Cardiology

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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

image Acute treatment and prevention of atrial fibrillation and flutter
image Acute treatment and prevention of ventricular fibrillation and ventricular tachycardia

Contraindications

image Caution must be exercised when giving amiodarone to patients with hypotension.
image Second- or third-degree heart block: conduction blocks can become worse (e.g., second-degree can progress to third-degree block) and escape rhythms (ventricular rhythm in 3rd degree block) can be suppressed, leading to no ventricular contractions and cardiac standstill.

Side Effects

image Side effects of amiodarone are rare but serious. They can be categorized as cardiac (usually not too serious) and noncardiac (more serious).

image Cardiac:

• Bradycardia and heart block
• Hypotension

image Noncardiac:

• Pulmonary fibrosis (interstitial lung disease)
• Thyroid dysfunction (hyperfunction or hypofunction)
• Blue skin
• Nausea, constipation, anorexia (loss of appetite)
• Liver damage (shown as an increase in liver enzymes in the blood)

image Dronedarone appears to have fewer side effects related to the thyroid, lung fibrosis, skin discoloration, and liver enzymes; however, it is associated with more GI side effects.

Important Notes

image Dronedarone is a newer class III drug. Indications for its use, compared with amiodarone, are still being evaluated in clinical trials.

Evidence

image Atrial fibrillation (AF) and multiple outcomes: 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 (the most common arrhythmia).

image Mortality: When compared with controls, amiodarone showed no significant difference in mortality. Compared with class I drugs, amiodarone showed a significant reduction in mortality (OR 0.39, NNT 17).
image AF recurrence: Amiodarone appeared to be the most effective of the antiarrhythmics at preventing AF recurrence; the NNT was 3 to prevent 1 recurrence of AF in 1 year.
image Adverse effects: Amiodarone did not appear to show any increased proarrhythmic effects, but there were more withdrawals caused by other side effects than there were with placebo.

FYI Notes

image There is similarity between the molecular structure of thyroid hormone and that of both amiodarone and dronedarone; it is likely that the structural similarity is the basis for the thyroid-related side effects seen with amiodarone.

Calcium Channel Blockers

Description

CCBs are agents that act by blocking calcium channels, either in the heart or on blood vessels. There are two major classes within CCBs: dihydropyridine (DHP) and non-DHP.

Prototype and Common Drugs

Dihydropyridines

image Prototype: nifedipine
image Others: amlodipine, felodipine, nicardipine, nimodipine, clevidipine

Nondihydropyridines

image Prototypes: diltiazem, verapamil

MOA (Mechanism of Action)

Hypertension

image Calcium channels are designated as L-, T-, P/Q-, N-, and R-type, depending on kinetics and receptor specificity. L means long duration, and T means transient.
image L-type calcium channels are located on the heart, skeletal muscle, neurons, vascular smooth muscle, and uterus.
image All CCBs are antagonists of L-type calcium channels. By blocking the influx of calcium through L-type channels, these agents inhibit contraction of smooth muscle (Figure 11-6).
image The dihydropyridine (DHP) CCBs have greater selectivity for the vasculature than either diltiazem or verapamil, the non-DHP CCBs.
image DHPs have little effect on the recovery of the calcium channel and thus minimal effects on cardiac Ca channels involved with automaticity (HR), conduction speed, and refractory periods (important with regard to the AV node).
image As a result, the DHPs have a greater vasodilatory effect than the non-DHPs and essentially no direct clinical effect on the heart. In other words, DHPs are vasodilators, and non-DHPs are cardiac depressants with some vasodilator activity.
image

Figure 11-6

Tachycardia and Arrhythmia

The non-DHPs (but not the DPHs) are also class IV antiarrhythmics.

Blocking Ca+2 channels in phase 0 of the action potential lengthens the depolarizing current in SA and AV nodal cells. This results in more time before the next action potential. In the SA node, the result is a slower pacemaker. In the AV node, the result is a longer refractory period (Figure 11-7).

image

Figure 11-7

Pharmacokinetics

image Amlodipine has a slow onset and much longer half-life (40 hours) than nifedipine (4 hours). This slow onset helps to mitigate the reflex tachycardia commonly seen with these agents, particularly nifedipine.
image Clevidipine is a newer DHP that is metabolized by esterases and therefore has a short half-life of 10 minutes. It is given only by intravenous infusion because of its short half-life.
image Oral verapamil undergoes extensive hepatic metabolism. Therefore the oral dose is much greater than the intravenous dose (80 to 160 mg orally [PO] versus 2.5 to 5 mg intravenously [IV]).

Indications

Nondihydropyridines

image Stable angina
image Sinus tachycardia
image Atrial tachycardia
image Reentry tachycardias
image HTN (diltiazem)

Dihydropyridines

image HTN
image To prevent or treat coronary spasm in variant angina (Prinzmetal’s angina)
image To prevent or treat cerebral artery spasm after brain hemorrhage
image Preterm labor

Contraindications

Nondihydropyridines

image Wolff-Parkinson-White (WPW) syndrome: In WPW the accessory pathway (bundle of Kent) is not blocked by Ca+2 channel blockers, but the AV node is. Therefore the use of Ca+2 channel blockers will promote conduction through the accessory pathway. Because the accessory pathway does not have a conduction delay as the AV node does, conduction through the accessory pathway can result in very high ventricular rates in the presence of atrial fibrillation or atrial flutter.
image Hypotension: Ca+2 channel blockers lower BP and should not be used in patients who already have low BP.
image Acute CHF: Non-DHPs have a depressant effect on the heart and must be avoided in acute CHF.
image AV blocks: Ca+2 channel blockers can make an AV block more severe.

Dihydropyridines

image Pregnancy—teratogenic effects seen in animals
image Conditions in which tachycardia is harmful:

image Coronary artery disease
image Aortic stenosis
image Mitral stenosis

Side Effects

Nondihydropyridines

image Bradycardia: caused by SA node or AV node suppression
image Heart failure and hypotension: secondary to reduced contractility

Dihydropyridines

image Vasodilation-related symptoms:

image Flushing: Caused by cutaneous vasodilation
image Dizziness: Caused by decreased cerebral perfusion from low BP
image Headache: Caused by cerebral vasodilation
image Tachycardia: A baroreceptor reflex response to decreased BP

Important Notes

image Vasodilation results in lower BP, and low BP often induces a baroreceptor-mediated reflex tachycardia. An important clinical consequence of DHPs is that they can indirectly induce tachycardia, which can be very dangerous in conditions in which tachycardia is contraindicated (e.g., coronary artery disease).

Advanced

image The DHPs are predominantly metabolized by the CYP3A4 enzyme system and thus have numerous interactions with either inducers or inhibitors of this enzyme.
image Grapefruit juice: The bioflavonoids in grapefruit juices inhibit the metabolism of most DHPs, especially felodipine. Evidence suggests that amlodipine is not affected by this interaction.

Evidence

As First-Line Agents in 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. Only one randomized controlled trial (RCT) was found that included a CCB, and in this trial it reduced stroke (RR 0.58) but not coronary heart disease or mortality. Thiazides (19 trials) reduced mortality (RR 0.89), stroke (RR 0.63), and coronary heart disease (RR 0.84).

For Aneurysmal Subarachnoid Hemorrhage

image A 2007 Cochrane review (16 studies, N = 3361 patients) examined whether DHP calcium antagonists alone or combined with magnesium sulfate (three studies) improved outcomes in patients with subarachnoid hemorrhage. Overall, calcium antagonists reduced the risk of poor outcomes (death or disability), with an NNT of 19 (1 to 51). When separated by individual calcium antagonists, only oral nimodipine was statistically significant versus control. Calcium antagonists also reduced the risk of secondary ischemia.

FYI Notes

image Patients have been known to take advantage of the interaction between felodipine and grapefruit juice to save themselves a few dollars on the drug cost. They will reduce their dose of felodipine by consuming grapefruit juice on a consistent basis. The bioflavonoids are found in the peel, however, so patients who grind their own juice may find they are not getting adequate drug levels if they do not include the peel.
image Remember, when trying to distinguish between DHP and non-DHP CCBs: dihydropyridines dilate.

Anticholinergics

Description

Antagonists of cholinergic (muscarinic) receptors relevant to the cardiovascular system are discussed here. Because of the diverse range of effects, anticholinergics as a class are also discussed elsewhere.

Prototype and Common Drugs

image Prototype is atropine
image Others:

image Glycopyrrolate
image Scopolamine
image Benztropine
image See other chapters for more examples of non-cardiac anticholinergics

• Autonomics (Chapter 3)
• Anticholinergics for airways section (Chapter 24)
• Anticholinergics for overactive bladder (Chapter 25)

MOA (Mechanism of Action)

image Anticholinergics block the activity of acetylcholine (ACh) of the parasympathetic system at muscarinic receptors (M).
image With respect to the cardiovascular system, this effect is most pronounced on the SA node and AV node, resulting in increased pacemaker rates of the SA node and sometimes increased conduction through the AV node. The primary result is a faster HR. The effect of AV node conduction is not clinically important unless a conduction block such as first-, second-, or third-degree AV block is present.
image Another (less clinically important) cardiovascular effect is reversal of vasodilation of some vascular beds, such as the mesentery (intestinal) vessels. ACh liberates NO from the endothelium, and atropine counteracts this.
image Atropine does not preferentially act on cardiovascular tissues; muscarinic receptors are present throughout the body, and therefore the actions of atropine and other anticholinergics are determined by the effects of the parasympathetic nervous system on each organ (Table 11-2).

TABLE 11-2 Effects of Anticholinergic Drugs

Heart Increased heart rate
Airways Bronchodilation
Secretions Reduced
Pupils Dilated
Urinary function Decreased
Gastrointestinal motility Decreased
Central nervous system Increased temperature, confusion

Indications

Cardiovascular

image Sinus bradycardia with hypotension
image May be useful in second-degree heart block causing bradycardia
image Usually not effective in third-degree heart block, but can be tried
image Treatment of anticholinesterase side effects (common) or poisoning (rare)

Noncardiovascular

image To dry oral and bronchial secretions (for bronchoscopy)
image To relax the bladder (see also section on anticholinergics and overactive bladder)

Contraindications

image Caution must be exercised in situations in which tachycardia is dangerous. This includes patients with coronary artery disease, aortic (valve) stenosis, and mitral (valve) stenosis.

Side Effects

These side effects can be predicted by understanding the effects (and consequences of blockade) of the parasympathetic nervous system on the different organs and tissues in the body.

image Cardiac

image Tachycardia

image Noncardiac

image Dry mouth
image Flushing
image Urinary retention (inability to empty bladder)

image CNS: These effects are not strictly considered part of the autonomic nervous system:

image Hyperthermia
image Delirium

Important Notes

image Red, hot, dry, and confused is a tetrad of atropine overdose.
image Glycopyrrolate has a weaker tachycardia profile and is therefore good for drying secretions for airway procedures such as bronchoscopy because it does not cause excessive increases in HR.
image Many antiarrhythmic drugs (classified I to IV) also possess some degree of muscarinic blockade, but to a lesser degree than their primary mechanism of action.

FYI Notes

image One chemical used in a form of chemical warfare is an anticholinesterase. An anticholinesterase blocks cholinesterase, which is an enzyme that degrades ACh. The result is too much ACh, which mimics an overactive parasympathetic system and can even cause paralysis from overstimulation of the nicotinic receptor in the neuromuscular junction. Atropine is the antidote.
image One class of anesthetic drug is a neuromuscular blocking reversal drug. It is an anticholinesterase and is used to increase the concentration of ACh in the neuromuscular junction. However, in addition to increased ACh in the neuromuscular junction, increased ACh at all other muscarinic receptors also occurs, leading to muscarinic side effects. Usual side effects of a normal dose include bradycardia and bronchorrhea (bronchial secretions). Antimuscarinic drugs including atropine and glycopyrrolate are used to minimize the side effects of these medications.
image A massive outpouring of parasympathetic activity (via the vagus nerve) caused by stress or fear is called a vasovagal attack. It results in bradycardia and hypotension and sometimes loss of consciousness.
image A scopolamine patch is used as an antinauseant.
image Benztropine is used to help motor control in the management of Parkinson’s disease. This is an effect in the brain and not related to the autonomic nervous system.
image Ipratropium can be used as an alternative to β2-agonists for bronchodilation in the management of asthma, particularly in the elderly. This drug is covered in Chapter 24 on inhaled anticholinergics.

Adenosine

Description

Adenosine is an antiarrhythmic that does not fall into the Vaughan Williams classification (class I to IV) scheme.

MOA (Mechanism of Action)

image Adenosine stimulates adenosine A1 receptors in the AV node, which results in:

image Increased outward K+ currents
image Decreased inward Ca+2 currents
image Decreased inward Na+ currents (If)

image These ionic actions hyperpolarize the cell (i.e., make the inside of the cell more negative because there are fewer positive ions inside the cell) and render it refractory for a prolonged period (a few seconds or more).
image Essentially, the AV node is completely turned off for a brief period of time, creating a third-degree heart block for a few seconds. Through this action, tachycardias that originate in the atria can be diagnosed more easily because all the QRSs are absent from the ECG for a few seconds.
image Because the AV node is turned off, any reentry circuit that was originating inside or travelling through the AV node will be terminated. Through this action, reentry circuits can be treated and normal sinus rhythm resumes (Figure 11-8).
image

Figure 11-8

Pharmacokinetics

image Adenosine has a half-life of about 10 seconds. It must be given as an intravenous push (quickly) with a saline flush (otherwise it will be metabolized in the arm veins before it gets to the heart, where it exerts its effects).
image Caffeine acts on the same adenosine A1 receptor and can block the action of adenosine.

Indications

image Adenosine is used for the diagnosis and treatment of supraventricular tachycardias (SVTs).

Contraindication

image None of major significance.

Side Effects

image Because the half-life of adenosine is very short, side effects usually last for only a few minutes.
image Dyspnea (shortness of breath) is caused by adenosine agonism in the bronchioles.
image Angina and feelings of extreme discomfort and unpleasantness may occur. Adenosine is liberated when there is a deficiency of ATP, which occurs when there is a deficiency of oxygen; adenosine is one of the mediators of symptoms when myocardial ischemia occurs.
image Nausea may occur.
image Transient complete heart block is common (and in fact is the method by which adenosine is diagnostic for SVTs). Therefore ECG monitoring is required during adenosine administration.

Important Notes

image Diagnostic for SVT: If the HR is so fast that you cannot determine what the underlying rhythm is, then adenosine will temporarily shut down the AV node, which will block conduction that leads to ventricular activity. This gives the observer an opportunity to assess the underlying atrial activity.
image Treatment for reentry tachycardias: When adenosine is given, the AV node is turned off for a few seconds. This is usually sufficient to completely abolish a reentry tachycardia (which almost always uses the AV node as part of its pathway).
image If a patient’s heart converts to sinus rhythm after the administration of adenosine, then a diagnosis of reentry tachycardia is confirmed.
image If a patient’s heart resumes the SVT after an ECG pause, then the rhythm is probably atrial fibrillation, flutter, or tachycardia or sinus tachycardia and should be diagnosable while the ventricles are temporarily stopped.
image Patients sometimes refuse the drug if they have had it before because of the severity of the unpleasant sensation.

Evidence

Adenosine versus Verapamil for Supraventricular Tachycardia

image A Cochrane review in 2006 (eight trials, N = 577 patients) found that both drugs were 90% effective in treating SVTs and that there were no differences in efficacy; however, adenosine converted heart rhythm to sinus rhythm a little bit faster than verapamil did. Adenosine caused unpleasant side effects in about 10% of patients, and verapamil caused hypotension in 2% of patients.

FYI Notes

image Adenosine is an endogenous nucleotide (i.e., occurs naturally) that is part of the well known ATP molecule. In the body, adenosine is liberated during ischemia and in fact is a mediator of the symptoms of cardiac ischemia.
image Warn the patient how terrible he or she will feel for about 3 minutes.
image Sometimes adenosine has absolutely no effect (caffeine blocks its effect).

Digoxin

Description

Digoxin is classified as a cardiac glycoside. It is an inotrope that does not have its effects mediated through β receptors.

Digoxin is also loosely classified as an antidysrhythmic.

Prototype and common drugs

image Protoype: digoxin
image Others include digitoxin and digitalis (much less commonly used)

MOA (Mechanism of Action)

Digoxin has two mechanisms of action:

1 Inotropic action:

image Through the action of Na/K/ATP ion pump blockade (Figure 11-9), the following sequence of ionic events occurs:

• ↓ Na exits the cell
• ↑ Intracellular Na
• ↓ Na electrochemical gradient for Na-Ca exchanger
• ↓ Ca exits the cell
• ↑ Intracellular Ca
image The increase in intracellular calcium results in increased contractility, SV, and CO.
image In heart failure, sympathetic tone is increased as a compensatory mechanism to increase CO. Digoxin increases contractility and hence SV and CO, therefore reducing the need for sympathetic compensation; thus digoxin reduces the sympathetic tone in heart failure.

2 Increased parasympathetic nervous system activity:

image In addition to the indirect reduction of the SNS as outlined previously, there is a direct increase in the parasympathetic system.
image Digoxin sensitizes arterial baroreceptors in the carotid sinus and activates the vagal nuclei (in the brainstem). These baroreceptors induce a response via the vagus nerve that decreases HR and causes vasodilation when the receptors are stretched (which occurs with high BP). HR decreases owing to increased parasympathetic tone of the SA and AV nodes. By this mechanism on the AV node, digoxin is useful in patients with atrial fibrillation.

image

Figure 11-9

Pharmacokinetics

image The therapeutic index is very low. The therapeutic range for digoxin is 0.5 to 2.5 nmol/L (in the blood). The probability of toxicity is significant when the level is > 2.6, and toxicity is virtually guaranteed when the level is >3. Contrast this to acetaminophen (Tylenol), in which the toxic oral dose is 10 times the normal dose.
image Children experience less toxicity than adults and have a higher therapeutic range (2.5 to 3.5).
image It is estimated that 20% of patients taking digoxin will experience toxicity.
image Signs or symptoms of toxicity may not correlate well with digoxin levels. A normal level of digoxin does not rule out toxicity.
image The half-life is 30 hours in normal adults.
image Clearance is via the kidneys. Renal dysfunction increases the elimination half-time, which increases digoxin levels and increases the risk of toxicity. The dose must be reduced accordingly.
image Certain drug interactions increase digoxin levels.

image Diuretics: spironolactone, amiloride, triamterene
image Antiarrhythmics: quinidine (most commonly cited in books), amiodarone
image Calcium antagonists: verapamil only
image HMG-CoA reductase inhibitors: atorvastatin at high doses (80 mg daily)

image Factors that increase digoxin sensitivity (and thus increase toxicity risk):

image Hypokalemia (most common cause)
image Hypercalcemia (less common)
image Hypomagnesemia (less common)
image Hypothyroidism
image Hypoxia, acidosis

Indications

image CHF (third-line drug in adults, first-line drug in children)

image Digoxin increases contractility.

image Atrial fibrillation

image Digoxin decreases AV node conduction and slows the ventricular rate.

Contraindication

image Care must be exercised when prescribing to patients at risk for toxicity (see later).

Side Effects (Toxicity)

Signs and Symptoms

image GI: Nausea, vomiting, diarrhea, abdominal pain and anorexia (loss of appetite)
image CNS: Confusion, dizziness, and agitation
image Cardiovascular: Arrhythmias and heart block
image Visual: Orange tinted vision, visual disturbances

Electrocardiographic Changes

image Increased automaticity occurs. Atrial or ventricular dysrhythmias such as premature atrial contractions (PAC’s), premature ventricular contractions (PVC’s), atrial or ventricular tachycardia can occur. The mechanisms include the following:

image After depolarizations
image Decreased slope of phase 0
image Increased slope of phase 4

image Long PR interval or AV block (caused by slow AV suppression) may be present.
image Ventricular fibrillation can occur and may result in sudden death.
image Scooping of ST segment can occur (Figure 11-10).
image

Figure 11-10

Important Notes

image The toxicity of digoxin is very important to understand because toxicity is so common. Treatment is to stop giving the drug for a short period, or, if there are severe cardiac arrhythmias, an antibody called Digibind can be given; Digibind binds digoxin and increases the rate of clearance.

FYI Notes

image Digoxin is the most commonly used cardiac glycoside, but its use in adults has decreased over the last two decades.
image Differences between digoxin and digitalis are that digitalis has better oral absorption, a longer elimination half-life (5 to 7 days), and hepatic clearance.
image Digitalis is derived from the foxglove plant (Digitalis purpurea). This purple flower looks like fingers of a glove, and the name digitalis means relating to fingers. What color do you think purpuric rashes are?

Inhibitors of Cholesterol Synthesis: Statins

Description

Statins are designed to reduce low-density–lipoprotein (LDL) cholesterol and raise HDL cholesterol.

Prototype and Common Drugs

image Prototype: atorvastatin
image Others: simvastatin, pravastatin, lovastatin, fluvastatin, rosuvastatin, pitavastatin

MOA (Mechanism of Action)

image These drugs are HMG-CoA reductase inhibitors. HMG-CoA reductase mediates the first step in the biosynthesis of cholesterol.
image Reduced biosynthesis of cholesterol causes an increase in the number of LDL receptors, through the actions of sterol regulatory element binding proteins (SREBPs). Additional LDL receptors increase the catabolic rate of LDL, and the liver’s extraction of LDL precursors. These actions reduce the plasma pool of LDL (Figure 11-11).
image Other effects of statins include the following:

image Small increase in plasma HDL (approximately 5%)
image Reduction in plasma triglycerides by 10% to 25%

image Statins are also increasingly being recognized for a large number of effects that are independent of cholesterol-lowering. See advanced notes, later, for further details.
image

Figure 11-11

Pharmacokinetics

image Atorvastatin, simvastatin, and lovastatin are metabolized by CYP3A4; thus drug interactions are of concern with these agents.

image Pravastatin is the only statin that is not metabolized by the CYP450 enzyme pathways.

Indications

image Used as first-line agents in the management of hyperlipidemia

Contraindications

image Pregnancy: HMG-CoA reductase inhibitors cause birth defects and should not be used in pregnancy.

Side Effects

image Statins are generally well tolerated.
image Myalgia: muscle pain and associated weakness. The pathophysiology is not fully understood, and it is probable that this is a very mild form of myositis. This occurs in about 10% of patients.

Rare, Serious Side Effects

image Myositis and rhabdomyolysis are rare (1% for myositis) but serious adverse effects of statin therapy, which tend to occur at higher doses or when a drug interaction is present.

image Myositis is inflammation of muscle cells and is associated with a 10 times increase in CK levels in the blood.
image Rhabdomyolysis is an extreme form of myositis and results in lysis of skeletal muscle cells and release of myoglobin in high quantities, which results in damage to renal glomeruli and renal failure. This condition usually occurs in the presence of other risk factors in addition to statin administration, such as coadministration with cyclosporine (an immunosuppressant) or gemfibrozil (another lipid-lowering agent).

image Hepatotoxicity: Increases in serum aminotransferase have been observed in <1% of patients. As long as the elevations are not too great, patients who have no other risk factors for liver impairment can continue taking the statin without undue risk for liver injury, provided close monitoring is maintained.

Important Notes

image Statins can be used in combination with other agents such as bile acid sequestrants or inhibitors of cholesterol absorption. Fibrates and niacin (other drugs used to achieve a more favorable lipid profile) should be used with caution, as both can interact with statins.
image Ezetimibe is a cholesterol-lowering agent that is used in combination with the statins. Unlike the statins, which lower cholesterol by inhibiting its synthesis, ezetimibe reduces the absorption of cholesterol from the intestine. The fact that these two classes use distinct and complementary strategies to lowering cholesterol has made them a natural fit for combination therapy.

Advanced

image Statins are being studied for their potential role in neuroprotection, with indications such as Alzheimer’s disease, Parkinson’s disease, stroke, and multiple sclerosis (MS). Statins appear to activate neuroprotective pathways and also may play a role in neurogenesis. The mechanisms of all these effects are still being worked out; however, some researchers believe that the use of statins may become even more widespread than it is today.
image Statins may also improve vascular function. Studies have shown that they can reduce the generation of reactive oxygen species and regulate nitric oxide (NO) production. Other potential applications include sepsis and infection.

Evidence

Patients with Cardiac Risk Factors But Without Cardiac Disease (Primary Prevention)

image A 2009 systematic review (10 studies, N = 70,388 participants) examined the use of statins in people without established cardiovascular disease but with cardiovascular risk factors. The included studies had a mean follow-up of 4.1 years. Statins reduced the risk of all-cause mortality (OR 0.88), major coronary events (OR 0.70), and major cerebrovascular events (OR 0.81).

Prevention of Stroke Recurrence (Secondary Prevention)

image A 2009 Cochrane review (eight studies, N ≈10,000 participants) examined the effect of altering serum lipids for prevention of subsequent cardiovascular disease and stroke in patients with a history of stroke. Statins marginally reduced subsequent cerebrovascular events (OR 0.88) but not all-cause mortality or sudden deaths. Three trials showed a subsequent reduction in serious vascular events (OR 0.74).

FYI Notes

image Statins are among the most often-prescribed drugs worldwide. Their use has become so routine and their safety profile is thought to be so innocuous that consideration has been given in the United Kingdom and the United States to making them available without a prescription.
image Cerivastatin was withdrawn from the market earlier this decade owing to concerns over serious drug interactions, which lead to a higher risk of rhabdomyolysis.

Fibrates

Description

Fibrates are lipid-modifying agents used to reduce the risk of cardiovascular disease.

Prototype and Common Drugs

image Prototype: clofibrate
image Others: gemfibrozil, fenofibrate

MOA (Mechanism of Action) (Figure 11-12)

image Transcription factors are proteins that bind DNA and increase or decrease transcription (production of RNA and thus proteins) of selected genes.
image Fibrates activate transcription factors called peroxisome proliferator–activated receptors (PPARs). These are nuclear hormone receptors that respond to lipid based ligands, including hormones, vitamins, and fatty acids.
image Very-low–density–lipid (VLDL) particles are converted into fibrate agonism, resulting in:

image Increased HDL

• Via increased apolipoprotein (apo) A-I and apo A-II expression (apolipoproteins are major constituents of HDL)

image Reduced LDL

• As a result of increased hepatic fatty acid uptake, conversion and catabolism of free fatty acids
• Reduced production of VLDL particles
• Increased catabolism via lipoprotein lipase, an enzyme that breaks down VLDL particles

image

Figure 11-12

Pharmacokinetics

image No significant issues; fibrates are well absorbed orally
image Eliminated renally and hepatically

Drug Interactions

image Gemfibrozil competes for the same glucuronosyltransferases that metabolize statins. This is important because statins are used for the same indication (high cholesterol) as fibrates are, and both drugs can cause muscle breakdown and muscle pain (rhabdomyositis). Coadministration can result in increased levels of both drugs and an increase in the risk for this side effect.
image Fibrates can potentiate warfarin, an anticoagulant. Anticoagulation levels (measured by the international normalized ratio [INR]) should be measured more closely if fibrates are initiated in a patient already taking warfarin.

Indications

image To reduce the risk of cardiovascular complications in patients with:

image Elevated LDL or triglycerides
image Reduced HDL

Contraindications

image Renal or hepatic failure (because of excretion issues)

Side Effects

image Rash
image GI symptoms, specifically cholelithiasis (gallstones)

image Clofibrate is the fibrate most likely to result in gallstones.

image Hepatic: Small elevations in liver enzymes

Rare Side Effects

image Pancreatitis
image Reversible decreased renal function (indicated by an increased serum creatinine)
image Myositis, myopathy, or rhabdomyositis: all terms generally refer to the same process of skeletal muscle lysis resulting in pain and release of the enzyme creatinine kinase (CK) into the blood, causing CK levels to become elevated.

Important Notes

image Fibrates are usually administered in combination with statins and are not frequently first-line single agents.
image Chylomicron and VLDL particles are triglyceride rich.
image Good cholesterols lower atherosclerotic risk and include HDL and apolipoproteins apo A, apo B, and apo E.
image Bad cholesterols raise atherosclerotic risk and include chylomicrons, VLDL, LDL, and triglycerides.

Advanced

image Fenofibrate is metabolized by different hepatic enzymes, and these enzymes are not involved in statin glucuronidation. Thus, fenofibrate-statin combinations are less likely to cause myopathy than are other fibrate-statin combinations.

Evidence

Fibrates and Cholesterol and Cardiovascular Endpoints

image A 2007 meta-analysis (10 RCTs, N = 36,489 patients) demonstrated the following:

image Fibrates did not significantly reduce the odds of:

• Cardiovascular mortality
• Fatal MI
• Stroke

image But fibrates did significantly:

• Reduce total cholesterol by 8% (versus placebo)
• Reduce triglycerides by 30% (versus placebo)
• Increase HDL by 9% (versus placebo)
• Reduce the odds of nonfatal MI by about 22% (P < .00001)

image The odds of developing cancer were not significantly higher with the use of fibrates.

FYI Notes

image Although the word fibrate is suggestive of fiber, the fibrates do not act as GI lipid-absorbing fiber resins. This mechanism of action belongs to a class of drug called bile acid sequestrants.
image Clofibrate was approved for use in 1967 in the United States. An initial study (1978) that was not properly analyzed led to the belief that clofibrate increased mortality, but these results were not supported by subsequent data and analyses.
image There have been concerns that fibrates could increase the incidence of cancer based on data from studies published in the mid 1990s. The evidence is not strong, and the association was not supported in the previously quoted meta-analysis.

Bile Acid Sequestrants

Description

Bile acid sequestrants comprise a family of drugs that share the physicochemical property of binding to negatively charged ions in the gut.

Prototype and Common Drugs

image Prototype: cholestyramine
image Others: colestipol, colesevelam

MOA (Mechanism of Action)

image Bile acids facilitate the digestion and absorption of dietary fats. The bile acids are normally enterohepatically recycled, which means they are secreted into the GI tract through the bile duct and then reabsorbed and transported back to the liver for the cycle to repeat (Figure 11-13).
image Bile acid binding resins carry a large positive charge and are therefore attracted to and bind negatively charged bile acids in the gut. The resins are large and therefore not absorbed, so the bound bile acids are excreted with the resins in the feces.
image The binding of bile acids by the resins therefore interrupts the process of enterohepatic recycling, depleting the pool of bile acids. With a deficiency of recycled bile acids the liver must synthesize more.
image Cholesterol is a precursor of bile acids, so to create more bile acids the liver must obtain more cholesterol. It does this by increasing the number of LDL receptors, which in turn leads to a lowering of plasma LDL and total cholesterol.
image The bile acid binding resins are not designed to increase HDL levels, and they have a minimal impact on HDL.
image

Figure 11-13

Pharmacokinetics

image Cholestyramine and colestipol are available in powdered dosage forms, which are administered by suspending in water and drinking.
image The bile acid binding resins are not absorbed, and they exert their actions only within the GI tract.
image Binding to negatively charged molecules can interfere with the absorption of a number of different negatively charged drugs. Some of the more notable examples include thiazide diuretics, furosemide, propranolol, digoxin, and warfarin. Because of the large number of drugs that may be affected by this interaction, it is typically recommended that the administration of bile acid resins be separated from administration of other drugs by at least 1 hour if taken before the resin, or by 3 hours if taken after the resin.
image Bile acids also facilitate the absorption of fat-soluble vitamins. Because these drugs sequester bile acids, the absorption of vitamins A, D, E, and K may be reduced in the presence of bile acid binding resins.

Indications

image Hypercholesterolemia
image Pruritus associated with partial biliary obstruction
image Diarrhea associated with excess fecal bile acids in short bowel syndrome

Contraindications

image Hypertriglyceridemia

Side Effects

image GI: constipation is the most common side effect. Others can include bloating, gas, nausea, and upper abdominal pain.

Serious Side Effects

image Hyperchloremic acidosis (rare): The bile acid binding resins are chloride salts and in susceptible individuals (typically children) may increase chloride levels enough to induce acidosis. Chloride and bicarbonate are the primary anions in the blood, and if one goes up, the other usually goes down to maintain electrical neutrality. Dropping bicarbonate results in metabolic acidosis.

Important Notes

image To compensate for the actions of the bile acid binding resins, upregulation occurs in the activity of the HMG-CoA reductase enzyme, which is the rate-limiting enzyme in the production of cholesterol. This is the rationale for using the statins, which are HMG-CoA reductase inhibitors, in combination with the bile acid binding resins.
image Interruption of enterohepatic recycling by the bile acid binding resins leads to an increase in plasma triglyceride levels. This is because the activity of the enzyme phosphatidic acid phosphatase, which is involved in triglyceride formation, is suppressed when the enterohepatic recycling system is functioning normally. When enterohepatic recycling is interrupted, it can lead to problematic increases in triglyceride levels, and patients who have preexisting problems with hypertriglyceridemia should avoid taking these agents.
image The GI side effects of the powdered formulations may be reduced by allowing the suspension to sit, refrigerated, for several hours before consumption.
image Some patients with chronic diarrhea caused by malabsorption of bile acids respond favorably to the bile acid binding resins.
image There is some indication that bile acid sequestrants may lower blood glucose levels in patients with hyperglycemia. The mechanism behind this effect has not been identified.

FYI Note

image Cholestyramine powder is also available in light formulations that are sugar-free.

Inotropes and Pressors

Description

An inotrope is a drug that results in an increase in inotropy (contractility). Pressors are drugs that primarily cause vasoconstriction. Both drugs are given to increase BP in an attempt to maintain adequate organ perfusion. This section focuses only on drugs that are administered intravenously.

Common Drugs

image Dopamine
image Dobutamine
image Norepinephrine
image Epinephrine
image Phenylephrine

Metabolism

image The synthesis of natural catecholamines is as follows:

image

image Hydroxylation (addition of OH) of dopamine yields norepinephrine. Methylation (addition of CH3) of norepinephrine yields epinephrine.
image Dobutamine and phenylephrine are synthetic compounds.

MOA (Mechanism of Action)

image These drugs all exert their actions via the autonomic nervous system α and β receptors. In addition to these receptors, dopamine (and only dopamine) also acts via dopaminergic (DA) receptors.
image Drugs that are β1 agonists are inotropes; drugs that are α1 agonists are pressors. Activation of DA receptors results in mesenteric and renal vasodilation. Note: β2 agonists are vasodilators (on skeletal muscle).
image Most drugs are agonists to both the α and β receptors. However, each drug has different potencies for the receptors. Thus at low doses some drugs are primarily agonists for one receptor. At higher doses, both receptors will be stimulated, but one receptor will be more stimulated. The exception to this rule is phenylephrine. It is a pure α1 agonist.
image Stimulation of a β receptor activates the class of proteins called G proteins. This results in increased cyclic adenosine monophosphate (cAMP) levels, which then stimulate protein kinases, which result in increased intracellular calcium. Calcium enhances the actin-myosin interaction and results in increased myocardial contractile force.
image Stimulation of an α1 receptor results in increased inositol triphosphate (IP3), which results in increased smooth muscle intracellular calcium, resulting in increased contractile force and increased vascular tone (vasoconstriction).
image In simple summary, dobutamine is an inotrope but not a pressor (in fact, it is a dilator). Norepinephrine and phenylephrine are primarily pressors. Epinephrine and dopamine are both pressors and inotropes (Table 11-3).

TABLE 11-3 Properties of Inotropes and Pressors

image

Pharmacokinetics

image These drugs are all administered intravenously. They have short half-lives (minutes) and therefore mostly are given as infusions.
image Phenylephrine is commonly used in anesthesia and is given in small intravenous boluses.
image An exception to infusions is the administration of bolus epinephrine in cardiac arrest resuscitations (code blue) or for the treatment of anaphylaxis using syringes preloaded with epinephrine.

Indications

1 Hypotension
2 Circulatory shock (severe form of hypotension)

image Cardiogenic shock (shock caused by a weakly contracting heart)
image Septic shock (shock caused by vasodilation resulting from sepsis)
image Anaphylactic shock (extreme vasodilation caused by massive histamine release)
image Neurogenic shock (loss of sympathetic nervous system activity from spinal cord injury, causing vasodilation)

3 Acute CHF (but not chronic CHF)

image Dobutamine and dopamine are the most commonly used for CHF

Contraindications

image Usually the need for hemodynamic support outweighs most other factors. Therefore when inotropes or pressors are indicated, there is little to prevent their use. Side effects of the drugs (tachycardia, extreme vasoconstriction, increased myocardial work) can limit their maximum dose.

Side Effects

image Increased myocardial work: secondary to ↑ contractility, ↑ afterload, and ↑ HR
image Tachycardia: β1 agonists are also positive chronotropes.
image Decreased organ and tissue perfusion: extreme vasoconstriction will increase BP but decrease flow to tissues or organs.

Important Notes

image A thorough assessment to determine the specific cause(s) of hypotension or shock must always be performed, and the primary cause of the problem must be corrected. For example, a patient who is bleeding and has hypotension has a preload (volume) problem, and therefore the preload should be corrected before the contractility or afterload is manipulated.
image Phosphodiesterase-3 (PDE3) inhibitors are also inotropes, but they are strong vasodilators and are covered separately; however, phosphodiesterase inhibitors are frequently used together with other inotropes and pressors.

FYI Notes

image A mnemonic for the nor of norepinephrine is “no radical.” Remember that a radical is a CH group. Therefore, adding a CH3 group to norepi produces epi.
image Epi starts with a vowel but stimulates the nonvowel (β) receptor more.
image Norepi starts with a nonvowel but stimulates the vowel (α) receptor more.
image Oxymetazoline and xylometazoline are both α1-agonist decongestants but are not used systemically; they are prepared as nasal sprays and function to decrease nasal stuffiness and congestion by vasoconstricting vessels in the nasal mucosa. However, frequent use of these medications results in a rebound congestion when they are stopped, and therefore they must be used sparingly. They are more commonly recognized by their brand names, which in North America include Otrivin and Dristan.

Phosphodiesterase-3 Inhibitors

Description

PDE3 inhibitors are inodilators used in heart failure. They increase contractility and dilate vessels.

Prototype and Common Drugs

image Prototype: amrinone
image Others: milrinone

MOA (Mechanism of Action) (Figure 11-14)

image PDE breaks down intracellular cAMP and cyclic guanosine monophosphate (cGMP).
image PDE inhibitors therefore result in increased intracellular cAMP and cGMP, which cause increased intracellular calcium. Which cell or tissue type is affected will dictate the effect of the PDE inhibitor.
image PDE3 is distributed in the body primarily in cardiac tissue, vascular smooth muscle, and platelets; thus its effects primarily involve these cell and tissue types.
image Increased cAMP results in increased intracellular calcium, which causes increased inotropy (contraction).
image PDE3 inhibitors also have intracellular actions that should theoretically improve diastolic function:

image Stimulation of intracellular calcium uptake into the sarcoplasmic reticulum (SR) during diastole; the net effects are a lower calcium concentration during diastole and improved relaxation of actin and myosin coupling.
image Increased cAMP results in increased protein kinase A (PKA) activity, which increases the phosphorylation of a protein called titin; this results in a more compliant form of titin, and this helps the cell elongate (relax) during diastole.

image PDE3 inhibitors result in the following physiologic changes:

image Increased CO
image Decreased end diastolic pressures
image Mild increases in HR (because of vasodilation and baroreceptor reflex)
image No change in myocardial work

image

Figure 11-14

Pharmacokinetics

image The half-life is about 6 hours. This is important because it is administered as an intravenous infusion. Most cardiovascular drugs (e.g., dopamine, nitroglycerin [NTG]) that are administered as intravenous infusions (to optimize BP and CO) have half-lives of 3 to 5 minutes. Therefore, milrinone is less titratable than these other drugs, and the drug levels can become unexpectedly high.
image Because PDE3 inhibitors are renally cleared, they can accumulate and result in overdose when given to patients with renal dysfunction. This manifests as excessive vasodilation and hypotension.

Indication

image Acute heart failure

Contraindications

image Renal failure is a relative contraindication because the steady state plasma levels with an infusion can become dangerously elevated.

Side Effects

image Hypotension secondary to vasodilation: This is a very important side effect. Because of the relatively long half-life of milrinone and the fact that it is administered as an infusion, the potential for steadily increasing serum levels of drug over a period of many hours after the start of the infusion, especially in patients with renal dysfunction, results in hypotension being a frequent side effect. Hypotension induced by PDE3 infusions is treated with vasoconstrictors (usually norepinephrine) and by decreasing the infusion rate. With the longer half-life, hypotension usually persists for many hours even after the infusion is decreased.
image Thrombocytopenia: Amrinone causes a decrease in platelet count in about 30% of patients. Milrinone causes decreased platelet counts in far fewer patients.

Important Notes

image Milrinone is not used for chronic heart failure. It is used only in select patients with severe acute heart failure.
image PDE3 inhibitors have a physiologic effect similar to that of β agonists because β agonists also result in increased cAMP, leading to:

image Increased contractility
image Increased vasodilation (with β agonism it is the result of β2 receptors)

image However, there are important clinical differences between the two PDE3 inhibitors and β agonists:

image PDE3 inhibitors are not direct positive chronotropes (increased HR), whereas β agonists are. Lack of a chronotropic effect can be a benefit when the patient is already tachycardic or has disease in which tachycardia would be undesirable (e.g., coronary artery disease).
image PDE3 inhibitors do not use β receptors, which are frequently down-regulated or often already maximally stimulated by endogenous catecholamines, rendering them virtually unresponsive to additional exogenous β stimulation. Thus PDE3 inhibitors usually are clinically much stronger drugs in the setting of acute decompensated heart failure.

image PDE3 inhibitors are frequently used with a pulmonary artery catheter in a critical care setting, and the cardiac index (which is CO divided by body mass index) is used for titrating the dose and for determining when the patient can be weaned off the drug.
image PDE3 inhibitors increase myocardial work via increased contractility but decrease myocardial work via afterload reduction through vasodilation. The net effect on total myocardial work is difficult to predict but is usually about neutral.

Advanced

image PDE3 breaks down both cAMP and cGMP. The subtype of PDE determines the ratio of activity against cAMP versus cGMP. PDE3 preferentially acts on cAMP 10 times more than it does cGMP. The changes in cAMP and cGMP in different cells dictate the clinical effects seen in either the heart or the vasculature.
image PDEs are a superfamily. There are 11 subtypes. Currently, the other PDE inhibitor in clinical use is PDE5, used for treatment of erectile dysfunction.

Evidence

image In an RCT of 1,088 patients in 1991, long-term treatment of chronic congestive heart failure with oral milrinone was associated with a 28% increased risk of mortality, primarily attributed to increased arrhythmias. PDE3 inhibitors are not used at all in chronic heart failure.

FYI Notes

image cAMP was first identified in 1958 by Earl Sutherland, for which he received the 1971 Nobel Prize in Physiology or Medicine “for his discoveries concerning the mechanisms of the action of hormones.”
image Caffeine is a weak, nonspecific PDE inhibitor. This results in increased HR and paradoxically (compared with PDE5 inhibitors) vasoconstriction.
image Theophylline, used in treatment of airway disease, is also a PDE (see also methylxanthines).
image Amrinone is also called inamrinone, a rare example of a drug having two generic names.

Nitrates

Description

Nitrates are agents that release nitric oxide (NO).

Prototype and Common Drugs

image Prototype: nitroglycerin (NTG)
image Others: isosorbide dinitrate (ISDN), isosorbide-5-mononitrate

MOA (Mechanism of Action)

image These agents all release NO, through a variety of incompletely understood biochemical mechanisms.
image NO, also known as endothelium-derived relaxing factor (EDRF), induces vasodilation primarily on the venous side of the circulation (venodilation). It does this by activating guanylyl cyclase, an enzyme that produces cGMP, which decreases Ca+ entry into cells and causes relaxation of vascular smooth muscle (Figure 11-15).
image This venodilatory effect produces a pooling of blood in the venous capacitance vessels, resulting in a reduction in venous return, preload, and end diastolic pressure, which:

image Lowers ventricular wall tension and reduces oxygen demand
image Improves the coronary pressure gradient, which is calculated as:

image

Figure 11-15

image

image These two mechanisms improve the supply-demand balance of the myocardium and are the primary mechanisms by which NTG relieves angina (Figure 11-16).

image At higher doses, nitrates can have a vasodilatory (arterial) effect; however, this is not the major mechanism in the management of stable angina. The vasodilation reduces afterload, again reducing ventricular wall tension and oxygen demand.
image To a minor extent, these agents also dilate coronary arteries, although this is again of secondary importance in their antianginal effects. It is important to realize that atherosclerotic plaques do not dilate in response to drugs, but that collateral coronary vessels might provide an increase in blood flow to an ischemic myocardium that is downstream from such a blockage.
image

Figure 11-16

Pharmacokinetics

image The elimination half-time of NTG is 1.5 minutes.
image NTG has very low oral bioavailability and therefore is administered topically (patch or ointment), sublingually (pill or spray), or intravenously.
image The sublingual preparations have a rapid onset and therefore are useful in relieving acute angina attacks.
image ISDN and isosorbide mononitrate have longer half-lives and the advantage of oral administration.
image Tolerance can develop to nitrates (the mechanism of tolerance is unclear). This is particularly true of long-acting agents. Patches are therefore usually worn 12 hours on and then 12 hours off.

Indications

image Stable angina: treatment and prevention
image Acute coronary syndromes (ACSs):

image Unstable angina
image Acute MI

image CHF
image Hypertensive emergency
image To decrease uterine muscle tone (a less common use):

image To treat premature labor
image To treat fetal distress caused by high uterine contraction

Contraindications

image Hypotension
image Coadministration of PDE5 inhibitors
image Elevated intracranial pressure (ICP)—Vasodilation of cerebral arteries increases cerebral blood volume, which further increases ICP.

Side Effects

image Headache: A direct result of the cerebral dilation
image Flushing: Caused by cutaneous vasodilation
image Orthostatic hypotension: Low BP upon standing
image Presyncope or syncope: Caused by the hypotensive effect

Important Notes

image The drug interaction with PDE5 inhibitors (vasodilators used for treatment of erectile dysfunction) is significant. Many men with erectile dysfunction are older and have heart problems, such as angina. Both classes of drugs increase intracellular cGMP, and the hypotension that develops from the profound vasodilation can be severe and refractory to treatment. Hence there is great potential for this interaction to occur and for potentially serious consequences if it does occur.
image NTG can relax any and all smooth muscle. Esophageal spasm can mimic angina. NTG will relax the esophagus and trick the healthcare provider into thinking that the patient does indeed have cardiac ischemia when the “angina equivalent” is relieved.

Advanced

image Nitrates have some antiplatelet and antithrombotic properties; however, the clinical importance of these effects is unclear.
image Formation of NO from nitrates requires the enzyme mitochondrial aldehyde dehydrogenase (ALDH2). The gene for this enzyme is often homozygous and sometimes missing in Chinese people, and they demonstrate reduced response to NTG.

Evidence

image Nitrates have not been as well studied as β-blockers and CCBs in the prevention of stable angina. A meta-analysis measuring a variety of outcomes, including mortality, found that the efficacy of long-acting nitrates did not differ significantly from that of β-blockers or CCBs.
image There is no evidence that nitrates reduce mortality or cardiovascular complications associated with coronary artery disease. However, nitrates are effective at relieving symptoms associated with coronary artery disease.

FYI Notes

image NTG was the first medication used for angina pectoris, in 1879 by William Murrell.
image The tolerance that has become a characteristic feature of nitrate therapy was discovered accidentally. TNT stands for trinitrotoluene and has three nitrate groups. Munitions workers exposed to high levels of nitrates found that the headaches they experienced diminished as the work week progressed, only to reappear with intensity after the start of each new week. These “Monday morning headaches” were originally attributed to heavy drinking over the weekend. It was later determined that the workers were actually experiencing side effects of nitrates at the start of the week and then developed tolerance during the course of the week. The tolerance wore off during the weekend, when no exposure occurred.
image cAMP and cGMP sometimes have opposing effects on Ca+ levels in cells.
image NTG and ISDN have very different chemical structures.

Vasodilators

Description

Vasodilators cause dilation of arterioles and, to a lesser extent, veins. Not included in this section are vasodilators that act via α1-blockade.

Prototype and Common Drugs

image Prototype: Hydralazine
image Others: Sodium nitroprusside (SNP)

MOA (Mechanism of Action)

image The underlying mechanism of vasodilation of arteriolar smooth muscle by the direct vasodilators is still not confirmed, but theories include interference with the release of Ca+2 from the SR and activation of potassium channels.

Hydralazine

image Hydralazine is not a coronary artery dilator.
image It does not relax venous smooth muscle (i.e., is not a venodilator). Hence, it will have no effect on preload. For this reason it is not a very useful drug for treatment of chronic heart failure.

Sodium Nitroprusside

image SNP is a prodrug that breaks apart to liberate NO, a mediator of dilation.
image It dilates arterioles and, to a lesser extent, veins.

Pharmacokinetics

Hydralazine

image Metabolized in the bowel and/or liver by acetylation. The rate of acetylation varies among individuals, with “fast acetylators” requiring higher doses of the drug.
image If given by intravenous bolus, hydralazine has a peak action 20 minutes after administration. It is also available in an oral form, although the oral form is rarely used.

Sodium Nitroprusside

image Has a virtually immediate onset of action and very short duration (minutes) and is administered only by intravenous infusion.
image SNP breaks down in red blood cells, using hemoglobin as a carrier for cyanide, the primary breakdown product.

Indications

image HTN

Contraindications

image Vasodilators drop SVR. The cardiovascular system compensates for low BP from SVR by increasing CO, primarily by increasing HR and contractility via sympathetic nervous stimulation. Therefore situations in which tachycardia is harmful would be contraindications:

image Coronary artery disease
image Aortic stenosis
image Mitral stenosis

Hydralazine

image Systemic lupus erythematosus (SLE) can provoke an SLE-like effect, including glomerulonephritis, in some patients. The mechanism of these immunologic reactions is not known.

Side Effects

image Tachycardia: Caused by SNS compensation
image Palpitations: Caused by tachycardia
image Flushing: When the vessels in the skin dilate, the skin turns more pink.
image Hypotension

Hydralazine

image Immunologic effects (see list of contraindications). The mechanism is unknown.

Sodium Nitroprusside

image Cyanide poisoning: The human body can detoxify a certain amount of cyanide. When this amount is exceeded, then cyanide toxicity ensues.
image Methemoglobinemia: See FYI notes.

Important Notes

image The role of hydralazine in treating chronic HTN has severely diminished over time, and its use is now limited largely to hypertensive emergencies. Because of their toxicities, both SNP and hydralazine are considered second-line agents for hypertensive emergencies in many jurisdictions.

FYI Notes

image These agents are rarely ever prescribed anymore because significant compensatory responses and numerous side effects limit their usefulness in the management of HTN.
image The iron (Fe) molecule in hemoglobin is normally in the Fe2+ state and can bind O2 appropriately. If the iron is oxidized to Fe3+, then the hemoglobin is called methemoglobin. Methemoglobin is unable to bind oxygen. In normal humans, about 0.5% of hemoglobin is in the form of methemoglobin. Methemoglobinemia reduces the oxygen carrying capacity of blood.
image SNP is 33% cyanide by weight.

Natriuretic Peptides

Description

Also called natriuretic factors, natriuretic peptides are endogenous hormones that are used to treat heart failure. The drug is recombinant human brain natriuretic peptide (BNP). Despite the name, the main source of BNP is the ventricle.

Prototype

image Prototype: Nesiritide

MOA (Mechanism of Action)

image A number of hormonal and neurologic mechanisms are activated in heart failure, of which natriuretic factors (peptides) are one.
image Endogenous natriuretic factors are increased during heart failure in response to atrial stretch and ventricular stretch, when the chambers are volume overloaded because of heart failure.
image BNP binds to BNP receptors on blood vessels and kidneys, which activates the cGMP system, resulting in the following effects:

image Blood vessels: vasodilation
image Kidneys: natriuresis and diuresis
image Kidneys: inhibition of renin and aldosterone

image Through these effects, the abnormally high preload (filling volume) of the heart is reduced and abnormally high afterload (vasoconstriction) is also reduced. Both reduction of preload and reduction of afterload are important components of treating patients with heart failure (Figure 11-17).
image

Figure 11-17

Pharmacokinetics

image Natriuretic factor is a peptide. Taken orally, it would be digested down to amino acids and would therefore be completely ineffective.
image BNP has a half-life of 21 minutes. Therefore it is given as an intravenous infusion, because intermittent administration is not convenient, nor does it result in stable serum levels of drugs with such short half-lives.

Indication

image Advanced decompensated acute heart failure

Contraindication

image Hypotension: Vasodilators will exacerbate low BP.

Side Effects

image Hypotension: caused by vasodilation
image Possible worsening renal dysfunction (current evidence not conclusive)

Important Notes

image Endogenous BNP is elevated in patients with heart failure. Most systems that are activated in heart failure (such as the renin-angiotensin-aldosterone system and the SNS) result in vasoconstriction and water retention, which is the opposite effect of BNP. Therefore BNP acts as a counterbalancing hormone system in heart failure.

Advanced

image The body produces proBNP (inactive), which is subsequently cleaved into BNP (active) and NT-proBNP (inactive).
image NT refers to the N terminal end of the original (proBNP) protein.
image Both BNP and NT-proBNP can be measured in patients with heart failure.
image Heart failure is not the only pathologic condition in which BNP is elevated. Other conditions, including shock, hypoxia, renal failure, and pulmonary HTN, can also increase circulating levels of BNP and NT-proBNP.

Evidence

image A meta-analysis in 2005 (three trials, N = 862 patients) showed a possibility of increased death and renal dysfunction in patients with acute decompensated heart failure treated with nesiritide. All studies were double blinded. However, another meta-analysis in 2006 (seven trials, N = 1717 patients) did not show increased mortality or renal failure in patients with acute heart failure treated with nesiritide. Two of the trials were not blinded.
image A third meta-analysis in 2009 (14 trials, N = 934 patients) evaluating the effect of nesiritide on renal function in patients immediately after cardiac surgery demonstrated reduced need for dialysis in patients treated with nesiritide (OR = 0.32). However, all studies included were small and underpowered to provide statistical significance on their own.
image More evidence is required to clearly understand the effects of exogenous administration of BNP on mortality and renal function when administered to patients with acute heart failure.

FYI Notes

image The body produces several different forms of natriuretic factor:

image Atrial (type A or ANP)
image Ventricular, also called brain (type B or BNP)
image Vascular (type C)

image Natriuretic factor was identified first in pig brain in 1988, which is why it is called brain natriuretic peptide and not ventricular natriuretic peptide.
image Natrium is the Latin word for sodium, and uresis refers to in the urine.
image Natriuresis means losing sodium in the urine.
image Diuresis means losing water in the urine.
image Enuresis means involuntary passing of urine.

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