King Saud University Pharmacy College Pharmacology Department

513 PHL

HYPERTENSION
Prepared by Asma Al-Oneazi

I.Introduction: Hypertension is a common disease that is defined simply as persistently elevated arterial blood pressure (BP). Although elevated BP was supposed to be necessary for adequate perfusion of essential organs during the early and middle 1900s, it is now identified as one of the most significant risk factors for cardiovascular disease. (Joseph J. and Barry L. , 2005). Its the most common cardiovascular disease. The prevalence varies with age, race and many other variables. Elevated blood pressure is usually caused by a combination of several (multifactorial) abnormalities. ( genetic inheritance, psychological stress, and environmental and dietary factors (increased salt and decreased potassium or calcium intake) as perhaps contributing to the development of hypertension. Also, other risk factors include smoking, hyperlipidemia, diabetes and a family history of cardiovascular disease.(Goodman. et al, 2006) Epidemiologic studies indicate the hypertension (blood pressure 140/90 mm Hg) increases the risk of eventual end organ damage. Starting at 115/75 mm Hg cardiovascular disease risk doubles with each rise of 20/10 mm Hg throughout the blood pressure range. Sustained arterial hypertension damages blood vessels in kidney, heart, and brain and leads to an increased incidence of renal failure, coronary disease, cardiac failure, and stroke.(Goodman. et al, 2006) Increasing awareness and diagnosis of hypertension and improving control of BP with appropriate treatment are considered critical public health initiatives to reduce cardiovascular morbidity and mortality.(Joseph J. and Barry L. , 2005).

II.Normal regulation blood pressure: Arterial blood pressure (BP) is directly proportionate to the product of cardiac output and the peripheral vascular resistance; BP= CO PVR.(Katzung, et al, 2006) Physiologically, in both normal and of hypertension individuals, blood pressure is maintained by: 1) Blood vessels (arterioles and postcapillary venules capacitance vessels), this affect peripheral vascular resistance. Local release of vasoactive substances from vascular endothelium may also be involved in the regulation of vascular resistance. For example, endothelin-1 constricts and nitric oxide dilates blood vessels. 2) Heart, affect cardiac output. CO is the major determinant of SBP. CO is a function of stroke volume, heart rate, and venous capacitance. Under normal physiologic conditions, arterial BP fluctuates throughout the day. It typically follows a circadian rhythm, where it decreases to its lowest daily values during sleep. This is followed by a sharp rise starting a few hours prior to awakening, with the highest values occurring midmorning. BP is also increased acutely during physical activity or emotional stress.(Joseph J. and Barry L. , 2005). 3) Kidney, contributes to maintenance of blood pressure by regulating the volume of intravascular fluid. This regulation via Activation of the renin-angiotensin-aldosterone system (RAAS) in acute situations is intended for preservation of intravascular volume, maintenance of BP, and repair of tissue injury. (Alan H. Gradman, and Philadelphia, 2009)

4) Maintenance of cardiovascular homeostasis depends on complex interplays between a variety of local, humoral, neural, and reflex factors that modify cardiac and vascular performance according to the changing requirements of daily life. As far as reflex mechanisms are concerned, appear to be the main reflexogenic areas participating at blood pressure regulation. These include: Arterial baroreceptors, anatomically located in the aortic arch (aortic baroreceptors) and in the carotid sinuses (carotid baroreceptors), which are sensitive to blood pressure changes and modulate heart rate (vagal fibers). Peripheral vasoconstrictor tone (sympathetic fibers) They also include reflexes stemming from the so-called cardiopulmonary receptors, that is, stretch receptors located within the cardiac walls and the pulmonary circulation, which modulate, to a major extent, sympathetic cardiovascular drive and the release of humoral substances such as plasma vasopressin, plasma renin activity, and atrial natriuretic peptides. Other reflexes such as reflexes originating from muscle metabaroceptors (sensitive to metabolic and exercise-induced changes in local pH values) and from arterial chemoreceptors, which are sensitive to oxygen and carbon dioxide content of the arterial blood as well as to systemic acidemia (decrease in arterial pH values). These 2 reflexogenic areas are mainly involved in the modulation of sympathetic vascular drive, whereas their influence on vagal control of sinus node activity appears, at least in humans, negligible.(Guido Grassi, 2006).

Figure-1: Baroreceptors regulation of blood pressure.

III.Pathophsiology of hypertension: Increased blood pressure can result from increased cardiac output and/or increased total peripheral resistance. Increased cardiac output: Increased cardiac preload; which can be result from increased fluid volume from excess sodium intake or renal sodium retention. Venous constriction; due to excess stimulation of the RAAS and sympathetic nervous system over activity. Increased peripheral resistance: Functional vascular constriction and structural vascular hypertrophy; due to excess stimulation of the RAAS, sympathetic nervous system overactivity, genetic alterations of cell membranes and endothelial-derived factors. Structural vascular hypertrophy can result also from hyperinsulinemia resulting from obesity or the metabolic syndrome.(Joseph J. and Barry L. , 2005). The increase in cardiac output and/or peripheral vascular resistance mainly due to: 1.Renin-angiotensin-aldosterone system: In contrast to its protective effects in acutely stressful circumstances, chronic stimulation of the RAAS exerts effects that are damaging to long-term cardiovascular health. The effects are mediated by a number of pathogenic processes including: Chronic vasoconstriction Elevation of BP Vascular smooth muscle cell growth/migration Endothelial dysfunction Oxidative stress Release of cytokines and immune/inflammatory cell activation Fibrosis, and thrombosis. Through these mechanisms, chronic RAAS activation contributes to development of vascular and myocardial hypertrophy, left ventricular remodeling, atherosclerosis, and glomerulosclerosis. These structural alterations form the permissive anatomical substrate that precedes catastrophic cardiovascular events such as myocardial infarction (MI), stroke, and end-stage renal disease.
(Alan H. Gradman, and Philadelphia, 2009).

Figure-2: Regulation of blood pressure by renin-angiotensin-aldosterone system (RAAS). Most of these effects in both acute and chronic are mediated directly or indirectly by AII. The first reaction and rate-limiting step in the production of AII is the cleavage of angiotensinogen by the circulating enzyme renin. Angiotensin-converting enzyme converts the inactive product of this reaction, angiotensin I (AI), into the active octapeptide AII. Only approximately 10% of ACE circulates in the plasma, whereas 90% is found in the tissues such as heart, brain, kidney, and arteries.(Alan H. Gradman, and Philadelphia, 2009). The circulating RAAS that controls acute hemodynamic modulation is an ACE-dependent system that: 1) Regulates BP by inducing vasoconstriction 2) Na+/water retention 3) Acutely enhancing myocardial contractility. Tissue-specific RAAS uses local AI to form AII. Angiotensin II acts on both the AT1 and AT2 receptors. AT1 receptor stimulation has benefit effect for acute stimulation and harmful effect for chronic stimulation: Benefit effect of acute AT1 receptor stimulation by AII; mediates most of the acute effects of the RAAS, including vasoconstriction, aldosterone release, central sympathetic activation, and renal Na+/water retention.(Alan H. Gradman, and Philadelphia, 2009). The Harmful effects of AII on the vasculature are also mediated by AT1 receptor stimulation, which promotes endothelial dysfunction, smooth muscle cell proliferation, atherosclerosis, and vascular hypertrophy. AT1 receptor stimulation of cardiac myocytes results in hypertrophy, gene reprogramming, and necrosis. Activation of the AT1 receptor on cardiac fibroblasts results in proliferation and upregulation of transforming growth factor, collagen (type I and III), and fibronectin, leading to tissue fibrosis. The effects of AT1 receptor

stimulation on cardiac myocytes and fibroblasts ultimately lead to left ventricular hypertrophy. (Alan H. Gradman, and Philadelphia, 2009). In most, but not all, experimental situations, AT2 receptor stimulation mediates effects that are thought to be beneficial, such as vasodilation, nitric oxide release, increased renal Na+ excretion, and inhibition of cellular hypertrophy and proliferation. (Alan H. Gradman, and Philadelphia,
2009).

2.Endothelial dysfunction: Endothelial dysfunction, a hallmark of essential hypertension, refers to significant impairment of a majority of endothelial activities e.g. modulation of vasomotor tone and inhibition of smooth muscle cell proliferation and/or migration. Several factors including: a) increased synthesis of vasoconstrictor agents through the cyclooxygenase pathway. b) dys-regulation of the gene encoding endothelial type of nitric oxide synthase in endothelium have been proposed to account for this defect in hypertensive subjects. However, a growing body of evidence has recently implicated diminished bio-availability of nitric oxide (NO), the most important endogenous vasodilator agent, due to excessive synthesis or reduced destruction of reactive oxygen species (ROS).( Ulvi Bayraktutan , 2005).

3.Left Ventricular Hypertrophy: Left Ventricular Hypertrophy is a risk factor for major cardiovascular diseases as stroke, myocardial infarction and sudden death. Hemodynamic and anatomic characteristics of LVH are represented by the alteration of coronary blood flow, endothelial dysfunction, extracellular collagen deposition and ventricular fibrosis. However, other biological phenomena such as genotype, gender, body size, environmental factors can influence left ventricular mass. The most important mechanism remains the activation of neurohormonal systems (first of all, reninangiotensin system, secondarily catecolamines, insulin and leptin).( Alberto Palazzuoli, et al, 2005) 4.Natriuretic hormone: Natriuretic hormone inhibits sodium and potassium ATPase and thus interferes with sodium transport across cell membranes. Inherited defects in the kidneys ability to eliminate sodium can cause an increased blood volume. A compensatory increase in the concentration of circulating natriuretic hormone theoretically could increase urinary excretion of sodium and water. However, this same hormone is also thought to block the active transport of sodium out of arteriolar smooth muscle cells. The increased intracellular concentration of sodium ultimately would increase vascular tone and BP.(Joseph J. and Barry L. , 2005). 5. Another possible pathology of hypertension: Reduced contractile capacity of vascular smooth muscle could result in hypertension is still unknown. Smoothelin-B, recognized as the actin-binding protein, is expressed specifically in vascular smooth muscle cells and involved in the contractile process of vascular smooth muscle. Recently, found that deficiency of smoothelin-B resulted in reduced contractile capacity of vascular smooth muscle and hypertension in mice, which reminds us that reduced contractile capacity of vascular smooth muscle cells may be another mechanism leading to hypertension.

Smoothelin-B in vascular smooth muscle cells Although the contraction of vascular smooth muscle plays an important role in the pathogenesis of hypertension, the process of contraction itself has not been clarified. In vascular tissues, the expression of smoothelin-B is different according to the types of the blood vessel, high expression in smooth muscle cells of arteries but relatively low expression in smooth muscle cells of veins. Moreover, not all vascular smooth muscle cells express smoothelin-B. The expression of smoothelin- B in muscular arteries, such as the femoral artery, is higher than that in elastic arteries. Deficiency of smoothelin-B resulting in reduced contractile capacity of vascular smooth muscle and hypertension.(Shao-Hua Li, and Ru-Tai
Hui, 2009)

Types of hypertension: 1) Essential hypertension: In most cases, elevated blood pressure is associated with an overall increase in resistance to flow of blood through arterioles, while cardiac output is usually normal. Meticulous investigation of autonomic nervous system function, baroreceptor reflexes, the reninangiotensin-aldosterone system, and the kidney has failed to identify a primary abnormality as the cause of increased peripheral vascular resistance. So, patients with no specific cause of hypertension have essential hypertension.(Katzung, et al, 2006) 2) Secondary hypertension: A specific cause of hypertension can be established in only 1015% of patients. Secondary hypertension either a comorbid disease such as renal artery constriction, pheochromocytoma, Cushing's disease, and primary aldosteronism.(Katzung, et al, 2006). or a drug is responsible for elevating BP. In most of these cases, renal dysfunction resulting from chronic kidney disease or renovascular disease is the most common secondary cause. Certain drugs, either directly or indirectly, can cause hypertension or exacerbate hypertension by increasing BP. Some of these agents are herbal products. Although these are not technically drugs, they have been identified as causes of elevated BP and secondary hypertension. When a secondary cause is identified, removing the offending agent or treating/correcting the underlying comorbid condition should be the first step in management.(Joseph J. and Barry L. , 2005). Classification of BP: Classification Systolic Blood Pressure(mm Hg) Less than 120 120139 140159 > or equal to 160 Diastolic Blood Pressure(mm Hg) Less than 80 or 8089 or 9099 or > or equal to 100 Comment

Normal Prehypertension Stage 1 hypertension Stage 2 hypertension

Hypertensive crises

>180

>120mmHg

accompanied by acute or progressing targetorgan damage. Such as encephalopathy, intracranial hemorrhage, acute LVF with pulmonary edema.

Table-1: Classification of blood pressure.(Joseph J. and Barry L. , 2005).

Diagnosis of hypertension: Diagnostic procedures are aimed at: (1) establishing blood pressure levels (2) identifying secondary causes of hypertension (3) evaluating the overall cardiovascular risk by searching for other risk factors, target organ damage and concomitant diseases or accompanying clinical conditions. The diagnostic procedures include: 1. repeated blood pressure measurements. 2. medical history. 3. physical examination. 4. laboratory and instrumental investigations, some of which should be considered part of the routine approach in all subjects with high blood pressure, some which are recommended and may be used extensively, and some which are indicated only when suggested by some of the core examinations or the clinical course of the patient.(Zanchetti, 2003). Prognosis of hypertension: Hypertension is a major risk factor for cardiovascular mortality and morbidity through its effects on target organs like the brain, heart, and kidney. Structural alterations in the microcirculation form a major link between hypertension and target organ damage. High blood pressure can affect the eye leading to retinopathy, affect the brain lead to dementia and stroke, affect the kidney lead to end stage renal disease and glomerulopathy, affect heart lead to ischemia and heart failure.(Cohuet and Struijker, 2006). Goals of treatment: The primary goal of treatment of the hypertensive patient is to achieve the maximum reduction in the long-term total risk of cardiovascular morbidity and mortality. This requires treatment of all the reversible risk factors identified, including smoking, dyslipidaemia or diabetes, and the appropriate management of associated clinical conditions, as well as treatment of the raised blood pressure.(Zanchetti, 2003).

Treatment of hypertension: Patient Case Prehypertension Possible treatment Comment Lifestyle modification: Weight loss Sodium restriction Potassium intake Alcohol restriction. Exercise 30 min/day. (Joseph
Torre. et al , 2006)

J.

Hypertension with Type 2 diabetes

1) ACEI or ARB as 1st or 2nd line agent. 2) Thiazide diuretic as 1st or 2nd line agent (in low dosage with adequate k+ replacement or sparing) 3) BB (preferably drugs that block both and receptors) as 2nd or 3rd line agent. 4) CCB as 2nd , 3rd , or 4th line agent. (Joseph J. Torre. et
al, 2006)

Hypertension due to Pheochromocytoma

, and - Adrenergic blocker as first-line agent, in conjunction with CCB as needed. (Joseph J. Torre, et al ,2006) ACEIs, CCB, ARB. (Lisa
Nainggolan and Laurie, 2007)

Hypertension with LVH Hypertension with Renal dysfunction Hypertension with Heart failure

ACEIs, ARB. (Lisa Nainggolan

and Laurie, 2007)

Diuretics, beta blocker, ACEIs, ARB, antialdosterone agents. (Lisa Nainggolan and Laurie,
2007)

Hypertension with previous MI Hypertension with Pregnancy

Beta blockers, ACE inhibitors, angiotensin receptor blockers.

(Lisa Nainggolan and Laurie, 2007)

methyldopa or nifedipine.
(Joseph J. Torre. et al , 2006)

References: 1) Alan H. Gradman, MD Pittsburgh and Philadelphia, PA(2009). Evolving understanding of the renin-angiotensin-aldosterone system: Pathophysiology and targets for therapeutic intervention: American Heart Journal June 2009, Volume 157, Number 6, Supplement 1. 2) Alberto Palazzuoli, Giovanna Giannotti, Stefano Capobianco and Ranuccio Nuti , (2005). Left Ventricular Hypertrophy Beyond Hemodynamics: Genetic, Metabolic and Hormonal Factors: Current Hypertension Reviews: Volume 1, Number 3, November 2005, Pp.217.

3) Bertram G. Katzung, Emmanuel T. Akporiaye, Michael J. Aminoff,etl. (2006). ANTIHYPERTENSIVE AGENTS: INTRODUCTION: Basic and Clinical Pharmacology, New York, McGraw-Hill. 4) Brian B. Hoffman. THERAPY OF HYPERTENSION: GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 11th edition. Laurence L. Brunton, John S Lazo, Keith L. Parker. New York, McGraw-Hill, (2006). 5) Cohuet. G, Struijker-Boudier. H. (2006). Mechanisms of target organ damage caused by hypertension:Therapeutic potential: Pharmacology & Therapeutics: 111 (2006) 81 98.

6) Guido Grassi, Fosca Quarti Trevano, Gino Seravalle, Francesco Scopelliti, and Giuseppe Mancia (2006). Baroreflex Function in Hypertension: Consequences for Antihypertensive Therapy: Progress in Cardiovascular Diseases, Vol. 48, No. 6 (May/June), 2006: pp 407415. 7) Joseph J. Torre, MD, Zachary T. Bloomgarden, MD, Richard A. Dickey, MD, Michael J. Hogan, MD, John J. Janick, MD, Sathya G. Jyothinagaram, MD, Helmy M. Siragy, MD, (2006). AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS MEDICAL GUIDELINES FOR CLINICAL PRACTICE FOR THE DIAGNOSIS AND TREATMENT OF HYPERTENSION: ENDOCRINE PRACTICE,2006;12(No. 2) Pp: 195-219. 8) Joseph J. Saseen and Barry L. Carter.(2005). HYPERTENSION: Joseph T. Dipiro, Robert L. Talbert, Gary R. Matzke: Pharmacotherapy, New York, McGraw-Hill.p185-215. 9) Lisa Nainggolan, Laurie Barclay, MD (2007). New European Guidelines on Treatment of Hypertension CME/CE: Journal of Hypertension: June 20, 2007. 10) Shao-Hua Li, Ru-Tai Hui (2009). Reduced contractile capacity of vascular smooth muscle: Another mechanism of hypertension?:Medical Hypotheses: (2009) 6264.

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11) Ulvi Bayraktutan , (2005). Reactive Oxygen Species, Nitric Oxide and Hypertensive Endothelial Dysfunction: Current Hypertension Reviews: Volume 1, Number 3, November 2005 Pp.201.

12) Zanchetti A. , Cifkova. R. , Fagard. R. , S. Kjeldsen, G. Mancia, N. Poulter, K.H. Rahn, J.L. Rodicio, L.M. Ruilope, J. Staessen, P. van Zwieten, B. Waeber, B. Williams.(2003) European Society of HypertensionEuropean Society of Cardiology guidelines for the management of arterial Hypertension Guidelines Committee:Journal of Hypertension: 2003, 21:10111053.

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