Β-Blockers Angiotensin Converting Enzyme Inhibitors Angiotensin Receptor Blockers And Ca2+ Channel Blockers - pediagenosis
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Β-Blockers Angiotensin Converting Enzyme Inhibitors Angiotensin Receptor Blockers And Ca2+ Channel Blockers

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-Adrenoceptor antagonists (β-blockers)
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.

Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers
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.
 Propranolol, a ‘first generation’ β-blocker, acts on both β1 and β2-receptors, whereas second generation β-blockers (e.g. atenolol, metoprolol, bisoprolol) selectively antagonize β1-receptors. Third generation β-blockers also cause vasodilatation; for example, carvidelol does this by blocking α

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