Β-Blockers, Angiotensin Converting
Enzyme Inhibitors, Angiotensin Receptor Blockers And Ca2+ Channel Blockers
The
four classes of drugs described in this chapter each stand out as being useful
in treating multiple disorders of the cardiovascular system. Core aspects of
their mechanisms of action and properties are described here and further
details on their use are presented in the chapters dealing specifically with
the disorder.
β-Blockers are used to treat angina, cardiac
arrhythmias, myocardial infarction and chronic heart failure. Once a first line
treatment for hypertension, they are now used only in combination with other
antihypertensive drugs if these fail to lower blood pressure sufficiently.
Their usefulness derives mainly from their blockade of cardiac β1-receptors
(Figure 35). When stimulated by noradrenaline released from sympathetic nerves,
and by blood-borne adrenaline, these receptors increase the rate and force of
cardiac contraction, thereby increasing the output, work and O2
requirement of the heart. Although these responses are important for the normal
physiological response to stress, they have the undesirable effect of promoting
cardiac ischaemia and its downstream effects if coronary blood flow is
compromised by atherosclerotic stenosis or thrombosis (see Chapters 40 and 45).
Activation of β1-receptors also increases atrioventricular (AV) nodal conduction
and the excitability of the heart, effects that can sometimes cause or promote
cardiac arrhythmias (see Chapters 48 and 51). Chronic activation of the
sympathetic system, as in congestive heart failure, causes cardiac fibrosis and
remodelling, leading to a progressive deterioration of cardiac function and
increasing the occurrence of life-threatening arrhythmias (see Chapters 46 and
48).
β-Blockers have additional useful effects. Importantly,
renal afferent arterioles contain renin-producing granular cells which
are stimulated by sympathetic nerves to release renin via their β1-
receptors. Thus, the renin–angiotensin–aldosterone (RAA) axis (see Chapter 29)
can be stimulated by the sympathetic system, an effect that β-blockers inhibit.
β-Blockers also decrease the release of noadrenaline from sympathetic nerves by
inhibiting presynaptic β-receptors on sympathetic varicosities that act to
facilitate its release. oxide. Pindolol belongs to a fourth group of β-blockers with intrinsic
sympathomimetic activity; it antagonizes β1-receptors but stimulates
β2-receptors, thereby causing vasodilatation. Although in all cases
the main therapeutic effect of these drugs lies in their effect on β1-receptors,
these various properties, as well as differences between β-blockers with
respect to their pharmacokinetics and adverse effects (see below) mean that
specific β-blockers may be more or less appropriate for individual patients.
Adverse effects of β-blockers as a class include exercise intolerance, as well
as excessive bradycardia and negative inotropy, all due to their cardiosuppressive
effects. Their block of vascular β-receptors, which promote blood flow to
skeletal muscle by causing vasodilatation, can also cause fatigue and cold or
tingling extremities. β-Blockers also can cause bronchospasm, and are contraindicated
in asthma. These drugs can also have the potentially dangerous effect of masking the
perception of hypoglycaemia in diabetics.
The RAA system, acting through its effectors angiotensin
II and aldosterone, has a crucial role in conserving body Na+ and fluid, thereby acting to maintain blood volume and
pressure (see Chapter 29). However, even this normal functioning of the RAA
system contributes to raised blood pressure in many hypertensives (see Chapter
39), and abnormal activation of this system in those with heart failure (see
Chapter 46) leads to additional adverse effects shown in the lower part of
Figure 35. Angiotensin II also enhances sympathetic neurotransmission by
promoting noradrenaline release and by stimulating the CNS to increase
sympathetic drive, leading to further increases in blood pressure. The activity
of angiotensin II can be suppressed either with angiotensin-converting enzyme
inhibitors (ACEI), which block its synthesis by ACE (see Chapter 29), or by
angiotensin II receptor blockers (ARBs) that inhibit its action at AT1
receptors, which mediate its various deleterious effects.
Because both block RAA system function, ACEI and ARBs
suppress the various vasoconstricting effects of angiotensin II on the
vasculature, thereby reducing total peripheral resistance and blood pressure.
Both also cause natriuresis and diuresis which contribute to their blood
pressure lowering effects and also help to reverse the pulmonary and systemic
oedema and cardiac remodelling which contribute to the symptoms and progression
of chronic heart failure. ACEI have the additional effect of preventing the
breakdown of the peptide bradykinin, which is synthesized in the plasma
by ACE and causes vasodilatation by releasing nitric oxide, prostacyclin and
endothelium-derived hyperpolarizing factor (EDHF) from the endothelium.
Increases in bradykinin may contribute to the ability of ACEI to reduce blood
pressure and possibly to prevent cardiac remodelling, but may also cause the
chronic cough that ACEI evoke in ∼10% of people. ARBs differ from ACEI in that they do not increase
bradykinin, and also in that they may cause a greater functional suppression of
the RAA system because ACEI do not block chymase, another enzyme that
synthesizes angiotensin II. Excepting the fact that ARBs cause less cough than
do ACEI, the extent to which these mechanistic differences between the two
types of drug are therapeutically relevant remains to be fully elucidated. At
present, both ACEI and ARBs are used to treat hypertension, heart failure,
myocar- dial infarction, and to protect against renal complications in
diabetes.
The vast majority of ACEI (e.g. enalopril, ramopril,
trandolapril; Class II) are taken orally as inactive prodrugs which,
being lipophilic, are processed in the liver to produce an active metabolite
(e.g. enalopril yields enaloprilat). Captopril (Class 1), the
oldest ACEI, is itself active, but is also acted on by the liver to give active
metabolites. Lisinopril (Class III) is active and, being water soluble,
is excreted by the kidneys rather than being metabolized in the liver. Examples
of ARBs include losartan and candesartan. Apart from cough, ACEI
and ARBs share common contraindications and side effects. They should not be
used by pregnant women because they retard fetal growth, or by those with
bilateral renal stenosis, because in these individuals decreased renal blood
flow typically leads to a powerful activation of the RAA system which is
crucial for maintaining glomerular filtration. Because they diminish levels of
aldosterone, which promotes renal K+ excretion, both also can elevate the plasma K+
concentration (hyperkalaemia).
Ca2+ channel blockers
Ca2+ channel blockers (CCBs) inhibit
the influx of Ca2+ into cells through L-type Ca2+
channels. The interaction of blocker and Ca2+ channel is best
understood for the dihydropyridines (DHPs), which include nifedipine,
amlodipine and felodipine. The affinity of DHPs for the channel
increases enormously when the channel is in its inactivated state (see
Chapter 10). Channel inactivation is favoured by a less negative membrane
potential (Em). DHPs therefore have a relatively selective effect on
vascular muscle (Em ∼–50) compared
with cardiac muscle (Em ∼–90). This functional selectivity is further enhanced because
DHP-mediated vasodilatation stimulates the baroreceptor reflex and increases
sympathetic drive, overcoming any direct negative inotropic effects of these
drugs. If rapid, such sympathetic activation is thought to lead to cardiac
ischaemia and unstable angina, and therefore the DHPs in current use have a
slow onset and prolonged effect.
The phenylalkylamine verapamil interacts
preferentially with the channel in its open state. Verapamil binding is
therefore less dependent on Em; thus both cardiac and vascular Ca2+
channels are blocked. In addition to its vasodilating properties, verapamil
therefore has negative inotropic effects and severely depresses AV nodal
conduction. The benzothiazepine diltiazem has similar properties; at
therapeutic doses it vasodilates but also depresses AV conduction and has
negative inotropic/chronotropic effects.
The DHPs are currently first line agents for treating
hypertension (see Chapter 38) and also all forms of angina pectoris (see
Chapters 40 and 41). The non-DHPs (verapamil and diltiazem) are also used for
these conditions, and are additionally used for supraventricular cardiac
arrhythmias, based on their ability to suppress AV nodal conduction (see
Chapters 49 and 51). Adverse effects of the DHPs are due to their profound
vasodilating properties, and include headache, flushing and oedema. The
non-DHPs can cause powerful negative inotropic and chronotropic effects, pamil can
cause constipation.
