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82 Chapter 5 Hypertension
At this point LV pressure >
aortic pressure
aortic valve opens—
Blood flow starts
Aortic pressure
Left ventricle (LV) pressure
Ventricular contraction begins
Figure 5.5 Changes in ventricular and aortic pressures.
Note that blood can only be ejected from the heart when the pressure in the left ventricle (red line)
exceeds the pressure in the aorta (blue line). LV, left ventricle. See also Chapter 7, Box 7.1.
changes will shorten the ventricular ejection phase (when
blood is being pumped out), and so for a given force of
contraction there will be a reduced volume of blood
ejected, i.e. there will be a reduced stroke volume.
At this point aortic pressure >
LV pressure
aortic valve closes—
Blood flow stops
Isovolumetric contraction
During this phase the bicuspid valve
has closed and the aortic valve is
not open. The ventricular muscle is
contracting in a closed chamber
of the renin–angiotensin–aldosterone system (RAAS), and
of the regulation of total peripheral resistance by the
autonomic nervous system.
e impact of these determinants of stroke volume is
summarized in Figure 5.6. It shows that if you have a
healthy cardiovascular system, your heart will respond to
an increased arterial pressure by reducing cardiac output,
thus bringing arterial pressure down. Conversely, an
increase in central venous pressure will stimulate a
compensatory increase in cardiac output, and so prevent
a build-up of pressure on the venous side.
What we must consider, though, is what happens when
this adaptive system breaks down; this can lead to a
chronic rise in either arterial pressure (hypertension) or
central venous pressure (heart failure, Chapter 7).
Understanding these conditions requires an exploration
Length of
muscle bre—
Preload
+ve +ve
+ve
Stroke volume
contraction—
Contractility
5.1.4 What determines peripheral
resistance?
Peripheral resistance is determined by the pre-capillary
arterioles, with their vast distribution and small lumen
regulated by contraction of smooth muscle cells.
(Changes to the diameter of the larger blood vessels do
not signicantly alter the resistance to the ow of blood,
and the lumen of the smaller capillaries cannot be
regulated, as they lack smooth muscle.) e presence of a
suitable resistance to ow at the arteriolar level is
essential for the maintenance of normal blood pressure
and perfusion of tissues. is is illustrated graphically in a
patient in anaphylactic shock. In this situation cardiac
Force of
Arterial blood
-ve
pressure—
Afterload
Figure 5.6 Summary of regulation of stroke volume.
5.1 The physiological control of arterial blood pressure 83
output is high but, because of massive vasodilatation of
arteriolar smooth muscle, blood pressure is too low to
eectively perfuse the tissues. In such a case it is essential
to cause rapid vasoconstriction in order to re-establish
resistance to blood ow and therefore restore blood
pressure. is is achieved using intramuscular adrenaline
(see below).
Normally there is a degree of tonic contraction of the
arterioles, oering sucient resistance to ow to generate
the systolic and diastolic blood pressures. is is
important since it explains how we can have drugs that
increase or decrease peripheral resistance.
Receptors for noradrenaline or adrenaline in the
arterioles are of two subtypes: 1-adrenoceptors (which
stimulate contraction of smooth muscle) and 2adrenoceptors (which mediate its relaxation). In
determining peripheral resistance it is the 1adrenoceptors which dominate, as their distribution is
more widespread, regulating resistance to blood ow in
the major vascular beds of the mesenteries and skin. is
explains the increase in peripheral resistance that is part
of the clinical response to administration of adrenaline to
a patient in anaphylactic shock. e 1-receptors are
Gq-coupled, producing stimulation leading to the
activation of the enzyme phospholipase C. e
downstream eect is raised intracellular Ca2+ which
stimulates the smooth muscle contractile mechanism
and hence brings about vasoconstriction.
Adrenaline, though, will stimulate both 1-adrenoceptors
and 2-adrenoceptors in the pre-capillary arterioles. As
already stated, the activation of 2-adrenoceptors will
lead to vasodilatation via increases in intracellular cAMP
(Gs-coupled receptors). However, the expression of
vascular 2-adrenoceptors is much more limited, being
mainly restricted to the vasculature of skeletal muscle and
cardiac arterioles. e relaxation response evoked by
adrenaline is the same as that mediated by 2adrenoceptors on the smooth muscle of the airways,
directly targeted by anti-asthma drugs (Chapter 11). e
vascular 2-adrenoceptor response is not, however,
intentionally manipulated in therapeutics.
is apparently perplexing conict in action between
1- and 2-adrenoceptors makes sense when considering
the classic ght-or-ight scenario. Here, an urgent
necessity for physical response is accompanied by an
increased release of adrenaline (from the adrenal
medulla) and noradrenaline (via the sympathetic nervous
system). As a consequence of the dierent receptor
subtypes activated, unnecessary blood supply to the skin
and viscera is reduced (by 1-mediated vasoconstriction),
while the vital supply of blood (and therefore oxygen) to
the skeletal muscle and heart is increased (by 2-mediated
vasodilatation). e two eects combine to ensure that
the subject is able to respond as the situation demands.
e control of peripheral resistance by the RAAS is
mainly due to the direct and potent vasoconstrictor
action of angiotensin II, which increases blood pressure.
However, both angiotensin II and aldosterone are
physiologically active products of the RAAS. is is
important when considering that this system is a central
target for antihypertensive drugs (see Box 5.1 for a review
of the organization of the RAAS). Aldosterone is a
mineralocorticoid steroid hormone secreted from cells of
the adrenal cortex in response to angiotensin II. It acts to
increase sodium reabsorption from the distal convoluted
tubule and cortical collecting duct of the kidney,
promoting sodium retention and thereby increasing
blood volume. As a result arterial blood pressure is
elevated due to the increase in cardiac output.
Drugs that modify the inuence of angiotensin II and
aldosterone are now amongst the most widely prescribed
in the clinical management of cardiovascular conditions,
so it is not surprising that they have been prescribed to
our ctional patient Andreas in Workbook 2. e key to
the pharmacological control of the system is that
angiotensin II acts not only to regulate peripheral
resistance at the arterioles, but also to control the
secretion of aldosterone from the adrenal cortex (see
Box 5.1 and Figure 5.7). Angiotensin II exerts both these
eects by stimulating AT1 receptors. Figure 5.7 shows that
the physiological control of the system, however, lies
upstream, at the secretion of renin by the juxtaglomerular
cells of the kidney.
e role of aldosterone in the kidney is not limited to
sodium retention but also enhances potassium secretion
into the urine by the cortical collecting duct cells. An
increase in potassium levels in the plasma directly
enhances aldosterone production by the adrenal cortex,
resulting in a compensatory secretion of the excess
potassium. Importantly, this provides control of
aldosterone which is independent of the RAAS.
Aldosterone antagonists such as spironolactone and
eplerenone promote loss of Na+, whilst preventing K+
excretion, and are therefore referred to as potassiumsparing diuretics.
84 Chapter 5 Hypertension
Vascular endothelium
Box 5.1
The renin-angiotensin-aldosterone system (RAAS)
Vascular smooth
muscle
Liver
Angiotensinogen
Kidney
Aldosterone
Salt retention
Renin
Angiotensin I
ACE
Angiotensin II
Contraction of
vascular smooth
muscle cells
Adrenal
cortex
Blood volume
Vascular resistance
Blood pressure
Figure a The influence of the renin–angiotensin–aldosterone system (RAAS) on
the control of arterial blood pressure.
The relationships between the various organs and tissues of the body involved in the RAAS
are illustrated here. The impact of the component parts on blood pressure is shown in orange.
The main features of the renin–angiotensin–
aldosterone system Angiotensinogen is a large
plasma protein constitutively released from the liver to
circulate in the blood. is protein is a substrate for
the proteolytic enzyme renin, made in the
juxtaglomerular cells of the kidney. e release of
renin is stimulated by the sympathetic nervous system
through activation of -adrenoceptors by
5.1 The physiological control of arterial blood pressure 85
Box 5.1 The renin-angiotensin-aldosterone system (RAAS)
noradrenaline. Renin cleaves angiotensinogen in the
blood to form angiotensin I which is then converted to
angiotensin II by angiotensin-converting enzyme
(ACE). Angiotensin II has the eect of raising blood
pressure by acting on its receptors, the AT1 receptors.
ese are found on vascular smooth muscle cells and
their activation here leads to vasoconstriction and
• ↓Blood volume
• ↓Renal blood pressure
• ↓Blood ow and ↓Na
macula densa in kidney
• ↑Sympathetic activity at
juxtaglomerular cells
(β–adrenoceptors)
+
Na
reabsorbed
(Decreased Na
and H2O
excretion)
+
+
at
Juxtaglomerular cells
↑Renin secretion
-ve
↑Arterial BP
↑TPR
↑Plasma angiotensin II↑Aldosterone
increased peripheral resistance. AT1 receptors are also
located on adrenal cortex cells from which their
stimulation leads to the release of aldosterone. is
hormone then acts on the distal convoluted tubule
and cortical collecting duct of the kidney to promote
Na+ reabsorption, resulting in increased blood
volume.
activity of renin is lower in black people of African or
African Caribbean origin, thought to result from a
decreased rate of secretion of renin. Such dierences
explain why the recommendations for initial
antihypertensive drug treatment depend on ethnicity
(e.g. Figure 5.10).
5.1.5 The role of baroreceptors in
controlling blood pressure
Baroreceptors in blood vessels are stretch receptors. e
location of two of those in major arteries is indicated in
Figure 5.8. When the walls of the blood vessel are stretched
Figure 5.7 The central role of renin in regulating arterial
blood pressure.
Renin secretion by the juxtaglomerular cells of the kidney is
highly regulated, as indicated by the number of items in the blue
box. Its increased secretion signals physiological changes
involving the hormones angiotensin II and aldosterone, which
combine to bring about compensatory increases in peripheral
resistance and cardiac output (through enhanced Na+
reabsorption and therefore increased blood volume). These
corrective actions are sensed by the juxtaglomerular cells (green
dotted arrow) which respond by decreasing their secretion of
renin. BP, blood pressure; TPR, total peripheral resistance.
Ethnicity correlates with the role of renin in
hypertension
We may note from the above that kidney function, and
specically renin secretion, are central to the control of
blood pressure, particularly when facing the challenge
of the high sodium intake characteristic of modern
diets. ere is individual variation in the manner in
which we respond to this challenge, and some of this
correlates with race. More specically the plasma
Baroreceptors in the common
carotid artery and the aortic arch
Figure 5.8 Location of arterial baroreceptors.
Baroreceptors are stretch receptors found in the strategic
locations shown. They sense raised arterial blood pressure
through increased neuronal activity at their sensory nerve
endings, and send this information to the CNS.
86 Chapter 5 Hypertension
by raised arterial blood pressure, there is an increase in the
rate of ring of the sensory nerve endings in the
baroreceptor. is encoded information is sent to the
cardiovascular control centres in the brain. Compensatory
changes are then brought into play, mediated by
parasympathetic and sympathetic inputs, to complete the
feedback loop and restore blood pressure to its set point.
Baroreceptors are also found in other strategic locations.
For example, we have already encountered the
juxtaglomerular cells of the kidney—these are
baroreceptors, and when stretched they respond directly
by decreasing their secretion of renin, providing a short
feedback loop that is independent of the autonomic
nervous system.
5.2 Antihypertensive drugs
At the beginning of this chapter we described the blood
pressure measurements that dene clinical hypertension
and form the basis for criteria for treatment. In practice,
treatment is guided by sets of recommendations, as we
describe below. ese guidelines derive from clinical
trials and past experience.
It is perhaps not surprising that, owing to the number of
factors which combine to inuence blood pressure, its
control often requires drugs targeting multiple processes.
Eective prescribing must be informed not only by clinical
experience, but by knowledge of how antihypertensive
drugs work to modify these underlying processes. is will
enable the interpretation of the clinical response in terms
of the cellular changes brought about by the drug, and will
also provide an understanding of how dierent
combinations of drugs may achieve the best outcome for
the patient. Here we will rst set out the mode of action of
the most widely used classes of antihypertensive agents,
as well as briey covering others that are less commonly
used. We will then discuss the therapeutic strategies used
in the treatment of hypertension.
5.2.1 Drugs that act on the RAAS
e RAAS (Box 5.1) is modied by three main classes of
clinically useful drugs: angiotensin-converting enzyme
(ACE) inhibitors, angiotensin II receptor antagonists, and
aldosterone antagonists. Only the rst two of these are
used in the management of hypertension. In addition, a
new class of antihypertensive agent, which directly
inhibits renin, has recently been introduced.
e existence of these multiple feedback loops explains
some of the complexities in the clinical control of blood
pressure, and why it is not possible simply to reduce
blood pressure using a drug that decreases peripheral
resistance. A drop in arterial blood pressure in response
to a vasodilator drug is detected by baroreceptors. ere
is then a compensatory increase in sympathetic activity to
raise cardiac output and peripheral resistance, and blood
pressure therefore rises. e successful long-term
management of hypertension (and here we are talking
about lifelong drug taking) often requires several drugs
which manipulate the dierent regulatory mechanisms
described above.
ACE inhibitors
e conversion of the liver-derived plasma protein
angiotensinogen into angiotensin I by the enzyme renin
represents the rst step in the RAAS (depicted in Box 5.1,
Figure a). e 10 amino acid peptide angiotensin I has the
last two amino acid residues clipped o by ACE to form
the 8 amino acid peptide angiotensin II. is occurs
within the circulation, particularly at the surface of
endothelial cells. Angiotensin II then acts at AT1
receptors, stimulating both vasoconstriction and
aldosterone release.
ACE inhibitors lower blood pressure by reducing the
vasoconstriction induced by angiotensin II, thereby
decreasing total peripheral resistance (reducing
afterload). In addition, the lower levels of angiotensin II
lead to reduced secretion of aldosterone, which in turn
promotes Na+ and water excretion, and so reduces venous
return (reducing preload).
Issues relevant to prescribing ACE inhibitors including
adverse effects
ACE inhibitors are commonly-prescribed and eective
oral antihypertensives, which are generally well tolerated.
Issues of particular note for prescribers are as follows.
• ACE is not the only enzyme capable of converting
plasma angiotensin I into angiotensin II. ere is
therefore a theoretical reason for believing that AT1
antagonists (see below) may be more eective in
blocking angiotensin II-mediated responses.
5.2 Antihypertensive drugs 87
• Use of ACE inhibitors produces a compensatory rise in
renin secretion, increasing the production of
angiotensin I. Since the conversion of angiotensin I to
angiotensin II can occur independently of ACE, this
elevation in renin secretion limits the eectiveness of
ACE inhibitors.
• ACE also acts on bradykinin, in this case to break it
down; ACE inhibitors therefore lead to accumulation of
bradykinin. is is signicant since it is thought to be
the cause of the persistent dry cough experienced by
about 10% of patients taking these drugs. It is the most
common adverse eect of ACE inhibitors; the cough
can be intolerable, requiring an alternative drug choice,
such as an AT1 antagonist.
• ere is a potentially serious interaction between ACE
inhibitors and NSAIDs such as ibuprofen (see Section
9.3.1), increasing the risk of renal failure. is risk is
heightened with the concomitant use of diuretics
(sometimes called the triple whammy), and is of
particular concern given that NSAIDs are available as
non-prescription drugs, and that ACE inhibitors and
diuretics are often prescribed together (see Section
5.3). e hypotensive eect of ACE inhibition is also
counteracted by NSAIDs.
A large number of ACE inhibitors (’pril drugs) are
available, including the rst to be marketed, captopril.
is drug has a short plasma half-life of approximately 2
hours and therefore requires dosing two to three times per
day. e more recent drugs have longer durations of action
allowing for once-daily dosing (e.g. enalapril, ramipril).
Captopril and lisinopril are the only ACE inhibitors
which are not pro-drugs; all others require hepatic
biotransformation to generate the active metabolite.
Factors inuencing the choice of which drug to use will
include coexisting conditions. For example, lisinopril may
be favoured for a patient suering liver impairment, since
this drug does not require hepatic metabolism and, like
most ACE inhibitors, is mainly cleared by the kidney.
e vasoconstrictor action of angiotensin II is crucial to
maintaining adequate glomerular ltration when arterial
blood pressure falls, and so it follows that the use of ACE
inhibitors carries a risk of causing, or worsening, renal
failure. Kidney function should be monitored closely in
patients at risk. ese drugs are contraindicated in
patients with certain types of renal impairment (e.g. renal
artery stenosis). As mentioned above, concomitant use of
NSAIDs may increase the risk of renal damage.
Other factors to be considered in the choice of drug
include its duration of action; long-acting once-daily
preparations have obvious advantages in terms of
adherence.
e most common adverse eect, as already noted, is the
development of a persistent, sometimes intolerable, dry
cough. e accumulation of bradykinin believed to be
responsible for the cough is also thought to underlie
delayed angioedema, or swelling of the face and lips. is
can aect the tongue and airways, when it is potentially
life-threatening. Risk of developing angioedema is about
ve times higher in black people of African or African
Caribbean origin for whom angiotensin II receptor
blockers may be preferred (see below). e rst dose of
ACE inhibitors is often associated with profound
hypotension and consequent dizziness, especially in
patients on diuretics; it is often recommended that the
rst dose is taken at bedtime. Hyperkalaemia may also
result from the reduction in aldosterone secretion and
consequent retention of K+.
Angiotensin II receptor antagonists (ARBs, A2RAs)
Angiotensin II receptor antagonists are also referred to as
angiotensin receptor blockers (ARBs), angiotensin II
receptor antagonists (A2RAs/AIIRAs), and AT1
antagonists. ese orally available drugs are known
collectively as sartans; examples include candesartan,
eprosartan, losartan, olmesartan, and valsartan. e
antihypertensive action of ARBs derives from the
inhibition of the action of angiotensin II at its receptors,
reducing vasoconstriction and stimulation of aldosterone
secretion. ARBs therefore share similarities in clinical
response with ACE inhibitors, both drugs serving to
decrease the eects of angiotensin II. However, ACE is not
the only route by which angiotensin II is formed, and in
some patients ARBs may therefore be more eective than
ACE inhibitors in some patients. ARBs do not aect
bradykinin metabolism and are prescribed as an
alternative where ACE inhibitors are not tolerated. is
may be particularly relevant in the treatment of black
patients of African or African Caribbean descent who are
at greater risk of bradykinin-related angioedema.
Adverse effects of ARBs
Like ACE inhibitors, ARBs have an associated risk of renal
failure and hyperkalaemia, and can also give rise to
rst-dose hypotension. ey similarly interact with
88 Chapter 5 Hypertension
NSAIDs to increase risk of renal failure (see above) and
are contraindicated in patients with certain types of renal
impairment.
Aldosterone antagonists
Aldosterone antagonists (spironolactone and
eplerenone) are the third major class of drugs that
directly modify the RAAS by inhibiting the eects of
aldosterone on Na+ retention and K+ secretion. ese
drugs are therefore potassium-sparing diuretics.
Aldosterone antagonists, however, do not modify the
vasoconstrictor responses elicited by angiotensin II,
which explains why they are not routinely used as
antihypertensives. ey are, though, useful in heart
failure (see Chapter 7).
Renin inhibitors
Inhibiting renin, the rst step in the RAAS, makes sense as
a strategy to control hypertension. Aliskiren was the rst
direct renin inhibitor to be licensed, used alongside ACE
inhibitors and ARBs as an alternative fourth- or fth-line
drug. Reported to give a good blood pressure response in
combination with ACE inhibitors and ARBs, aliskiren may
prove to be a useful class of drug in the management of
hypertension. It may assume a role as an alternative to
ARBs for those patients unable to tolerate ACE inhibitors
because of the persistent dry cough.
e compensatory increase in renin release, which
follows sensing of the drop in blood pressure by the
juxtaglomerular cells in the kidney (see Figure 5.7),
should have less impact on the eectiveness of aliskiren
compared with ACE inhibitors.
Adverse effects and cautions
e use of renin inhibitors has an associated risk of renal
failure, diarrhoea, dizziness, and hyperkalaemia. Use is
contraindicated in renally impaired patients or those with
diabetes mellitus.
5.2.2 Diuretics
Diuretic drugs act by increasing output of urine by the
kidney. Most commonly used in the treatment of
hypertension are the thiazide diuretics, which exert
relatively weak diuretic action by acting on the distal
tubule of the kidney. Here they directly inhibit the
reabsorption of Na+ and Cl– ions from the ltrate by
targeting the Na+/Cl– co-transporter. is promotes the
loss of these ions in the urine and consequently, by
osmosis, an increased volume of water is also excreted.
Stimulating natriuresis (sodium excretion), and the water
loss which follows, is an important mechanism by which
thiazide diuretics have their antihypertensive eect. e
consequences for blood volume and cardiac output can
be deduced from the information presented above.
However, what can also be predicted is that the reduction
in blood volume will be sensed by the juxtaglomerular
cells of the kidney, which will respond with an increase in
renin output. e consequent increase in angiotensin II
activity will therefore counteract the eect of the diuretic
(Figure 5.9). is feedback provides another example of
the complexity of antihypertensive therapy, leading to the
scientic rationale for the use of drug combinations with
more than one site of action.
It should be noted that while thiazides are correctly
classied as diuretics, they also have a benecial direct
vasodilatory eect, the mechanism of which is poorly
understood; this is believed to have an important role in
Distal tubule
lumen
+
Na
Thiazide
diuretics
• Increased renin
• Increased
angiotensin II
Figure 5.9 Thediureticactionofthiazidesleadstoa
compensatory increase in renin output.
Thiazide diuretics act at the distal tubule to increase the amount
of Na+ lost in the urine. This results in reduced blood volume,
which contributes to lowering blood pressure. However, this will
be detected by the renin-secreting cells of the kidney, which
respond by increasing their release of renin (orange box). This in
turn will lead to increased formation of angiotensin II, and a
consequent increase in blood pressure. Thiazide
antihypertensive drugs also have an entirely separate
vasodilatory effect, which may underlie their sustained
therapeutic effect.
Tubule
wall
Increased
Blood
Reduced by
thiazides
Reduced blood
volume
Blood pressure
+
Na
Reduced
5.2 Antihypertensive drugs 89
sustaining their antihypertensive actions by
counteracting the eects of the enhanced angiotensin II
activity mentioned above. With long-term use the
vasodilatory eect persists after the diuretic eect has
diminished, strongly suggesting that this is the major
mechanism through which thiazides achieve sustained
lowering of blood pressure in the clinical context.
e most widely used thiazide diuretics are
bendroumethiazide (bendrouazide) and, with a
slightly longer duration of action, the thiazide-like drugs
chlortalidone and indapamide. All of these drugs are
orally available. Patients are encouraged to take the
once-daily dose early in the day so that the diuretic eect
does not interfere with sleep.
e more powerful loop diuretics (e.g. furosemide) are
not routinely used in hypertension, but may be added to
antihypertensive treatment where blood pressure is
resistant to therapy, or for patients with heart failure (see
Chapter 7). ey are discussed more fully in Chapter 7,
Section 7.5.2.
Adverse effects
e thiazide and thiazide-like diuretics are generally well
tolerated. eir use may be associated with cardiac
arrhythmias through decreases in the plasma levels of Na+
and K+; they should not be used in patients who are
already hyponatraemic or hypokalaemic. Since these
drugs reduce uric acid excretion, they may precipitate
acute attacks of gout. e most common adverse eects
are mild gastrointestinal disturbance and postural
hypotension as well as erectile dysfunction.
5.2.3 Calcium channel blockers
e calcium channel blockers (sometimes referred to as
calcium antagonists) in clinical use can be classied
according to the location of the calcium channels they
aect. In the treatment of hypertension, the drugs used are
those which target the L-type calcium channels, which are
found in both heart and vascular muscle cells. ese drugs
bind to the channel to prevent its opening and so reduce
Ca2+ inux. e eects may be seen at three locations.
• e vascular smooth muscle cells—these drugs cause
vasodilatation widely across vascular beds,
predominantly on the arterial side. is includes the
pre-capillary arterioles which determine peripheral
resistance; therefore vasodilatation leads to reduced
resistance to blood ow.
ere are three kinds of L-type calcium channel blocker
in common clinical use: dihydropyridines,
phenylalkylamines, and benzothiazepines. (e last two
groups are often collectively termed nondihydropyridines.) e main functional dierence
between the groups concerns the selectivity of their
action on the heart or vascular smooth muscle.
Dihydropyridines
Drugs in this class, dened by chemical structure, act
relatively selectively on the vasculature as vasodilators,
explaining why they are the most common choice of
calcium channel blockers in the management of
hypertension. Examples of dihydropyridines include
amlodipine, nifedipine, felodipine, lercanidipine, and
nisoldipine. Since they have little or no action on heart
contractile strength, some of these drugs (e.g. amlodipine
and felodipine) can also be considered for patients with
heart failure (see Chapter 7). Dihydropyridines are useful
for some types of angina (particularly when associated
with coronary artery spasm; see Chapter 6).
In the management of hypertension, the resultant
lowering of blood pressure caused by these drugs can
lead to an adaptive reex increase in cardiac output (e.g.
via baroreceptors and increased sympathetic activity in
the heart). Short-acting preparations of nifedipine, in
particular, are associated with reex tachycardia
(increased heart rate) and large variations in blood
pressure. ey are not recommended for angina or
long-term management of hypertension.
Dihydropyridines are well absorbed following oral
administration and are eliminated by the liver. ey are
most usually given once daily as slow-release
formulations, except amlodipine which has a longer
duration of action.
• e conducting system of the heart—these drugs slow
the conductance of cardiac excitation particularly
across the atrioventricular node.
• e contractile cardiac myocytes—these drugs reduce
the force of contraction.
Non-dihydropyridines
Verapamil is the major phenylalkylamine used in clinical
practice. Of the non-dihydropyridines, this is the most
cardioselective drug. It has distinct cardiac eects,
90 Chapter 5 Hypertension
prolonging the refractory period within the sinoatrial and
atrioventricular nodes, as well as a marked negative
inotropic eect. In addition it has some eects on blood
vessels. Overall, verapamil reduces:
• heart rate
• conduction of the excitation from atria to ventricles
• calcium inux in the ventricular action potential
plateau (reducing force of contraction)
• calcium inux in the vasculature, giving generalized
arterial vasodilatation.
ese combined responses explain the antihypertensive
action of verapamil. Its cardiac eects, however, make it
unsuitable for patients with heart failure, but explain its
usefulness in the treatment of supraventricular
arrhythmias (see Chapter 7). In hypertension it may be
particularly useful in heart attack or angina patients who
cannot be prescribed -blockers, for example because
they are asthmatic. Verapamil is available in slow-release
form to be taken once daily.
Diltiazem represents the class of benzothiazepines. is
drug is orally available for the treatment of hypertension,
particularly as slow-release preparations. Its eects are
predominantly exerted on cardiac calcium channels, but
those in the vasculature are also aected. e eects on
heart rate are not as marked as for verapamil, but it does
extend the refractory period within the sinoatrial and
atrioventricular nodes. is, combined with peripheral
vasodilatation, reduces the workload, and therefore the
oxygen demand, of the heart. is explains its use in the
management of angina (Chapter 6). Like verapamil,
diltiazem is used in the treatment of supraventricular
arrhythmias including atrial brillation (see Chapter 7).
Neither verapamil nor diltiazem should be prescribed
together with -blockers, as the combined negative
chronotropic and inotropic eects may precipitate heart
failure.
Adverse effects
Calcium channel blockers are generally well tolerated.
eir possible side eects are mainly predictable,
deriving from their mechanism of action. For
dihydropyridines they include ushing and headache in
the short-term, and ankle swelling with longer use. eir
use can also result in compensatory tachycardia, as
mentioned above. e adverse eects for drugs
interfering with cardiac channels include bradycardia,
heart block, and cardiac failure. In addition, verapamil is
associated with constipation.
5.2.4 1-Adrenoceptor antagonists
1-Adrenoceptors are widespread on vascular smooth
muscle cells (see Section 5.1.4); stimulation of these
receptors by noradrenaline and adrenaline leads to
vasoconstriction, generating normal vascular tone that
maintains the peripheral resistance necessary to generate
an arterial blood pressure that can eectively perfuse our
tissues. is is known as sympathetic tone. In addition,
noradrenaline released from the local sympathetic
terminals undergoes rapid uctuations in response to
demand. For example, when standing up from a lying
position peripheral resistance in the viscera is increased
so as to maintain blood ow to the brain. Similar rapid
adaptive responses are seen in the ght-or-ight scenario
described in Section 5.1.4, when the eects of
noradrenaline are supplemented by those of the hormone
adrenaline, acting on the same receptors.
Drugs that act as competitive antagonists at 1adrenoceptors reduce peripheral resistance and
therefore, not surprisingly, have a place in the treatment
of hypertension. Two issues are relevant to understanding
the usefulness, and limitations, of these drugs as
antihypertensive agents.
• A reduction in blood pressure brought about by an
1-antagonist will be detected by baroreceptors
(Figure 5.8), leading to a compensatory increase in
release of noradrenaline from the sympathetic nervous
system. is will reduce the eectiveness of the
competitive antagonist by increased competition with
noradrenaline for vascular 1-adrenoceptors. In
addition, -adrenoceptors in the heart will be
stimulated by the increased sympathetic activity, which
increases cardiac output. is will tend towards a reex
restoration of the blood pressure and explains why
blood pressure cannot simply be titrated down with an
1-adrenoceptor antagonist. As a consequence these
drugs are normally taken in combination with other
antihypertensives (see below). eir use is generally
restricted to add-on therapy in cases of resistant
hypertension.
• 1-Adrenoceptor antagonists do not act at the 2-
adrenoceptors that are located presynaptically at
noradrenergic nerve terminals. Noradrenaline can
therefore still act at these presynaptic receptors to
5.2 Antihypertensive drugs 91
inhibit the further release of noradrenaline. Nonselective -adrenoceptor antagonists, which act on
both 1 and 2 subtypes, will block this presynaptic
inhibition, thereby enhancing noradrenaline release.
is will enhance the reex tachycardia associated with
agents that lower blood pressure. e 1-adrenoceptor
selective agents are therefore generally preferred for the
treatment of commonly presenting hypertension.
1-Adrenoceptor antagonists used for hypertension
include doxazosin, prazosin, terazosin, and indoramin.
is type of drug is also used in the treatment of benign
prostatic hyperplasia, in which prostate enlargement
leads to obstruction of the urethra and diculty
urinating. Relaxation of smooth muscle of the prostate
and bladder neck, brought about by 1-adrenoceptor
antagonists, can help improve the ow rate of urine.
e very potent non-selective (1 and 2) antagonists
phenoxybenzamine and phentolamine are used in the
treatment of the very rare cases of hypertension caused by
tumours of the adrenal medulla (phaeochromocytoma).
Phenoxybenzamine binds irreversibly to its receptor
targets, and therefore has a long duration of action but
also many associated side eects. Phentolamine is
shorter acting.
A common unwanted eect of all these drugs is postural
hypotension (leading to dizziness on standing).
5.2.5 -Adrenoceptor antagonists
Commonly referred to as -blockers, this widely used
class of drugs has in the past been the mainstay of
antihypertensive therapy. However, in some parts of the
world -blockers are no longer routinely prescribed to
newly presenting hypertensive patients (see the strategy
set out below). Despite this, because there are many
patients for whom -blockers were prescribed and whose
blood pressure was controlled by them, these drugs will
remain common in the treatment of hypertension for a
considerable time to come. For other patients there is a
particular reason for using them (see below). In addition
they are important medications for the treatment of other
conditions, notably angina, myocardial infarction,
arrhythmias, and heart failure (see later chapters).
Mode of action
In Section 5.1 we mentioned the prevalence of 1adrenoceptors in the heart, stimulation of which leads to
increased heart rate and force of contraction, increasing
cardiac output and therefore blood pressure. At rst sight,
therefore, it seems that the antihypertensive action of
-blockers, competitive antagonists for -adrenoceptors,
is simple—a reduction in cardiac output. However, such a
drop in blood pressure will be sensed by baroreceptors
(Section 5.1.5) which will mediate feedback, leading to
increased sympathetic activity. e increased
noradrenaline released will directly compete with the
-blocker for occupation of the 1-adrenoceptors.
Combined with additional feedback mechanisms, this
will tend towards restoring blood pressure even in the
continued presence of the drug. It would appear that
there must be a broader explanation for the
antihypertensive action of -blockers. e overall
mechanism is incompletely understood, but includes
combined actions:
• at the heart to reduce cardiac output
• at the kidney to reduce renin release (by inhibition of
the -receptors on the juxtaglomerular cells—Section
5.1.4 and Box 5.1)
• in the brain, where the eect is to reduce the activity of
the sympathetic nervous system, reducing the release
of noradrenaline to act at the -receptors.
It is notable that the major eects of -adrenoceptor
antagonists are seen when sympathetic activity is high
(e.g. physical activity, stress). Understandably, therefore,
the argument for using these drugs is strongest in patients
where excess sympathetic activity contributes most to
their hypertension (patients with high sympathetic tone).
Not all -adrenoceptor antagonists are the same ere
are a large number of -adrenoceptor antagonists from
which a prescriber must choose the most appropriate for
each individual. Signicant dierences are to be found in
selectivity between - and -adrenoceptors and between
-adrenoceptor subtypes. ere are also -blockers
which exert their antagonistic eect by acting as partial
agonists (see Chapter 2, Section 2.1.3).
1- and 2-subtype selectivity of -adrenoceptor
antagonists e early -adrenoceptor antagonist
propranolol is equally eective at both 1- and 2-
subtypes. is is of particular clinical importance for
asthmatic patients, since stimulation of 2-adrenoceptors
on bronchiolar smooth muscle helps to keep airways
open—antagonists at these 2-receptors may precipitate
bronchospasm, which can be life-threatening (see
Chapter 11). In addition, -adrenoceptor antagonists will
counteract the eect of the 2-receptor agonist used for