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Chapter 11 Cardiology

Angiotensin-Converting Enzyme Inhibitors (ACEIs)

Description

Inhibitors of the angiotensin-converting enzyme (ACE)

Prototype and Common Drugs

image Prototype: captopril
image Others: ramipril, enalapril, fosinopril, lisinopril, perindopril, quinapril, benazepril, cilazapril

MOA (Mechanism of Action)

image ACE performs two functions:

image Catalyzing the conversion of angiotensin I to angiotensin II
image Breaking down bradykinin

image Through inhibition of ACE with an ACEI, the following effects occur:

1 Lower levels of angiotensin II are produced.

• Angiotensin II is a direct vasoconstrictor.
• Angiotensin II results in aldosterone secretion, which causes Na and water reabsorption in the kidney.

2 Higher levels of bradykinin are produced.

• Bradykinin is a vasodilator.

image Net result: Because angiotensin II levels are lower and bradykinin levels are higher, there is more vasodilation; SVR (systemic vascular resistance) and afterload are lowered. Because aldosterone levels are lower, less Na and water are reabsorbed in the kidney; therefore preload is reduced (Figure 11-1).
image

Figure 11-1

Pharmacokinetics

image Most ACEIs are cleared predominantly by the kidneys. Dose adjustment should be considered in renal impairment.
image With the exception of captopril, all ACEIs have intermediate (12 to 24 hours) durations of action and thus have the advantage of once-daily administration. The duration of action of captopril is shorter (6 to 12 hours); therefore it is given two or three times daily.

Indications

image Hypertension (HTN)
image Chronic congestive heart failure (CHF)
image After myocardial infarction (MI)

Contraindications

image Pregnancy: During the second and third trimesters, the teratogenic effects are thought to be caused in part by fetal hypotension.
image Renal dysfunction: See side effects.

Side Effects

image Dry cough: Attributed to increased bradykinin levels. Can be persistent enough to affect compliance and may lead to discontinuation.
image Hyperkalemia: Particularly in combination with K+-sparing diuretics. Hyperkalemia occurs via the reduction in aldosterone but is usually clinically significant only with the addition of oral K+ or in patients with renal dysfunction.
image Hypotension: Caused by vasodilation from lower levels of angiotensin II. Patients with ventricular dysfunction (low ejection fraction) are at greater risk.
image Renal dysfunction: Angiotensin II plays an important role in maintaining glomerular filtration rate (GFR) by constricting the efferent (outgoing) arteriole of the glomerulus. This is particularly important when the blood flow to the kidneys has been compromised. ACEIs cause vasodilation of the efferent arteriole. This decreases the glomerular pressure and reduces GFR. Volume depletion amplifies this effect.
image Angioedema: A rare but serious adverse effect, often attributed to the increased bradykinin levels, although a definitive mechanism has not been established. Angioedema is edema caused by pathologically leaky blood vessels. It can cause swollen lips or tongue, and death can also result from airway obstruction.

Important Notes

image The renin-angiotensin system (RAS) plays an important role in the body’s compensation for a failing heart. Activation of the sympathetic nervous system (SNS) leads to the release of renin, which in turn increases vascular tone and sodium and water retention.
image ACEIs might be of particular use in the management of HTN in the diabetic patient, as they may delay the development of diabetic nephropathy. This is primarily because of a reduction in intraglomerular pressure, through relaxation of the efferent arteriole and the overall reduction in systemic blood pressure (BP).

Advanced

image In addition to the beneficial effects of RAS inhibitors in diabetic nephropathy, there is emerging evidence that RAS inhibitors may reduce the incidence of new-onset diabetes. Potential mechanisms for this effect include improvements in blood flow that improve the delivery of insulin and glucose to skeletal muscle, as well as effects on glucose transport and insulin signaling. If this preventative effect of RAS inhibition in diabetes becomes established, it could change the way these agents are used.
image ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) was a large (approximately 8500 patients per arm), long-term (median follow-up of 56 months) study comparing an angiotensin-receptor blocker (ARB), an ACEI, and a combination of the two in patients with vascular disease or high-risk diabetes. The study found that the combination of ARB and ACEI failed to demonstrate benefit versus either agent alone, with an increased incidence of adverse events in this population.

Evidence

Hypertension

image A 2009 Cochrane review (24 trials, N = 58,040 participants) compared benefits and harms of first-line antihypertensives with those of placebo or no treatment over a minimum of 1 year in patients with hypertension. ACEIs (three trials) reduced mortality (relative risk [RR] 0.83), stroke (RR 0.65), coronary heart disease (RR 0.81), and cardiovascular events (RR 0.76).

FYI Notes

image It has yet to be shown that any one ACEI is significantly superior to another.
image Brady means slow (e.g., bradycardia). Bradykinin is so named because it causes slow contractions of the gastrointestinal (GI) tract.
image Bradykinin is also implicated in the edema that accompanies sepsis, allergic reactions, and carcinoid syndrome. Angioedema is associated with a deficiency of C1 esterase, an enzyme that cleaves bradykinin.
image Several ACEIs are available in fixed-dose combinations with hydrochlorothiazide.

Angiotensin Receptor Blockers (ARBs)

Description

ARBs antagonize the angiotensin receptor.

Prototype and Common Drugs

image Prototype: losartan
image Others: candesartan, irbesartan, valsartan, eprosartan, telmisartan

MOA (Mechanism of Action)

image ARBs are antagonists of the angiotensin-1 (AT1) receptor. Therefore they block the actions of angiotensin II.
image Angiotensin II is a vasoactive hormone that induces vasoconstriction and stimulates the secretion of aldosterone by the adrenal cortex, which results in sodium and water retention.
image Blocking AT1 results in vasodilation, natriuresis (renal loss of sodium), and diuresis (renal loss of water).
image Effects of ARBs are downstream of ACE.
image ACEIs block the degradation of bradykinins. ARBs have no effect on bradykinin levels. Because bradykinins are vasodilators, ARBs might not produce as much vasodilation as ACEIs.
image Conversely, ACE is not the only enzyme that forms angiotensin II. Thus ARBs might provide more complete inhibition of the vasopressor activity of angiotensin II compared with ACEIs (Figure 11-2).
image

Figure 11-2

Pharmacokinetics

image All ARBs have intermediate (12 to 24 hour) half-lives and thus provide the advantage of once-daily dosing.
image Losartan has an active metabolite (EXP 3174) that is a more potent inhibitor of the AT1 receptor than the parent drug.

Indications

image Hypertension (HTN)
image Chronic congestive heart failure (CHF)
image For patients who require an ACEI but cannot tolerate it because of cough

Contraindication

image Pregnancy, because of teratogenicity

Side Effects

image ARBs are well tolerated.
image The most common side effects are dizziness and hypotension.
image Hyperkalemia (high potassium) can occur when combined with K+ supplements or K+-sparing diuretics.
image Renal failure can occur in patients whose renal function is marginal or highly dependent on the RAS, because of the same mechanism seen with ACEIs.
image Angioedema occurs less often than with the ACEIs.

Important Notes

image Perhaps because of the lack of increased bradykinin levels, ARBs are not typically associated with the side effect of cough, which can be a significant limitation to the use of ACEIs.
image The mechanism behind the cough has not been established.

Advanced

image In addition to the beneficial effects of RAS inhibitors in diabetic nephropathy, there is emerging evidence that RAS inhibitors may reduce the incidence of new-onset diabetes. Potential mechanisms for this effect include improvements in blood flow that improve the delivery of insulin and glucose to skeletal muscle, as well as effects on glucose transport and insulin signaling. If this preventative effect of RAS inhibition in diabetes becomes established, it could change the way these agents are used.
image ACEIs reduce the effect of both AT1 and AT2 receptors by lowering levels of angiotensin II; only AT1 receptors are inhibited by ARBs. Chronic stimulation of the AT2 receptor may be beneficial in providing neuroprotection in older patients with HTN and thus could mean that ARBs have a potential advantage in this patient subset.
image ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) was a large (approximately 8500 patients per arm), long-term (median follow-up of 56 months) study comparing an ARB, an ACEI, and a combination of the two in patients with vascular disease or high-risk diabetes. The study found that the combination of ARB and ACEI failed to demonstrate benefit versus either agent alone, with an increased incidence of adverse events in this population.

Pharmacogenetics

image People of African descent have a smaller average BP response to ARBs.

Evidence

Hypertension

image A 2009 Cochrane review (24 trials, N = 58,040 participants) compared benefits and harms of first-line antihypertensives with those of placebo or no treatment over a minimum of 1 year. No studies were found that included ARBs.

FYI Notes

image All ARBs except eprosartan (the newest ARB) are also available in combination (i.e., same pill, two drugs) with hydrochlorothiazide.
image Candesartan is actually candesartan cilexetil, a prodrug that is hydrolyzed to the active form, candesartan, during absorption from the GI tract.

Direct Renin Inhibitors

Description

Agents that directly inhibit renin, an enzyme in the RAS

Prototype and Common Drugs

image Prototype: aliskiren

MOA (Mechanism of Action)

image Renin is an enzyme released from the kidneys that converts angiotensinogen to angiotensin I. It is considered to be the rate-limiting step in the eventual formation of angiotensin II.
image Renin and its inactive precursor, prorenin, are stored in the juxtaglomerular cells of the kidney. Renin is released in response to three different stimuli:

image Change in Na and Cl reabsorption at the macula densa
image Change in BP (via the baroreceptor pathway)
image β1-receptor stimulation

image Angiotensin II performs two main functions via the AT1 receptor:

image Direct vasoconstriction
image Stimulation of aldosterone secretion which leads to Na+ and H2O reabsorption

image Other agents that target the RAS, such as the ACEIs and ARBs, elicit a compensatory increase in plasma renin activity, resulting in increased binding of angiotensin II to AT1 receptors and other AT receptors.
image It is not yet clear what the implications are of activating these other AT receptors.
image Therefore, one potential advantage of renin antagonists over ACEIs and ARBs is avoiding the compensatory increase in the RAS. It is yet to be established whether these theoretical advantages translate into clinically meaningful advantages (Figure 11-3).
image

Figure 11-3

Pharmacokinetics

image The elimination half-life of aliskiren is approximately 40 hours, meaning that it is administered once daily.

Indications

image HTN
image Chronic congestive heart failure (currently being investigated)

Contraindication

image Pregnancy: As with other agents that act in the RAS, renin antagonists are contraindicated in pregnancy.

Side Effects

image Generally well tolerated.
image Diarrhea: mechanism not established.
image Angioedema (rare): swelling of face and neck. This side effect also rarely occurs with ACEIs.

Important Notes

image Angiotensin II binding at the AT1 is also believed to have several other less well-defined effects:

image Possible contribution to the generation of reactive oxygen species
image Endothelial dysfunction
image Mitogenic effects that may further contribute to endothelial disease (and thus vascular disease)

Evidence

Blood-Pressure Lowering Efficacy versus Placebo

image A 2008 Cochrane review (six trials, 3694 participants) compared the blood-pressure–lowering efficacy of renin inhibitors versus placebo in primary HTN. The authors found that aliskiren elicits a dose-dependent reduction in both systolic and diastolic pressure similar to that seen with ACEIs or ARBs. In the included trials, aliskiren did not increase withdrawals due to adverse events versus placebo.

FYI Notes

image Renin was first identified in 1898, when it was extracted from kidneys and discovered to have pressor properties. It would be another 40 years before it was determined that renin was an enzyme that catalyzed the formation of a pressor substance (angiotensin II), rather than being the pressor itself.
image Although renin inhibitors were considered to be the most obvious target for inhibition of the RAS, it took several decades to develop the first direct renin inhibitor. Two main hurdles were finding an agent with sufficient bioavailability and an agent with high affinity for the active site of the renin enzyme.
image Early renin inhibitors were all peptides and therefore were unsuitable for oral administration. Given that all commonly used antihypertensives are delivered via the oral route, renin inhibitors were not considered feasible until a nonpeptide, oral version could be developed.

Sodium Channel Blockers (Class I Antiarrhythmics)

Description

Na channel blockers are Vaughan Williams class I antiarrhythmics. There are three subclasses: Ia, Ib, and Ic. The use of Na channel blockers as local anesthetics is discussed in the discussion of local anesthetics in Chapter 21.

Prototypes

image Class Ia: procainamide, disopyramide, and quinidine
image Class Ib: lidocaine
image Class Ic: propafenone and flecainide

MOA (Mechanism of Action)

image Na channels are blocked, so Na ion movement during phase 0 of the action potential is inhibited. The result is a “slow” phase 0, which results in a wider (and slower) QRS wave on the electrocardiogram (ECG). The net result is slower conduction (Figure 11-4).
image Phase 3 can be longer or shorter, depending on the subclass (a, b, or c). This is omitted in the diagram for simplicity.
image Changing the duration of the action potential (not shown in diagram) influences the QT interval (distance from the QRS to the T wave). This distance can be thought of as the refractory period of the ECG. Therefore changing the action potential durations will change the refractory times of atrial, Purkinje or ventricular tissues.
image Because abnormal electrical circuits require a delicate balance between conduction speed and refractory times, changing these parameters will sometimes terminate dysrhythmias or create new ones.
image

Figure 11-4

Specific Differences Among the Subclasses (Table 11-1)

Class Ia

image Moderate slowing of phase 0 (medium Na blockade)
image Action potential duration is longer, therefore longer QT interval on the ECG

TABLE 11-1 Sodium Channel Blocker Summary Chart

image

Class Ib

image Minimal slowing of phase 0 (least Na blockade)
image Action potential duration is shorter, therefore shorter QT interval
image Because of the weak Na blockade:

image The agents basically act only on diseased or ischemic tissue
image They have basically no effect on atrial tissue

Class Ic

image Maximal slowing of phase 0 (greatest Na blockade)
image Action potential duration essentially unchanged
image Most pronounced slowing of phase 0 in all cardiac tissues; therefore:

image Can inhibit the slow Na channels of the atrioventricular (AV) node and therefore can prolong the AV node refractory period and thus prolong the PR interval

Pharmacokinetics

image Quinidine interacts with digoxin (CP450). This can result in increased levels of digoxin, a toxic drug with a narrow therapeutic index. Both drugs are antiarrhythmic drugs and have the potential to be coadministered.
image Lidocaine has a very short half-life (about 20 minutes) and is administered intravenously, because of a large first-pass metabolism effect.

Contraindications

image Class Ic antiarrhythmics increase mortality in infarct- and ischemia-related dysrhythmias; therefore they are not used in these settings. They also increase mortality in patients with poor left ventricular function (decreased ejection fraction).

Side Effects

image Proarrhythmic: As with all antiarrhythmics, changing the delicate balance of conduction speed and refractory times might provoke another area of the conducting system into developing a dysrhythmia.
image Nervous system dysfunction: Na channels are required for nerve function. Numbness and tingling of the lips and tongue, ringing in the ear, inappropriate behavior, decreased consciousness, and seizures can all occur.
image Nausea and vomiting may occur.

Important Notes

image Procainamide and lidocaine are used on crash carts for cardiac arrest resuscitation. They are used for ventricular fibrillation and ventricular tachycardia but have been mostly replaced by amiodarone as the first-line drug used for ventricular fibrillation and ventricular tachycardia.

Evidence

image Atrial fibrillation and prevention of recurrence: A Cochrane review in 2007 (45 studies, 12,559 patients) evaluated the efficacy and safety of multiple different antiarrhythmics in patients who had previously experienced atrial fibrillation (a very common arrhythmia). Class Ia antiarrhythmics were associated with increased mortality compared with controls (odds ratio [OR] 2.39; number needed to harm [NNH] 109). Class Ia and Ic were associated with reduced occurrences of atrial fibrillation (OR 0.19 to 0.6). There were many withdrawals from treatment because of side effects for all antiarrhythmics (NNH 17 to 36).

FYI Notes

image Lidocaine is most commonly used as a local anesthetic.
image Class Ia drugs work fast and can be remembered by the acronym PDQ (pretty darn quick) for procainamide, disopyramide, and quinidine.

β Antagonists (β-Blockers)

Description

β-Blockers antagonize β receptors of the SNS.

Prototype and Common Drugs

image Propranolol
image β-Blockers are a heterogeneous family and can be subclassified according to the receptors they antagonize (it is important to know which are β1 selective):

image Cardioselective (β1): atenolol, metoprolol, nebivolol, esmolol
image Noncardioselective (β1, β2): propranolol, nadolol, timolol
image Mixed α and β: labetolol, carvedolol
image Partial agonists (stimulate mildly when receptor is inactive, inhibit when active): pindolol, acebutolol

image Selectivity is relative. This means that β1-selective blockers will block β2 receptors, but to a much lower degree than nonselective β-blockers.

MOA (Mechanism of Action)

To understand β-blockers, you must understand the effects of the adrenergic system and which effects are mediated via β receptors. β-Blockers competitively antagonize the action of catecholamines at β receptors. There are many cardiac and noncardiac consequences of β-blockade. More details on the autonomic nervous system are described in Chapter 3.

Hypertension

image Antagonism of β1 receptors results in reductions in heart rate (HR) and stroke volume (SV). Recall:

image

image Cardiac output (CO) is therefore reduced, which leads to a reduction in BP. Recall:

image

where SVR = systemic vascular resistance.

image In addition, β1 antagonism leads to a reduction in renin secretion, which in turn reduces production of angiotensin II, a hormone that induces vasoconstriction and, via aldosterone, sodium retention.
image The utility of β-blockers in myocardial ischemia and infarction results from their ability to reduce HR and contractility and therefore lower O2 demand. They have also proven useful after a MI for the same reason, reducing the workload of the heart.
image β-Blockers also have direct inhibitory effects on the SNS.
image Mixed α and β antagonists will additionally cause vasodilation via α-blockade.

Tachycardia and Arrhythmia

The properties of β-blockers that make them antitachycardics include the following:

1 Depression of the sinoatrial (SA) node (slows automaticity)

image Catecholamine β1 stimulation results in an increase in the slow Na+ current (If) of the action potential phase 4 in the SA node. This results in a faster rising (and shorter) phase 4, a shorter time to the next heartbeat, and thus a faster HR. β-Blockers will oppose this action, slowing the SA pacemaker rate.
image This mechanism is useful in sinus tachycardia only.

2 Depression of the AV node (prolongs the refractory period)

image Same mechanism as SA node: a decrease in the slow Na+ current (If) leaves the AV node in a refractory state longer.
image This mechanism is useful in making the AV node a protector of the ventricles. In situations (atrial fibrillation and atrial flutter) in which the AV node is bombarded by electrical signals from the atria, the depressed AV node can permit only a fraction of these signals to enter into the ventricular conducting system, controlling the ventricular rate.
image This mechanism may also be able to terminate a reentry circuit that involves the AV node.
image This mechanism can result in a long PR interval and first-degree AV block.

3 Prevention of after-depolarizations

image After-depolarizations can produce premature ventricular contractions (PVCs), which can deteriorate into ventricular tachycardia or ventricular fibrillation.

4 Membrane stabilization

image This is probably not a significant mechanism; however, it is frequently described.
image Some of the β-blockers are designated as having membrane-stabilizing properties.
image Membrane stabilization is mediated through Na+ channel blockade (class I antiarrhythmic effect).

5 Special antiarrhythmic β-blockers include the following:

image Sotalol:

• Also has class III properties (and often is listed as a class III drug)
• Prolongs the action potential and thus atrial and ventricular refractoriness
• Used for ventricular tachycardia (other β-blockers are not) because it can influence ventricular refractoriness

image Acebutolol:

• Also has class I properties
• Used for PVC suppression

Myocardial Ischemia and Infarction

image One of the main cornerstones of treating myocardial ischemia and infarction is to increase oxygen supply to and decrease oxygen demand of the myocardium. β-Blockers result in the following:

image Slower HR = less work = lower oxygen demand
image Slower HR = longer diastolic time = more time for myocardial perfusion (which occurs only during diastole)
image Lower contractility = less work = lower oxygen demand
image Lower BP = less work = lower oxygen demand

Chronic Congestive Heart Failure

image Patients with a dysfunctional cardiovascular system have an inefficient system and thus require extra support; this support is in the form of increased levels of SNS activation, renin-angiotensin activity, endothelin activity, and many other compensatory mechanisms.
image Sustained activation of the SNS results in fibrosis and apoptosis of myocytes. Through low level blockade of the SNS, the fibrosis and apoptosis (and other damaging mechanisms) are slowed or inhibited.
image Unfortunately, the long-term (years) gain of using β-blockers in heart failure is often counterbalanced by the short-term (months) worsening of symptoms, and therefore β-blocker titration in chronic heart failure must be made carefully and judiciously.

Pharmacokinetics

image Shorter half-lives (3 to 4 hours): propranolol, metoprolol (sustained-release forms with longer half-lives are available)
image Long(er) half-lives (10 to 20 hours): nadolol (longest), atenolol
image Distribution to the central nervous system (CNS) has been implicated as a source of drug-induced confusion with some β-blockers. Specifically, metoprolol is lipid soluble and therefore crosses the blood-brain barrier, whereas atenolol, another selective β1 blocker does not.
image Esmolol is designed to be broken down by esterases and therefore has a very short half-life of 9 minutes. It is given only intravenously as a single bolus for short-term HR or BP control or as an infusion.

Indications

image HTN
image Chronic congestive heart failure

image After MI (a damaged heart is a risk for CHF)

image Tachyarrhythmias

image Sinus tachycardia

• Hyperthyroidism
• Cocaine abuse
• Pheochromocytoma (adrenaline secreting tumor—very rare)

image Atrial fibrillation and atrial flutter
image Prevention of ventricular tachycardia and ventricular fibrillation

image Angina and MI
image Noncardiac indications

image Migraine prevention, public speaking, anxiety, glaucoma (eye drops), tremor

Contraindications

image Asthmatics should not use nonselective (β1, β2) β-blockers, as blocking β2 receptors may lead to bronchoconstriction. Stimulation of β2 receptors in the airways causes smooth muscle relaxation of the bronchioles and is the basis of bronchodilators that are β2 agonists.

image Cardioselective β1-blockers are usually safe in asthmatics, but some patients can have severe bronchoconstriction in response to these drugs.

image Second-degree heart block: It can be converted to third-degree heart block, resulting in very low HRs.
image Bradycardia: β-Blockers could make the already slow heart so slow that CO and BP fall below levels that are required by the body for adequate perfusion.
image Acute heart failure: Note that chronic heart failure is an indication for β-blockers, and acute heart failure is a contraindication. In acute heart failure the patient is decompensated and probably being kept alive by the SNS being ramped up. Blocking the effects of the flight-or-fight response would further decompensate the patient and potentially kill him or her.

Side Effects

image Hypotension: β-Blockers are negative chronotropes and inotropes.
image CHF: β-Blockers are negative inotropes.
image Asthma and bronchoconstriction: Nonselective β-blockers block β2 receptors in the airways.
image Bradycardia and heart block: The SA and AV nodes are under adrenergic influence.
image Raynaud’s phenomenon: Cold extremities (fingers in particular) may result from antagonism of β2 receptors, leading to vasoconstriction in the periphery.
image Impotence: Erectile function is dependent on changes in blood flow and vasodilation in the corpora cavernosa, and these mechanisms can be blocked by β-blockers.
image Fatigue: This is likely a result of the reduction in CO.
image Hypoglycemia: Nonselective β-blockers may interfere with recovery from hypoglycemia in type 1 (insulin-dependent) diabetes, as they antagonize the ability of catecholamines to promote glycogenolysis and mobilize glucose. Also, in diabetics, the β-blockade prevents symptoms caused by hypoglycemia and so masks early mild hypoglycemia, which can then deteriorate.
image CNS effects: Insomnia, nightmares, and depression are side effects. The mechanism is not well understood, but in theory these effects should occur more frequently with lipophilic drugs that cross the blood-brain barrier, such as propranolol and metoprolol.
image Lipid profiles: β-Blockers (except partial agonists) increase triglyceride levels and reduce high-density lipoprotein (HDL), without changing total cholesterol. The long-term effects of these changes are not known.

Important Notes

image β-blockers should not be discontinued abruptly, because of a rebound effect that might result in tachycardia and exacerbate the symptoms of coronary artery disease or might induce a hypertensive effect. The rebound appears to be an overactivity of the SNS, caused perhaps by receptor up-regulation.
image The use of β-blockers for HTN is generally avoided in elderly patients, whereas younger hypertensive patients tend to respond well to these agents.
image Not only might β-blockers impair the response to hypoglycemia in type 1 diabetes, but the negative chronotropic effects of these agents may mask the tachycardia that normally provides an important indicator of hypoglycemia to the diabetic. Despite these concerns, β-blockers have proven effective in the treatment of people with type 1 diabetes who have experienced an MI, and thus the decision whether to use them is one of risk versus benefit in this population.
image β-blockers were once contraindicated in chronic heart failure, but current evidence is very strong that they reduce mortality. It is very important to note that β-blockers are contraindicated in patients with acute decompensated heart failure.

Advanced

image Intrinsic sympathomimetic activity (ISA) is described for some β-blockers. ISA refers to a partial agonist effect in which the drug mostly blocks β receptors but does have a very small amount of agonist activity (however, far less than if compared with no drug at all).

Evidence

Chronic Heart Failure

image A meta analysis in 2009 (23 studies, N = 19,209 patients) shows a reduction in mortality with β-blockers for patients with chronic heart failure (RR 0.76) when compared with placebo. Decreases in HR were statistically associated with lower mortality.

After Myocardial Infarction

image Evidence for the role of β-blockers in secondary prevention after an MI comes from several trials and was summarized in a 1999 systematic review (82 trials, N = 54,234 patients). There was a 23% reduction in the odds of death in long-term trials but only a 4% reduction in short-term trials. The review found that the number needed to treat (NNT) to avoid a fatality over the course of 2 years is 42. The greatest amount of evidence available was for propranolol, timolol, and metoprolol.

Hypertension and Associated Stroke and Coronary Artery Disease

image A Cochrane review in 2007 (13 studies, N = 91,561 patients) compared β-blockers with other agents for HTN. Atenolol was the β-blocker most frequently used. The authors found that β-blockers had only weak effects in reducing stroke and no effect on coronary heart disease versus placebo. There was also a trend toward worse outcomes when compared with calcium channel blockers (CCBs), RAS inhibitors, and thiazides, prompting the authors to suggest that β-blockers should not be considered as first-line agents for HTN.

Obstructive Airway Disease (Asthma and Chronic Obstructive Pulmonary Disease)

image A Cochrane review in 2002 (29 studies, N = 381 patients) examined the impact of single-dose or short-term selective β1-blockers in patients with mild to moderate obstructive airway disease. There were no differences in pulmonary flow measurements compared with placebo except for a small decrease in FEV1 after the first treatment—an effect that disappeared with subsequent doses.

FYI Notes

image Nervous about public speaking? β-blockers have been used to reduce HR, palpitations, and sweating just before public speaking engagements.
image Metoprolol (selective β1) is currently one of the most commonly used β-blockers for cardiac indications.

Potassium Channel Blockers (Class III Antiarrhythmics)

Description

K channel blockers are Vaughan Williams class III antiarrhythmics. Amiodarone is currently one of the most commonly used K channel blocker antiarrhythmics, and therefore this section will focus on amiodarone.

Prototypes and Other Drugs

image Prototype: bretylium (now discontinued)
image Other drugs in this class:

image Amiodarone, dronedarone
image Ibutilide, dofetilide, azimilide
image Sotalol (also a β-blocker)

MOA (Mechanism of Action)

image Blocking K channels in phase 3 of the action potential slows the efflux of K back out of the myocyte, which slows the rate at which the cell repolarizes and therefore lengthens the plateau phase of the action potential. This increases the refractory period of atrial, ventricular, and Purkinje cells. This also increases the QT interval on the ECG (Figure 11-5).
image Amiodarone contains multiple antiarrhythmic properties and is an Na blocker, a K blocker, a Ca blocker, and β-blocker, all rolled into one chemical. However, it is primarily referred to as a class III drug.
image

Figure 11-5

Pharmacokinetics

image Amiodarone has a half-life of 25 to 60 days (extremely long).
image Drug interactions:

image Amiodarone and dronedarone are metabolized by and are inhibitors of CYP3A4; this is important because other drugs used in the control of dysrhythmias, including verapamil and diltiazem, are also metabolized by CYP3A4, and drug levels can be increased when drugs are coadministered.
image There is an interaction with digoxin, another drug used for treatment of arrhythmias: levels of digoxin can be increased up to 2.5 times as a result of P-glycoprotein interactions at the kidney.
image Dronedarone is also a CYP2D6 inhibitor and can increase levels of metoprolol in some patients.

image It is administered orally and intravenously.

Indications

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