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M ODULE : HYPERTENSION Contributor: Dr. Nur Samsu, SpPD-KGH LEARNING OBJECTIVE: After completing this module, the students be able to: 1. 2. 3. 4. 5. 6. 7. Explain the definitions of normal blood pressure, prehypertension and hypertension Explain the risk factors associated with essential hypertension Describe and explain the secondary causes of hypertension Explain the complication of hypertension Describe white coat hypertension, mask hypertension, and resistant hypertension Evaluation and management of hypertension Describe mode of action, indications and side-effects of antihypertensive drugs OVERVIEW: INTRODUCTION — Hypertension is a disorder in which the blood pressure is raised above normal levels and its persistence leads to the damage of target organs such as the kidneys, brain, heart and blood vessels. Hypertension causes an excessive increase in the workload of the heart which can lead to heart failure (HF). Hypertension is also an important factor in the causation of stroke and coronary heart disease. Although hypertension is very common a significant proportion of those affected are unaware until they develop complications thus making the disease a silent killer. The number of patients with hypertension is likely to grow as the population ages, since either pure systolic hypertension or combined systolic and diastolic hypertension occurs in over one-half of persons older than 65 years. The rising incidence of obesity will also increase the number of hypertensive individuals. The incidence of hypertension increases with age and is more common in African Americans than in whites. It is more common in younger men than in women, although this difference does not exist after the age of 55 and is reversed after the age of 75. Approximately one billion people worldwide have hypertension. 21% of adults in Canada are hypertensive while only 57% of them are aware of it. The prevalence rate in the US is similar (20% ) but the awareness rate is higher (70%). Another peculiarity of hypertension is that in approximately 95% of cases the cause is unknown and this variety is labeled Primary or Essential Hypertension while in the remaining 5% it is the direct result of another disorder, and it is known as Secondary Hypertension. The implication is that in that 5% when the disorder is cured the hypertension is also cured. Despite the prevalence of hypertension and its associated complications, control of the disease is far from adequate. Data from NHANES show that only 34 percent of persons with hypertension have their blood pressure under control, defined as a level below 140/90 mmHg. There are numerous potential reasons for low rates of blood pressure control, including poor access to health care and medications, and lack of adherence with long-term therapy for a condition that is usually asymptomatic. The latter may be particularly true when the therapy may interfere with the patient's quality of life and when its immediate benefits may not be obvious to the patient. Thus, hypertension will likely remain the most common risk factor for heart attack and stroke. 1|P a g e DEFINITIONS — The following definitions have been suggested by the seventh report of the Joint National Committee (JNC 7). Based upon the average of two or more properly measured readings at each of two or more visits after an initial screen, the following classification is used: Normal blood pressure: systolic <120 mmHg and diastolic <80 Prehypertension: systolic 120-139 or diastolic 80-89 Hypertension: Stage 1: systolic 140-159 or diastolic 90-99 Stage 2: systolic 160 or diastolic 100 These definitions apply to adults on no antihypertensive medications and who are not acutely ill. If there is a disparity in category between the systolic and diastolic pressures, the higher value determines the severity of the hypertension. The addition of the prehypertension category recognizes that the correlation between the risk of adverse outcomes (including death) and blood pressure level is a continuous variable in which there is an increased incidence of poor outcomes as the blood pressure rises, even within the previously delineated "normal" range. ESSENTIAL (PRIMARY) HYPERTENSION Pathogenesis — The pathogenesis of essential hypertension is poorly understood. A variety of factors have been implicated, including: Increased sympathetic neural activity, with enhanced beta-adrenergic responsiveness. Increased angiotensin II activity and mineralocorticoid excess. Hypertension is about twice as common in subjects who have one or two hypertensive parents and multiple epidemiologic studies suggest that genetic factors account for approximately 30 percent of the variation in BP in various populations. Reduced adult nephron mass may predispose to hypertension, which may be related to genetic factors, intrauterine developmental disturbance (eg, hypoxia, drugs, nutritional deficiency), and post-natal environment (eg, malnutrition, infections). Risk factors — The etiology of essential (idiopathic or primary) hypertension and secondary hypertension (due to a known cause) differ. A variety of risk factors have been associated with essential hypertension: Hypertension tends to be both more common and more severe in blacks. Evidence for a relationship between sodium intake and essential hypertension continues to mount. It is likely that increased salt intake is a necessary but not sufficient cause for hypertension. Multiple studies show a clear association between excess alcohol intake and the development of hypertension. Obesity is associated with an increased prevalence and incidence of hypertension, and weight gain appears to be a main determinant of the rise in BP that is commonly seen with aging. 2|P a g e Dyslipidemia may also associated with the development of hypertension, and is independent of obesity. Hypertension may be more common among those with certain personality traits, such as hostile attitudes and time urgency/impatience. SECONDARY HYPERTENSION — A number of identifiable disorders may be associated with secondary hypertension, and the pathogenesis of hypertension is related to the underlying condition. Primary renal disease — Hypertension is a frequent finding in both acute and chronic renal disease, particularly with glomerular or vascular disorders. Oral contraceptives — Oral contraceptives often raise the blood pressure within the normal range but can induce overt hypertension. Pheochromocytoma — About one-half of patients with pheochromocytoma have paroxysmal hypertension, most of the rest have what appears to be essential hypertension. Primary hyperaldosteronism — The presence of primary mineralocorticoid excess, primarily aldosterone, should be suspected in any patient with the triad of hypertension, unexplained hypokalemia, and metabolic alkalosis. Some patients have a normal plasma potassium concentration. Renovascular disease — Renovascular disease is an important correctable cause of secondary hypertension. The frequency with which it occurs is variable. Cushing's syndrome — Moderate diastolic hypertension is a major cause of morbidity and death in patients with Cushing's syndrome. Other endocrine disorders — Hypertension may be induced by both hypothyroidism, hyperthyroidism, and hyperparathyroidism. Sleep apnea syndrome — Disorder breathing during sleep appears to be an independent risk factor for awake systemic hypertension. Coarctation of the aorta — Coarctation of the aorta is one of the major causes of hypertension in young children. COMPLICATIONS — Hypertension is associated with a number of serious adverse effects. The likelihood of developing these complications varies with the BP. The increase in risk begins as the BP rises above 110/75 mmHg and, at any BP, is importantly affected by the presence or absence of other risk factors. Hypertension is quantitatively the major risk factor for premature cardiovascular disease, being more common than cigarette smoking, dyslipidemia, and diabetes, the other major risk factors. In older patients, systolic pressure and perhaps pulse pressure are more powerful determinants of risk than diastolic pressure. Hypertension increases the risk of HF at all ages with the hazard increasing with the degree of BP elevation. 3|P a g e Left ventricular (LV) hypertrophy is a common problem in patients with hypertension, and is associated with an enhanced incidence of HF, ventricular arrhythmias, death following myocardial infarction, and sudden cardiac death. Hypertension is the most common and most important risk factor for stroke, the incidence of which can be markedly reduced by effective antihypertensive therapy. Hypertension is the most important risk factor for the development of intracerebral hemorrhage. Hypertension is a risk factor for chronic renal insufficiency and end-stage renal disease. It can both directly cause renal disease, called hypertensive nephrosclerosis, and accelerate the progression of a variety of underlying renal diseases. Marked elevations in BP can cause an acute, life-threatening emergency. DIAGNOSIS Measurement — Proper measurement and interpretation of the BP is essential in the diagnosis and management of hypertension. In the absence of end-organ damage, the diagnosis of mild hypertension should not be made until the BP has been measured on at least 3 to 6 visits, spaced over a period of weeks to months. Sequential studies have shown that the BP drops by an average of 10 to 15 mmHg between visits one and three in patients who appear to have mild hypertension on a first visit to a new doctor, with a stable value not being achieved until more than 6 visits in some cases. Thus, many patients considered to be hypertensive at the initial visit are in fact normotensive. White coat hypertension and ambulatory monitoring — Approximately 20 to 25 percent of patients with mild office hypertension (diastolic pressure 90 to 104 mmHg) have what is called "white-coat" or isolated office hypertension in that their BP is repeatedly normal when measured at home, at work, or by ambulatory blood pressure monitoring (ABPM). This problem is more common in the elderly, but is infrequent (less than 5 percent) in patients with office diastolic pressures 105 mmHg. One way to minimize the white coat effect is to have the BP in the office taken by a nurse or technician, rather than the physician. ABPM, which typically involves automated inflation of the BP cuff and recording of the BP at preset intervals (usually every 15 to 20 minutes during the day and every 30 to 60 minutes during sleep), can be used to confirm or exclude the presence of white coat hypertension in patients with persistent office hypertension but normal BP readings in the ambulatory setting. Masked hypertension — 24-hour monitoring of larger populations has revealed a significant number of patients with elevated out-of-office readings despite normal office readings (eg, masked hypertension). Cardiovascular risk appears to be elevated in such patients to a similar extent as patients with sustained hypertension. This is consistent with the risk of hypertensive cardiovascular complications (including the development and regression of LV hypertrophy) being more closely correlated with 24-hour or daytime ambulatory monitoring than with the office pressure. 4|P a g e Indications for ABPM — In addition to patients with suspected white coat hypertension, ambulatory monitoring should be considered in the following circumstances: Suspected episodic hypertension (eg, pheochromocytoma) Hypertension resistant to increasing medication Hypotensive symptoms while taking antihypertensive medications Autonomic dysfunction EVALUATION — Once it has been determined that the patient has persistent hypertension, an evaluation should be performed to ascertain the following information: To determine the extent of target organ damage. To assess the patient's overall cardiovascular risk status. To rule out identifiable and often curable causes of hypertension. Patients with essential hypertension undergo a relatively limited work-up because extensive laboratory testing is of limited utility. However, it is important to be aware of the clinical clues suggesting the possible presence of secondary hypertension. Many of these disorders can be cured, leading to partial or complete normalization of the blood pressure; but it is not cost-effective to perform a complete evaluation in every hypertensive patient. History — The history should search for those facts that help determine the presence of precipitating or aggravating factors, the natural course of the BP, the extent of target organ damage, and the presence of other risk factors for cardiovascular disease. Physical examination — The main goals on the physical examination are to evaluate for signs of endorgan damage (such as retinopathy) and for evidence of a cause of secondary hypertension. Laboratory testing — The only testing that should be routinely performed includes: Hematocrit, urinalysis, and routine blood chemistries (glucose, creatinine, electrolytes) Fasting (9 to 12 hours) lipid profile (total and HDL-cholesterol, triglycerides) Electrocardiogram Additional tests — Additional tests may be indicated in certain settings: Testing for microalbuminuria is at present primarily limited to patients with diabetes to screen for early nephropathy, although it is increasingly recognized to be an independent risk factor for cardiovascular disease. A discussion of screening for microalbuminuria among nondiabetics with hypertension is presented separately. Limited echocardiography is a more sensitive method to detect LV hypertrophy than the ECG and is considerably less expensive than a complete echocardiographic examination. The main indication for echocardiography is to detect possible end-organ damage in a patient with borderline BP values, thereby identifying some patients who would not be treated based upon clinical criteria alone. 5|P a g e Testing for renovascular hypertension — Renovascular hypertension is likely the most common correctable cause of secondary hypertension. The incidence of this condition varies with the clinical setting. It probably occurs in less than 1 percent of patients with mild hypertension. In comparison, between 10 and 45 percent of white patients with severe or malignant hypertension have renal artery stenosis. Radiographic testing for renovascular disease is indicated only in patients in whom the history is suggestive and in whom a corrective procedure will be recommended if significant renal artery stenosis is detected. The following are settings in which renovascular hypertension or another cause of secondary hypertension should be suspected: Severe or refractory hypertension, including retinal hemorrhages or papilledema; bilateral renovascular disease may be present in those patients who also have a plasma creatinine above 1.5 mg/dL (132 µmol/L). An acute rise in BP over a previously stable baseline — this includes renovascular disease superimposed upon underlying and often well-controlled essential hypertension. Proven age of onset before puberty or above age 50. An acute elevation in the plasma creatinine concentration that is either unexplained or occurs after the institution of therapy with an ACE inhibitor or angiotensin II receptor blocker (in the absence of an excessive reduction in BP). Moderate to severe hypertension in a patient with diffuse atherosclerosis or an incidentally discovered asymmetry in renal disease. A unilateral small kidney ( 9 cm) has a 75 percent correlation with the presence of large vessel occlusive disease. A systolic-diastolic abdominal bruit that lateralizes to one side. This finding has a sensitivity of approximately 40 percent (and is therefore absent in many patients) but has a specificity as high as 99 percent. Systolic bruits alone are more sensitive but less specific. The patient should be supine, moderate pressure should be placed on the diaphragm of the stethoscope, and auscultation should be performed in the epigastrium and all four abdominal quadrants. Negative family history for hypertension. Moderate to severe hypertension in patients with recurrent episodes of acute (flash) pulmonary edema or otherwise unexplained CHF. The recommended tests will vary based upon renal function and the clinical suspicion of renovascular disease. Testing for other causes of identifiable hypertension — Other causes of identifiable hypertension also must be excluded in the appropriate settings. The presence of primary renal disease is suggested by an elevated plasma creatinine concentration, a calculated GFR below 60 mL/min per 1.73 m2, or proteinuria. Pheochromocytoma should be suspected if there are paroxysmal elevations in BP (which may be superimposed upon stable chronic hypertension), particularly if associated with the triad of headache (usually pounding), palpitations, and sweating. 6|P a g e Measurement of plasma renin activity and aldosterone concentration is usually performed only in patients with possible low-renin forms of hypertension, such as primary hyperaldosteronism. Otherwise unexplained hypokalemia is the primary clinical clue to the latter disorder in which the plasma aldosterone to plasma renin activity ratio should be obtained as a screening test. Cushing's syndrome (including that due to corticosteroid administration) is usually suggested by the classic physical findings of cushingoid facies, central obesity, ecchymoses, and muscle weakness. The sleep apnea syndrome should be suspected in obese individuals who snore loudly while asleep, awake with headache, and fall asleep inappropriately during the day. Coarctation of the aorta is characterized by decreased or lagging peripheral pulses and a vascular bruit over the back. Hypertension may be induced by both hypothyroidism, suspected because of suggestive symptoms or an elevated plasma thyroid stimulating hormone level, and primary hyperparathyroidism, suspected because of otherwise unexplained hypercalcemia. TREATMENT Benefits of BP control — In clinical trials, antihypertensive therapy has been associated with 35 to 40 percent mean reductions in stroke incidence; 20 to 25 percent in MI; and more than 50 percent in HF. It is estimated that control of hypertension to below 140/90 mmHg could, in men and women, prevent 19 and 31 percent of coronary heart disease events, respectively, whereas optimal control to below 130/80 mmHg could prevent 37 and 56 percent of coronary heart disease events, respectively. Who should be treated? — Using the above definitions from JNC 7, the following general approach can be used to determine which patients with hypertension require antihypertensive therapy. This approach largely includes the recommendations of JNC 7 for risk stratification and treatment and assumes accurate measurement of the BP. All patients should undergo appropriate lifestyle (nonpharmacologic) modification. The following decisions about antihypertensive medications are generally not made until there has been an adequate trial of nonpharmacologic therapy. Antihypertensive medications should generally be begun if the systolic pressure is persistently 140 mmHg and/or the diastolic pressure is persistently 90 mmHg in the office and at home despite attempted nonpharmacologic therapy. Starting with two drugs may be considered in patients with a baseline blood pressure above 160/100 mmHg. In patients with diabetes or proteinuric chronic renal failure, antihypertensive therapy is indicated when the systolic pressure is persistently above 130 mmHg and/or the diastolic pressure is above 80 mmHg. Patients with office hypertension, normal values at home, and no evidence of end-organ damage should undergo ABPM to see if they are truly hypertensive. In a number of conditions (eg, HF, post-MI), certain antihypertensive drugs are given to improve survival or the underlying disease, independent of the BP. 7|P a g e Lifestyle modifications — Treatment of hypertension generally begins with nonpharmacologic therapy, including moderate dietary sodium restriction, weight reduction in the obese, avoidance of excess alcohol intake, and regular aerobic exercise. Patient education is an important component of lifestyle modification, and has been demonstrated to result in improved BP control. Drug treatment Initial drug choice in uncomplicated hypertension — The JNC 7 report recommended a low-dose thiazide diuretic (eg, 12.5 to 25 mg of hydrochlorothiazide or chlorthalidone) for initiating therapy in uncomplicated hypertensives unless there is a specific indication for a drug from another class. This regimen is associated with a low rate of metabolic complications, such as hypokalemia, glucose intolerance, and hyperuricemia. Thiazides have other actions that may be desirable in specific patient populations. In particular, they lower urinary calcium excretion, which may be beneficial in patients with hypercalciuria and recurrent calcium stones and in those with osteoporosis. If low-dose thiazide monotherapy fails to attain goal BP in uncomplicated hypertensives, an ACE inhibitor, angiotensin II receptor blocker (ARB), beta blocker, or calcium channel blocker can be sequentially added or substituted. Indications for specific drugs — These general recommendations for initial therapy should be amended in certain clinical settings in which specific agents might offer particular benefit. ACE inhibitors — ACE inhibitors are considered first-line therapy in all patients who have HF or asymptomatic LV dysfunction, in all patients who have had an ST elevation MI, in patients with a non-ST elevation MI who have had an anterior infarct, diabetes, or systolic dysfunction, and in patients with proteinuric chronic renal failure. ARBs — It is highly likely that the indications for and efficacy of ARBs are not different from those with ACE inhibitors. An ARB is particularly indicated in patients who do not tolerate ACE inhibitors (mostly because of cough). Beta blockers — A beta blocker without intrinsic sympathomimetic activity should be given after an AMI and to stable patients with HF or asymptomatic LV dysfunction (beginning with very low doses to minimize the risk and degree of initial worsening of myocardial function). The use of beta blockers in these settings is in addition to the recommendations for ACE inhibitors in these disorders. If such compelling indications are not present, beta-blockers should not be used since, for primary prevention, they are no better than other drugs against MI and are inferior to other drugs against stroke. Beta blockers are also given for rate control in patients with atrial fibrillation, for control of angina, and for symptom control in a number of other disorders. Diuretics — Findings from ALLHAT suggest that a low dose thiazide diuretic (eg, 12.5 to 25 mg of chlorthalidone) in both younger and older patients provides better cardioprotection than an ACE inhibitor or a calcium channel blocker in patients with risk factors for coronary artery disease, including LV hypertrophy, type 2 diabetes, previous MI or stroke, current cigarette smoking habits, hyperlipidemia, 8|P a g e or atherosclerotic cardiovascular disease. The effects may reflect a greater fall in BP seen with the diuretic than with other agents. However, there are compelling indications for the use of ACE inhibitors, ARBs, and/or beta blockers in many of these settings. Thus, a thiazide diuretic should be prescribed in the absence of an indication for any other specific drug(s) or when goal BP has not been attained. Diuretics should also be given for fluid control in patients with HF or nephrotic syndrome; these settings usually require loop diuretics. In addition, an aldosterone antagonist is indicated in patients with advanced HF who have relatively preserved renal function and, in patients with less severe disease, for the treatment of hypokalemia. Calcium channel blockers — There are no absolute indications for calcium channel blockers in hypertensive patients. Like beta blockers, they can be given for rate control in patients with atrial fibrillation or for control of angina. Calcium channel blockers may be preferred in patients with obstructive airways disease. Other specific settings — Beyond these indications, a number of specific recommendations can be made for drugs with favorable effects in various settings. As an example, an alpha blocker in high-risk hypertensive patients is associated with an increased risk of HF and should not generally be used as a first-line antihypertensive drug. However, an alpha blocker may be preferred in older men with symptoms of prostatism, particularly if they are not at high risk. Combination therapy — It remains unclear when a second drug should be considered if there is a suboptimal response to initial therapy. The alternatives are to push the first drug to maximum recommended dosage or to add a second drug after a moderate dose of the first drug. The latter approach given the potential advantage of fewer side effects. Administering two drugs as initial therapy should also be considered in patients with BP 160/100 mmHg. This strategy may increase the likelihood that target BP are achieved in a reasonable time period, but should be used cautiously in patients at increased risk for orthostatic hypotension (such as diabetics and the elderly). If two drugs are required, use of a low dose of a thiazide diuretic as one of the drugs increases the response rate to all other agents. By minimizing volume expansion, diuretics tend to increase the antihypertensive effect of all other antihypertensive drugs. The combination of a thiazide diuretic with a beta blocker, an ARB, or an ACE inhibitor has a synergistic effect, controlling the BP in up to 85 percent of patients. Other common combinations include an ACE inhibitor with a calcium channel blocker, and a beta blocker with a vasodilator or a dihydropyridine calcium channel blocker. Other combinations may not have an additive antihypertensive effect, such as the combination of an ACE inhibitor with a beta blocker or a diuretic with a calcium channel blocker. There are also combinations that have additive side effects. In particular, a beta blocker should be used with caution in combination with verapamil and to a lesser degree diltiazem. These drugs can potentiate the cardiac depressant effect of the beta blocker, possibly leading to bradycardia or heart block. 9|P a g e Goal blood pressure — The goal BP presented below refer to the levels at which more intensive antihypertensive therapy to produce a further reduction in BP is not recommended. These goals are in keeping with the JNC 7 and assume that the patient is at average risk (eg, uncomplicated hypertension). The goal of antihypertensive therapy in patients with uncomplicated combined systolic and diastolic hypertension is a BP of below 140/90 mmHg; treatment goals are determined by the higher BP category. Similar goals have been recommended for nondiabetic patients with coronary heart disease. For the rapidly growing population of hypertensive individuals over age 65 with isolated systolic hypertension (eg, a DBP below 90 mmHg), caution is needed not to inadvertently lower the DBP to below 65 mmHg to attain a goal systolic pressure <140 mmHg, since this level of diastolic pressure has been associated with an increased risk of stroke. Thus, the level of SBP that is reached with two or three antihypertensive agents (even if greater than 140 mmHg) may be a more reasonable interim goal in such individuals. A number of clinical trials guidelines suggest a goal BP of <130/80 mmHg in two clinical settings: patients with diabetes mellitus; and patients with chronic renal disease, particularly those excreting more than 1 g of protein per day. These recommendations assume that the BP is being gradually reduced, since acutely lowering BP in patients with severe underlying hypertension can clearly lead to deleterious cerebrovascular and coronary events. Resistant hypertension — Some patients have hypertension that is seemingly resistant to conventional medical therapy. Resistance is usually defined as a DBP above 95 to 100 mmHg despite intake of three or more antihypertensive medications. One or more of the following problems usually contributes to the inability to adequately lower the BP in this setting: Suboptimal therapy Extracellular volume expansion Poor compliance with medical or dietary therapy Secondary hypertension Office or "white coat" hypertension Pseudohypertension Ingestion of substances that can elevate the blood pressure Discontinuing therapy — Some patients with mild hypertension are well controlled, often on a single medication. After a period of years, the question arises as to whether antihypertensive therapy can be gradually diminished or even discontinued. Several studies that have evaluated the effect of discontinuation of treatment have shown that between 5 and 55 percent of patients remain normotensive for at least one to two years; a larger fraction of patients do well with a decrease in the number and/or dosage of medications taken. Gradual discontinuation of therapy is most likely to be effective in patients with mild initial hypertension who are well controlled on a single drug and who can often be maintained on nonpharmacologic therapy such as weight loss and sodium restriction. More gradual tapering of drug dosage is indicated in wellcontrolled patients taking multiple drugs. 10 | P a g e Abrupt cessation of therapy with a short-acting beta-blocker (such as propranolol) or the short-acting alpha-2-agonist clonidine can lead to a potentially fatal withdrawal syndrome. Gradual discontinuation of these agents over a period of weeks (including switching to longer-acting drugs of the same class such as atenolol or methyldopa) should prevent this problem. Modul Task A 40-year-old man presents with nausea and vomiting. He has suffered from that since 1 month ago. He also has decreased of apetite, feel weekness and fatique. On physical examination, conjunctiva was pallor, heart rate was 100 beats/min, respirations were 24/ min, blood pressure was 180/100 mmHg, and enlargement of cardiac. Results of urinalysis were erythrosituria 10-15 per hpf (high power field) and proteinuria +2. Laboratory test results were as follows: hemoglobin, 8.4 g/dL; creatinine, 3.26 mg/dL; BUN 65 mg/dl. Questions: 1. What are the patient’s problems? 2. What is your planning? 3. What is the cause of hypertension of this patient and how the pathophysiology of hypertension in renal disease patients (renal/kidney hypertension)! 4. What kind of antihypertensive drugs will you give and what is your reasoning? 5. What is the target of blood pressure in general population, diabetic patients and chronic kidney disease patients? Suggested Reading 1. Kaplan NM, Domino FJ. Overview of hypertension in adults. Up to date, 2007 2. Beevers G, Lip GYH, O’Brien E. The pathophysiology of hypertension. BMJ, 2001, 322:912-916 3. Moser M, John F. Setaro JF. Resistant or Difficult-to-Control Hypertension. N Engl J Med 2006;355:385-92. 4. August P. Initial Treatment of Hypertension. N Engl J Med 2003;348:610-7 5. The Seventh Report of the Joint National Committee on (JNC VII) Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, 2003. 6. NICE guideline. Management of hypertension in adults in primary care: partial update. 2007 7. ESH – ESC guidelines for the management of arterial hypertension. Journal of Hypertension 2003, 21:1011–1053 11 | P a g e