Overview

Nitroglycerin (glyceryl trinitrate [GTN]) was first synthesized in 1847 by Ascanio Sobrero, who described a “violent headache” upon self-administration of a “minute quantity” of the drug. A number of reports of the therapeutic effects of GTN in the latter half of the nineteenth century included those of Field, Brunton, and Murrell. Although sublingual GTN has been commonly used for more than a century to treat acute attacks of angina, the development of organic nitrates with sustained activity was limited by their poor oral bioavailability. Eventually, this difficulty was overcome with transdermal formulations of GTN and the development of long-acting oral nitrate preparations, including isosorbide dinitrate, isosorbide-5-mononitrate, erythrityl tetranitrate, and pentaerythritol tetranitrate. Today, the organic nitrates continue to play an important role in the management of both angina and congestive heart failure (CHF).

Mechanisms of Action

Organic nitrates are prodrugs that must undergo enzymatic denitrification to mediate their pharmacodynamic effects ( Figures 7-1 and 7-2 ). In 1977, Murad first suggested that nitric oxide (NO) mediated the effects of GTN. Since that time, it has generally been accepted that all the organic nitrates exert their effects via release of NO or some NO-containing moiety. As the understanding of NO biology grew and the importance of decreased NO bioavailability in cardiovascular (CV) disease was recognized, it was postulated that the organic nitrates could supplement endogenous NO with favorable biologic effects. Despite its appeal, this hypothesis has never been formerly tested, and no available evidence suggests that exogenous NO donors favorably modify the natural history of CV disease.

Pathways of organic nitrate bioactivation in vascular cells. ALDH2, aldehyde dehydrogenase 2; cGMP, cyclic guanosine monophosphate; cGK-I, cGMP dependent protein kinase-I; Cyt Ox, cytochrome oxidase; ER, endoplasmic reticulum; GDN, glycerol dinitrate; GMN, glycerol mononitrate; GTN, glyceril trinitrate (nitroglycerin); ISDN, isosorbide dinitrate; ISMN, isosorbide mononitrate; NO, nitric oxide; PEDN, pentaerythrityl dinitrate; PEMN, pentaerythrityl mononitrate; PETN, pentaerythrityl tetranitrate; PETriN, pentaerythrityl trinitate; sGC, soluble guanylate cyclase.

Molecular mechanisms of nitrate tolerance. ALDH2, aldehyde dehydrogenase; AT-II, angiotensin II; BH2, dihydrobiopterin; BH4, tetrahydrobiopterin; cGMP, cyclic guanosine monophosphate; ET-1, endothelin-1; GMP, guanosine monophosphate; GTN, glyceril trinitrate (nitroglycerin); GTP-CH, guanosine triphosphate cyclohydrolase; NOS, nitric oxide synthetase; PDE, phosphodiesterase; PGI, prostacyclin; PKC, protein kinase C; RAAS, renin-angiotensin-aldosterone system; NADPH-Ox, nicotinamide adenine dinucleotide phosphate oxidase; sGC, soluble guanylate cyclase.

The exact mechanism of nitrate biotransformation (denitrification) was the subject of debate for several decades. Multiple enzymatic candidates were proposed, including cytochrome P450 (CYP), endothelial NO synthase, and glutathione transferase. Interest in defining the denitrification pathway was intense because it was believed that the development of abnormalities in this process might explain the loss of nitrate effects during sustained therapy, a phenomenon termed nitrate tolerance. More recent studies have proposed a role for mitochondrial aldehyde dehydrogenase type 2 (mALDH-2) in the biotransformation of GTN. The role of this enzyme in the activation of GTN supported the dependence of GTN-induced cyclic guanosine monophosphate (cGMP) production, based on the presence of this enzyme and the fact that specific antagonists of mALDH-2 inhibit the vasoactive actions of GTN. The relevance of this biotransformation pathway in humans is supported by observations of reduced hemodynamic responses to GTN in Asian subjects, who are genetically deficient in the enzyme aldehyde dehydrogenase. Importantly, the function of this biotransformation pathway is consistent with a number of observations concerning nitrate tolerance (see the discussion below). Although the discovery of the mALDH-2 biotransformation pathway provided important new insights concerning the actions of GTN, many unanswered questions remain. Most importantly, the denitrification of other organic nitrates, including isosorbide dinitrate and isosorbide-5-mononitrate, does not depend on mALDH-2. These observations emphasize that our knowledge of these processes remains incomplete.

Following organic nitrate bioactivation, and despite uncertainties concerning the exact nature of the NO moiety derived, there is activation of soluble guanylate cyclase and increased cGMP synthesis. The subsequent increase in the bioavailability of cGMP triggers a molecular cascade that mediates vasorelaxation through multiple pathways, which lead to a reduction in intracellular Ca ²⁺ concentrations, including activation of protein kinases involved in the regulation of intracellular Ca ²⁺ levels, such as the sarcoplasmic Ca ²⁺ -ATPase. NO donors, as with endogenous NO, appear to have multiple biologic effects, including thiol modification, regulation of mitochondrial respiration, modulation of K ⁺ channel activity, and protein nitration, although less evidence is available concerning the therapeutic relevance of these effects. As discussed below, these diverse biochemical responses to the organic nitrates appears to be responsible for their recently described nonhemodynamic effects.

Pharmacokinetics

Organic nitrates are available in a variety of formulations with differing routes of administration. GTN undergoes hepatic and intravascular metabolism with a half-life of approximately 1 to 4 minutes with biologically active dinitrate metabolites that have a half-life of approximately 40 minutes. GTN is very effective when given by the sublingual and transdermal routes. Transdermal administration of GTN is the only method of administration that provides a clinically effective long-acting form of GTN. When given orally, first-pass metabolism of GTN is extensive. Oral GTN is available for the therapy of angina, but no evidence of clinical efficacy exists.

Although it provides hemodynamic and antianginal effects, isosorbide dinitrate is rapidly metabolized, with a plasma half-life of approximately 40 minutes. Its major metabolites, isosorbide-2-mononitrate and isosorbide-5-mononitrate, are both biologically active, with half-lives of approximately 2 and 4 hours, respectively. Isosorbide-5-mononitrate does not undergo first-pass hepatic metabolism and is completely bioavailable. Both of these nitrates are available in sustained-release preparations; the sustained, phasic-release form of isosorbide-5-monitrate is the most popular, with once-daily dosing and favorable pharmacokinetics that avoid tolerance. Although not prescribed in North America, both erythrityl tetranitrate and pentaerythritol tetranitrate are used in certain parts of the world for the treatment of angina.

Pharmacodynamic Effects

The organic nitrates are potent vasodilators, whose vascular effects vary widely in different distributions of the vasculature ( Figure 7-3 ). They have potent effects in the venous capacitance bed and reduce ventricular volume and preload. They also dilate conduit arteries, and at the doses used clinically, they have no effect on peripheral vascular resistance. The nitrates dilate epicardial coronary arteries but have little or no effect on the coronary resistance vessels. In patients with coronary artery disease (CAD), nitrates can dilate coronary stenoses and collateral vessels, which can improve and redistribute coronary blood flow. Because they do not reduce coronary vascular resistance, nitrates avoid the risk myocardial ischemia because of coronary steal, which can occur with arteriolar dilators, such as dipyridamole and short-acting dihydropyridines (DHPs), in which coronary blood flow is diverted away from areas of ongoing ischemia. Therefore, the nitrates possess a unique combination of vascular effects that can favorably affect the mismatch between myocardial oxygen supply and demand in patients with CAD.

Antianginal effects of acutely administered glyceryl trinitrate ( GTN ; nitroglycerin). LVEDP, left ventricular end-diastolic pressure.

Side Effects of Organic Nitrates

Headaches are common during nitrate therapy and are generally most pronounced early after initiation of therapy ( Table 7-1 ). In some patients, the headache diminishes over a few days, but not uncommonly, the nitrate must be discontinued. Hypotension can occur with all nitrates but is more common when nitrates with a rapid onset of action are used, such as sublingual GTN or short-acting isosorbide dinitrates. Many patients experience dizziness, presyncope, or even syncope on initial exposure to sublingual GTN or initial doses of isosorbide dinitrate. Symptomatic hypotension is less common after transdermal GTN administration. In general, patients taking their first dose of nitrates should sit or lie down during administration if necessary. In the case of isosorbide dinitrate, the dose should be uptitrated over several days, starting with the 10-mg dose. Reduction in dose or a change of agent should be considered when such symptomatic hypotension occurs. Other side effects are uncommon. With transdermal GTN, some patients develop marked erythema and some local edema at the site of the application of the transdermal preparation. This likely represents a marked response to local hyperemia, but in some patients, it may represent a local allergic reaction to the preparation itself. In some this reaction is troublesome enough that the transdermal preparation must be discontinued. Although rare, methemoglobinemia has been reported after high-dose intravenous GTN therapy.

Clinical Efficacy of Organic Nitrates

Nitrate Tolerance

When given acutely, nitrates have potent hemodynamic and therapeutic effects. As long-acting nitrates were developed for clinical use, questions arose concerning their potency. Early investigations questioned the efficacy of the oral isosorbide dinitrate, as first-pass metabolism was felt to be complete, because portal vein administration in animals had no hemodynamic effects. Subsequent studies in patients with CAD refuted these findings because oral isosorbide dinitrate clearly produced significant hemodynamic and antianginal effects. However, later investigations confirmed that the clinical effects of nitrates were lost rapidly during sustained therapy, documenting that the phenomenon of nitrate tolerance is a significant clinical problem. Tolerance develops in response to all nitrates, although evidence suggests that it is not as prominent with pentaerythritol tetranitrate. When nitrates are administered using dosing regimens that lead to significant plasma concentrations throughout a 24-hour period, their hemodynamic and symptomatic effects are almost completely lost. Tolerance develops early, within 24 hours of the initiation of therapy, and it cannot be overcome with the administration of higher doses. This loss of therapeutic effect in the face of continued therapeutic plasma concentrations has led to more than three decades of intense investigation concerning the etiology of tolerance, a controversy that continues to this day. Shortly after the initial description of tolerance, it was recognized that nitrate effects could be maintained using dosing regimens that allowed for a nitrate-free or low-nitrate concentration for several hours each day. This observation led to the adoption of intermittent or eccentric dosing regimens that now represent the standard of care, particularly in the setting of stable exertional angina. The mechanisms of nitrate tolerance have been the subject of extensive investigation for decades. Several hypotheses have been proposed, although agreement concerning a single unifying hypothesis has never been obtained. A brief overview of approaches to this classic pharmacologic question is outlined below.

Nonhemodynamic Effects of Organic Nitrates

A number of studies have documented that the organic nitrates can inhibit platelet aggregation. Platelets produce NO, which acts to inhibit granule release and aggregation. GTN has been shown to inhibit platelet aggregation both in vitro and in a number of human experiments. Whether tolerance develops to this antiplatelet effect is controversial, and in general, the clinical relevance of this effect is unclear; however, it has been postulated that this effect may be particularly important in the setting of acute coronary syndromes (ACS), although the efficacy of GTNs in this situation remains only hypothetical.

Another impact of the organic nitrates unrelated to their hemodynamic effects is their ability to precondition. GTN has been shown to have important preconditioning effects in a number of animal models. In humans, short-term exposure to a GTN leads to decreased evidence of ischemia during percutaneous coronary intervention (PCI) and in the setting of exercise-induced ischemia. Human models have documented that development of the preconditioned phenotype is inhibited by the administration of an antioxidant during exposure to GTN. Little information is available concerning the ability of other organic nitrates to precondition, but one human study found that protection from ischemia and reperfusion was not found after administration of isosorbide-5-mononitrate.

The observation that mALDH-2 plays a critical role in the development of ischemic preconditioning draws an interesting link between the biotransformation of GTN, the subsequent increase in free radical bioavailability, and the preconditioning phenotype. To date, this capacity of the GTN to precondition has not found any meaningful clinical application. Of note, a recent report on normal volunteers suggested that the acute preconditioning effects of a single short-term exposure (2 hours) to transdermal GTN were lost during sustained daily exposure to GTN, suggesting that tolerance develops to the preconditioning effect.

As the importance of NO bioavailability in CV disease became clear, it was believed that NO donors, such as the organic nitrates, would have a beneficial effect as supplemental sources of NO. Although this benefit remained a matter of conjecture, it was never believed that organic nitrates could have adverse effects on vascular function. Given this background, the demonstration that animals exposed to GTN developed significant abnormalities of endothelial function was unexpected. GTN has long been considered a non–endothelium-dependent vasodilator with actions confined to vascular smooth muscle cells. Nevertheless, these observations in animals were followed by human experiments, which confirmed that sustained nitrate exposure causes significant and surprising abnormalities of vascular function. In patients with CAD, 48 hours of intravenous GTN increased the sensitivity of the arterial resistance vessels to angiotensin II and phenylephrine. Further studies revealed that continuous GTN therapy also caused important abnormalities in endothelial function in normal volunteers and worsened endothelial function in those with CAD. Similar abnormalities of vascular function have also been documented during both intermittent transdermal GTN and once-daily administration of isosorbide-5-mononitrate.

The importance of NO biology in the function of the sympathetic nervous system has been recognized. Nitric oxide and NO donors have been shown to have inhibitory effects on sympathetic outflow at multiple sites, both peripheral and central. When given acutely, the pronounced hemodynamic effects of these drugs causes reflex stimulation of the sympathetic nervous system, which complicates experimental observations in this area. Animal observations suggest that sustained nitrate therapy might be associated with an increase in sympathetic outflow. Interestingly, in a human model, continuous transdermal GTN caused a reduction in tonic and reflex modulation of heart rate, leading to a relatively greater sympathetic influence. The overall effect was a blunting of spontaneous baroreflex function, an abnormality usually associated with specific CV diseases. The clinical implications of this are not clear but are an example of a “nitrate effect” associated with abnormalities that generally are believed to have a negative effect on prognosis.

Current Perspectives on Therapy with Organic Nitrates

Despite approximately 150 years of clinical use, many biologic effects of the organic nitrates remain poorly understood. Given the current state of knowledge, it appears that these drugs can have both beneficial and potentially harmful effects, depending on how they are prescribed and for what indication. The understanding of the potential for harm is limited, but it warrants both attention and further study.

In terms of benefits, the effectiveness of organic nitrates in the relief of episodes of angina is unquestioned. Although their use in ACS and acute decompensated heart failure has not been evaluated in large-scale clinical trials, their utility is these settings is widely accepted. They are effective in the treatment of chronic angina, although the development of tolerance is a limitation, and their impact in long-term clinical outcome has never been tested in this population. The clear beneficial role of nitrates in combination with hydralazine in the treatment of chronic CHF was previously discussed. Of note, it has yet to be documented that a nitrate alone can benefit long-term outcome in this patient population. It is now known the GTN has preconditioning effects that limit the adverse effects of ischemia and reperfusion; however, as with other preconditioning approaches, a clearly beneficial application of this biologic effect of nitrates has yet to be defined.

With respect to adverse effects, the finding that sustained nitrate therapy is associated with increased free radical production and evidence of endothelial dysfunction suggests the possibility that these drugs could have harmful effects during chronic therapy. Although these nitrate-induced abnormalities in vascular function have been documented for more than a decade, they have not yet modified the clinical utilization of nitrate therapy. The clinical implications of these findings are unclear, serving to highlight the paucity of clinical data available with respect to clinical outcome during sustained administration with nitrates. Nitrates have been tested in relatively large numbers of patients in the early postinfarction period ; however, the treatment and follow-up periods of these trials were too short to examine the question of safety. Of note, two retrospective analyses of post-MI patients have suggested that long-acting nitrate therapy is associated with an increased mortality rate. Although studies in heart failure (discussed above) have documented a beneficial effect of isosorbide-5-mononitrate when given in combination with hydralazine, the safety and efficacy of a nitrate alone in the setting of chronic heart failure has never been examined. Although it is unclear whether clinical outcome studies will ever be completed, it can be stated that there should be no assumption of clinical safety when these drugs are used as long-term therapy.

It is also important to recall that almost all available information concerning the development of tolerance and/or endothelial dysfunction during nitrate therapy was obtained in normal volunteers or patients not taking other cardiac medications. Of note are both animal and human studies in which tolerance is prevented by concurrent therapy with 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitors as well as agents that inhibit the renin-angiotensin system. In the absence of concurrent therapy with either of these classes of medications, studies were carried out in patients with stable angina; these represent the classic human model of tolerance to the symptomatic benefit of nitrates. A recent study in humans demonstrated that atorvastatin given concomitantly with continuous GTN completely prevented the development of both tolerance and abnormalities of endothelial dysfunction during sustained therapy. Given this background, it can be said that some historic models of nitrate tolerance should be revisited in the current era of pharmacotherapy.

Fundamental Mechanisms of Calcium Channel Blockers

Calcium Channel as Site of Action

CCBs interfere with the entry of Ca ²⁺ into cells through voltage-dependent L- and T-type calcium channels. The major cardiovascular sites of action are 1) vascular smooth muscle cells, 2) cardiac myocytes, and 3) SA and AV nodal cells. By binding to specific sites in the proteins of the calcium channel known as subunits, these agents are able to diminish the degree to which the calcium channel pores open in response to voltage depolarization ( Figure 7-4 ).

Proposed arrangement of the polypeptide chain of the channel forming a 12 subunit of the L-type calcium channel in humans. Four motifs—I, II, III, and IV—are repetitive, and each consists of six putative transmembrane segments. Both the N terminal and the C terminal point to the cytoplasm. Rings separate the segments encoded by numbered exons. The transmembrane segments encoded by alternative exons 8 or 8A, 21, or 22, and 31 or 32 are shown. Sequences encoded by invariant exons 7, 33, and 45, which are subject to constitutive splicing, are also shown. Exons 40, 41, and 42 are subject to alternative splicing. Putative sites of glycosylation and of phosphorylation involving protein kinase C ( C ) and protein kinase A ( A ) are shown, as are the discrete binding areas of the three types of calcium antagonists—phenylalkylamine (verapamil-like), benzothiazepine (diltiazem-like), and dihydropyridine (nifedipine-like).

(From Abernethy DR, Schwartz JB. Calcium-antagonist drugs. N Engl J Med 1999;341:1448.)

Molecular Structure

The calcium channel consists of four high-molecular-weight subunits: α1, α2, β, and γ. Of these, the α1 subunit contains the calcium channel pores and the binding sites for CCBs. The subunits have a complex structure with four major domains (see Figure 7-4 ), each with six transmembrane units. The calcium channel pores exist between the fifth and sixth units, and the voltage sensor is located near the fourth transmembrane unit of each domain.

Two regulatory aspects of calcium channel blockade are important. First, when cyclic adenosine monophosphate (cAMP) activates protein kinase A to phosphorylate the calcium channel, a number of phosphorylation sites are available on the COOH-terminal portion of each of the α1 subunits. Such phosphorylation allows the channel to persist in a more open state. Second, the β subunit binds to the cytoplasmic link between domains I and II of the γ1 subunit and thereby enhances calcium channel opening.

Drug Binding Sites

At least three binding sites exist for these drugs, commonly identified by the prototype agents verapamil, nifedipine, and diltiazem, respectively; these are known as the V-, or phenylalkylamine-; N-, or DHP-; and D-, or benzothiazepine-, binding sites. The N-binding site is also termed the DHP site, to which all DHPs are thought to bind. Each of the different agents binds to specified sites on various domains, and none binds to all of the pores in all of the domains. Thus, calcium channel blockade can never be complete.

Calcium Channels: L and T Types

The most important property of the CCBs is to selectively inhibit the inward flow of charge-bearing Ca ²⁺ when the calcium channel becomes permeable, or “open.” At least two types of calcium channels are relevant to the treatment of CV disorders: the L and T types. The major calcium channel related to pharmacologic antagonism, the voltage-gated L-type (long-acting, slowly activating) channel, is blocked by all available CCBs. The function of the L-type channel is to allow entry of sufficient Ca ²⁺ for initiation of contraction by calcium-induced intracellular calcium release from the sarcoplasmic reticulum.

The T-type (transient) channel appears at more negative potentials than the L type and probably plays an important role in the initial depolarization of SA and AV nodal tissue. The L-type calcium channel is found in vascular smooth muscle, in nonvascular smooth muscle in many tissues, and in a number of noncontractile tissues. Blockade of the L-type channel is responsible for the pharmacologic actions of the available CCBs.

Pharmacologic Properties of Calcium Channel Blockers

Classification of Calcium Channel Blockers

The differing pharmacodynamic effects of various CCBs accounts for their classification. All the DHPs bind to the same sites on the α1 subunit and exert a greater Ca ²⁺ inhibitory effect on vascular smooth muscle than on the myocardium, which explains their common property of vascular selectivity; thus their major hemodynamic and therapeutic effect is peripheral and coronary vasodilation.

Nifedipine is the prototypical DHP. The fast-acting capsular form produces rapid vasodilation, alleviates hypertension, and terminates attacks of coronary spasm. However, the brisk peripheral vasodilation produced by this formulation may result in significant hypotension and reflex adrenergic activation that often causes tachycardia and stimulation of the sympathetic and renin-angiotensin systems. The introduction of truly long-acting DHP compounds—such as amlodipine or sustained-release formulations of nifedipine, felodipine, or isradipine—has resulted in substantially fewer symptoms from the vasodilatory side effects. It is a commonly held belief that the short-acting DHPs, particularly nifedipine, account for the majority of presumed negative or adverse clinical results in many older trials. The second-generation DHPs are distinguished by a longer half-life, as in the case of amlodipine, or by a greater vascular selectivity.

Although each binds to a different site on the α1 subunit, the NDHPs verapamil and diltiazem have many properties in common. Both act on nodal (SA and AV) tissue and are therapeutically effective in supraventricular tachycardias. Both decrease the sinus discharge rate. These drugs inhibit myocardial contractility more than the DHPs; in effect, they are less vascularly selective. Both verapamil and diltiazem have greater effects on the AV node than on the SA node, and the explanation for this may relate to frequency dependence; thus there is better access to the binding sites when the calcium channel pore is open. During supraventricular tachycardia, the calcium channel of the AV node opens more frequently, so the CCB binds more avidly, hence it more specifically inhibits the AV node to interrupt the reentry circuit.

Regarding side effects, because NDHPs are less active on vascular smooth muscle, they produce fewer vasodilatory adverse reactions than the DHPs. Sinus tachycardia is uncommon, in part because of the inhibitory effects on the SA node. High-degree AV block is a risk with preexisting AV nodal disease or during cotherapy with other AV node–depressant drugs, such as β-blockers. NDHPs have a more marked depressive effect on ventricular function than DHPs. In addition, constipation occurs as a side effect with verapamil but seldom with diltiazem, although the latter may cause peripheral edema.

Vascular Selectivity

The cellular mechanism of vascular smooth muscle contraction differs from that of the myocardium. Although smooth muscle contraction is ultimately calcium dependent, it is the myosin light-chain kinase that is activated by calcium calmodulin. In the human myocardium, Godfraind and associates proposed that the ratios of vasodilation to negative inotropy for the prototype CCBs were 10 : 1 for nifedipine, 1 : 1 for diltiazem, and 1 : 1 for verapamil. Other DHP compounds have even greater vascular selectivity, up to 1000 : 1. In terms of clinical use, these observations provide the basis for considering a clinical division of the CCBs into two groups: DHPs, which include nifedipine and its analogs, and NDHPs, such as verapamil, diltiazem, and their derivatives.

Noncardiovascular Effects

Although highly active on vascular smooth muscle, CCBs have little or no effect on other smooth muscle throughout the body, such as that of the bronchi, gut, or genitourinary tract. These agents may relax uterine smooth muscle and have been used in therapy for preterm contractions, although it is generally recommended that they be stopped before delivery. This action probably reflects variations between tissues in either the structure or function of their calcium channels. Also crucial to the therapeutic applicability of CCBs is the fact that skeletal muscle does not respond to conventional CCBs. As a result, skeletal muscle weakness is not a side effect of calcium channel blockade. In skeletal muscle, depolarization-activated calcium release from the sarcoplasmic reticulum is the principal source of the myoplasmic calcium rise. Thus only the myocardium, not skeletal muscle, responds to calcium entry through the voltage-dependent calcium channels; and the myocardium, not skeletal muscle, has its rise in contractile calcium inhibited by CCBs.

Pharmacokinetics

From the point of view of drug interactions, all of the CCBs are metabolized in the liver by an enzyme system that is inhibited by cimetidine, azole antifungals, and hepatic dysfunction; CCBs are increased in activity by phenytoin and phenobarbital.

Major Indications for Calcium Channel Blockers

Specific Calcium Channel Blockers

Drug Interactions of Calcium Channel Blockers

Calcium Channel Blockers: The “Safety” Controversy

Beginning in 1995, a question about the safety of all CCBs was raised when a retrospective analysis of the short-acting form of nifedipine appeared to increase heart attacks in ACS patients, but the data were grouped with all CCBs. As prospective trials did not confirm these fears, and as physicians gained experience with the slow-release NDHPs and long-acting DHPs such as amlodipine, this issue gradually died. In fact, several antihypertensive trials have established the safety and benefit of these agents.

There has been a burst of data on the use of CCBs in the past decade, which offers important and reassuring safety data regarding CCB use in patients with ischemic heart disease. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a study of 33,357 patients aged older than 55 years with hypertension and at least one other common heart disease risk factor. The patients were randomized to one of four antihypertensive regimens: chlorthalidone, a diuretic; doxasin, an α-blocker; amlodipine, a CCB; and lisinopril, an ACE inhibitor. The doxasin arm was terminated early because of an increased CV risk; however, no differences were evident in the diuretic, CCB, or ACE-inhibitor arms in terms of the primary outcome of combined fatal CHD and nonfatal MI or all-cause mortality.

A second trial, the Valsartan Antihypertensive Long-term Use Evaluating (VALUE) trial, was designed specifically to test the hypothesis that the angiotensin receptor blocker valsartan would be superior to amlodipine for the same blood pressure (BP) control. A total of 15,245 patients older than 50 years were followed for a mean of 4.2 years, until 1450 events had accumulated. BP was reduced by both treatments, but the amlodipine-based therapies were more effective in BP control, particularly early in the study, achieving 4.0/2.1 mm Hg lower pressure compared with the valsartan group at 1 month, and achieving 1.5/1.3 mm Hg lower pressure at 1 year. Most importantly, no evidence of harm was found in the patient population, and a nonstatistically significant slightly lower overall event rate occurred in the amlodipine group: 810 patients in the valsartan group (25.5 per 1000 patient-years) and 789 in the amlodipine group (24.7 per 1000 patient-years). In addition, of the secondary outcomes, MI occurred more frequently ( P = .02) in the valsartan group compared with the amlodipine group ( Figure 7-5 ). The authors hypothesized that the lower BPs in the calcium channel group may explain the lack of superiority of the angiotensin receptor blocker, but it seems unlikely that it could also explain the statistically significantly lower infarction rate.

Systolic and diastolic blood pressure ( BP ) and differences (valsartan and amlodipine) in BP between treatment groups during follow-up. BP difference between the two groups in the Valsartan Antihypertensive Long-Term Use Evaluating (VALUE) trial was significant ( P < .0001) at every time point, favoring the amlodipine-based regimen. Overall differences in systolic BP were 2.23 mm Hg (standard error, 0.18); overall differences in diastolic BP were 1.59 mm Hg (standard error, 0.11).

(Modified from Julius S, Kjeldsen V, Weber M, et al, for the VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363:2024.)

The Comparison of Amlodipine Versus Enlapril to Limit Occurrences of Thrombosis (CAMELOT) trial randomized 1992 patients with angiographically proven CAD who were normotensive at baseline (mean BP, 129/78 mm Hg for both arms) to amlodipine or enalapril versus placebo. The incidence of CV events was 23% in the placebo arm, 20% with enalapril, and 17% with amlodipine, with similar BP results in the two active treatment arms that were significantly lower than the placebo; this reduction was driven solely by coronary revascularization and angina, not hard endpoints, although a nonsignificant trend was observed toward benefit in hard CV endpoints for both treatment arms compared with placebo. Importantly, given data from Action to Control Cardiovascular Risk in Diabetes (ACCORD)—which suggests that aggressive therapy in high-risk diabetic patients to a systolic BP less than 120 mm Hg may not be beneficial compared with a goal of less than 140 mm Hg —the mean systolic BP after therapy dropped by only 4.5 mm Hg, meaning that BPs in the treatment arm were still higher than the goal in the ACCORD trial.

As is commonly found in clinical practice, combination therapy to reach target BP is often required, which limits the generalizability of prior trials that tested single-agent regimens. More recent trials have attempted to address this concern by comparing predefined combination therapies. One of these trials to assess the prevention of CV events with an antihypertensive regimen of amlodipine, adding perindopril as required, versus atenolol, adding bendroflumethiazide as required, was the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT-BPLA). It examined of the efficacy of CCBs or β-blockers as first-line therapy, in combination with a renin-angiotensin-aldosterone system (RAAS) inhibitor, versus diuretic in 19,257 patients with hypertension who were 40 to 79 years old and at high CV risk. The primary outcome was a combined endpoint of fatal coronary events and nonfatal MI. In the CCB arm, 39% of patients were concomitantly on an RAAS inhibitor, and in the β-blocker arm, 49% were concomitantly on a diuretic. The trial was stopped early because of increased CV events in the β-blocker arm. Patients in the CCB arm had fewer CV events (27.4 vs. 32.8 per 1000 patient-years; relative risk [RR], 0.84), a lower all-cause mortality (13.9% vs. 15.5%; RR, 0.89), and although not a primary endpoint, less incidence of diabetes, the latter reflecting known side effects of both β-blocker and thiazide diuretics. In contrast to the beneficial finding of NDHP in the ASCOT trial, another large trial of DHP CCBs did not demonstrate any benefit compared with RAAS inhibition. The International Verapamil-Trandolapril Study (INVEST) randomized 22,576 patients with CAD to verapamil or trandolarpril and found no difference in either arm in terms of the primary endpoint of first occurrence of all-cause death, nonfatal MI, or nonfatal stroke.

An important question addressed partially in ASCOT is what to do when multiple agents need to be started in patients at high CV risk. In particular, it is uncertain which agent to add to RAAS inhibition, which is often already indicated in patients with diabetes, in post-MI patients, and in those with established CV disease. The largest trial to address this question is the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, which randomized 11,506 patients to a two-drug regimen. Both arms included benazepril, and the trial compared the addition of the CCB amlodipine versus diuretic therapy with hydrochlorthiazide. The primary outcome of the trial was the composite of death from CV causes, nonfatal MI, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization. BP goals were achieved in both arms, yet the combination with the CCB had a 2.2% absolute risk reduction in the primary endpoint compared with the diuretic regimen (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.72 to 0.90; P < .001; Figure 7-6 ).

Cardiovascular morbidity and mortality with combination therapy. Primary outcomes in the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial were significantly different and favored the use of benazepril-amlodipine to amlodipine-hydrochlorothiazide. The relative risk reduction was 20% (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P < .001).

(From Jamerson K, Weber MA, Bakris GL, et al, for the ACCOMPLISH trial investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359[23]:2417-2428.)

There is a theoretical concern that DHP CCBs may worsen renal function, in particular in patients with diabetes. In contrast to the effect of RAAS inhibitors, CCB may preferentially vasodilate the afferent arteriole and thereby worsen renal function. This was specifically evaluated in the Gauging Albuminuria Reduction with Lotrel in Diabetic Patients with Hypertension (GUARD) trial, which randomized 332 patients with hypertension and albuminuric type 2 diabetes to benazepril, with either hydrochlorthiazide or amlodipine, and followed them for 1 year. This was a noninferiority trial, and the primary endpoint was urinary creatinine ratio as a measure of albuminuria. Both arms demonstrated a regression in proteinuria that likely reflected improved BP control. However, a near 30% change favored the combination of RAAS inhibitor and diuretic, although these findings should be tempered by the more rapid decline in estimated glomerular filtration rate (GFR) in the diuretic arm, which may have biased the results. The results of the GUARD and ACCOMPLISH trials together make tailoring combined therapy more challenging for the physician, in that GUARD suggests that a trade-off may exist such that reducing CV risk may come at the cost of proteinuria when using a combined DHP and CCB. Given the small size of the trial and the confounding progression in kidney disease, this issue requires further investigation.

Regarding the particular issue of whether to use a DHP instead of an NDHP CCB for the treatment of essential hypertension, concern has been raised over the use of a short-acting DHP (nifedipine) and NDHP (verapamil, diltiazem) in patients at high risk for MI. This concern came from an observational study conducted in the 1990s. In this case-control study, patients treated with nifedipine, diltiazem, or verapamil had an increased risk for MI that was not seen with other antihypertensives, particularly when these drugs were used at high doses. However, this finding was likely confounded by the fact that the use of calcium channel blockade is much higher in patients with symptomatic CAD given the potent role these agents have as antianginal medications. It is important to note that no concern has been reported for the long-acting DHP CCBs and any increased risk of MI in patients treated for essential hypertension in multiple trials. The INVEST investigators specifically examined the risk of CV outcomes between long-acting verapamil versus atenolol in a subgroup of patients with prior MI and found no difference between treatment arms. Although results of substudies must be interpreted with caution, these data in the context of other studies suggest that NDHPs are at least as effective as β-blocker therapy.

In summary, based on the trials above, convincing evidence suggests that DHP CCBs are safe and efficacious for most patients with high CV risk who require further BP control or angina treatment, and that in particular, these are useful in combination therapy. Concerns initially raised about the risks observed in studies of short-acting CCBs are not seen in contemporary trials of long-acting CCBs. In a meta-analysis that included 27 trials and 175,634 patients, the authors examined DHP CCBs versus others agents or placebo in patients with hypertension who also had other high-risk features and found that although the odds ratio (OR) for a heart failure was increased (and may reflect the side effect of pedal edema), the OR was 0.96 ( P = .026) for all-cause death favoring DHP CCBs, with no increase in MI in the subgroup of patients with CAD.

β-Adrenergic Receptors

The effects of an endogenous hormone or exogenous drug ultimately depend on physiochemical interactions with macromolecular structures of cells called receptors. Agonists interact with a receptor and elicit a response; antagonists interact with receptors and prevent the action of agonists.

In the case of catecholamine action, the circulating hormone or drug (“first messenger”) interacts with its specific receptor on the external surface of the target cells. The drug hormone/receptor complex, mediated by the G protein (Gs), activates the adenyl cyclase enzyme on the internal surface of the plasma membrane of the target cell, which accelerates the intracellular formation of cAMP, whereupon cAMP-dependent protein kinases (“second messengers”) then stimulate or inhibit various metabolic or physiologic processes. Catecholamine-induced increases in intracellular cAMP are usually associated with the stimulation of β-adrenergic receptors, whereas α-adrenergic receptor stimulation is mediated by glycoprotein Gi and is associated with lower concentrations of cAMP and possibly increased amounts of GMP in the cell. These different receptor effects may result in the production of opposing physiologic actions from catecholamines, depending on which adrenergic receptor system is activated.

Most research on receptor action previously bypassed the initial binding step and the intermediate steps and examined either the accumulation of cAMP or the end step, the physiologic effect. Radioactive agonists or antagonists (radioligands) that attach to and label the receptors have been used to study binding and hormone action. The cloning of adrenergic receptors has also revealed important clues about receptor function. The crystal structure of the human β-adrenergic receptor has also been identified.

In contrast to the older concept of adrenergic receptors as static entities in cells that simply initiate the chain of events, newer theories hold that the adrenergic receptors are subject to a wide variety of controlling influences that result in dynamic regulation of adrenergic receptor sites or their sensitivity to catecholamines or both. Changes in tissue concentration of receptor sites are probably involved in mediating important fluctuations in tissue sensitivity to drug action. These principles may have significant clinical and therapeutic implications. For example, an apparent increase in the number of β-adrenergic receptors, and thus a supersensitivity to agonists, may be induced by long-term exposure to antagonists. With prolonged adrenergic receptor blocker therapy, receptor occupancy by catecholamines can be diminished, and the number of available receptors can be increased. When the β-adrenergic receptor blocker is suddenly withdrawn, an increased pool of sensitive receptors is available for endogenous catecholamine stimulation. The resultant adrenergic stimulation may precipitate unstable angina pectoris, an MI, or both. Specific gene polymorphisms of both the β1 and β2 receptors may also influence the pharmacologic response to β-blocking agents.

Effects in Angina Pectoris

Ahlquist demonstrated that sympathetic innervation of the heart causes the release of norepinephrine, activating β-adrenergic receptors in myocardial cells. This adrenergic stimulation causes an increment in heart rate, isometric contractile force, and maximal velocity of muscle-fiber shortening, all of which lead to an increase in cardiac work and myocardial oxygen consumption. The decrease in intraventricular pressure and volume caused by the sympathetic-mediated enhancement of cardiac contractility tends to reduce myocardial oxygen consumption by reducing myocardial wall tension (LaPlace’s law). Although there is a net increase in myocardial oxygen demand, this is normally balanced by an increase in coronary blood flow. Angina pectoris is believed to occur when oxygen demand exceeds supply (i.e., when coronary blood flow is restricted by coronary atherosclerosis). Because the conditions that precipitate anginal attacks—exercise, emotional stress, food—cause an increase in sympathetic cardiac activity, it might be expected that blockade of cardiac β-adrenergic receptors would relieve anginal symptoms. It is on this basis that the early clinical studies with β-blocking drugs in patients with angina pectoris were initiated.

Three main factors contribute to the myocardial oxygen requirements of the LV: heart rate, ventricular systolic pressure , and size of the LV . Of these, heart rate and systolic pressure appear to be important, and the product of heart rate multiplied by the systolic BP is a reliable index for predicting the precipitation of angina in a given patient ; however, myocardial contractility may be even more important.

The reduction in heart rate effected by β-blockade has two favorable consequences: a decrease in blood pressure, thus reducing myocardial oxygen needs, and a longer diastolic filling time associated with a slower heart rate, allowing for increased coronary perfusion. β-Blockade also reduces exercise-induced BP increments, the velocity of cardiac contraction, and oxygen consumption at any patient’s workload ( Box 7-1 ). After treatment, a reduced heart rate variability, a marker for abnormal autonomic control of the heart, or low exercise tolerance may predict those patients who will respond best to treatment with β-blockade. Despite the favorable effects on heart rate, the blunting of myocardial contractility with β-blockers may be the primary mechanism of their antianginal benefit. In normal human coronary arteries, β2-adrenergic receptor–mediated vasodilation enhances coronary perfusion, an effect that is impaired by severe atherosclerosis.

Box 7-1

Possible Mechanisms by Which β-Adrenergic–Blocking Agents Protect the Ischemic Myocardium

• 
  

  Reduction in myocardial consumption, heart rate, blood pressure, and myocardial contractility

  
  
• 
  

  Augmentation of coronary blood flow, increase in diastolic perfusion time by heart rate reduction, augmentation of collateral blood flow, and redistribution of blood flow to ischemic areas

  
  
• 
  

  Prevention or attenuation of atherosclerotic plaque rupture and subsequent coronary thrombosis

  
  
• 
  

  Alterations in myocardial substrate utilization

  
  
• 
  

  Decrease in microvascular damage

  
  
• 
  

  Stabilization of cell and lysosomal membranes

  
  
• 
  

  Shift of oxyhemoglobin dissociation curve to the right

  
  
• 
  

  Inhibition of platelet aggregation

  
  
• 
  

  Inhibition of myocardial apoptosis, which allows natural cell regeneration to occur

From Frishman WH. Alpha- and beta-adrenergic blocking drugs. In Frishman WH, Sonnenblick EH, Sica DA, editors: Cardiovascular pharmacotherapeutics, 2nd ed. New York, 2003, McGraw-Hill, pp 67-97.

Studies in dogs have shown that propranolol causes a decrease in coronary blood flow. However, subsequent experimental animal studies have demonstrated that β-blocker–induced shunting occurs in the coronary circulation, maintaining blood flow to ischemic areas, especially in the subendocardial region. In humans, concomitant with the decrease in myocardial oxygen consumption, β-blockers can cause a reduction in coronary blood flow and an increase in coronary vascular resistance. On the basis of coronary autoregulation, the overall reduction in myocardial oxygen needs with β-blockers may be sufficient cause for this clinically tolerated decrease in coronary blood flow.

Virtually all β-blockers produce some degree of increased work capacity without pain in patients with angina pectoris, regardless of whether they have partial agonist activity, α-adrenergic receptor-blocking effects, direct vasodilating effects, membrane-stabilizing activity, or general or selective β-blocking properties. Therefore, it must be concluded that this results from their common property: blockade of cardiac β-adrenergic receptors ( Table 7-5 ). Both d- and l-propranolol have membrane-stabilizing activity, but only l-propranolol has significant β-blocking activity. The racemic mixture (d,l-propranolol) causes decreases in both heart rate and force of contraction in dogs, whereas the d-isomer has hardly any β-adrenergic receptor–blocking effect. In humans, d-propranolol, which has “membrane” activity but no β-blocking properties, has been found to be ineffective in relieving angina pectoris even at very high doses.

Although exercise tolerance improves with β-blockade, the increments in heart rate and BP with exercise are blunted, and the rate/pressure product (systolic BP multiplied by heart rate) achieved when pain occurs is lower than that reached during a control run. The depressed rate/pressure product at the onset of pain, about 20% reduction from control, is reported to occur with various β-blockers, probably related to decreased cardiac output and possibly to a decrease in coronary perfusion. Thus, although exercise tolerance is increased with β-blockade, patients exercise less than might be expected. This may also relate to the action of β-blockers in increasing LV size, causing increased LV wall tension and an increase in oxygen consumption at a given BP.

Comparison with Other Antianginal Therapies

In a meta-analysis of clinical trial experience over 20 years that compared β-blockers, CCBs, and nitrates in patients who had stable angina pectoris, it was demonstrated that β-blockers provide an equivalent reduction in angina and lead to similar or reduced rates of adverse experiences compared with either CCBs or long-acting nitrates. The rates of cardiac death and MI were not significantly different for β-blockers than for CCBs.

Angina at Rest and Vasospastic Angina

Unstable angina pectoris can be caused by multiple mechanisms, including coronary vasospasm, myocardial bridging, and thrombosis, which appear to be responsible for ischemia in a significant proportion of patients with unstable angina and angina at rest. Therefore, because β-blockers primarily reduce myocardial oxygen consumption but fail to exert vasodilating effects on coronary vasculature, they may not be totally effective in patients whose angina is caused or increased by dynamic alterations in coronary luminal diameter. Despite potential dangers in rest and vasospastic angina, β-blockers have been used successfully as monotherapy and in combination with vasodilating antianginal agents in the majority of patients. In addition, there is evidence that β-blockers can reduce C-reactive protein levels, an inflammatory marker of increased CV morbidity and mortality.

Combined Use of β-Blockers with Other Antianginal Therapies in Angina Pectoris

Conditions Associated with Angina Pectoris

Other Cardiovascular Conditions Associated with Angina Pectoris

Although β-blockers have been studied extensively in patients with angina pectoris, arrhythmias, and hypertension, they have also been shown to be safe for other CV conditions associated with angina pectoris.

Perioperative Therapy in High-Risk Patients with Ischemic Heart Disease

β-Adrenergic drugs will reduce the risk of perioperative ischemia and arrhythmias. Based on these studies, several national organizations have endorsed the perioperative use of β-blockers as a best practice. However, some recent evidence would suggest that the routine use of β-blockers may actually cause harm in some patients. Currently, the best available evidence supports their use in two patient groups: 1) those undergoing vascular surgery who have known ischemic heart disease or multiple risk factors for it and 2) those undergoing vascular surgery who are already receiving β-blockers for cardiovascular conditions. When feasible, β-blockers should be started 1 month before cardiac surgery, with the dose titrated to achieve a heart rate of 60 beats/min, and should be continued for 1 month after surgery.

Pharmacologic Differences Among β-Adrenergic Receptor–Blocking Drugs

More than 100 β-blockers have been synthesized, and more than 30 are available worldwide for clinical use. Selectivity for two subgroups of the β-adrenergic–receptor population has been prominent in the development of β-blockers: β1-adrenergic receptors in the heart and β2-adrenergic receptors in the peripheral circulation and bronchi. More controversial has been the introduction of β-blockers with α-adrenergic receptor–blocking actions, varying amounts of selective and nonselective intrinsic sympathomimetic activity (partial agonist activity), CCB activity, nitric oxide potentiating action, and nonspecific membrane-stabilizing effects ( Table 7-6 ). Pharmacokinetic differences also exist among β-blockers that may be of clinical importance.

Sixteen β-blockers are marketed in the United States for CV disorders: propranolol for angina pectoris, arrhythmias, systemic hypertension, migraine prophylaxis, essential tremor, hypertrophic cardiomyopathy, and reduction in the risk of CV death in survivors of an acute MI; nadolol for hypertension and angina pectoris; timolol for hypertension and to reduce the risk of CV death and nonfatal reinfarction in survivors of MI and for a topical form for glaucoma; atenolol and metoprolol for hypertension and angina and in IV and oral formulations to reduce the risk of CV death in survivors of MI; penbutolol, bisoprolol, nebivolol, pindolol, and carvedilol for hypertension; betaxolol and carteolol for hypertension and in a topical form for glaucoma; acebutolol for hypertension and ventricular arrhythmias; IV esmolol for supraventricular arrhythmias; sotalol for atrial and ventricular arrhythmias; and labetalol for hypertension and in an IV form for hypertensive emergencies. Carvedilol, metoprolol, and bisoprolol are approved for clinical use in the treatment of CHF.

Despite extensive experience with β-blockers in clinical practice, no studies have been done that suggest any of these agents provides major advantages or disadvantages compared with the others for the treatment of many CV diseases. When any available β-blocker is titrated properly, it can be effective in patients with arrhythmia, hypertension, or angina pectoris (see Table 7-6 ). However, one agent may be more effective than other agents in reducing adverse reactions in some patients and in managing specific situations.

Adverse Effects of β-Adrenergic Receptor Blockers

An evaluation of adverse effects is complex because of the use of different definitions of side effects, the kinds of patients studied, study design features, and different methods of ascertaining and reporting adverse side effects among studies. Overall, the types and frequencies of adverse effects attributed to various β-blocker compounds appear similar. The side-effect profiles resemble those seen with concurrent placebo treatments, attesting to the remarkable safety margin of β-blockers.

Adverse effects of β-blockers are an exaggeration of the normal cardiac therapeutic effects, resulting in excess bradycardia, AV nodal block, and excess negative inotropic effect. All β-blockers tend to promote bronchospasm, with low doses of β1-selective agents being the least harmful. Cold extremities occur with both selective and nonselective agents, yet agents with intrinsic sympathomimetic activity may provide a slightly better skin temperature than propranolol, at least during an acute study. The adverse effects of all β-blockers on the peripheral circulation may be less marked than previously thought.

Fatigue is a frequent side effect, again found particularly with propranolol, with less of an effect when a β1-selective or vasodilatory blocker is used, so both central and peripheral hemodynamic mechanisms may be involved. Although one double-blind study shows no difference between the effects of the β1-selective agent atenolol and placebo, exercise physiologists find that some impairment in peak exercise occurs with all β-blockers.

Impotence is often reported by patients who receive β-blockers, usually middle-aged men with atherosclerotic arterial disease. In one study, erectile dysfunction occurred in 11% of patients administered a β-blocker for hypertension compared with 26% of these patients administered a diuretic and 3% of placebo-treated patients.

An impaired quality of life found especially with propranolol is theoretically ascribed to its lipid solubility and brain penetration. Yet a variety of β-blockers other than propranolol, and with different pharmacologic properties, preserve quality of life in hypertensive patients. Central effects of β-blockers are often subtle and are not always explicable by the lipid-penetration hypothesis.

β-Blockers have effects on various metabolic parameters, including blood glucose and blood lipids. In a prospective cohort study of 12,550 nondiabetic individuals with hypertension, β-blockers were shown to increase the risk of developing type 2 diabetes, a finding not observed with thiazide diuretics, ACE inhibitors, or CCBs. This increased risk of diabetes must be weighed against the proven benefits of β-blockers in reducing the risk of CV events in patients with ischemic heart disease. Studies are needed to determine whether the use of ACE inhibitors in conjunction with β-blockers might counteract the adverse effects of β-blockers with respect to glucose tolerance. Carvedilol has been shown not to affect glycemic control, and it improves some components of the metabolic syndrome relative to metoprolol in diabetic patients.

Similarly, β-blockers without intrinsic sympathomimetic activity have been shown in hypertensive patients to decrease high-density lipoprotein cholesterol concentrations by 7% to 10% and to raise triglyceride concentrations by 10% to 20%. These small changes in lipids induced by β-blockers do not appear to diminish the beneficial effects of BP lowering on morbidity and mortality rates from coronary heart disease and stroke.

Contraindications to β-Adrenergic Receptor Blockers

Several absolute contraindications exist, which include CV contraindications such as severe bradycardia (heart rate <40 beats/min); preexisting high-degree AV nodal block (PR interval of >0.24 seconds without a functioning pacemaker); overt LV failure, except when the β-blocker is administered initially at low doses and under supervision to patients already receiving diuretics, digoxin, and an ACE inhibitor; and active peripheral vascular disease with rest ischemia. Severe bronchospasm is an absolute contraindication, even to β-selective agents; severe psychological depression is an important relative contraindication, particularly for propranolol.

Overdosage

Suicide attempts and accidental overdosing with β-blockers are being described with increasing frequency. Because β-blockers are competitive pharmacologic antagonists, their life-threatening effects—bradycardia, myocardial failure, and ventilatory failure—can be overcome with an immediate infusion of a β-agonist agent such as isoproterenol or dobutamine. When catecholamines are not effective, IV glucagon, amrinone, or milrinone has been used. There are no published recommended doses of IV catecholamines or phosphodiesterase inhibitors to treat β-blocker overdose; such agents should be used in their usual pharmacologic concentration until it is certain that reversal of β-blocker toxicity—reversal of heart blocks, excessive bradycardia, and myocardial depression—has occurred.

Monitoring of cardiorespiratory function is necessary for at least 24 hours in an intensive care unit after the patient responds to treatment of the β-blocker overdose. Patients who recover usually have no long-term sequelae; however, they should be observed for the cardiac signs of sudden β-blocker withdrawal.

β-Adrenergic Receptor Blocker Withdrawal

After abrupt cessation of long-term β-blocker therapy, exacerbation of angina pectoris and, in some cases, acute MI and death have been reported. Observations made in multiple double-blind randomized trials have confirmed the reality of a propranolol withdrawal reaction. The mechanism for this reaction is unclear, but some evidence suggests that the withdrawal phenomenon may be due to the generation of additional β-adrenergic receptors during the period of β-blockade. When the β-blocker is then withdrawn, the increased β-adrenergic receptor population readily results in excessive β-adrenergic receptor stimulation, which is clinically important when the delivery and use of oxygen are finely balanced, as occurs in ischemic heart disease. Other suggested mechanisms for the withdrawal reaction include heightened platelet aggregability, an elevation in thyroid hormone activity, and an increase in circulating catecholamines. Similar withdrawal problems have been seen with β-blocker discontinuation in patients with heart failure previously responsive to treatment.

Drug-Drug Interactions

β-Blockers are commonly used with other cardiovascular and noncardiovascular drugs, and the list of drugs with which they interact is extensive ( Table 7-7 ). The majority of the reported interactions have been associated with propranolol, the best-studied β-blocker, and such findings may not necessarily apply to other drugs in this class.

TABLE 7-7

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