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doi: 10.1093/bjaceaccp/mku061
Advance Access Publication Date: 14 January 2015
Antihypertensive drugs
RE Jackson BSc MB ChB FRCA1 and MC Bellamy MB BS MA FRCA FRCP (Edin)
FFICM2, *
1
Specialty Registrar in Anaesthesia, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK, and
2
Professor, Intensive Care Unit, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK
*To whom correspondence should be addressed. Tel: +44 113 206 5789; E-mail: m.c.bellamy@leeds.ac.uk
© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
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Antihypertensive drugs
The appropriate choice of antihypertensive drug depends on angiotensin II, or reduce its receptor binding (Fig. 2). Angiotensin
which groups of drugs are most likely to be effective both in con- II has high affinity for AT1 G-protein-coupled receptors, activa-
trolling arterial pressure and in preventing complications such as tion of which causes increased arteriolar tone and SVR. It also
end-organ damage. Current NICE guidance recommends that pa- causes sympathetic nervous system activation, increased pituit-
tients under the age of 55 be initiated on drugs which target the ary secretion of antidiuretic and adrenocortocotrophic hor-
RAS as first-line therapy. Patients aged over 55 and black people mones, and increased adrenocortical secretion of aldosterone.4
of African or Caribbean family origin are initially treated with By antagonizing the RAS pathway, SVR and arterial pressure are
drugs which act through non-RAS mechanisms, as these latter reduced. This effect is potentiated by a reduction in aldosterone
patient groups typically have low-renin hypertension. Addition- secretion with resultant reduction in renal sodium and water re-
ally, there may be compelling individual indications or contrain- tention. Negative feedback results in increased renin release by
dications for the use of a particular drug class.1 the juxtaglomerular apparatus.
Fig 1 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.
with potential upper airway obstruction; this can occur several renal dysfunction in combination with ACEIs. They can also re-
years after initiation of ACEI therapy. ACEIs are contraindicated duce the efficacy of ACEIs by decreasing prostaglandin synthesis.
in pregnancy as they are associated with birth defects. Interactions with diuretics may cause hypovolaemia and hypo-
ACEIs are administered orally with the exception of i.v. natraemia, while concurrent use of potassium supplements or
enalaprilat (the active form of enalapril). Enalapril, ramipril, potassium-sparing diuretics may result in hyperkalaemia.
and perindopril are prodrugs requiring hepatic esterification Drugs which are renally excreted (e.g. digoxin and lithium) may
for activation. Captopril is an active drug converted to active accumulate in patients taking ACEIs.
metabolites by the liver. Lisinopril is an active drug, excreted There is increased risk of hypotension on induction of anaes-
unchanged. Most ACEIs are excreted predominantly by the thesia in patients who have recently taken an ACEI, which may
kidney. necessitate the use of vasopressor drugs in order to restore arter-
ACEIs may interact with drugs used perioperatively. For ex- ial pressure.6 7 To date, there is no high level evidence of worse
ample, non-steroidal anti-inflammatory drugs can precipitate clinical outcomes in patients who have taken ACEIs on the day
of surgery.
Fig 2 Sites of action of drugs affecting the renin–angiotensin system. ACEI, angiotensin-converting enzyme inhibitor. ARB, angiotensin receptor blocker.
to norepinephrine release with resultant tachycardia and in- Thiazide diuretics act on the proximal part of the distal tubule
creased cardiac output. to inhibit sodium and chloride reabsorption, with resultant
Labetalol is a non-selective β-blocker which also acts as an α1 reduction in water reabsorption leading to diuresis. The diuretic
adrenoceptor blocker. Therefore, it manipulates arterial pressure effect is dependent upon their excretion into the renal tubule and
by acting upon multiple pathways. Adverse effects of α-block is therefore reduced in renal impairment.
include orthostatic hypotension with a reflex tachycardic re- Some of the antihypertensive effect of thiazides can be
sponse, especially after a first dose. In patients unable to mount attributed to their diuretic effect leading to a reduction in blood
a tachycardic response, for instance, those taking rate-limiting volume. However, thiazides also cause vasodilatation and reduce
drugs, this can lead to profound hypotension and syncope. the responsiveness of vascular smooth muscle to vasoactive sub-
Other side-effects include oedema, headache, incontinence, stances resulting in a reduction in SVR. One direct mechanism by
and drowsiness. which thiazides cause these effects is through opening of cal-
cium-activated potassium channels.
Thiazide diuretics have many clinically relevant biochemical
Calcium channel blockers side-effects including hypokalaemia, hypercalcaemia, hypona-
CCBs are first-line treatment for primary hypertension in traemia, hypomagnesaemia, hyperglycaemia, hyperuricaemia,
patients over the age of 55 and black patients of African or hypercholesterolaemia, and hypochloraemic alkalosis. Plasma
Caribbean family origin. Rate-controlling CCBs (diltiazem, verap- volume loss may precipitate dehydration and acute kidney injury.
amil) are also used to manage tachyarrhythmias and angina, Less common side-effects include skin rashes, photosensitivity
where their negative inotropic and chronotropic effects improve reactions, and blood dyscrasias including thrombocytopaenia.
the myocardial oxygen supply:demand ratio. Some CCBs have Aldosterone antagonists, for example, spironolactone, are re-
specific non-cardiac indications, for example, nimodipine in commended as fourth-line treatment of primary hypertension.
neurosurgery to reduce cerebral vasospasm in patients after The use of these drugs carries a risk of hyperkalaemia, particular-
spontaneous subarachnoid haemorrhage, and verapamil in ly in patients with impaired renal function or who are taking
neurology to treat cluster headache. other potassium-sparing agents. Loop diuretics are indicated
CCBs act on -type calcium channels present in vascular for resistant hypertension in patients with heart failure, chronic
smooth muscle and in myocardial and nodal tissues. The vari- kidney disease, and in those at risk of hyperkalaemia.
able affinity of the different CCBs to these different tissues deter- While diuretic therapy may be continued during the peri-
mines their effects. Those with higher affinity to cardiac tissue operative period, attention should be paid to the patient’s fluid
(diltiazem, verapamil) cause negative chronotropy and inotropy. status and the potential for precipitating an acute kidney injury
Those with higher affinity to vascular smooth muscle cause and metabolic or electrolyte abnormalities.
peripheral vasodilatation and reduced SVR, which may result in
reflex cardiac stimulation.
Cardiovascular side-effects include reflex tachycardia which Other antihypertensives
may potentiate myocardial ischaemia, disturbance of the periph-
eral microcirculation leading to swelling of the hands and feet, Vasodilators
flushing, and headache. Rate-limiting agents prolong atrio-
Directly acting vasodilators, for example, hydralazine and
ventricular conduction and cause bradycardia; the negative
minoxidil, are seldom used due to their side-effect profiles.
inotropic and chronotropic effects may worsen heart failure.
Hydralazine is used in hypertension secondary to pre-eclampsia.
CCBs are a chemically diverse group of drugs, which comprise
In addition to its antihypertensive effects, minoxidil is used top-
phenylalkylamines, for example, verapamil; dihydropyridines,
ically as a treatment for male pattern baldness.
for example, amlodipine and nifedipine; and benzothiazepines,
Vasodilators cause relaxation of vascular smooth muscle in
for example, diltiazem. CCBs have varying pharmacokinetic
resistance (arteriolar) vessels. Minoxidil achieves this via adeno-
properties. Most are orally administered, although their bioavail-
sine triphosphate-dependent potassium channels on smooth
ability is generally low due to extensive first-pass metabolism. I.V.
muscle cell membranes. Hydralazine acts through activation of
preparations are available for some drugs (verapamil, nimodipine,
adenylate cyclase, increasing intracellular cyclic guanosine
nicardipine), while nifedipine may be administered sublingually.
monophosphate. Vasodilatation provokes reflex cardiac stimula-
Most have half-lives of <12 h, although there are exceptions,
tion (which may precipitate cardiac ischaemia) and RAS activa-
including amlodipine, which has a significantly longer half-life.
tion. These compensatory responses may be offset by β-blockers
There is little evidence that commencing or continuing the
or diuretics.
use of CCBs perioperatively reduces the risk of myocardial infarc-
Vasodilator drugs are poorly tolerated. Side-effects include
tion or death. While there is evidence that continued use of CCBs
headache, fluid retention, and oedema. Other specific side-
in the presence of β-blockers may lead to increased incidence of
effects include left ventricular hypertrophy, pericardial and
hypotension under anaesthesia, it is not generally recommended
pleural effusions, hypertrichosis and coarsening of features
that CCBs be withheld before surgery.7
with minoxidil, while peripheral neuropathy, blood dyscrasias,
and a lupus-like reaction can occur with hydralazine.
Diuretics
Thiazide (bendroflumethiazide, hydrochlorothiazide) and thia-
Centrally acting agents
zide-like (chlortalidone, indapamide) diuretics are the most com-
monly prescribed diuretic agents used to treat hypertension. Centrally acting agents include clonidine (α2 adrenoceptor agon-
They are used in patients intolerant of CCBs and in patients ist), methyldopa ( precursor of an α2 adrenoceptor agonist), and
with heart failure, or at risk of heart failure. They are also used moxonidine (agonist at imidazoline binding sites). Their use in
as ‘add on’ drugs in patients who have not responded to first- primary hypertension is limited to difficult to treat cases, while
and second-line antihypertensive treatments.1 methyldopa is used to treat hypertension in pregnancy. The
evidence base for the use of centrally acting drugs in hyperten- 2. Therapeutics. British Hypertension Society. Available from
sion is limited and adverse effects are common. http://www.bhsoc.org/resources/therapeutics/ (accessed 1
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hypertension. converting enzyme inhibitors reduce mortality in hyper-
tension: a meta-analysis of randomized clinical trials of
renin–angiotensin–aldosterone system inhibitors involving
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