a maximum of 25 mg) or a thiazide-like diuretic. Higher doses are not recommended because of the risk of new diabetes. Low-dose diuretics are the most effective first-line antihypertensive therapy and are less expensive. Low-dose diuretics are also the first-line therapy for older patients. Step 2 and 3 Where there are no other compelling indications, then one of the following is recommended as second- or third-line therapy: - ACE inhibitor (or an angiotensinll receptor blocker (ARB) in the case of ACE inhibitor intolerance) - A calcium channel blocker (longacting dihydropyridines or nondihydropyridines). Note: Short-acting calcium channel blockers are not recommended for the management of hypertension. Most people will require more than one antihypertensive agent to control blood pressure. Combination therapy may be provided as separate products or as a Stage All stages of hypertension High-risk patients e.g. those with diabetes mellitus, renal disease or congestive heart failure fixed-dose combination product. The latter has an advantage of allowing BP control to be achieved with a reduced number of daily tablets so that patient adherence to therapy is improved. Effective antihypertensive combinations are: Diuretic plus ACE inhibitor (or ARB) Calcium channel blocker with ACE inhibitor (or ARB) Beta blocker with alpha blockade Diuretic plus beta-blocker * Note: * While a diuretic-beta-blocker combination comprises effective combination therapy, the combination of a thiazide diuretic with a beta-blocker should be discouraged as both classes of antihypertensives have potentially adverse metabolic consequences and increase the risk of new onset diabetes. Patients with certain pre-existing medical conditions may be preferentially managed using certain antihypertensive agents, while other antihypertensive agents may be contraindicated. The table below lists the compelling indications as well as possible and compelling contraindications. More about the antihypertensive agents Thiazide and thiazide-like diuretics Thiazides and related agents are firstline medicines in the treatment of hypertension. The thiazides are sulphonamide derivatives. They act by inhibition of sodium and chloride reabsorption at proximal sites of the distal renal tubules. The antihypertensive effect is of slow onset, requiring up to two months for full effect. In hypertension, the thiazide diuretics may be used alone, in combination with a potassium-sparing diuretic or with other antihypertensive agents. The antihypertensive effect is enhanced by a low-salt diet The thiazides and thiazide-like diuretics are contraindicated in patients allergic to sulphonamides. Table 4: Blood pressure target levels (Adapted from SA Hypertension guideline 2006) BP Target (mm Hg) < 140/90 < 130/80 Comment In isolated systolic hypertension, do not lower the DBP to < 65 mm Hg Ideally these target levels should be reached within three months The maximum antihypertensive dose is 25 mg of hydrochlorothiazide (or equivalent) per day. Electrolyte imbalances are the most frequently occurring major adverse effects. Hypokalaemia does not necessarily cause symptoms. However, hypokalaemia and hypomagnesaemia potentiate digoxin toxicity in patients receiving digoxin therapy. Potassium and magnesium supplementation may be necessary. ACE-inhibitors ACE-inhibitors act by preventing the conversion of angiotensin l to angiotensin ll (a powerful vasoconstrictor). There are several ACE-inhibitors available and all are considered safe and effective in the treatment of hypertension. A low salt diet with concurrent diuretic therapy enhances the antihypertensive effect. In black patients, the ACE-inhibitors are considered less effective in the absence of concurrent diuretic therapy. In hypertensive patients under the age of 55 years, an ACE-inhibitor or an ARB may be considered for initial therapy. ACE-inhibitors may cause rapid reductions in blood pressure. Therefore, initiate therapy with a low dose, especially in patients receiving diuretics. Renal function and electrolytes should be checked before starting therapy and monitored during treatment. All ACE-inhibitors are contraindicated in pregnancy. Cough, the most common adverse effect may respond to a decreased dose or may resolve with continued treatment. 26 SA Pharmaceutical Journal April 2008

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CLINICAL Table 5: Compelling indications and contraindications for the use of antihypertensives Class Diuretics (thiazide; thiazidelike)(low-ceiling diuretics) Diuretics (loop) e.g. furosemide (high-ceiling diuretics) Diuretics (aldosterone antagonist) e.g. spironolactone (potassium-sparing diuretics) Calcium channel blocker (longacting dihydropyridine) e.g. amlodipine Calcium channel blocker (non dihydropyridine) e.g. verapamil; diltiazem ACE inhibitors e.g. enalapril ARBs e.g. losartan Beta blockers e.g. carvedilol, bisoprolol Indications Elderly hypertensives Isolated systolic hypertension Black hypertensives Renal insufficiency Post myocardial infarction Resistant hypertension Elderly hypertensives Isolated systolic hypertension Angina pectoris Peripheral vascular disease Carotid atherosclerosis Black hypertensives Angina pectoris Carotid atherosclerosis Supraventricular tachycardia Left ventricular dysfunction Post myocardial infarction Non-diabetic nephropathy Type 1 diabetic nephropathy Type 2 diabetes mellitus Proteinuria Type 2 diabetic nephropathy Type 2 diabetic microalbuminuria Proteinuria Left ventricular hypertrophy ACE inhibitor cough or intolerance Angina pectoris Post myocardial infarction (only selected beta blockers e.g. carvedilol) Tachyarrhythmias Gout Compelling Not used in other hypertensive patients Renal failure Hyperkalaemia Atrioventricular block (grade 2 or 3) Hyperkalaemia Bilateral renal artery stenosis Hyperkalaemia Bilaterial renal artery stenosis Asthma Chronic obstructive pulmonary disease Atrioventricular block (grade 2 or 3) Contraindications Possible Concurrent use with a beta blocker Tachyarrhythmias Concurrent antiretroviral therapy Constipation (verapamil) Concurrent antiretroviral therapy Peripheral vascular disease Bradycardia Glucose intolerance Metabolic syndrome Athletes and physically active patients Concurrent use with nondihydropyridine calcium channel blockers Angioedema is a rare major side effect that contraindicates the future use of other ACE inhibitors and angiotensin ll receptor blockers. Use with caution in patients taking potassium-sparing diuretics or potassium supplements as serious hyperkalaemia may occur. Angiotensin ll receptor blockers (ARBs) This class of antihypertensives inhibits the effect of angiotensin ll on its receptor (the AT1 receptor) and block angiotensinll-induced vasoconstriction. The ARBs have many properties similar to the ACEinhibitors, except they do not inhibit the breakdown of bradykinin and other kinins and thus do not cause the persistent dry cough that commonly complicates ACE-inhibitor therapy. The ARBs are therefore a useful alternative for patients who have to discontinue an ACEinhibitor because of persistent cough. Dose-related hypotension may occur, especially in patients receiving diuretics. Like the ACE-inhibitors, the ARBs are contraindicated in pregnancy. Use with caution, if at all, in patients who have previously experienced angioedema with an ACE-inhibitor. Hyperkalaemia may occur. Potassium levels should be monitored, especially in the elderly and in patients with renal impairment. Concurrent use with potassium-sparing diuretics or potassium supplements should generally be avoided. Calcium channel blockers Calcium channel blockers (CCBs) interfere with the inward displacement of calcium ions through the slow channels of 28 SA Pharmaceutical Journal April 2008

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CLINICAL active cell membranes. They influence the myocardial cells, the cells within the specialised conducting system of the heart and the cells of vascular smooth muscle. Calcium channel blockers vary in their predilection for these various possible sites of action and therefore, in their therapeutic effects. There are important differences between verapamil, diltiazem and dihydropyridine calcium channel blockers used in hypertension e.g. amlodipine, isradipine, felodipine. In the treatment of hypertension, the dominant effect is a decrease in peripheral vascular resistance. Short-acting nifedipine has been associated with adverse myocardial outcomes and should not be used in the treatment of hypertension. The elderly patient may be preferentially treated with a calcium channel blocker alone or in combination with a thiazide diuretic. Calcium channel blockers should not be used together with alpha-blockers as severe hypotension may occur. The combination of a CCB and a beta-blocker should also be used with caution. The most common adverse effects include headache, flushing, dizziness and light-headedness. Serious cardiac adverse effects are rare. Beta-blockers Beta-blockers block beta-adrenoreceptors, primarily in the heart, bronchi, peripheral vasculature, pancreas and liver. The mechanism of action in hypertension is not clear but may include reduction of cardiac output, altered baroreceptor reflex sensitivity, depression of plasma renin and decreased release of neurotransmitters such as noradrenaline. Certain beta blockers (such as atenolol) are no longer considered as routine treatment for patients with uncomplicated hypertension, in view of several major considerations, including the failure of atenolol-based therapy in the ASCOT-BPLA * study. Beta-blockers do not reduce cardiovascular mortality or myocardial infarct mortality when given for hypertension. Betablockers may precipitate new onset diabetes, especially when used with diuretics. Note:The newer beta-blockers such as carvedilol, bisoprolol and nebivolol were not included in the two large meta-analyses of the effects of beta-blockers when used for hypertension. Carvedilol is a nonspecific adrenergic receptor blocker, blocking not only beta-1 and beta-2 receptors but alpha-receptors as well. * ASCOT-BPLA compared the effect on non-fatal myocardial infarction (MI) and fatal CHD of atenolol with a thiazide diuretic and amlodipine with perindopril. ASCOT-BPLA suggests that atenolol is not an acceptable initial therapy for hypertension and that an initial strategy using a calcium channel blocker is more effective. While beta-blocker therapy will continue to be used in patients with a compelling indication (See Table 5) for their use e.g. in post myocardial infarction, it is recommended that the use of atenolol as initial therapy or as initial combination therapy in the treatment of hypertension, should be restricted. Alpha-blockers Alpha-blockers have post-synaptic alphablocking and vasodilator properties. These agents are not used as first-line therapy but may be added to treatment with other antihypertensives. They may, however, be useful for patients with diabetes mellitus or lipid disorders. The hypotensive effects may be pronounced, especially in the elderly, and therefore treatment should be initiated slowly. In conclusion Pharmacotherapy to lower blood pressure is worthwhile, even if the blood pressure does not reach the targets defined in Table 4. Lifestyle modifications are difficult to sustain and therefore it is important to offer patients with hypertension ongoing support, regular blood pressure monitoring and advice on the appropriate use of antihypertensive medication. References: 1. Laurent S. Guidelines from the British Hypertension Society. BMJ 2004;328:593-4. 2. Joint National Hypertension Guideline Working Group. South African Hypertension Guideline 2006. SAMJ 2006;96(4):337-362. 3. Williams B. Recent hypertension trials Implications and controversies. J Am Coll Cardiol 2005;45(6):813-827. 4. Eds. South African Medicines Formulary 7 th Ed. 2005. 5. Eds. British National Formulary. 48 th Ed. 2004 6. NICE Clinical Guideline. www.nice.org 30 SA Pharmaceutical Journal April 2008

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