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Antihypertensive drugs 
RE Jackson, BSc MB ChB FRCA, MC Bellamy, MB BS MA FRCA FRCP (Edin) FFICM 

Continuing Education in Anaesthesia Critical Care & Pain, Volume 15, Issue 6, 1 December 2015,
Pages 280–285, https://doi.org/10.1093/bjaceaccp/mku061
Published: 14 January 2015

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Key points
Antihypertensive drugs are frequently used by patients and may in uence conduct of
anaesthesia.

Relatively few drug classes are used to treat hypertension, the newest of which are
direct renin inhibitors.

The renin–angiotensin system is targeted at di erent points by many of the

commonly used antihypertensive drugs.

Antihypertensive drugs have diverse indications, both cardiac and non-cardiac.

Guidance on antihypertensive agents is provided by the National Institute for Health

and Care Excellence.

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Antihypertensive drugs comprise several classes of compound with the therapeutic intention
of preventing, controlling, or treating hypertension. The classes of antihypertensive drug
 di er both structurally and functionally. They are important in anaesthetic practice because
they are commonly prescribed to the general population, with the overall prevalence of
hypertension being 31% in the UK [de ned by the National Institute for Health and Care
Excellence (NICE) as a measurement of 140/90 mm Hg or higher in clinic, with subsequent
1
ambulatory or home measurement of 135/85 mm Hg or higher]. Antihypertensive drugs are
used frequently in other unrelated conditions, for example, β-blockers in thyrotoxicosis and
anxiety, or angiotensin-converting enzyme inhibitors (ACEIs) in heart failure. Hence both
the drug and its indication are relevant to the conduct of anaesthesia.

This article focuses on the applied pharmacology of agents commonly encountered in UK

clinical practice, their therapeutic and side-e ects, drug interactions, and implications for
anaesthesia and surgery. The causes of hypertension are summarized in Table 1.

Table 1
Summary of causes of hypertension

Primary (essential hypertension) 

Secondary 

Renal  Polycystic kidney disease; chronic kidney disease; urinary tract obstruction; renin-secreting
tumour 

Vascular  Renovascular disease; vasculitis; coarctation of the aorta; collagen disorders 

Hormonal 

Hyperaldosteronism; phaeochromocytoma; Cushing's syndrome; congenital adrenal

Endogenous  hyperplasia; hyper/hypothyroidism; hyperparathyroidism; excess growth hormone;
hypercalcaemia 

Steroids; oral contraceptive pill 

Exogenous 

Space-occupying lesion; intracranial hypertension 

Neurogenic 

Toxins  Alcohol; non-steroidal anti-inflammatory drugs; adrenoceptor agonists; liquorice 

Others  Obstructive sleep apnoea; pregnancy induced; pre-eclampsia 

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Pharmacological management of hypertension

 The majority of hypertensive patients have primary (or essential) hypertension, that is,
hypertension in which secondary causes are not present. Management aims to control
arterial pressure, prevent end-organ damage (cerebrovascular, cardiovascular, and renal),
1
and reduce the risk of premature death.

Arterial pressure may be lowered by reducing cardiac output, systemic vascular resistance
(SVR), or both (Fig. 1). Drugs manipulating SVR may also bring about clinical improvement
through modi cation of vascular compliance and reactivity. For example, the β-blockers
carvedilol and atenolol reduce arterial pressure similarly at rest, but carvedilol is associated
with improved vascular compliance.

Fig 1

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Overview of the mechanisms of action of common classes of antihypertensive drugs. There may be
considerable overlap between some of the groups, for instance, thiazide and loop diuretics cause
vasodilatation and diuresis.

2
Drugs may be classi ed by mechanism or site of action. Within each class, there are multiple
drugs with structural and pharmacological variations resulting in di ering therapeutic and
side-e ects (Table 2). Many agents do not have a ‘clean’ mechanism of action, but act on
multiple pathways.

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Table 2
Classes and subclasses of antihypertensive medications with common examples
 Class  Examples 

Targeting renin–angiotensin system 

Angiotensin-converting enzyme Captopril, lisinopril, ramipril 

inhibitors 

Angiotensin receptor antagonists  Candesartan, losartan, valsartan 

Direct renin antagonists  Aliskiren 

Adrenoceptor antagonists 

β-Blockers  Atenolol, metoprolol, propranolol 

α-Blockers  Doxazosin, labetalol (also a β-blocker), phentolamine,

phenoxybenzamine 

Calcium channel blockers 

Phenylalkamines  Verapamil 

Dihydropyridines  Amlodipine, nifedipine, nimodipine 

Benzothiazepines  Diltiazem 

Diuretics 

Thiazides  Bendroflumethiazide, hydrochlorothiazide 

Loop  Furosemide, bumetanide 

Potassium sparing/ aldosterone Amiloride, spironolactone 

antagonist 

Vasodilators  Hydralazine, minoxidil 

Centrally acting agents  Clonidine, methyldopa 

Ganglion block  Trimetaphan 

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3
Antihypertensives may be divided into two broad groups, the rst group being those which
directly or indirectly block the renin–angiotensin system (RAS), for example, ACEIs,
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angiotensin receptor antagonists (ARAs), direct renin inhibitors (DRIs), and to a lesser extent
β-blockers. While these drugs have multiple mechanisms of action, their predominant e ect
is to cause vasodilatation. The second group of drugs works by increasing water and sodium
 excretion, thereby reducing intravascular volume, or by causing vasodilatation through non-
RAS pathways, for example, diuretics and calcium channel blockers (CCBs). The actions of
this second group increase RAS activity through negative feedback, a result of which is that
they can potentiate the activity of drugs which target and inhibit the RAS.

The appropriate choice of antihypertensive drug depends on which groups of drugs are most
likely to be e ective both in controlling arterial pressure and in preventing complications
such as end-organ damage. Current NICE guidance recommends that patients under the age
of 55 be initiated on drugs which target the RAS as rst-line therapy. Patients aged over 55
and black people of African or Caribbean family origin are initially treated with drugs which
act through non-RAS mechanisms, as these latter patient groups typically have low-renin
hypertension. Additionally, there may be compelling individual indications or
1
contraindications for the use of a particular drug class.

Drugs which target the RAS

Three drug classes directly target points of the RAS pathway. They act to reduce production of
the peptide hormone angiotensin II, or reduce its receptor binding (Fig. 2). Angiotensin II has
high a nity for AT1 G-protein-coupled receptors, activation of which causes increased
arteriolar tone and SVR. It also causes sympathetic nervous system activation, increased
pituitary secretion of antidiuretic and adrenocortocotrophic hormones, and increased
4
adrenocortical secretion of aldosterone. By antagonizing the RAS pathway, SVR and arterial
pressure are reduced. This e ect is potentiated by a reduction in aldosterone secretion with
resultant reduction in renal sodium and water retention. Negative feedback results in
increased renin release by the juxtaglomerular apparatus.

Fig 2

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 View large Download slide

Sites of action of drugs a ecting the renin–angiotensin system. ACEI, angiotensin-converting enzyme inhibitor.
ARB, angiotensin receptor blocker.

ACEI drugs
The discovery that the venom of the Brazilian pit viper, which causes a massive decrease in
arterial pressure, works by inhibition of angiotensin-converting enzyme (ACE) led to the
development of synthetic, orally administered ACEIs.

1
ACEIs are rst-line treatment in patients under 55 yr old with primary hypertension. They
are also indicated in heart failure, post-myocardial infarction, diabetic nephropathy, and
chronic kidney disease (although not acute kidney injury). The renal and cardiac protective
5
e ects of ACEIs are greater than those expected by arterial pressure control alone.

ACE is a metallopeptidase enzyme which occurs mainly within the pulmonary vasculature.
The inhibition of ACE reduces the cleavage of the peptide hormone angiotensin I to
angiotensin II and reduces metabolism of the peptide bradykinin to inactive substances. The
reduction in angiotensin II is responsible for most of the therapeutic e ects. The
accumulation of bradykinin has some therapeutic advantage through vasodilatation, but is
also responsible for a dry cough in susceptible individuals. ACEIs can also precipitate renal
dysfunction by decreasing renal e erent arteriolar tone, thereby decreasing e ective renal
perfusion pressure, a particular risk in renal artery stenosis. Other side-e ects include
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hyperkalaemia due to reduced aldosterone secretion, agranulocytosis, skin rashes, and taste
disturbance. A rare idiosyncratic reaction to ACEIs can cause angiooedema with potential
 upper airway obstruction; this can occur several years after initiation of ACEI therapy. ACEIs
are contraindicated in pregnancy as they are associated with birth defects.

ACEIs are administered orally with the exception of i.v. enalaprilat (the active form of
enalapril). Enalapril, ramipril, and perindopril are prodrugs requiring hepatic esteri cation
for activation. Captopril is an active drug converted to active metabolites by the liver.
Lisinopril is an active drug, excreted unchanged. Most ACEIs are excreted predominantly by
the kidney.

ACEIs may interact with drugs used perioperatively. For example, non-steroidal anti-
in ammatory drugs can precipitate renal dysfunction in combination with ACEIs. They can
also reduce the e cacy of ACEIs by decreasing prostaglandin synthesis. Interactions with
diuretics may cause hypovolaemia and hyponatraemia, while concurrent use of potassium
supplements or potassium-sparing diuretics may result in hyperkalaemia. Drugs which are
renally excreted (e.g. digoxin and lithium) may accumulate in patients taking ACEIs.

There is increased risk of hypotension on induction of anaesthesia in patients who have

recently taken an ACEI, which may necessitate the use of vasopressor drugs in order to
6,7
restore arterial pressure. To date, there is no high level evidence of worse clinical outcomes
in patients who have taken ACEIs on the day of surgery.

ARA drugs
ARAs are commonly used in patients who are intolerant of ACEIs as they are less likely to
cause a dry cough. The therapeutic and side-e ects are broadly similar to those of ACEIs,
with evidence of reduced risk of new onset diabetes, stroke, progression of cardiac failure,
and all-cause mortality in patients with chronic kidney disease.

ARAs are orally administered drugs which target AT1 G-protein-coupled receptors to
antagonize the e ect of the peptide hormone angiotensin II. Some drugs (candesartan and
telmisartan) bind irreversibly, while others (losartan and valsartan) are competitive
antagonists.

Direct targeting of angiotensin II receptors has theoretical advantages over ACE inhibition.
Angiotensin II may be produced through non-ACE pathways, for example, by the enzyme
chymase in kidney tissue, which is not a ected by ACEIs. ARAs do not inhibit bradykinin
metabolism, and therefore, the incidence of cough is much less than with ACEIs. The risk of
angiooedema
Skip is greatly reduced with ARAs compared with ACEIs.
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As with ACEIs, patients taking ARAs are at increased risk of episodes of hypotension after
7
induction of anaesthesia, particularly when taken in combination with diuretics.
 Direct renin inhibitors
Aliskiren, a piperidine derivative, is the only available drug in this class and is used by
specialists in patients who are unresponsive to, or intolerant of, other antihypertensives.
Aliskiren directly inhibits the enzyme renin, which is secreted by granular cells of the
juxtaglomerular apparatus. Renin inhibition reduces the conversion of the hepatically
secreted polypeptide angiotensinogen to angiotensin I. Its e ect on the RAS is therefore
‘upstream’ of ACEIs and ARAs and it does not cause bradykinin accumulation. DRIs have the
same potential to cause renal dysfunction and electrolyte disturbances as ACEIs and ARAs.
Diarrhoea is a speci c side-e ect to higher doses of DRIs.

Aliskiren is orally administered, although it is poorly absorbed and its bioavailability is low
(2.7%); therefore, therapeutic plasma concentration is only achieved by repeat dosing. It is
minimally metabolized and its main route of elimination is biliary. Therefore, it has a long
3
elimination half-life (24–40 h).

Aliskiren may have a larger role in the management of hypertension in future, possibly in
combination with other drugs. Evidence relating to the implications of aliskiren therapy on
anaesthetic conduct is limited, although there are case reports of patients having prolonged
and refractory hypotension after induction of general anaesthesia.

Should drugs which target the RAS be used perioperatively?

There are currently no universal guidelines on whether RAS-blocking drugs should be
withheld before surgery. However, in many departments, local guidelines recommend that
ACEIs and ARAs be withheld on the day of surgery in order to reduce the risk of hypotension
and organ hypoperfusion under anaesthesia. This approach should be balanced against the
potential bene cial e ects of continuing these drugs perioperatively. Some authors
recommend that patients with heart failure or resistant hypertension continue to take ACEIs
perioperatively. The potential bene ts of this approach may outweigh the risks, provided
care is taken to maintain euvolaemia and episodes of hypotension are managed with volume
expansion and vasopressors. Other described bene ts of continuing RAS antagonists in the
perioperative period include renal protection, reduced rates of perioperative atrial
8
brillation, and neuroprotection in cerebrovascular surgery.

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Adrenoceptor antagonists
 β-Blockers
β-Blockers are not used as rst-line antihypertensives unless there are other indications, for
example, after myocardial infarction, or in tachyarrhythmias such as atrial brillation. Their
diverse indications include stable heart failure, thyrotoxicosis, oesophageal varices, anxiety,
and glaucoma.

β-Blockers antagonize catecholamines at β-adrenoceptors. These Gs type G-protein-

coupled receptors are classi ed as β1, present mainly within the heart and kidneys; and β2,
present throughout the body in lungs, blood vessels, and muscle. The reduction in arterial
pressure achieved by β-blockers is attributable to their e ects upon multiple pathways. Block
of β1 receptors in the sinoatrial node reduces heart rate and block of myocardial receptors
reduces contractility (reduced chronotropy and inotropy, respectively). They also reduce
sympathetic nervous system activity, while block of receptors in the juxtaglomerular
apparatus reduces renin secretion.

β-Blockers are categorized according to cardioselectivity. Metoprolol, esmolol, and atenolol

have greater a nity for β1 receptors than β2 at therapeutic doses (selectivity is reduced at
higher doses). This contrasts with non-cardioselective drugs such as propranolol and sotalol.
Most β-blockers are pure antagonists; however, some drugs are partial antagonists at β
receptors and exhibit some agonist/sympathetomimetic activity (pindolol, timolol). The
clinical relevance of this is uncertain. Some β-blockers (propranolol, metoprolol) block
sodium channels and have membrane stabilizing activity, that is, may be classed as
Vaughan-Williams class 1 antiarrhythmics. Labetalol is a β-blocker which also has α-
blocking activity. In addition to their antihypertensive e ects, β-blockers improve the
myocardial oxygen supply:demand ratio and help reduce myocardial ischaemia by
prolonging the period of diastole. While β-blockers are used in stable heart failure, they have
the potential to worsen symptoms in some patients by reducing cardiac output. Poor
peripheral circulation and Raynaud's phenomenon may be precipitated both by reduced
cardiac output and block of peripheral β2 receptors. Bronchospasm caused by β2 block may
be a signi cant respiratory side-e ect in susceptible individuals, for example, asthmatics.
Central nervous system e ects include malaise, tiredness, and vivid dreams, particularly
with lipid-soluble drugs. In insulin-dependent diabetic patients, the symptoms of
hypoglycaemia may be suppressed by sympathetic block.

More than 30 β-blockers are currently available. Oral administration is common as most
have
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to Main absorption and bioavailability. I.V. preparations are available for some, including
atenolol, metoprolol, and esmolol. Lipid-soluble drugs, for example, metoprolol and
propranolol, are generally metabolized by the liver and have shorter half-lives than water-
 soluble drugs, for example, atenolol, which are excreted largely unchanged in the urine. An
exception is esmolol, which is metabolized by ester hydrolysis accounting for its rapid o set
of action.

There is evidence that β-blockers have cardioprotective bene ts when used perioperatively.
Patients taking β-blockers who su er myocardial infarction in the perioperative period are
more likely to survive than those who are not. Patients on established β-blocker therapy are
9
therefore recommended to continue treatment through the perioperative period. Initiation
of therapy before operation is more controversial, particularly in patients with low
cardiovascular risk. The POISE study evaluated the e ect of commencing metoprolol at a
xed dose on the day of surgery in patients with the risk of atherosclerotic disease
undergoing non-cardiac surgery. While fewer patients in the metoprolol group su ered a
myocardial infarction, their risks of stroke and all-cause mortality were greater than the
10
placebo group. There may, however, be a role for carefully titrated preoperative β-blockers
in planned procedures.

α-Blockers
α-Blockers are used to treat hypertension in patients resistant to, or intolerant of, other
treatments. Speci c indications for their use in secondary hypertension include labetalol for
pre-eclampsia and phentolamine in the perioperative management of phaeochromocytoma.
α-Blockers are also commonly used to improve urinary ow in benign prostatic hyperplasia,
for example, tamsulosin.

Most α-blockers selectively target post-ganglionic α1 Gq protein-coupled receptors leading

to peripheral vasodilatation and reduced SVR. Non-selective α-blockers, for example,
phentolamine and phenoxybenzamine, act at α1 and α2 receptors. Blockade of presynaptic α2
Gi-protein-coupled receptors leads to norepinephrine release with resultant tachycardia and
increased cardiac output.

Labetalol is a non-selective β-blocker which also acts as an α1 adrenoceptor blocker.

Therefore, it manipulates arterial pressure by acting upon multiple pathways. Adverse e ects
of α-block include orthostatic hypotension with a re ex tachycardic response, especially
after a rst dose. In patients unable to mount a tachycardic response, for instance, those
taking rate-limiting drugs, this can lead to profound hypotension and syncope. Other side-
e ects include oedema, headache, incontinence, and drowsiness.
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Calcium channel blockers

 CCBs are rst-line treatment for primary hypertension in patients over the age of 55 and
black patients of African or Caribbean family origin. Rate-controlling CCBs (diltiazem,
verapamil) are also used to manage tachyarrhythmias and angina, where their negative
inotropic and chronotropic e ects improve the myocardial oxygen supply:demand ratio.
Some CCBs have speci c non-cardiac indications, for example, nimodipine in neurosurgery
to reduce cerebral vasospasm in patients after spontaneous subarachnoid haemorrhage, and
verapamil in neurology to treat cluster headache.

CCBs act on L -type calcium channels present in vascular smooth muscle and in myocardial
and nodal tissues. The variable a nity of the di erent CCBs to these di erent tissues
determines their e ects. Those with higher a nity to cardiac tissue (diltiazem, verapamil)
cause negative chronotropy and inotropy. Those with higher a nity to vascular smooth
muscle cause peripheral vasodilatation and reduced SVR, which may result in re ex cardiac
stimulation.

Cardiovascular side-e ects include re ex tachycardia which may potentiate myocardial

ischaemia, disturbance of the peripheral microcirculation leading to swelling of the hands
and feet, ushing, and headache. Rate-limiting agents prolong atrio-ventricular conduction
and cause bradycardia; the negative inotropic and chronotropic e ects may worsen heart
failure.

CCBs are a chemically diverse group of drugs, which comprise phenylalkylamines, for
example, verapamil; dihydropyridines, for example, amlodipine and nifedipine; and
benzothiazepines, for example, diltiazem. CCBs have varying pharmacokinetic properties.
Most are orally administered, although their bioavailability is generally low due to extensive
rst-pass metabolism. I.V. preparations are available for some drugs (verapamil,
nimodipine, nicardipine), while nifedipine may be administered sublingually. Most have
half-lives of <12 h, although there are exceptions, including amlodipine, which has a
signi cantly longer half-life.

There is little evidence that commencing or continuing the use of CCBs perioperatively
reduces the risk of myocardial infarction or death. While there is evidence that continued use
of CCBs in the presence of β-blockers may lead to increased incidence of hypotension under
7
anaesthesia, it is not generally recommended that CCBs be withheld before surgery.

Diuretics
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Thiazide (bendro umethiazide, hydrochlorothiazide) and thiazide-like (chlortalidone,
indapamide) diuretics are the most commonly prescribed diuretic agents used to treat
 hypertension. They are used in patients intolerant of CCBs and in patients with heart failure,
or at risk of heart failure. They are also used as ‘add on’ drugs in patients who have not
1
responded to rst- and second-line antihypertensive treatments.

Thiazide diuretics act on the proximal part of the distal tubule to inhibit sodium and chloride
reabsorption, with resultant reduction in water reabsorption leading to diuresis. The diuretic
e ect is dependent upon their excretion into the renal tubule and is therefore reduced in
renal impairment.

Some of the antihypertensive e ect of thiazides can be attributed to their diuretic e ect
leading to a reduction in blood volume. However, thiazides also cause vasodilatation and
reduce the responsiveness of vascular smooth muscle to vasoactive substances resulting in a
reduction in SVR. One direct mechanism by which thiazides cause these e ects is through
opening of calcium-activated potassium channels.

Thiazide diuretics have many clinically relevant biochemical side-e ects including
hypokalaemia, hypercalcaemia, hyponatraemia, hypomagnesaemia, hyperglycaemia,
hyperuricaemia, hypercholesterolaemia, and hypochloraemic alkalosis. Plasma volume loss
may precipitate dehydration and acute kidney injury. Less common side-e ects include skin
rashes, photosensitivity reactions, and blood dyscrasias including thrombocytopaenia.

Aldosterone antagonists, for example, spironolactone, are recommended as fourth-line

treatment of primary hypertension. The use of these drugs carries a risk of hyperkalaemia,
particularly in patients with impaired renal function or who are taking other potassium-
sparing agents. Loop diuretics are indicated for resistant hypertension in patients with heart
failure, chronic kidney disease, and in those at risk of hyperkalaemia.

While diuretic therapy may be continued during the perioperative period, attention should be
paid to the patient's uid status and the potential for precipitating an acute kidney injury and
metabolic or electrolyte abnormalities.

Other antihypertensives

Vasodilators
Directly acting vasodilators, for example, hydralazine and minoxidil, are seldom used due to
their
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to Main ect pro les. Hydralazine is used in hypertension secondary to pre-eclampsia. In
Content
addition to its antihypertensive e ects, minoxidil is used topically as a treatment for male
pattern baldness.
 Vasodilators cause relaxation of vascular smooth muscle in resistance (arteriolar) vessels.
Minoxidil achieves this via adenosine triphosphate-dependent potassium channels on
smooth muscle cell membranes. Hydralazine acts through activation of adenylate cyclase,
increasing intracellular cyclic guanosine monophosphate. Vasodilatation provokes re ex
cardiac stimulation (which may precipitate cardiac ischaemia) and RAS activation. These
compensatory responses may be o set by β-blockers or diuretics.

Vasodilator drugs are poorly tolerated. Side-e ects include headache, uid retention, and
oedema. Other speci c side-e ects include left ventricular hypertrophy, pericardial and
pleural e usions, hypertrichosis and coarsening of features with minoxidil, while peripheral
neuropathy, blood dyscrasias, and a lupus-like reaction can occur with hydralazine.

Centrally acting agents

Centrally acting agents include clonidine (α2 adrenoceptor agonist), methyldopa (precursor
of an α2 adrenoceptor agonist), and moxonidine (agonist at imidazoline binding sites). Their
use in primary hypertension is limited to di cult to treat cases, while methyldopa is used to
treat hypertension in pregnancy. The evidence base for the use of centrally acting drugs in
hypertension is limited and adverse e ects are common.

Clonidine is an analgesic and sedative drug which reduces the minimum alveolar
concentration of inhalation anaesthetic agents. Both of these drugs cause side-e ects
including dry mouth and sedation. Methyldopa has immunological side-e ects, including
pyrexia, haemolytic anaemia, and hepatitis. Cessation of treatment with clonidine can cause
rebound hypertension.

Ganglion blockers
Ganglion blockers, such as trimetaphan, antagonize acetylcholine at nicotinic receptors,
including those at the adrenal cortex. Trimetaphan causes vasodilatation with a consequent
rapid reduction in arterial pressure. Although ganglion blockers may be used to manage
hypertensive crises or to provide hypotensive anaesthesia, their use is increasingly rare.

Declaration of interest
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declared.
 MCQs

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