Downloaded from https://academic.oup.com/bjaed/article/4/3/71/292146 by guest on 03 June 2021
`
`Key points
`
`Hypertension is a cause of
`morbidity and mortality.
`
`In general practice, the level of
`blood pressure above which
`treatment of hypertension is
`indicated is now set at
`140/90 mm Hg.
`
`Increased systemic vascular
`resistance, increased vascular
`stiffness, and increased
`vascular responsiveness to
`stimuli are central to the
`pathophysiology of
`hypertension.
`
`Morbidity and mortality
`attributable to hypertension
`result from target organ
`involvement.
`
`Newer antihypertensive
`agents such as ACE inhibitors
`and angiotensin II receptor
`antagonists are effective, but
`not more than diuretics and
`b-blockers.
`
`P Foe¨x DPhil FRCA FMedSci
`
`Emeritus Nuffield Professor of
`Anaesthetics
`Nuffield Department of Anaesthetics
`The John Radcliffe Hospital
`Headley Way
`Oxford
`OX3 9DU
`Tel: 01865 851138
`Fax: 01865 220027
`E-mail: pierre.foex@nda.ox.ac.uk
`(for correspondence)
`
`JW Sear PhD FRCA
`
`Professor of Anaesthetics
`Nuffield Department of Anaesthetics
`The John Radcliffe Hospital
`Headley Way
`Oxford
`OX3 9DU
`
`Hypertension: pathophysiology and
`treatment
`P Foe¨x DPhil FRCA FMedSci
`JW Sear PhD FRCA
`
`Arterial hypertension is a major cause of
`morbidity and mortality because of its associ-
`ation with coronary heart disease, cerebro-
`vascular disease and renal disease. The extent
`of target organ involvement (i.e. heart, brain
`and kidneys) determines outcome. North
`American studies have shown that hyperten-
`sion is a major contributor to 500 000 strokes
`(250 000 deaths) and 1 000 000 myocardial
`infarctions (500 000 deaths) per annum.
`National surveys continue to reveal that
`hypertension is often not detected and, where
`diagnosed,
`is often inadequately treated.
`Among hypertensive patients, only 25% appear
`to be well controlled. This is particularly true of
`isolated systolic hypertension. Yet the preval-
`ence of isolated systolic hypertension increases
`with age. Indeed, the proportion of subjects
`suffering from isolated systolic hypertension,
`as opposed to systolic and diastolic hyperten-
`sion, increases from 20% in the under 40 yr to
`80% in the 60–69 yr old, and to 95% in those
`>80 yr. There is increasing emphasis on the
`risk associated with systolic hypertension as
`the level of systolic pressure is a good predictor
`of coronary and cerebrovascular risk, espe-
`cially in the elderly. Treatment of systolic
`hypertension with its wide pulse pressure is
`effective in terms of control of blood pressure
`and reduced morbidity, especially in older
`patients with high risk profile.
`Over the past decade the management of
`hypertension has changed with the recognition
`that there is no threshold below which elevated
`blood pressure causes no threat to health.
`Recent guidelines,
`including those of
`the
`British Hypertension Society, make it clear
`that treatment of isolated systolic hypertension
`is as important as that of systolic and diastolic
`hypertension. The threshold above which
`hypertension should be treated to prevent
`long-term complications is now 140/90 mm Hg.
`Indeed, in Stage 1 hypertension, treatment of
`isolated systolic hypertension (systolic 140–
`159 mm Hg, diastolic <90 mm Hg), reduces
`the prevalence of left ventricular hypertrophy,
`a predictor of future morbidity and mor-
`tality. There is also a 42% reduction of the
`
`risk of stroke and a reduction in the risk of
`dementia.
`The hypertension optimal treatment (HOT)
`study indicates that the treatment goal is to
`reduce blood pressure to 140/85 mm Hg. It is
`alsoestablished thathigh normal bloodpressure
`(130–139/85–89 mm Hg) progresses to Stage 1
`hypertension (>140/>90 mm Hg) in >37% of
`individuals <64 yr and >49% of those >65 yr.
`The British National Formulary recom-
`mends the following approach:
`
`blood pressure >220/>120 mm Hg:
`immediate therapy;
`blood pressure 200–219/110–119 mm Hg:
`confirm over 1–2 weeks, then treat; or
`blood pressure 160–199/100–109 mm Hg
`confirm over 3–4 weeks, then treat.
`
`In patients with high blood pressure, the
`cumulative incidence of first cardiovascular
`events over 10 yr is 10% in males and 4.4%
`in females. Even high normal blood pressure
`is correlated with an increased risk of death
`attributable to coronary or cerebrovascular
`events. Whether treatment of high-normal
`blood pressure would prevent cardiovascular
`events is unknown.
`
`Regulation of blood pressure
`
`The control of blood pressure is complex and
`will be reviewed only briefly.
`
`Neurogenic control
`
`The vasomotor centre includes the nucleus
`tractus solitarius in the dorsal medulla (baro-
`receptors integration), the rostral part of the
`ventral medulla (pressor region), and other
`centres in the pons and midbrain. The arterial
`baroreceptors respond to vessel wall distension
`by increasing the afferent impulse activity. This
`in turn decreases the efferent sympathetic activ-
`ity and augments vagal tone. The net effect is
`bradycardia and vasodilatation.
`
`Renin-angiotensin system
`
`The protease renin cleaves angiotensin to yield
`the inactive peptide angiotensin I. The latter is
`
`DOI 10.1093/bjaceaccp/mkh020
`
`Continuing Education in Anaesthesia, Critical Care & Pain | Volume 4 Number 3 2004
`ª The Board of Management and Trustees of the British Journal of Anaesthesia 2004
`
`71
`
`Human Power of N Company
`EX1058
`Page 1 of 5
`
`

`

`Downloaded from https://academic.oup.com/bjaed/article/4/3/71/292146 by guest on 03 June 2021
`
`Key points
`
`Hypertension is a cause of
`morbidity and mortality.
`
`In general practice, the level of
`blood pressure above which
`treatment of hypertension is
`indicated is now set at
`140/90 mm Hg.
`
`Increased systemic vascular
`resistance, increased vascular
`stiffness, and increased
`vascular responsiveness to
`stimuli are central to the
`pathophysiology of
`hypertension.
`
`Morbidity and mortality
`attributable to hypertension
`result from target organ
`involvement.
`
`Newer antihypertensive
`agents such as ACE inhibitors
`and angiotensin II receptor
`antagonists are effective, but
`not more than diuretics and
`b-blockers.
`
`P Foe¨x DPhil FRCA FMedSci
`
`Emeritus Nuffield Professor of
`Anaesthetics
`Nuffield Department of Anaesthetics
`The John Radcliffe Hospital
`Headley Way
`Oxford
`OX3 9DU
`Tel: 01865 851138
`Fax: 01865 220027
`E-mail: pierre.foex@nda.ox.ac.uk
`(for correspondence)
`
`JW Sear PhD FRCA
`
`Professor of Anaesthetics
`Nuffield Department of Anaesthetics
`The John Radcliffe Hospital
`Headley Way
`Oxford
`OX3 9DU
`
`Hypertension: pathophysiology and
`treatment
`P Foe¨x DPhil FRCA FMedSci
`JW Sear PhD FRCA
`
`Arterial hypertension is a major cause of
`morbidity and mortality because of its associ-
`ation with coronary heart disease, cerebro-
`vascular disease and renal disease. The extent
`of target organ involvement (i.e. heart, brain
`and kidneys) determines outcome. North
`American studies have shown that hyperten-
`sion is a major contributor to 500 000 strokes
`(250 000 deaths) and 1 000 000 myocardial
`infarctions (500 000 deaths) per annum.
`National surveys continue to reveal that
`hypertension is often not detected and, where
`diagnosed,
`is often inadequately treated.
`Among hypertensive patients, only 25% appear
`to be well controlled. This is particularly true of
`isolated systolic hypertension. Yet the preval-
`ence of isolated systolic hypertension increases
`with age. Indeed, the proportion of subjects
`suffering from isolated systolic hypertension,
`as opposed to systolic and diastolic hyperten-
`sion, increases from 20% in the under 40 yr to
`80% in the 60–69 yr old, and to 95% in those
`>80 yr. There is increasing emphasis on the
`risk associated with systolic hypertension as
`the level of systolic pressure is a good predictor
`of coronary and cerebrovascular risk, espe-
`cially in the elderly. Treatment of systolic
`hypertension with its wide pulse pressure is
`effective in terms of control of blood pressure
`and reduced morbidity, especially in older
`patients with high risk profile.
`Over the past decade the management of
`hypertension has changed with the recognition
`that there is no threshold below which elevated
`blood pressure causes no threat to health.
`Recent guidelines,
`including those of
`the
`British Hypertension Society, make it clear
`that treatment of isolated systolic hypertension
`is as important as that of systolic and diastolic
`hypertension. The threshold above which
`hypertension should be treated to prevent
`long-term complications is now 140/90 mm Hg.
`Indeed, in Stage 1 hypertension, treatment of
`isolated systolic hypertension (systolic 140–
`159 mm Hg, diastolic <90 mm Hg), reduces
`the prevalence of left ventricular hypertrophy,
`a predictor of future morbidity and mor-
`tality. There is also a 42% reduction of the
`
`risk of stroke and a reduction in the risk of
`dementia.
`The hypertension optimal treatment (HOT)
`study indicates that the treatment goal is to
`reduce blood pressure to 140/85 mm Hg. It is
`alsoestablished thathigh normal bloodpressure
`(130–139/85–89 mm Hg) progresses to Stage 1
`hypertension (>140/>90 mm Hg) in >37% of
`individuals <64 yr and >49% of those >65 yr.
`The British National Formulary recom-
`mends the following approach:
`
`blood pressure >220/>120 mm Hg:
`immediate therapy;
`blood pressure 200–219/110–119 mm Hg:
`confirm over 1–2 weeks, then treat; or
`blood pressure 160–199/100–109 mm Hg
`confirm over 3–4 weeks, then treat.
`
`In patients with high blood pressure, the
`cumulative incidence of first cardiovascular
`events over 10 yr is 10% in males and 4.4%
`in females. Even high normal blood pressure
`is correlated with an increased risk of death
`attributable to coronary or cerebrovascular
`events. Whether treatment of high-normal
`blood pressure would prevent cardiovascular
`events is unknown.
`
`Regulation of blood pressure
`
`The control of blood pressure is complex and
`will be reviewed only briefly.
`
`Neurogenic control
`
`The vasomotor centre includes the nucleus
`tractus solitarius in the dorsal medulla (baro-
`receptors integration), the rostral part of the
`ventral medulla (pressor region), and other
`centres in the pons and midbrain. The arterial
`baroreceptors respond to vessel wall distension
`by increasing the afferent impulse activity. This
`in turn decreases the efferent sympathetic activ-
`ity and augments vagal tone. The net effect is
`bradycardia and vasodilatation.
`
`Renin-angiotensin system
`
`The protease renin cleaves angiotensin to yield
`the inactive peptide angiotensin I. The latter is
`
`DOI 10.1093/bjaceaccp/mkh020
`
`Continuing Education in Anaesthesia, Critical Care & Pain | Volume 4 Number 3 2004
`ª The Board of Management and Trustees of the British Journal of Anaesthesia 2004
`
`71
`
`Page 1 of 5
`
`

`

`Hypertension: pathophysiology and treatment
`
`Downloaded from https://academic.oup.com/bjaed/article/4/3/71/292146 by guest on 03 June 2021
`
`converted into an active octapeptide, angiotensin II by the
`angiotensin-converting enzyme (ACE). Though the renin–
`angiotensin system is widespread in the body, the main source
`of renin is the juxtaglomerular apparatus of the kidney. This
`apparatus senses the renal perfusion pressure and the sodium
`concentration in the distal tubular fluid. In addition, renin release
`is stimulated by b- and decreased by a-adrenoceptor stimulation.
`High angiotensin II concentrations suppress renin secretion via a
`negative feedback loop. Angiotensin II acts on specific angiotensin
`AT1 and AT2 receptors causing smooth muscle contraction and
`the release of aldosterone, prostacyclin, and catecholamines. The
`renin–angiotensin–aldosterone system plays an important role in
`the control of arterial pressure including the sodium balance.
`
`Atrial natriuretic peptide
`
`Atrial natriuretic peptide (ANP) is released from atrial granules. It
`produces natriuresis, diuresis and a modest decrease in blood
`pressure, while decreasing plasma renin and aldosterone.
`Natriuretic peptides also alter synaptic transmission from the
`osmoreceptors. ANP is released as a result of the stimulation of
`atrial stretch receptors. ANP concentrations are increased by
`raised filling pressures and in patients with arterial hypertension
`and left ventricular hypertrophy as the wall of the left ventricle
`participates in the secretion of ANP.
`
`Eicosanoids
`
`Arachidonic acid metabolites alter blood pressure through direct
`effects on vascular smooth muscle tone and interactions with
`other vasoregulatory systems: autonomic nervous system, renin–
`angiotensin–aldosterone system, and other humoral pathways.
`In hypertensive patients, vascular endothelial cell dysfunction
`could lead to reduction in endothelium-derived relaxing factors
`such as nitric oxide, prostacyclin, and endothelium-derived hyper-
`polarizing factor, or increased production of contracting factors
`such as endothelin-1 and thromboxane A2.
`
`Kallikrein-kinin systems
`
`Tissue kallikreins act on kininogen to form vasoactive peptides.
`The most important is the vasodilator bradykinin. Kinins play a
`role in the regulation of renal blood flow and water and sodium
`excretion. ACE inhibitors decrease the breakdown of bradykinin
`into inactive peptides.
`
`Endothelial mechanisms
`
`Nitric oxide (NO) mediates the vasodilatation produced by
`acetylcholine, bradykinin, sodium nitroprusside and nitrates. In
`hypertensive patients, endothelial-derived relaxation is inhibited.
`The endothelium synthesizes endothelins, the most powerful vaso-
`constrictors. The generation of, or sensitivity to, endothelin-1
`is no greater in hypertensive than it is in normotensive subjects.
`Nonetheless, the deleterious vascular effects of endogenous
`
`endothelin-1 may be accentuated by reduced generation of nitric
`oxide caused by hypertensive endothelial dysfunction.
`
`Adrenal steroids
`
`Mineralo- and glucocorticoids increase blood pressure. This effect
`is mediated by sodium and water retention (mineralocorticoids) or
`increased vascular reactivity (glucocorticoids). In addition, gluco-
`corticoids and mineralocorticoids increase vascular tone by upregu-
`lating the receptors of pressor hormones such as angiotensin II.
`
`Renomedullary vasodepression
`
`located mainly in the renal
`Renomedullary interstitial cells,
`papilla, secrete an inactive substance medullipin I. This lipid is
`transformed in the liver into medullipin II. This substance exerts a
`prolonged hypotensive effect, possibly by direct vasodilatation,
`inhibition of sympathetic drive in response to hypotension, and a
`diuretic action. It is hypothesized that the activity of the renome-
`dullary system is controlled by renal medullary blood flow.
`
`Sodium and water excretion
`
`Sodium and water retention are associated with an increase in blood
`pressure. It is postulated that sodium, via the sodium–calcium
`exchange mechanism, causes an increase in intracellular calcium
`in vascular smooth muscle resulting in increased vascular tone.
`The primary cause of sodium and water retention may be an
`abnormal relationship between pressure and sodium excretion
`resulting from reduced renal blood flow, reduced nephron
`mass, and increased angiotensin or mineralocorticoids.
`
`Pathophysiology
`
`Hypertension is a chronic elevation of blood pressure that, in the
`long-term, causes end-organ damage and results in increased mor-
`bidity and mortality. Blood pressure is the product of cardiac
`output and systemic vascular resistance. It follows that patients
`with arterial hypertension may have an increase in cardiac output,
`an increase in systemic vascular resistance, or both. In the younger
`age group, the cardiac output is often elevated, while in older
`patients increased systemic vascular resistance and increased stiff-
`ness of the vasculature play a dominant role. Vascular tone may be
`elevated because of increased a-adrenoceptor stimulation or
`increased release of peptides such as angiotensin or endothelins.
`The final pathway is an increase in cytosolic calcium in vascular
`smooth muscle causing vasoconstriction. Several growth factors,
`including angiotensin and endothelins, cause an increase in vas-
`cular smooth muscle mass termed vascular remodelling. Both an
`increase in systemic vascular resistance and an increase in vascular
`stiffness augment the load imposed on the left ventricle; this
`induces left ventricular hypertrophy and left ventricular diastolic
`dysfunction.
`In youth, the pulse pressure generated by the left ventricle is
`relatively low and the waves reflected by the peripheral vasculature
`
`72
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`Hypertension: pathophysiology and treatment
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`
`occur mainly after the end of systole, thus increasing pressure
`during the early part of diastole and improving coronary perfu-
`sion. With ageing, stiffening of the aorta and elastic arteries
`increases the pulse pressure. Reflected waves move from early
`diastole to late systole. This results in an increase in left ventricular
`afterload, and contributes to left ventricular hypertrophy. The
`widening of the pulse pressure with ageing is a strong predictor
`of coronary heart disease.
`The autonomic nervous system plays an important role in the
`control of blood pressure. In hypertensive patients, both increased
`release of, and enhanced peripheral sensitivity to, norepinephrine
`can be found. In addition, there is increased responsiveness to
`stressful stimuli. Another feature of arterial hypertension is a
`resetting of the baroreflexes and decreased baroreceptor sensitiv-
`ity. The renin–angiotensin system is involved at least in some
`forms of hypertension (e.g. renovascular hypertension) and is sup-
`pressed in the presence of primary hyperaldosteronism. Elderly or
`black patients tend to have low-renin hypertension. Others have
`high-renin hypertension and these are more likely to develop myo-
`cardial infarction and other cardiovascular complications.
`In human essential hypertension, and experimental hyperten-
`sion, volume regulation and the relationship between blood pres-
`sure and sodium excretion (pressure natriuresis) are abnormal.
`Considerable evidence indicates that resetting of pressure natri-
`uresis plays a key role in causing hypertension. In patients with
`essential hypertension, resetting of pressure natriuresis is char-
`acterized either by a parallel shift to higher blood pressures and
`salt-insensitive hypertension, or by a decreased slope of pressure
`natriuresis and salt-sensitive hypertension.
`
`Consequences and complications of
`hypertension
`
`The cardiac consequences of hypertension are left ventricular
`hypertrophy and coronary artery disease. Left ventricular hyper-
`trophy is caused by pressure overload and is concentric. There is an
`increase in muscle mass and wall thickness but not ventricular
`volume. Left ventricular hypertrophy impairs diastolic function,
`slowing ventricular relaxation and delaying filling. Left ventricu-
`lar hypertrophy is an independent risk factor for cardiovascular
`disease, especially sudden death. The consequences of hyperten-
`sion are a function of its severity. There is no threshold for com-
`plications to occur as elevation of blood pressure is associated with
`increased morbidity throughout the whole range of blood pressure
`(Table 1).
`Coronary artery disease is associated with, and accelerated by,
`chronic arterial hypertension, leading to myocardial ischaemia
`and myocardial
`infarction. Indeed, myocardial
`ischaemia is
`much more frequent in untreated or poorly controlled hyperten-
`sive patients than in normotensive patients. Two main factors
`contribute to myocardial ischaemia: a pressure related increase
`in oxygen demand and a decrease in coronary oxygen supply
`resulting from associated atheromatous lesions. Hypertension is
`a significant risk factor for death from coronary artery disease.
`
`Table 1 Stages of hypertension (Joint National Committee VI Guideline)
`
`Stage
`
`Optimal
`Normal
`High-normal
`HT stage 1
`HT stage 2
`HT stage 3
`
`Systolic
`
`<120
`120–129
`130–139
`140–159
`160–179
`>180
`
`Systolic and diastolic pressures given in mm Hg.
`HT, hypertension.
`
`Diastolic
`
`<80
`80–84
`85–89
`90–99
`100–109
`>110
`
`Heart failure is a consequence of chronic pressure overload. It
`may start as diastolic dysfunction and progresses to overt systolic
`failure with cardiac congestion. Strokes are major complications
`of hypertension; they result from thrombosis, thrombo-embolism,
`or intracranial haemorrhage. Renal disease, initially revealed by
`micro-albuminaemia may progress slowly and becomes evident in
`later years.
`
`Long-term treatment of hypertension
`
`All anti-hypertensive drugs must act by decreasing the cardiac
`output, the peripheral vascular resistance, or both. The classes
`of drugs most commonly used include the thiazide diuretics, b-
`blockers, ACE inhibitors, angiotensin II receptors antagonists,
`calcium channel blockers, a-adrenoceptor blockers, combined
`a- and b-blockers, direct vasodilators, and some centrally acting
`drugs such as a2-adrenoceptor agonists and imidazoline I1 recep-
`tor agonists.
`Life-style modification is the first step in the treatment of
`hypertension; it includes moderate sodium restriction, weight
`reduction in the obese, decreased alcohol intake, and an increase
`in exercise. Drug therapy is necessary when the above measures
`have not been successful or when hypertension is already at a
`dangerous stage (Stage 3) when first recognized.
`
`Drug therapy
`
`Diuretics
`Low-dose diuretic therapy is effective and reduces the risk of
`stroke, coronary heart disease, congestive heart failure, and total
`mortality. Whilst thiazides are most commonly used, loop diur-
`etics are also used successfully and the association with a potassium
`sparing diuretic reduces the risk of both hypokalaemia and hypo-
`magnesaemia. Even in small doses diuretics potentiate other anti-
`hypertensive drugs. The risk of sudden death is reduced when
`potassium-sparing diuretics are used. In the long-term, spirono-
`lactones reduce morbidity and mortality in patients with heart fail-
`ure that is a typical complication of long-standing hypertension.
`
`Beta-blockers
`High sympathetic tone, angina, and previous myocardial infarc-
`tion are good reasons for using b-blockers. As a low dose min-
`imizes the risk of fatigue (an unpleasant effect of b-blockade)
`
`Continuing Education in Anaesthesia, Critical Care & Pain | Volume 4 Number 3 2004
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`Hypertension: pathophysiology and treatment
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`
`addition of a diuretic or a calcium channel blocker is often bene-
`ficial. However, b-blockade therapy is associated with symptoms
`of depression, fatigue, and sexual dysfunction. These side-effects
`have to be taken into consideration in the evaluation of the benefits
`of treatment.
`Over the past few years b-blockers have been used increasingly
`frequently in the management of heart failure, a known complica-
`tion of arterial hypertension. They are effective but their introduc-
`tion in the presence of heart failure has to be very cautious, starting
`with very low doses to avoid an initial worsening of heart failure.
`
`Calcium channel blockers
`Calcium channel blockers can be divided into dihydropyridines
`(e.g. nifedipine, nimodipine, amlodipine) and non-dihydropyridines
`(verapamil, diltiazem). Both groups decrease peripheral vascular
`resistance but verapamil and diltiazem have negative inotropic
`and chronotropic effects. Short-acting dihydropyridines such as
`nifedipine cause reflex sympathetic activation and tachycardia,
`while long-acting drugs such as amlodipine and slow-release
`preparations of nifedipine cause less sympathetic activation.
`Short-acting dihydropyridines appear to increase the risk of
`sudden death. However, the systolic hypertension in Europe
`(SYST-EUR) trial which compared nitrendipine with placebo
`had to be stopped early because of significant benefits of active
`therapy.
`Calcium channel blockers are effective in the elderly and may
`be selected as monotherapy for patients with Raynaud’s phe-
`nomenon, peripheral vascular disease, or asthma, as such patients
`do not tolerate b-blockers. Diltiazem and verapamil are contra-
`indicated in heart failure. Nifedipine is effective in severe hyper-
`tension and can be used sublingually; there is need for caution
`because of the risk of excessive hypotension. Calcium channel
`blockers are often associated with b-blockers, diuretics and/or
`ACE inhibitors.
`
`Angiotensin converting enzyme inhibitors
`ACE inhibitors are increasingly being used as first line therapy.
`They have relatively few side-effects and contraindications except
`bilateral renal artery stenoses. Though ACE inhibitors are effect-
`ive in unilateral renovascular hypertension, there is risk of isch-
`aemic atrophy. Therefore, angioplasty or surgical renal artery
`reconstruction are preferable to long-term purely medical therapy.
`ACE inhibitors are first choice agents in diabetic hypertensive
`patients as they slow down the progression of renal dysfunction.
`In hypertension with heart failure, ACE inhibitors are also first
`choice drugs. The HOPE trial has shown that ramipril reduced the
`risk of cardiovascular events even in the absence of hypertension.
`Thus, this ACE inhibitor may exert a protective effect by mechan-
`isms other than the reduction in blood pressure.
`
`antihypertensive drugs. Losartan, valsartan and candesartan
`are effective and cause less coughing than ACE inhibitors.
`The LIFE study is the most recent landmark trial in hyperten-
`sion. More than 9000 patients were randomized to receive either
`the angiotensin receptor antagonist losartan or a b-blocker
`(atenolol). Patients in the losartan arm exhibited better reduction
`of mortality and morbidity, owing to greater reduction in strokes.
`Losartan was also more effective in reducing left ventricular
`hypertrophy, an independent powerful risk factor for adverse out-
`come. In patients with isolated systolic hypertension, the superi-
`ority of losartan over atenolol was even more pronounced than in
`those with systolic and diastolic hypertension. These favourable
`results led to an editorial entitled: ‘Angiotensin blockade in hyper-
`tension: a promise fulfilled’. It must be noted that the comparator
`in the LIFE study was a b-blocker, and that, in the past, b-blockers
`were found to be no better than placebo in the elderly.
`
`a1-Adrenergic blockers
`Free from metabolic side-effects, these drugs reduce blood cho-
`lesterol and reduce peripheral vascular resistance. Prazosin is
`shorter acting than doxazosin, indoramin and terazosin. These
`drugs are highly selective for a1-adrenoceptors. Drowsiness, pos-
`tural hypotension, and occasionally tachycardia, can be trouble-
`some. Fluid retention may require the addition of a diuretic.
`Phenoxybenzamine is a non-competitive a-adrenoceptor agonist
`used (in association with a b-blocker) in the management of
`patients with phaeochromocytoma, though recently doxazosin
`has been used successfully.
`
`Direct vasodilators
`Hydralazine and minoxidil are directly acting vasodilators. Their
`usage has declined because of the potential for serious side-effects
`(lupus syndrome with hydralazine, hirsutism with minoxidil).
`
`Central adrenergic inhibitors
`Methyldopa is both a false neurotransmitter and a2-adrenoceptor
`agonist. Clonidine and dexmedetomidine are agonists at cent-
`rally located a2-adrenoceptors. The selectivity for a2- vs a1-
`adrenoceptors is greatest for dexmedetomidine (1620:1), followed
`by clonidine (220:1), and least for a-methyldopa (10:1). Both
`clonidine and dexmedetomidine make the circulation more stable,
`reduce the release of catecholamines in response to stress, and
`cause sedation such that dexmedetomidine is now used for seda-
`tion in intensive care units.
`Moxonidine is representative of a new class of antihypertensive
`agents acting on imidazoline1 receptors (I1). Moxonidine reduces
`sympathetic activity by acting on centres in the rostral ventral
`lateral medulla, thereby reducing peripheral vascular resistance.
`
`Angiotensin II receptor blockers
`As angiotensin II stimulates AT1-receptors that cause vasocon-
`striction, angiotensin AT1-receptor antagonists are effective
`
`Natriuretic peptides
`Natriuretic peptides play a role in the control of vascular tone and
`interact with the renin–angiotensin–aldosterone system. By inhib-
`iting their degradation, peptidase inhibitors make these naturally
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`Hypertension: pathophysiology and treatment
`
`occurring peptides more effective, thereby reducing vascular resist-
`ance. However, there are only small scale trials of their efficacy.
`Overall, recent studies have failed to demonstrate the superiority
`of modern agents over the more traditional drugs, except in special
`circumstances, as demonstrated in a meta-analysis based on
`15 trials and 75 000 patients. In many patients, effective treatment
`is achieved by the association of two or more agents, with gain in
`efficacy and reduction of side-effects.
`
`Risk management
`
`As well as pharmacological measures for the control of blood
`pressure, there should be active treatment of those factors
`known to increase the risk of hypertension. There are two distinct
`measures. First, those that lower blood pressure, for example
`weight reduction, reduced salt intake, limitation of alcohol con-
`sumption, physical exercise, increased fruit and vegetable con-
`sumption, and reduced total and saturated fat intake. Second,
`those that that reduce cardiovascular risk, for example stopping
`smoking; replacing saturated with polyunsaturated and monoun-
`saturated fats; increased oily fish consumption; and reduced total
`fat intake.
`Because hypertensive patients are at very high risk of coronary
`artery disease, other therapeutic measures include aspirin and
`statin therapies. Lose-dose aspirin is effective in the prevention
`of thrombotic events such as stroke and myocardial infarction;
`this is also true in hypertensive patients whose blood pressure is
`well controlled. The risk of severe bleeding is very low provided
`blood pressure is reduced to below 150/90 mm Hg. The benefits of
`lipid-lowering drug treatment with statins are well established in
`coronary heart disease and in cerebrovascular disease, two con-
`ditions frequently associated with arterial hypertension.
`
`Key references
`
`Cain AE, Khalil RA. Pathophysiology of essential hypertension: role of the pump,
`the vessel, and the kidney. Semin Nephrol 2002; 22: 3–16
`
`Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is pulse pressure useful
`in predicting risk for coronary heart disease? The Framingham heart
`study. Circulation 1999; 100: 354–60
`
`Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-
`pressure lowering and low-dose aspirin in patients with hypertension:
`principal results of the Hypertension Optimal Treatment (HOT) random-
`ised trial. HOT Study Group. Lancet 1998; 351: 1755–62
`
`Haynes WG, Webb DJ. Endothelin as a regulator of cardiovascular function in
`health and disease. J Hypertension 1998; 16: 1081–98
`
`Howell SJ, Hemming AE, Allman KG, Glover L, Sear JW, Foe¨x P. Predictors of
`postoperative myocardial
`ischaemia. The role of intercurrent arterial
`hypertension and other cardiovascular risk factors. Anaesthesia 1997; 52:
`107–11
`
`Prys-Roberts C. Phaeochromocytoma—recent progress in its management.
`Br J Anaesth 2000; 85: 44–57
`
`Weinberger MH. Salt sensitivity of blood pressure in humans. Hypertension
`1996; 27: 481–90
`
`Williams B, Poulter NR, Brown MJ. British Hypertension Society guideline for
`hypertension management. Br J Med 2004; 328: 634–40
`
`Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an
`angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular
`events in high-risk patients. The Heart Outcomes Prevention Evaluation
`Study Investigators. New Engl J Med 2000; 342: 145–53
`
`Web resources
`
`British Hypertension Society/British Heart Society guidelines
`<www.hyp.ac.uk>
`
`See multiple choice questions 50–54.
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