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HYPERTENSION Various algorithms recommending nonpharmacologic and pharmacologic management for typical and atypical patients are proposed, with the underlying theme that achievement of blood pressure targets mitigate end-organ damage, leading to substantial reductions in stroke, myocardial infarction, and heart failure. Although references to other algorithms will be mentioned, we will focus primarily on the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure, more commonly referred to as the JNC 7 report. The JNC 7 report describes four stages of blood pressure classification and provides guidance on non-pharmacologic and pharmacologic approaches to managing patients with hypertension. The four stages of blood pressure classification include normal, prehypertension, stage 1 hypertension, and stage 2 hypertension. These stages are defined as such to connote a level of risk and thus the need for varying intensities of intervention with drug therapy. With the exception of individuals with “compelling indications,” recommendations for drug therapy typically begin with one or two (in the case of stage 2) antihypertensive drugs as an initial step. Specific drug selection is guided by the presence of compelling indications— specific comorbid conditions. These compelling indications, such as heart failure, diabetes, and chronic kidney disease (CKD). Selection of drug therapy consequently involves an iterative process of considering multiple antihypertensive drugs as needed to achieve target blood pressures of less than 140/90 mm Hg for all patients, with more aggressive targets of less than 130/80 mm Hg for patients with diabetes or chronic kidney disease. Treatment with drug therapy should be done in combination with recommended lifestyle modifications to manage hypertension and minimize risk. CLASSIFICATION OF BLOOD PRESSURE (BP) IN CHILDREN, ADOLESCENTS, AND ADULTS DEFINED AS 18 YEARS BP Classification Adult SBP (mm Hg) Adult DBP (mm Hg) Children/Adoles centsSBP or DBP Percentilea Normal Less than 120 and less than 80 Less than 90th Prehypertension 120–139 Or 80–89 90–95th or 120/80 mm Hg Stage 1 hypertension 140–159 or 90–99 95–99th + 5 mm Hgb Stage 2 hypertension Greater than or equal to 160 Greater than or equal to 100 Greater than 99th + 5 mm Hgc Arterial blood pressure is determined by cardiac output, peripheral vascular resistance and large artery compliance. Peripheral vascular resistance is determined by the diameter of resistance vessels (small muscular arteries and arterioles) in the various tissues. One or more of a ‘mosaic’ of interconnected predisposing factors (including positive family history, obesity and physical inactivity among others) are commonly present in patients with essential hypertension, some of which are amenable to changes in diet and other habits. Cardiac output may be increased in children or young adults during the earliest stages of essential hypertension, but by the time hypertension is established in middle life the predominant haemodynamic abnormality is an elevated peripheral vascular resistance. With ageing, elastic fibres in the aorta and conduit arteries are replaced by less compliant collagen causing arterial stiffening and systolic hypertension, which is common in the elderly. Etiology a. Essential hypertension: 90% (no identifiable cause) i. Contributed to obesity ii. Evaluate Na intake. b. Secondary hypertension i. Primary aldosteronism ii. Renal parenchymal disease iii. Thyroid or parathyroid disease iv. Medications (e.g., cyclosporine, NSAIDs, sympathomimetics) In addition to primary and secondary hypertension, the clinician may encounter what is referred to as resistant hypertension. Patients failing to achieve goal blood pressure despite maximum doses of three antihypertensives including a diuretic should be carefully screened for resistant hypertension. Benefits of lowering BP a. 40 % decrease in stroke b. 25 % decrease in MI c. 50 % decrease in HF 2. Select treatment goal. a. JNC 7 goals are less than 140/90 mm Hg for all patients except for patients with diabetes and/or significant chronic kidney disease (defined as estimated glomerular filtration rate less than 60 mL/minute/1.73 m2 [about when SCr is greater than 1.5 mg/dL in men or greater than 1.3 mg/dL in women]) OR albuminuria (greater than 300 mg/day or greater than 200 mg alb/g creatinine)] in which the goal is 130/80 mm Hg. b. Other treatment goals exist; however, they are controversial and not universally accepted. American Heart Association 2007 recommendation Most Patients for General Prevention (Primary Prevention Patients) < 140/90 mm Hg Patients with Diabetes mellitus; Significant chronic kidney disease; Known CAD (MI, stable angina, unstable angina)Non coronary atherosclerotic vascular disease (ischemic stroke, TIA, PAD, abdominal aortic aneurism); or Framingham risk score > 10% < 130/80 mm Hg Patients with left ventricular dysfunction (systolic heart failure) < 120/80 mm Hg Nonpharmacologic Treatment: Lifestyle Modifications Therapeutic lifestyle modifications consisting of nonpharmacologic approaches to blood pressure reduction should be an active part of all treatment plans for patients with hypertension. The most widely studied interventions demonstrating effectiveness include: • Weight reduction in overweight or obese individuals • Adoption of a diet rich in potassium and calcium • Dietary sodium restriction • Physical activity • Moderation of alcohol consumption Implementation of these lifestyle modifications successfully lowers blood pressure, often with results similar to those of therapy with a single antihypertensive agent. Combinations of two or more lifestyle modifications can have even greater effects with blood pressure lowering. In addition to their beneficial effects on lowering blood pressure, lifestyle modifications also have a favorable effect on other risk factors such as dyslipidemia and insulin resistance, which are commonly encountered in the hypertensive population, and lifestyle modifications should be encouraged for this reason as well. PHARMACOLOGIC TREATMENT JNC 7 provides a reasonable basis for guiding the selection of drug classes for individuals based on their stage of hypertension, comorbidities, and special circumstances. Many authorities recognize the value of diuretics as first-line agents for the majority of patients with hypertension (acquisition cost and availability as combination agents). The endorsement by JNC 7 as an initial drug therapy selection for stage 1 and stage 2 hypertensive patients without compelling indications is based on a litany of placebo-controlled studies. Who should be treated with pharmacotherapy? Recommendations JNC 8 Patients <60 years of age: start pharmacotherapy at 140/90 mmHg. Patients with diabetes: start pharmacotherapy at 140/90 mmHg. Patients with CKD: start pharmacotherapy at 140/90 mmHg. Patients 60 years of age and older: start pharmacotherapy at 150/90 mmHg. What is the goal blood pressure? Recommendations JNC 8 Patients <60 years of age: <140/90 mmHg Patients with diabetes: <140/90 mmHg Patients with CKD: <140/90 mmHg Patients 60 years of age and older: <150/90 mmHg What pharmacotherapy is recommended? Recommendation JNC 8 Nonblack, including those with diabetes: thiazide, CCB, ACEI, or ARB African American, including those with diabetes: thiazide or CCB CKD: regimen should include an ACEI or ARB (including African Americans) Can initiate with two agents, especially if systolic >20 mmHg above goal or diastolic >10 mmHg above goal. If goal not reached: Reinforce lifestyle and adherence Titrate medications to maximum doses or consider adding another medication (ACEI, ARB, CCB, Thiazide) If not reached Reinforce lifestyle and adherence Add a medication class not already selected (i.e. beta blocker, aldosterone antagonist, others) and titrate above medications to max if not refer to a specialist. ASH:2 Nonblack <60 years of age: First-line: ACEI or ARB Second-line (add-on): CCB or thiazide Third-line: CCB plus ACEI or ARB plus thiazide Nonblack 60 years of age and older: First-line: CCB or thiazide preferred, ACEI, or ARB Second-line (add-on): CCB, thiazide, ACEI, or ARB (don’t use ACEI plus ARB) Third-line: CCB plus ACEI or ARB plus thiazide African American: First-line: CCB or thiazide Second-line (add-on): ACEI or ARB Third-line: CCB plus ACEI or ARB plus thiazide Initial Drugs of Choice for Hypertension • ACE inhibitor (ACEI) • Angiotensin receptor blocker (ARB) • Thiazide diuretic • Calcium channel blocker (CCB) Strategy Description A Start one drug, titrate to maximum dose, and then add a second drug. B Start one drug, then add a second drug before achieving max dose of first C Begin 2 drugs at same time, as separate pills or combination pill. Initial combination therapy is recommended if BP is greater than 20/10mm Hg above goal Lifestyle changes: • Smoking Cessation • Control blood glucose and lipids • Diet Eat healthy Moderate alcohol consumption Reduce sodium intake to no more than 2,400 mg/day •Physical activity Moderate-to-vigorous activity 3-4 days a week averaging 40 min per session. 1- starting drug treatment Start with low moderate recommended dose of a first-line drug. If not well tolerated, change to a different drug class, again starting with a low moderate dose. 2- if target not reached after 3 months Add a second drug from a different pharmacological class at a low moderate dose, rather than increasing the dose of the first drug (max antihypertensive efficacy, min adverse effects). 3- if target not reached after 3 months If both antihypertensive drugs have been well tolerated, increase the dose of one drug (excluding thiazide duiretics) incrementally to the max recommended dose before increasing the dose of the other drug. 4- if target is not reached after 3 months If, despite max doses of at least 2 drugs, a third drug class may be started at a low-moderate dose. It is advisable for non-adherence secondary hypertension and hypertensive effects of other drugs, treatment resistant state due to sleep apnoea, undisclosed use of alcohol or recreational drugs or high salt intake. 5- if Bp remains elevated, consider seeking specialist advice. 3. SELECT APPROPRIATE THERAPY. Classes of antihypertensive drugs and their sites of action. Vasomotor centre α2-Adrenoceptor agonists (e.g. clonidine) Imidazoline receptor agonists (e.g. moxonidine) Vascular smooth muscle ACE inhibitors (‘A’ drugs) Angiotensin receptor blockers (‘A’ drugs) Calcium channel blockers (‘C’ drugs) Diuretics (‘D’ drugs) α1-Blockers (e.g. doxazosin) Mineralocorticoid antagonists Juxtaglomerular cells β-blockers (‘B’ drugs) Renin inhibitors Kidney tubules Diuretics (‘D’ drugs) ACE inhibitors Angiotensin receptor blockers GENERAL PRINCIPLES OF MANAGING ESSENTIAL HYPERTENSION Consider blood pressure in the context of other risk factors: use cardiovascular risk to make decisions about whether to start drug treatment and what target to aim for. (Guidance, together with risk tables, is available, for example, at the back of the British National Formulary). Use non-drug measures (e.g. salt restriction) in addition to drugs. • Explain goals of treatment and agree a plan the patient is comfortable to live with (concordance). • Review the possibility of co-existing disease (e.g. gout, angina) that would influence the choice of drug. • The ‘ABCD’ rule provides a useful basis for starting drug treatment. A (and B) drugs inhibit the renin–angiotensin–aldosterone axis and are effective when this is active – as it usually is in young white or Asian people. An A drug is preferred for these unless there is some reason to avoid it (e.g. in a young woman contemplating pregnancy) or some additional reason (e.g. co-existing angina) to choose a B drug. Older people and people of Afro-Caribbean ethnicity often have a low plasma renin and in these patients a class C or D drug is preferred. Use a low dose and, except in emergency situations, titrate this upward gradually. • Addition of a second drug is often needed. A drug of the other group is added, i.e. an A drug is added to patients started on a C or D drug, a C or D drug is added to a patient started on an A drug. A third or fourth drug may be needed. It is better to use such combinations than to use very high doses of single drugs: this seldom works and often causes adverse effects. • Loss of control – if blood pressure control, having been well established, is lost, there are several possibilities to be considered: non-adherence; drug interaction – e.g. with non-steroidal anti-inflammatory drugs (NSAIDs) intercurrent disease – e.g. renal impairment, atheromatous renal artery stenosis. DRUGS USED TO TREAT HYPERTENSION A DRUGS ANGIOTENSIN-CONVERTING ENZYME INHIBITORS Use Several angiotensin-converting enzyme inhibitors (ACEI) are in clinical use (e.g. ramipril, trandolapril, enalapril, lisinopril, captopril). These differ in their duration of action. Longer-acting drugs (e.g. trandolapril, ramipril) are preferred. They are given once daily and produce good 24-hour control. Their beneficial effect in patients with heart failure or following myocardial infarction makes them or a sartan particularly useful in hypertensive patients with these complications. Similarly an ACEI or sartan is preferred over other anti-hypertensives in diabetic patients because they slow the progression of diabetic nephropathy. Treatment is initiated using a small dose given last thing at night, because of the possibility of first-dose hypotension. If possible, diuretics should be withheld for one or two days before the first dose for the same reason. The dose is subsequently usually given in the morning and increased gradually if necessary, while monitoring the blood-pressure response i. Contraindicated in pregnancy ii. Contraindicated with bilateral renal artery stenosis iii. Monitor K closely, especially if renal insufficiency exists or another K-sparing drug is in use. iv. The presence of diabetic nephropathy should influence the choice of ACE inhibitor versus ARB. ACE inhibitors are a key class of antihypertensive agents used in a vast array of patients with or without comorbidities and/or cardiovascular risk factors. This broad utility extends to the list of compelling indications for patients as described in JNC 7. These compelling indications include their qualified role in managing patients with hypertension who have type 1 diabetes, heart failure, post–myocardial infarction, type 2 diabetes, chronic kidney disease, or recurrent stroke prevention. Adverse effects ACE inhibitors are generally well tolerated. Adverse effects include: • First-dose hypotension. • Dry cough – this is the most frequent symptom during chronic dosing. It is often mild, but can be troublesome. due to kinin accumulation stimulating cough afferents. Sartans do not inhibit the metabolism of bradykinin and do not cause cough. • Functional renal failure – this occurs predictably in patients with haemodynamically significant bilateral renal artery stenosis, and in patients with renal artery stenosis in the vessel supplying a single functional kidney. Plasma creatinine and potassium concentrations should be monitored and the possibility of renal artery stenosis considered in patients in whom there is a marked rise in creatinine. Provided that the drug is stopped promptly, such renal impairment is reversible. The explanation of acute reduction in renal function in this setting is that glomerular filtration in these patients is critically dependent on angiotensin-II-mediated efferent arteriolar vasoconstriction, and when angiotensin II synthesis is inhibited, glomerular capillary pressure falls and glomerular filtration ceases. This should be borne in mind particularly in ageing patients with atheromatous disease. Hyperkalaemia is potentially hazardous in patients with renal impairment and great caution must be exercised in this setting. This is even more important when such patients are also prescribed potassium supplements and/or potassium-sparing diuretics. Fetal injury – ACEI cause renal agenesis/failure in the fetus, resulting in oligohydramnios. ACEI are therefore contraindicated in pregnancy and other drugs are usually preferred in women who may want to start a family. Urticaria and angio-oedema – increased kinin concentration may explain the urticarial reactions and angioneurotic oedema sometimes caused by ACEI. Sulphhydryl group-related effects – high-dose captopril causes heavy proteinuria, neutropenia, rash and taste disturbance, attributable to its sulphhydryl group. DRUG INTERACTIONS Diuretic treatment increases plasma renin activity and the consequent activation of angiotensin II and aldosterone limits their efficacy. ACE inhibition interrupts this loop and thus enhances the hypotensive efficacy of diuretics, as well as reducing thiazide-induced hypokalaemia. Conversely, ACEI have a potentially adverse interaction with potassium-sparing diuretics and potassium supplements, leading to hyperkalaemia, especially in patients with renal impairment As with other antihypertensive drugs, NSAIDs increase blood pressure in patients treated with ACE inhibitors. ANGIOTENSIN RECEPTOR BLOCKERS Several angiotensin receptor blockers (ARB or ‘sartans’) are in clinical use (e.g. losartan, candesartan, irbesartan, valsartan). Use Sartans are pharmacologically distinct from ACEI, but clinically similar in hypotensive efficacy. However, they lack the common ACEI adverse effect of dry cough. Long-acting drugs (e.g. candesartan, which forms a stable complex with the AT1 receptor) produce good 24-hour control. Their beneficial effect in patients with heart failure or following myocardial infarction makes them or an ACEI useful in hypertensive patients with these complications. Similarly, an ACEI or a sartan is preferred over other antihypertensive drugs in diabetic patients where they slow the progression of nephropathy. Head to head comparison of losartan versus atenolol in hypertension (the LIFE study) favoured the sartan. Their excellent tolerability makes them first choice ‘A’ drugs for many physicians, but they are more expensive than ACEI. First-dose hypotension can occur and it is sensible to apply similar precautions as when starting an ACEI (first dose at night, avoid starting if volume contracted). AT1 receptor stimulation evokes a pressor response via a host of accompanying effects on catecholamines, aldosterone, and thirst. Consequently, inhibition of AT1 receptors directly prevents this pressor response and results in up-regulation of the RAAS. Upregulation of the RAAS results in elevated levels of angiotensin II, which have the added effect of stimulating the AT2 receptors. AT2-receptor stimulation is generally associated with antihypertensive activity; however, long-term effects of AT2-receptor stimulation that involve cellular growth and repair are relatively unknown. What is clear is that ARBs differ from ACE inhibitors in that the former cause up-regulation of the RAAS while the latter blocks the breakdown of bradykinin. Like ACE inhibitors, the antihypertensive effectiveness of ARBs is greatly enhanced by combining them with diuretics. Furthermore, they have proven their value as welltolerated alternatives to ACE inhibitors for patients with chronic kidney disease, diabetes mellitus, and post–acute myocardial infarction (AMI) B DRUGS β-ADRENOCEPTOR ANTAGONISTS Beta-blockers lower blood pressure and reduce the risk of stroke in patients with mild essential hypertension, but in several randomized controlled trials (particularly of atenolol) have performed less well than comparator drugs. The explanation is uncertain, but one possibility is that they have less effect on central (i.e. aortic) blood pressure than on brachial artery pressure. ‘B’ drugs are no longer preferred over ‘A’ drugs as first line in situations where an A or B would previously have been selected. They are, however, useful in hypertensive patients with an additional complication such as ischaemic heart disease or heart failure. The negative inotropic effect of beta-blocking drugs is particularly useful for stabilizing patients with dissecting aneurysms of the thoracic aorta, in whom it is desirable not only to lower the mean pressure, but also to reduce the rate of rise of the arterial pressure wave. β-Adrenoceptor antagonists reduce cardiac output (via negative chronotropic and negative inotropic effects on the heart), inhibit renin secretion and some have additional central actions reducing sympathetic outflow from the central nervous system (CNS). The JNC 7 identifies β-blockers as agents appropriate for first-line therapy for many individuals with hypertension. Based on JNC 7, the role of β-blockers in patients with select comorbidities is extensive. Patients with comorbidities such as heart failure, recent myocardial infarction, and diabetes represent opportunities for β-blocker use on the basis of proven outcome based studies. The role of β-blockers for patients with ischemic conditions including acute myocardial infarction is based on their hemodynamic effects on heart rate, blood pressure, and cardiac output, as well as their possibly anti-arrhythmic properties. Nonetheless, in the long run β-blockers, when judiciously used in patients with heart failure, have consistently been shown to reduce morbidity and mortality relative to standard heart failure therapies. Similarly, given their effects on pancreatic β-cell release of insulin and metabolic effects, such as reducing gluconeogenesis and glycogenolysis, their role in managing diabetic patients would also seem illogical. One of these properties is cardioselectivity—the property of some β-blockers that preferentially block β1- versus β2-receptors. Another property exhibited by some β-blockers is membrane stabilization activity, which relates to the propensity of the β-blocker to possess some capacity for antiarrhythmic properties, in addition to β-receptor blocking properties. Some β-blockers possess properties referred to as intrinsic sympathomimetic activity (ISA). β-Blockers possessing this property effectively block the βreceptor at higher circulating catecholamine levels, such as during exercise, while having modest βstimulating activity at times of lower catecholamine levels, such as at rest. Cardioselective drugs (e.g. atenolol, metoprolol, bisoprolol, nebivolol) inhibit β1-receptors with less effect on bronchial and vascular β2-receptors. However, even cardioselective drugs are hazardous for patients with asthma. Some beta-blockers (e.g. oxprenolol) are partial agonists and possess intrinsic sympathomimetic activity. There is little hard evidence supporting their superiority to antagonists for most indications although individual patients may find such a drug acceptable when they have failed to tolerate a pure antagonist (e.g. patients with angina and claudication). Beta-blockers with additional vasodilating properties are available. This is theoretically an advantage in treating patients with hypertension. Their mechanisms vary. Some (e.g. labetolol, carvedilol) have additional α-blocking activity. Nebivolol releases endothelium-derived nitric oxide. ADVERSE EFFECTS AND CONTRAINDICATIONS Intolerance – fatigue, cold extremities, erectile dysfunction; less commonly vivid dreams. Airways obstruction – asthmatics sometimes tolerate a small dose of a selective drug when first prescribed, only to suffer an exceptionally severe attack subsequently, and β-adrenoceptor antagonists should ideally be avoided altogether in asthmatics and used only with caution in COPD patients, many of whom have a reversible component. Decompensated heart failure – β-adrenoceptor antagonists are contraindicated (in contrast to stable heart failure) Peripheral vascular disease and vasospasm – β-adrenoceptor antagonists worsen claudication and Raynaud’s phenomenon. Hypoglycaemia – β-adrenoceptor antagonists can mask symptoms of hypoglycaemia and the rate of recovery is slowed, because adrenaline stimulates gluconeogenesis. Heart block – β-adrenoceptor antagonists can precipitate or worsen heart block. Metabolic disturbance – β-adrenoreceptor antagonists worsen glycaemic control in type 2 diabetes mellitus. CNS side effects (e.g. nightmares) occur more commonly. Polar (water-soluble) beta-blockers (e.g. atenolol) are excreted by the kidneys and accumulate in patients with renal impairment/failure. Drug interactions • Pharmacokinetic interactions: β-adrenoceptor antagonists inhibit drug metabolism indirectly by decreasing hepatic blood flow secondary to decreased cardiac output. This causes accumulation of drugs such as lidocaine that have such a high hepatic extraction ratio that their clearance reflects hepatic blood flow. • Pharmacodynamic interactions: Increased negative inotropic and atrioventricular (AV) nodal effects occur with verapamil (giving both intravenously can be fatal), lidocaine and other negative inotropes. C DRUGS CALCIUM-CHANNEL BLOCKERS (CCBAs) Dihydropyridine calcium-channel blockers. It is a good choice, especially in older patients and Afro-Caribbeans. Amlodipine is taken once daily. The daily dose can be increased if needed, usually after a month or more. Slowrelease preparations of nifedipine provide an alternative to amlodipine. Exhibiting considerable interclass diversity, CCBAs have been recognized as effective anti-hypertensives, for the elderly in particular. Earlier trials demonstrated effective event reduction for patients with isolated systolic hypertension Often used to augment blood pressure lowering, CCBAs are most commonly used as add-on therapy for patients who are in need of further blood pressure lowering above and beyond that afforded by diuretics or other antihypertensives. Nonetheless, they have demonstrated their efficacy in select patient populations as very effective blood pressure lowering agents. The diversity of pharmacologic properties within the CCBA class is significant. Knowledge of their subclass helps the clinician to recognize their predominant effects on the cardiovascular system and probable side-effect profile. Dihydropyridine CCBAs such as amlodipine are commonly associated with edema, especially when used at higher doses. Phenylalkylamine-verapamil and benzothiazepinediltiazem are more commonly recognized for their effects on the cardiac conduction system and their propensity to be negative inotropes and negative chronotropes. Adverse effects Calcium-channel blocking drugs are usually well tolerated. Short-acting preparations (e.g. nifedipine capsules) cause flushing and headache. Baroreflex activation causes tachycardia, which can worsen angina. These formulations of nifedipine should be avoided in the treatment of hypertension and never used sublingually. Ankle swelling (oedema) is common, often troublesome, but not sinister. The negative inotropic effect of verapamil exacerbates cardiac failure. Constipation is common with verapamil. Intravenous verapamil can cause circulatory collapse in patients treated concomitantly with β-adrenoceptor antagonists. D DRUGS DIURETICS A low dose of a thiazide, or related diuretic, e.g. chlortalidone, remains the best first choice for treating older patients and Afro- Caribbeans with uncomplicated mild essential hypertension, unless contraindicated by some co-existent disease (e.g. gout). They are also essential in more severe cases, combined with other drugs. Diuretics reduced the risk of stroke in several large clinical trials and in the Medical Research Council (MRC) trial they did so significantly more effectively than did beta blockade Thiazides (e.g. bendroflumethiazide) are preferred to loop diuretics for uncomplicated essential hypertension. They are given by mouth as a single morning dose. They begin to act within one to two hours and work for 12–24 hours. Loop diuretics are useful in hypertensive patients with moderate or severe renal impairment, and in patients with hypertensive heart failure. Thiazide diuretics inhibit reabsorption of sodium and chloride ions in the proximal part of the distal convoluted tubule. Excessive salt intake or a low glomerular filtration rate interferes with their antihypertensive effect. Natriuresis is therefore probably important in determining their hypotensive action. However, it is not the whole story since although plasma volume falls when treatment is started, it returns to normal with continued treatment, despite a persistent effect on blood pressure. During chronic treatment, total peripheral vascular resistance falls slowly, suggesting an action on resistance vessels. Responsiveness to pressors (including angiotensin II and noradrenaline) is reduced during chronic treatment with thiazides. hypokalaemia – kaliuretis is a consequence of increased sodium ion delivery to the distal nephron where sodium and potassium ions are exchanged. Mild hypokalaemia is common but seldom clinically important in uncomplicated hypertension; hypomagnesaemia; hyperuricaemia – most diuretics reduce urate clearance, increase plasma urate and can precipitate gout; hyperglycaemia – thiazides reduce glucose tolerance: high doses cause hyperglycaemia in type 2 diabetes; hypercalcaemia – thiazides reduce urinary calcium ion clearance (unlike loop diuretics, which increase it) and can aggravate hypercalcaemia in hypertensive patients with hyperparathyroidism; hypercholesterolaemia – high-dose thiazides cause a small increase in plasma LDL cholesterol concentration. Erectile dysfunction which is reversible on stopping the drug. Increased plasma renin, limiting the antihypertensive effect. Idiosyncratic reactions, including rashes (which may be photosensitive) and purpura, which may be thrombocytopenic or non-thrombocytopenic. Diuretics indirectly increase Li reabsorption in the proximal tubule, by causing volume contraction. This results in an increased plasma concentration of Li and increased toxicity. Diuretic-induced hypokalaemia and hypomagnesaemia increase the toxicity of digoxin. Combinations of a thiazide with a potassium-sparing diuretic, such as amiloride (coamilozide), triamterene or spironolactone can prevent undue hypokalaemia, and are especially useful in patients who require simultaneous treatment with digoxin, sotalol or other drugs that prolong the electrocardiographic QT-interval. These metabolic effects may clearly complicate the management of higher-risk patients with common comorbidities such as dyslipidemia or diabetes, or even those likely to be sensitive to the potassium- or magnesium- wasting effects of diuretics (patients with dysrhythmias or those taking digoxin). While rates of diabetes are higher following administration of thiazides, there is plenty of evidence that this can be greatly minimized by keeping potassium in the high normal range (i.e., above 4.0 mEq/L [4 mmol/L]) Another key feature of the thiazide-type diuretics is their limited efficacy in patients whose estimated renal function is reduced, such as the elderly. For example, patients with estimates of reduced renal function, such as those with a glomerular filtration rate (GFR) below 30 mL/minute, should be considered for more potent loop type diuretics such as furosemide. In situations in which a patient has poor renal function, a loop diuretic should be given at least twice a day, with the exception of furosemide to augment blood pressure control with combination antihypertensive therapy. Diuretic resistance may result from extended use of loop diuretics. In these circumstances, the addition of a thiazide to a loop diuretic may dramatically enhance overall diuresis. The most significant adverse effects related to loop diuretic use concern their potential for excessive diuresis leading to hyponatremia or hypotension. Additionally, hypokalemia, hypomagnesemia, and hypocalcemia may develop over time and contribute to the potential for cardiac arrhythmias. Overall relevance of drug-drug interactions and potential for aggravating select conditions (hyperglycemia, dyslipidemias, and hyperuricemia) should be routinely considered in the monitoring plan for those taking loop diuretics for extended periods of time. Potassium-sparing diuretics that do not act through mineralocorticoid receptors include triamterene and amiloride. These agents are often prescribed with potassium-wasting diuretics in an attempt to mitigate the loss of potassium. When administered as a single entity or as one component of a combination product, these agents result in moderate diuresis. Potassium-sparing diuretics act on the late distal tubule and collecting duct and thereby have limited ability to affect sodium reabsorption, which translates into modest diuresis. The most important adverse effects associated with these agents are their potential to contribute to hyperkalemia. This is especially relevant in the context of those patients receiving other agents with potassium-sparing properties, such as ACE inhibitors, ARBs, and potassium supplements, as well NSAIDs, in those with mild to moderate renal impairment. These inhibitors of aldosterone are commonly used in patients as components of select combination drug therapies to balance the potassium wasting effects of more potent diuretics, such as thiazide or loop diuretics, as well as for their direct antihypertensive effects through aldosterone modulation. Patients with resistant hypertension with and without primary aldosteronism had significant additive blood pressure reductions when adding low-dose spironolactone (12.5 to 50 mg/day) to diuretics, ACE inhibitors, and ARBs. Although functional for these purposes, it is important to recognize their potential to cause hyperkalemia when used in conjunction with other select agents or in patients with comorbidities resulting in reduced renal function. Classic examples include coadministration with ACE inhibitors and ARBs, known for their potassium-sparing effects, as well as agents that may directly or indirectly alter renal potassium load (e.g., potassium supplements) or potassium excretory function (e.g., NSAIDs). The most commonly used potassium-sparing diuretic is spironolactone; however, eplerenone has been increasingly used in patients with heart failure following acute myocardial infarction. Although spironolactone is commonly associated with gynecomastia, eplerenone rarely causes this complication. The risk of hyperkalemia is also more commonly reported with patients on spironolactone. Alpha-Blockers Generally, α1-blockers are considered as second-line agents to be added on to most other agents when hypertension is not adequately controlled. They may have a specific role in the antihypertensive regimen for elderly males with prostatism; however, their use is often curtailed by complaints of syncope, dizziness, or palpitations following the first dose and orthostatic hypotension with chronic use. Central Alpha2-Agonists Also limited by their tendency to cause orthostasis, sedation, dry mouth, and vision disturbances, clonidine, methyldopa and guanathedine represent rare choices in contemporary treatment of patients with hypertension Their central α2-adrenergic stimulation is thought to reduce sympathetic outflow and enhance parasympathetic activity thereby reducing heart rate, cardiac output, and total peripheral resistance. Occasionally used for cases of resistant hypertension, these agents may have a role when other more conventional therapies appear ineffective. The availability of a transdermal clonidine patch that is applied once weekly may offer an alternative to hypertensive patients with adherence problems. Key points Drugs used in essential hypertension Diuretics: thiazides (in low dose) are preferred to loop diuretics unless there is renal impairment. They may precipitate gout and worsen glucose tolerance or dyslipidaemia, but they reduce the risk of stroke and other vascular events. Adverse effects include hypokalaemia, which is seldom problematic, and impotence. They are suitable firstline drugs, especially in black patients, who often have low circulating renin levels and respond well to salt restriction and diuretics. Beta-blockers reduce the risk of vascular events, but are contraindicated in patients with obstructive pulmonary disease. Adverse events (dose-related) include fatigue and cold extremities. Heart failure, heart block or claudication can be exacerbated in predisposed patients. They are particularly useful in patients with another indication for them (e.g. angina, postmyocardial infarction). Patients of African descent tend to respond poorly to them as single agents. ACE inhibitors are particularly useful as an addition to a thiazide in moderately severe disease. The main adverse effect on chronic use is cough; losartan, an angiotensin-II receptor antagonist, lacks this effect but is otherwise similar to ACE inhibitors. Calcium-channel antagonists are useful, especially in moderately severe disease. Long-acting drugs/preparations are preferred. The main adverse effect in chronic use is ankle swelling. α1-Blockers are useful additional agents in patients who are poorly controlled on one or two drugs. Long-acting drugs (e.g. doxazosin) are preferred. Effects on vascular event rates are unknown. Unlike other antihypertensives, they improve the lipid profile. α-Methyldopa is useful in patients with hypertension during pregnancy. Other drugs that are useful in occasional patients with severe disease include minoxidil, hydralazine and nitroprusside. ADDITIONAL ANTIHYPERTENSIVE DRUGS USED IN SPECIAL SITUATIONS Minoxidil: Minoxidil sulphate (active metabolite) used in Very severe hypertension that is resistant to other drugs is a Kchannel activator. Nitroprusside Breaks down chemically to NO, which activates guanylyl cyclase Given by intravenous infusion in intensive care unit for control of malignant hypertension. Hydralazine Direct action on vascular smooth muscle; biochemical mechanism not understood. Previously used in ‘stepped-care’ approach to severe hypertension β-antagonist in combination with diuretic. Retains a place in severe hypertension during pregnancy α-Methyldopa Taken up by noradrenergic nerve terminals and converted to α-methylnoradrenaline which is released as a false transmitter. This acts centrally as an α2-agonist and reduces sympathetic outflow. Hypertension during pregnancy. Occasionally useful in patients who cannot tolerate other drugs. 4. Considerations with specific antihypertensive agents a. β-Blockers i. Caution with asthma, severe chronic obstructive pulmonary disease (especially higher doses) because of pulmonary β-receptor blockade ii. Increased risk of developing diabetes compared with ACE inhibitor, ARB, and calcium channel blocker; use caution in patients at high risk of diabetes mellitus (e.g., family history, obese) iii. May mask some signs of hypoglycemia in patients with diabetes mellitus iv. May cause depression b. Thiazides i. May worsen gout by increasing serum uric acid ii. Increased risk of developing diabetes compared with ACE inhibitor, ARBs, and calcium channel blocker; use caution in patients at high risk of diabetes mellitus (e.g., family history, obese) iii. May assist in the management of osteoporosis by preventing urine calcium loss c. Angiotensin-converting enzyme inhibitors and ARBs i. Contraindicated in pregnancy ii. Contraindicated with bilateral renal artery stenosis iii. Monitor K closely, especially if renal insufficiency exists or another K-sparing drug is in use. iv. The presence of diabetic nephropathy should influence the choice of ACE inhibitor versus ARB. d. Aliskiren i. A direct rennin antagonist ii. When combined with losartan (100 mg/day) in patients with hypertension, type 2 diabetes mellitus, and nephropathy (albumin-to-creatinine ratio greater than 300 mg/g or greater than 200 mg/g), aliskiren showed renoprotective effects independent of its BP effects (N Engl J Med 2008;358:2433–46). iii. Whether this combination is superior to ACE inhibitor/ARB combinations is questionable. Considerations within specific patient populations a. Patients with ischemic heart disease: Potent vasodilators may cause reflex tachycardia, thereby increasing myocardial oxygen demand (hydralazine, minoxidil, and dihydropyridine calcium channel blockers); can attenuate this by also using an atrioventricular nodal depressant (non-dihydropyridine calcium channel blocker or β-blocker). b. Elderly patients: i. Caution with antihypertensive agents and orthostatic hypotension ii. Initiate with low dose and titrate slowly. c. African American patients: β-Blockers and ACE inhibitors are generally less effective as monotherapy than in white patients; however, combination therapy with thiazides improves effectiveness, and it should still be used if comorbid conditions dictate. d. Pregnant women i. Methyldopa and hydralazine are recommended if a new therapy is initiated. ii. Most antihypertensives (except for ACE inhibitors and ARBs) can be safely continued in pregnancy. Monitoring a. Have the patient return in 4 weeks to assess efficacy. b. May have patient follow-up sooner if BP particularly worrisome c. If there is an inadequate response from the first agent (and adherence verified) and no compelling indication exists, initiate therapy with a drug from a different class. SPECIAL PATIENT POPULATIONS Compelling Indications and Special Considerations While the main goal of antihypertensive therapy is to achieve target blood pressures, the selection of agents for an individual should also account for certain special considerations and a patient’s comorbidities. Specific antihypertensive therapy is warranted for certain patients with comorbid conditions that may elevate their level of risk for cardiovascular disease. Clinical conditions for which there is compelling evidence supporting one or more classes of drug therapy include: • Ischemic heart disease • Heart failure • Diabetes • Chronic kidney disease • Cerebrovascular disease In patients with hypertension and chronic stable angina, β-blockers and long-acting calcium channel blockers are indicated due to their antihypertensive and antianginal effects. In patients at high risk of ischemic heart disease, such as diabetic patients with additional cardiovascular risk factors or chronic coronary artery or vascular disease, ACE inhibitors are particularly useful in reducing the risk of cardiovascular events regardless of whether the patient carries a concurrent diagnosis of hypertension. β-Blockers and ACE inhibitors are also indicated for post–myocardial infarction for the reduction of cardiovascular morbidity and mortality, as are aldosterone antagonists, in post–myocardial infarction patients with reduced left ventricular systolic function and diabetes or signs and symptoms of heart failure. Patients with asymptomatic left ventricular systolic dysfunction and hypertension should be treated with βblockers and ACE inhibitors. Those with heart failure secondary to left ventricular dysfunction and hypertension should be treated with drugs proven to also reduce the morbidity and mortality of heart failure, including βblockers, ACE inhibitors, ARBs, aldosterone antagonists, and diuretics for symptom control as well as antihypertensive effect. In African-Americans with heart failure and left ventricular systolic dysfunction, combination therapy with nitrates and hydralazine not only affords a morbidity and mortality benefit, but may also be useful as antihypertensive therapy if needed. The dihydropyridine calcium channel blockers amlodipine or felodipine may also be used in patients with heart failure and left ventricular systolic dysfunction for uncontrolled blood pressure, although they have no effect on heart failure morbidity and mortality in these patients. For patients with heart failure and preserved ejection fraction, antihypertensive therapies that should be considered include β-blockers, ACE inhibitors, ARBs, calcium channel blockers (including nondihydropyridine agents), diuretics, and others as needed to control blood pressure. Patients with diabetes and hypertension should initially be treated with either β-blockers, ACE inhibitors, ARBs, diuretics, or calcium channel blockers. There is a general consensus that therapy focused on RAAS inhibition by ACE inhibitors or ARBs may be optimal if the patient has additional cardiovascular risk factors such as left ventricular hypertrophy or chronic kidney disease. In patients with chronic kidney disease and hypertension, ACE inhibitors and ARBs are preferred, usually in combination with a diuretic. ACE inhibitors in combination with a thiazide diuretic are also preferred in patients with a history of prior stroke or transient ischemic attack. This therapy reduces the risk of recurrent stroke, making it particularly attractive in these patients for blood pressure control. A hypertensive emergency occurs when severe elevations in blood pressure are accompanied by acute or life-threatening target organ damage such as acute myocardial infarction, unstable angina, encephalopathy, intracerebral hemorrhage, acute left ventricular failure with pulmonary edema, dissecting aortic aneurysm, rapidly progressive renal failure, accelerated malignant hypertension with papilledema, and eclampsia among others. Blood pressure is generally greater than 220/140 mm Hg, although a hypertensive emergency can occur at lower levels, particularly in individuals without previous hypertension. The goal in a hypertensive emergency is to reduce mean arterial pressure by up to 25% to the range of 160/100 to 110 mm Hg in minutes to hours. Intravenous therapy Vasodilators: Sodium nitroprusside as IV infusion 0.25–10 mcg/kg/minute, Nicardipine hydrochloride 5–15 mg/hour IV, Fenoldopam mesylate 0.1–0.3 mcg/kg/minute as IV infusion, Nitroglycerin 5–100 mcg/kg/minute as IV infusion, Enalaprilat 1.25– 5 mg every 6 hours, Hydralazine hydrochloride10–20 mg IV 10–40 mg IM. Adrenergic Inhibitors Labetalol hydrochloride 20–80 mg IV bolus every 10 min, Esmolol hydrochloride 250–500 mcg/kg/minute IV bolus, then 50–100 mcg/kg/minute by infusion; may repeat bolus after 5 minutes or increase infusion to 300 mcg/minute, Phentolamine 5–15 mg IV bolus. A hypertensive urgency is manifested as a severe elevation in blood pressure without evidence of acute or lifethreatening target organ damage. In these individuals, blood pressure can usually be managed with orally administered short-acting medications (i.e., captopril, clonidine, or labetalol) and observation in the emergency department over several hours, with subsequent discharge on oral medications and follow-up in the outpatient setting within 24 hours. The treatment of elderly patients with hypertension, as well as those with isolated systolic hypertension, should follow the same approach as with other populations with the exception that lower starting doses may be warranted to avoid symptoms and with special attention paid to postural hypotension. This should include a careful assessment of orthostatic symptoms, measurement of blood pressure in the upright position, and caution to avoid volume depletion and rapid titration of antihypertensive therapy. In patients of African origin, diminished blood pressure responses have been seen with ACE inhibitors and ARBs compared to diuretics or calcium channel blockers. Hypertension in pregnancy is a major cause of maternal, fetal, and neonatal morbidity and mortality. There are many categories of hypertension in pregnancy Methyldopa Preferred first-line therapy on the basis of long-term follow-up studies supporting safety after exposure in utero. Surveillance data do not support an association between drug and congenital defects when the mother took the drug early in the first trimester. Labetalol Increasingly preferred to methyldopa because of reduced side effects. The agent does not seem to pose a risk to the fetus, except possibly in the first trimester. β-Blockers Generally acceptable on the basis of limited data. Reports of intrauterine growth restriction with atenolol in the first and second trimesters. Clonidine Limited data; no association between drug and congenital defects when the mother took the drug early in the first trimester, but number of exposures is small. Calcium antagonists Limited data; nifedipine in the first was not associated with increased rates of major birth defects, but animal data were associated with fetal hypoxemia and acidosis. This agent should probably be limited to mothers with severe hypertension. Diuretics Not first-line agents; probably safe; available data suggest that throughout gestation a diuretic is not associated with an increased risk of major fetal anomalies or adverse fetal-neonatal events. ACEIs and ARBs Contraindicated; reported fetal toxicity and death.