Hypertension: pathophysiology and

treatment
P Foëx DPhil FRCA FMedSci
JW Sear PhD FRCA

Arterial hypertension is a major cause of risk of stroke and a reduction in the risk of
morbidity and mortality because of its associ- dementia.
Key points
ation with coronary heart disease, cerebro- The hypertension optimal treatment (HOT)

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

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
Hypertension: pathophysiology and treatment

converted into an active octapeptide, angiotensin II by the endothelin-1 may be accentuated by reduced generation of nitric
angiotensin-converting enzyme (ACE). Though the renin– oxide caused by hypertensive endothelial dysfunction.
angiotensin system is widespread in the body, the main source
of renin is the juxtaglomerular apparatus of the kidney. This Adrenal steroids
apparatus senses the renal perfusion pressure and the sodium
concentration in the distal tubular fluid. In addition, renin release Mineralo- and glucocorticoids increase blood pressure. This effect
is stimulated by b- and decreased by a-adrenoceptor stimulation. is mediated by sodium and water retention (mineralocorticoids) or
High angiotensin II concentrations suppress renin secretion via a increased vascular reactivity (glucocorticoids). In addition, gluco-
negative feedback loop. Angiotensin II acts on specific angiotensin corticoids and mineralocorticoids increase vascular tone by upregu-

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AT1 and AT2 receptors causing smooth muscle contraction and lating the receptors of pressor hormones such as angiotensin II.
the release of aldosterone, prostacyclin, and catecholamines. The
renin–angiotensin–aldosterone system plays an important role in Renomedullary vasodepression
the control of arterial pressure including the sodium balance. Renomedullary interstitial cells, located mainly in the renal
papilla, secrete an inactive substance medullipin I. This lipid is
Atrial natriuretic peptide transformed in the liver into medullipin II. This substance exerts a
Atrial natriuretic peptide (ANP) is released from atrial granules. It prolonged hypotensive effect, possibly by direct vasodilatation,
produces natriuresis, diuresis and a modest decrease in blood inhibition of sympathetic drive in response to hypotension, and a
pressure, while decreasing plasma renin and aldosterone. diuretic action. It is hypothesized that the activity of the renome-
Natriuretic peptides also alter synaptic transmission from the dullary system is controlled by renal medullary blood flow.
osmoreceptors. ANP is released as a result of the stimulation of
atrial stretch receptors. ANP concentrations are increased by Sodium and water excretion
raised filling pressures and in patients with arterial hypertension Sodium and water retention are associated with an increase in blood
and left ventricular hypertrophy as the wall of the left ventricle pressure. It is postulated that sodium, via the sodium–calcium
participates in the secretion of ANP. exchange mechanism, causes an increase in intracellular calcium
in vascular smooth muscle resulting in increased vascular tone.
Eicosanoids The primary cause of sodium and water retention may be an
Arachidonic acid metabolites alter blood pressure through direct abnormal relationship between pressure and sodium excretion
effects on vascular smooth muscle tone and interactions with resulting from reduced renal blood flow, reduced nephron
other vasoregulatory systems: autonomic nervous system, renin– mass, and increased angiotensin or mineralocorticoids.
angiotensin–aldosterone system, and other humoral pathways.
In hypertensive patients, vascular endothelial cell dysfunction Pathophysiology
could lead to reduction in endothelium-derived relaxing factors Hypertension is a chronic elevation of blood pressure that, in the
such as nitric oxide, prostacyclin, and endothelium-derived hyper- long-term, causes end-organ damage and results in increased mor-
polarizing factor, or increased production of contracting factors bidity and mortality. Blood pressure is the product of cardiac
such as endothelin-1 and thromboxane A2. output and systemic vascular resistance. It follows that patients
with arterial hypertension may have an increase in cardiac output,
Kallikrein-kinin systems an increase in systemic vascular resistance, or both. In the younger
Tissue kallikreins act on kininogen to form vasoactive peptides. age group, the cardiac output is often elevated, while in older
The most important is the vasodilator bradykinin. Kinins play a patients increased systemic vascular resistance and increased stiff-
role in the regulation of renal blood flow and water and sodium ness of the vasculature play a dominant role. Vascular tone may be
excretion. ACE inhibitors decrease the breakdown of bradykinin elevated because of increased a-adrenoceptor stimulation or
into inactive peptides. 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,
Endothelial mechanisms
including angiotensin and endothelins, cause an increase in vas-
Nitric oxide (NO) mediates the vasodilatation produced by cular smooth muscle mass termed vascular remodelling. Both an
acetylcholine, bradykinin, sodium nitroprusside and nitrates. In increase in systemic vascular resistance and an increase in vascular
hypertensive patients, endothelial-derived relaxation is inhibited. stiffness augment the load imposed on the left ventricle; this
The endothelium synthesizes endothelins, the most powerful vaso- induces left ventricular hypertrophy and left ventricular diastolic
constrictors. The generation of, or sensitivity to, endothelin-1 dysfunction.
is no greater in hypertensive than it is in normotensive subjects. In youth, the pulse pressure generated by the left ventricle is
Nonetheless, the deleterious vascular effects of endogenous relatively low and the waves reflected by the peripheral vasculature

72 Continuing Education in Anaesthesia, Critical Care & Pain | Volume 4 Number 3 2004
 Hypertension: pathophysiology and treatment

occur mainly after the end of systole, thus increasing pressure Table 1 Stages of hypertension (Joint National Committee VI Guideline)
during the early part of diastole and improving coronary perfu-
Stage Systolic Diastolic
sion. With ageing, stiffening of the aorta and elastic arteries
increases the pulse pressure. Reflected waves move from early Optimal <120 <80
Normal 120–129 80–84
diastole to late systole. This results in an increase in left ventricular High-normal 130–139 85–89
afterload, and contributes to left ventricular hypertrophy. The HT stage 1 140–159 90–99
widening of the pulse pressure with ageing is a strong predictor HT stage 2 160–179 100–109
HT stage 3 >180 >110
of coronary heart disease.
The autonomic nervous system plays an important role in the Systolic and diastolic pressures given in mm Hg.

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HT, hypertension.
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 Heart failure is a consequence of chronic pressure overload. It
stressful stimuli. Another feature of arterial hypertension is a may start as diastolic dysfunction and progresses to overt systolic
resetting of the baroreflexes and decreased baroreceptor sensitiv- failure with cardiac congestion. Strokes are major complications
ity. The renin–angiotensin system is involved at least in some of hypertension; they result from thrombosis, thrombo-embolism,
forms of hypertension (e.g. renovascular hypertension) and is sup- or intracranial haemorrhage. Renal disease, initially revealed by
pressed in the presence of primary hyperaldosteronism. Elderly or micro-albuminaemia may progress slowly and becomes evident in
black patients tend to have low-renin hypertension. Others have later years.
high-renin hypertension and these are more likely to develop myo-
cardial infarction and other cardiovascular complications. Long-term treatment of hypertension
In human essential hypertension, and experimental hyperten-
sion, volume regulation and the relationship between blood pres- All anti-hypertensive drugs must act by decreasing the cardiac
sure and sodium excretion (pressure natriuresis) are abnormal. output, the peripheral vascular resistance, or both. The classes
Considerable evidence indicates that resetting of pressure natri- of drugs most commonly used include the thiazide diuretics, b-
uresis plays a key role in causing hypertension. In patients with blockers, ACE inhibitors, angiotensin II receptors antagonists,
essential hypertension, resetting of pressure natriuresis is char- calcium channel blockers, a-adrenoceptor blockers, combined
acterized either by a parallel shift to higher blood pressures and a- and b-blockers, direct vasodilators, and some centrally acting
salt-insensitive hypertension, or by a decreased slope of pressure drugs such as a2-adrenoceptor agonists and imidazoline I1 recep-
natriuresis and salt-sensitive hypertension. tor agonists.
Life-style modification is the first step in the treatment of
hypertension; it includes moderate sodium restriction, weight
Consequences and complications of
reduction in the obese, decreased alcohol intake, and an increase
hypertension
in exercise. Drug therapy is necessary when the above measures
The cardiac consequences of hypertension are left ventricular have not been successful or when hypertension is already at a
hypertrophy and coronary artery disease. Left ventricular hyper- dangerous stage (Stage 3) when first recognized.
trophy is caused by pressure overload and is concentric. There is an
increase in muscle mass and wall thickness but not ventricular Drug therapy
volume. Left ventricular hypertrophy impairs diastolic function,
slowing ventricular relaxation and delaying filling. Left ventricu- Diuretics
lar hypertrophy is an independent risk factor for cardiovascular Low-dose diuretic therapy is effective and reduces the risk of
disease, especially sudden death. The consequences of hyperten- stroke, coronary heart disease, congestive heart failure, and total
sion are a function of its severity. There is no threshold for com- mortality. Whilst thiazides are most commonly used, loop diur-
plications to occur as elevation of blood pressure is associated with etics are also used successfully and the association with a potassium
increased morbidity throughout the whole range of blood pressure sparing diuretic reduces the risk of both hypokalaemia and hypo-
(Table 1). magnesaemia. Even in small doses diuretics potentiate other anti-
Coronary artery disease is associated with, and accelerated by, hypertensive drugs. The risk of sudden death is reduced when
chronic arterial hypertension, leading to myocardial ischaemia potassium-sparing diuretics are used. In the long-term, spirono-
and myocardial infarction. Indeed, myocardial ischaemia is lactones reduce morbidity and mortality in patients with heart fail-
much more frequent in untreated or poorly controlled hyperten- ure that is a typical complication of long-standing hypertension.
sive patients than in normotensive patients. Two main factors
contribute to myocardial ischaemia: a pressure related increase Beta-blockers
in oxygen demand and a decrease in coronary oxygen supply High sympathetic tone, angina, and previous myocardial infarc-
resulting from associated atheromatous lesions. Hypertension is tion are good reasons for using b-blockers. As a low dose min-
a significant risk factor for death from coronary artery disease. imizes the risk of fatigue (an unpleasant effect of b-blockade)

Continuing Education in Anaesthesia, Critical Care & Pain | Volume 4 Number 3 2004 73
Hypertension: pathophysiology and treatment

addition of a diuretic or a calcium channel blocker is often bene- antihypertensive drugs. Losartan, valsartan and candesartan
ficial. However, b-blockade therapy is associated with symptoms are effective and cause less coughing than ACE inhibitors.
of depression, fatigue, and sexual dysfunction. These side-effects The LIFE study is the most recent landmark trial in hyperten-
have to be taken into consideration in the evaluation of the benefits sion. More than 9000 patients were randomized to receive either
of treatment. the angiotensin receptor antagonist losartan or a b-blocker
Over the past few years b-blockers have been used increasingly (atenolol). Patients in the losartan arm exhibited better reduction
frequently in the management of heart failure, a known complica- of mortality and morbidity, owing to greater reduction in strokes.
tion of arterial hypertension. They are effective but their introduc- Losartan was also more effective in reducing left ventricular
tion in the presence of heart failure has to be very cautious, starting hypertrophy, an independent powerful risk factor for adverse out-

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with very low doses to avoid an initial worsening of heart failure. come. In patients with isolated systolic hypertension, the superi-
ority of losartan over atenolol was even more pronounced than in
Calcium channel blockers those with systolic and diastolic hypertension. These favourable
Calcium channel blockers can be divided into dihydropyridines results led to an editorial entitled: ‘Angiotensin blockade in hyper-
(e.g. nifedipine, nimodipine, amlodipine) and non-dihydropyridines tension: a promise fulfilled’. It must be noted that the comparator
(verapamil, diltiazem). Both groups decrease peripheral vascular in the LIFE study was a b-blocker, and that, in the past, b-blockers
resistance but verapamil and diltiazem have negative inotropic were found to be no better than placebo in the elderly.
and chronotropic effects. Short-acting dihydropyridines such as
nifedipine cause reflex sympathetic activation and tachycardia, a1-Adrenergic blockers
while long-acting drugs such as amlodipine and slow-release Free from metabolic side-effects, these drugs reduce blood cho-
preparations of nifedipine cause less sympathetic activation. lesterol and reduce peripheral vascular resistance. Prazosin is
Short-acting dihydropyridines appear to increase the risk of shorter acting than doxazosin, indoramin and terazosin. These
sudden death. However, the systolic hypertension in Europe drugs are highly selective for a1-adrenoceptors. Drowsiness, pos-
(SYST-EUR) trial which compared nitrendipine with placebo tural hypotension, and occasionally tachycardia, can be trouble-
had to be stopped early because of significant benefits of active some. Fluid retention may require the addition of a diuretic.
therapy. Phenoxybenzamine is a non-competitive a-adrenoceptor agonist
Calcium channel blockers are effective in the elderly and may used (in association with a b-blocker) in the management of
be selected as monotherapy for patients with Raynaud’s phe- patients with phaeochromocytoma, though recently doxazosin
nomenon, peripheral vascular disease, or asthma, as such patients has been used successfully.
do not tolerate b-blockers. Diltiazem and verapamil are contra-
indicated in heart failure. Nifedipine is effective in severe hyper- Direct vasodilators
tension and can be used sublingually; there is need for caution Hydralazine and minoxidil are directly acting vasodilators. Their
because of the risk of excessive hypotension. Calcium channel usage has declined because of the potential for serious side-effects
blockers are often associated with b-blockers, diuretics and/or (lupus syndrome with hydralazine, hirsutism with minoxidil).
ACE inhibitors.
Central adrenergic inhibitors
Angiotensin converting enzyme inhibitors Methyldopa is both a false neurotransmitter and a2-adrenoceptor
ACE inhibitors are increasingly being used as first line therapy. agonist. Clonidine and dexmedetomidine are agonists at cent-
They have relatively few side-effects and contraindications except rally located a2-adrenoceptors. The selectivity for a2- vs a1-
bilateral renal artery stenoses. Though ACE inhibitors are effect- adrenoceptors is greatest for dexmedetomidine (1620:1), followed
ive in unilateral renovascular hypertension, there is risk of isch- by clonidine (220:1), and least for a-methyldopa (10:1). Both
aemic atrophy. Therefore, angioplasty or surgical renal artery clonidine and dexmedetomidine make the circulation more stable,
reconstruction are preferable to long-term purely medical therapy. reduce the release of catecholamines in response to stress, and
ACE inhibitors are first choice agents in diabetic hypertensive cause sedation such that dexmedetomidine is now used for seda-
patients as they slow down the progression of renal dysfunction. tion in intensive care units.
In hypertension with heart failure, ACE inhibitors are also first Moxonidine is representative of a new class of antihypertensive
choice drugs. The HOPE trial has shown that ramipril reduced the agents acting on imidazoline1 receptors (I1). Moxonidine reduces
risk of cardiovascular events even in the absence of hypertension. sympathetic activity by acting on centres in the rostral ventral
Thus, this ACE inhibitor may exert a protective effect by mechan- lateral medulla, thereby reducing peripheral vascular resistance.
isms other than the reduction in blood pressure.
Natriuretic peptides
Angiotensin II receptor blockers Natriuretic peptides play a role in the control of vascular tone and
As angiotensin II stimulates AT1-receptors that cause vasocon- interact with the renin–angiotensin–aldosterone system. By inhib-
striction, angiotensin AT1-receptor antagonists are effective iting their degradation, peptidase inhibitors make these naturally

74 Continuing Education in Anaesthesia, Critical Care & Pain | Volume 4 Number 3 2004
 Hypertension: pathophysiology and treatment

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<www.hyp.ac.uk>
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