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PATHOPHYSIOLOGY & TREATMENT OF ISCHEMIC HEART DISEASE

Supervised by professor : Munir GharibaPresented by : Omar Al Rais M.D

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Angina pectoris transient episodes of myocardial ischemia that are due to an imbalance in

the myocardial oxygen supply–demand relationship. This imbalance may be caused by an increase in myocardial oxygen demand

(which is determined by heart rate, ventricular contractility, and ventricular wall tension) or by a decrease in myocardial oxygen supply (primarily determined by coronary blood flow, but occasionally modified by the oxygen-carrying capacity of the blood) or sometimes by both

In some patients, anginal symptoms may occur without any increase in myocardial O2 demand, but rather as a consequence of an abrupt reduction in blood flow

result from coronary thrombosis (unstable angina) or localized vasospasm (variant or Prinzmetal angina). Regardless of the precipitating factors, the sensation of angina is similar in most patients

Typical angina is experienced as a heavy, pressing substernal discomfort (rarely described as a "pain"), often radiating to the left shoulder, flexor aspect of the left arm, jaw, or epigastrium. However, a significant minority of patients note discomfort in a different location or of a different character

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. Women, the elderly, and diabetics are more likely to experience myocardial ischemia with atypical symptoms. In most patients with typical angina, whose symptoms are provoked by exertion, the symptoms are relieved by rest or by administration of sublingual nitroglycerin.

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Angina pectoris may occur in a stable pattern over many years or may become unstable, increasing in frequency or severity and even occurring at rest. In typical stable angina, the pathological substrate is usually fixed atherosclerotic narrowing of an epicardial coronary artery, on which exertion or emotional stress superimposes an increase in myocardial O2 demand

In variant angina, focal or diffuse coronary vasospasm episodically reduces coronary flow. Patients also may display a mixed pattern of angina with the addition of altered vessel tone on a background of atherosclerotic narrowing. In most patients with unstable angina, rupture of an atherosclerotic plaque, with consequent platelet adhesion and aggregation, decreases coronary blood flow.

Superimposed thrombosis may lead to the complete abrogation of blood flow. Atherosclerotic plaques with thinner fibrous caps appear to be more "vulnerable" to rupture.

Myocardial ischemia also may be silent, with electrocardiographic, echocardiographic, or radionuclide evidence of ischemia appearing in the absence of symptoms. While some patients have only silent ischemia, most patients who have silent ischemia have symptomatic episodes as well.

The precipitants of silent ischemia appear to be the same as those of symptomatic ischemia. We now know that the ischemic burden (i.e., the total time a patient is ischemic each day) is greater in many patients than was recognized previously

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In most trials, the agents that are efficacious in typical angina also are efficacious in reducing silent ischemia. Adrenergic receptor antagonists appear to be more effective than the Ca2+ channel blockers in the prevention of episodes. Therapy directed at abolishing all silent ischemia has not been shown to be of additional benefit over conventional therapy.

Other drugs also have efficacy in treatment of both stable and unstable angina, including antiplatelet agents as well as statins (HMG CoA-reductase inhibitors) which may have a role in stabilizing the vulnerable plaque

A new class of medications that appears to be effective in treatment of angina is exemplified by ranolazine (RANEXA) , which has been approved for treatment of chronic angina. The mechanisms whereby ranolazine exerts its anti-anginal effect are incompletely understood, but the drug appears to exert direct effects on cardiac myocyte Na+ channels

Drugs used in typical angina function principally by reducing myocardial O2 demand by decreasing heart rate, myocardial contractility, and/or ventricular wall stress

By contrast, the principal therapeutic goal in unstable angina is to increase myocardial blood flow; strategies include the use of antiplatelet agents and heparin to reduce intracoronary thrombosis, often accompanied by efforts to restore flow by mechanical means, including percutaneous coronary interventions using coronary stents, or (less commonly) emergency coronary bypass surgery

The principal therapeutic aim in variant or Prinzmetal angina is to prevent coronary vasospasm.

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Anti-anginal agents may provide prophylactic or symptomatic treatment, but adrenergic receptor antagonists also reduce mortality apparently by decreasing the incidence of sudden cardiac death associated with myocardial ischemia and infarction.

The chronic use of organic nitrate vasodilators, which are highly efficacious in treatment of angina, is not associated with improvements in cardiac mortality, and some investigators have suggested that chronic use of nitroglycerin may have adverse cardiovascular effects

The treatment of cardiac risk factors can reduce the progression or even lead to the regression of atherosclerosis. Aspirin is used routinely in patients with myocardial ischemia, and daily aspirin use reduces the incidence of clinical events

Other antiplatelet agents such as oral clopidogrel and intravenous anti-integrin drugs such as abciximab, tirofiban, and eptifibatide have been shown to reduce morbidity in patients with angina who undergo coronary artery stenting

drugs such as the statins reduce mortality in patients with hypercholesterolemia with or without known coronary artery disease

Angiotensin-converting enzyme (ACE) inhibitors also reduce mortality in patients with coronary disease and are particularly recommended for patients when there is concomitant impairment of cardiac systolic function

Coronary artery bypass surgery and percutaneous coronary interventions such as angioplasty and coronary artery stent deployment can complement pharmacological treatment. In some subsets of patients, percutaneous or surgical revascularization may have a survival advantage over medical treatment alone. Intracoronary drug delivery using drug-eluting coronary stents represents an intersection of mechanical and pharmacological approaches in the treatment of coronary artery disease.

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Novel therapies that modify the expression of vascular or myocardial cell genes eventually may become an important part of the therapy of ischemic heart disease.

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ORGANIC NITRATES The NO-dependent relaxation of vascular smooth muscle leads to vasodilation;

NO-mediated guanylyl cyclase activation inhibits platelet aggregation and relaxes smooth muscle in the bronchi and GI tract

There are three distinct mammalian NO synthase isoforms termed nNOS, eNOS, and iNOS , and they are involved in processes as diverse as neurotransmission, vasomotion, and immunomodulation. In several vascular disease states, pathways of endogenous NO-dependent regulation appear to be deranged

Pharmacological Properties Mechanism of Action lead to the formation of the reactive gaseous free radical NO and related NO-

containing compounds. Nitric oxide gas also may be administered by inhalation The exact mechanism(s) of denitration of the organic nitrates to liberate NO

remains an active area of investigation Phosphorylation of the myosin light chain regulates the maintenance of the

contractile state in smooth muscle. NO can activate guanylyl cyclase, increase the cellular level of cyclic GMP.

In smooth muscle, the net result is reduced phosphorylation of myosin light chain, reduced Ca2+ concentration in the cytosol, and relaxation

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Cardiovascular Effects Hemodynamic Effects The nitrovasodilators promote relaxation of vascular smooth muscle. Low

concentrations of nitroglycerin preferentially dilate veins more than arterioles. This venodilation decreases venous return, leading to a fall in left and right ventricular chamber size and end-diastolic pressures, but usually results in little change in systemic vascular resistance.

Systemic arterial pressure may fall slightly, and heart rate is unchanged or may increase slightly in response to a decrease in blood pressure

Pulmonary vascular resistance and cardiac output are slightly reduced. Doses of nitroglycerin that do not alter systemic arterial pressure may still

produce arteriolar dilation in the face and neck, resulting in a facial flush, or dilation of meningeal arterial vessels, causing headache. The molecular basis for the differential response of arterial versus venous tissues to nitroglycerin remains incompletely understood.

Higher doses of organic nitrates cause further venous pooling and may decrease arteriolar resistance as well, thereby decreasing systolic and diastolic blood pressure and cardiac output and causing pallor, weakness, dizziness, and activation of compensatory sympathetic reflexes

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reflex tachycardia and peripheral arteriolar vasoconstriction tend to restore systemic vascular resistance; this is superimposed on sustained venous pooling. Coronary blood flow may increase transiently as a result of coronary vasodilation but may decrease subsequently if cardiac output and blood pressure decrease sufficiently

In patients with autonomic dysfunction and an inability to increase sympathetic outflow (multiple-system atrophy and pure autonomic failure are the most common forms, much less commonly seen in the autonomic dysfunction associated with diabetes), the fall in blood pressure consequent to the venodilation produced by nitrates cannot be compensated. In these clinical contexts, nitrates may reduce arterial pressure and coronary perfusion pressure significantly, producing potentially life-threatening hypotension and even aggravating angina

The appropriate therapy in patients with orthostatic angina and normal coronary arteries is to correct the orthostatic hypotension by expanding volume (fludrocortisone and a high-sodium diet), to prevent venous pooling with fitted support garments, and to carefully titrate use of oral vasopressors. Because patients with autonomic dysfunction occasionally may have coexisting coronary artery disease, the coronary anatomy should be defined before therapy is undertaken

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Effects on Total and Regional Coronary Blood Flow Myocardial ischemia is a powerful stimulus to coronary vasodilation, and regional

blood flow is adjusted by autoregulatory mechanisms. In the presence of atherosclerotic coronary artery narrowing, ischemia distal to

the lesion stimulates vasodilation; if the stenosis is severe, much of the capacity to dilate is used to maintain resting blood flow

When demand increases, further dilation may not be possible relieved anginal pain by dilating coronary arteries and thereby increasing

coronary blood flow because of: In the presence of significant coronary stenoses, there is a disproportionate

reduction in blood flow to the subendocardial regions of the heart, which are subjected to the greatest extravascular compression during systole; organic nitrates tend to restore blood flow in these regions toward normal.

The hemodynamic mechanisms responsible for these effects are not entirely clear. Most hypotheses have focused on the ability of organic nitrates to cause dilation and prevent vasoconstriction of large epicardial vessels without impairing autoregulation in the small vessels, which are responsible for ~90% of the overall coronary vascular resistance.

The resulting increase in blood flow would be distributed preferentially to ischemic myocardial regions as a consequence of vasodilation induced by autoregulation

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the increased blood flow in ischemic regions could be balanced by decreased flow in nonischemic areas, and an overall increase in coronary artery blood flow need not occur. Dilation of cardiac veins may improve the perfusion of the coronary microcirculation

Such redistribution of blood flow to subendocardial tissue is not typical of all vasodilators. Dipyridamole, e.g., dilates resistance vessels nonselectively by distorting autoregulation and is ineffective in patients with typical angina.

Effects on Myocardial O2 Requirements By their effects on the systemic circulation, the organic nitrates also can reduce

myocardial O2 demand. Increasing venous capacitance with nitrates decreases venous return to the heart,

decreases ventricular end-diastolic volume, and thereby decreases O2 consumption An additional benefit of reducing preload is that it increases the pressure gradient for

perfusion across the ventricular wall, which favors subendocardial perfusion Afterload is the impedance against which the ventricle must eject. In the absence of

aortic valvular disease, afterload is related to peripheral resistance. Decreasing peripheral arteriolar resistance reduces afterload and thus myocardial work and O2 consumption.

Organic nitrates decrease both preload and afterload as a result of respective dilation of venous capacitance and arteriolar resistance vessels. Organic nitrates do not appear to significantly alter the inotropic or chronotropic state of the heart, although NO synthesized by cardiac myocytes and fibroblasts may play a role in the modulation of cyclic nucleotide metabolism and may thereby alter autonomic responses

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Patients can exercise for considerably longer periods after the administration of nitroglycerin. Nevertheless, with or without nitroglycerin, angina occurs at the same value of the triple product (aortic pressure x heart rate x ejection time, which is roughly proportional to myocardial consumption of O2). The observation that angina occurs at the same level of myocardial O2 consumption suggests that the beneficial effects of nitroglycerin result from reduced cardiac O2 demand rather than an increase in the delivery of O2 to ischemic regions of myocardium. However, these results do not preclude the possibility that a favorable redistribution of blood flow to ischemic subendocardial myocardium may contribute to relief of pain in a typical anginal attack, nor do they preclude the possibility that direct coronary vasodilation may be the major effect of nitroglycerin in situations where vasospasm compromises myocardial blood flow.

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Mechanism of Relief of Symptoms of Angina Pectoris

The ability of nitrates to dilate epicardial coronary arteries, even in areas of atherosclerotic stenosis, is modest, and the preponderance of evidence continues to favor a reduction in myocardial work, and thus in myocardial O2 demand, as their primary effect in chronic stable angina.

Paradoxically, high doses of organic nitrates may reduce blood pressure to such an extent that coronary flow is compromised; reflex tachycardia and adrenergic enhancement of contractility also occur. These effects may override the beneficial action of the drugs on myocardial O2 demand and can aggravate ischemia. Additionally, sublingual nitroglycerin administration may produce bradycardia and hypotension, probably owing to activation of the Bezold-Jarisch reflex.

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. Prolonged upright posture results in some degree of pooling of blood in

the lower extremities that can lead to diminished intracardiac volume. This phenomenon is accentuated if the individual is dehydrated. The resultant arterial hypotension is sensed in the carotid sinus 

baroreceptors, and efferent fibers from these receptors trigger autonomic signals that increase cardiac rate and contractility.

However, pressure receptors in the wall and trabeculae of the underfilled left ventricle may then sense stimuli, indicating high-pressure C-fiber afferent nerves from these receptors.

They may respond by sending signals that trigger paradoxical bradycardia and decreased contractility, resulting in additional and relatively sudden arterial hypotension. It usually occurs in the nitrate therapy and in the use of serotonin agonists

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. OTHER EFFECTS Bronchial smooth muscle is relaxed irrespective of the preexisting tone The muscles of the biliary tract, including those of the gallbladder, biliary

ducts, and sphincter of Oddi, are effectively relaxed Smooth muscle of the GI tract, including that of the esophagus, can be

relaxed and its spontaneous motility decreased by nitrates both in vivo and in vitro.

The effect may be transient and incomplete in vivo, but abnormal "spasm" frequently is reduced. Indeed, many incidences of atypical chest pain and "angina" are due to biliary or esophageal spasm, and these too can be relieved by nitrates. Similarly, nitrates can relax ureteral and uterine smooth muscle, but these responses are of uncertain clinical significance.

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PREPARATIONS Nitroglycerin Isosorbide Dinitrate Isosorbide-5-Mononitrate Inhaled NO Nitric oxide gas administered by inhalation appears to exert most of its

therapeutic effects on the pulmonary vasculature because of the rapid inactivation of NO by hemoglobin in the blood. The selective pulmonary vasodilation observed when NO is administered by inhalation has formed the basis for the widespread use of inhaled NO to treat pulmonary hypertension in hypoxemic neonates

Tolerance Tolerance may result from a reduced capacity of the vascular smooth muscle to

convert nitroglycerin to NO, true vascular tolerance or to the activation of mechanisms extraneous to the vessel wall, pseudotolerance Multiple mechanisms have been proposed to account for nitrate tolerance,

including volume expansion, neurohumoral activation, cellular depletion of sulfhydryl groups, and the generation of free radicals

A reactive intermediate formed during the generation of NO from organic nitrates may itself damage and inactivate the enzymes of the activation pathway; tolerance could involve endothelium-derived reactive oxygen species

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Clinical data relating to the ability of agents that modify the renin–angiotensin–aldosterone system to prevent nitrate tolerance are contradictory

Despite experimental evidence that depletion of sulfhydryl groups may lead to impaired biotransformation of nitrates to NO and thereby result in nitrate tolerance, experimental results to date with sulfhydryl donors have been disappointing

Other changes that are observed in the setting of nitroglycerin tolerance include an enhanced response to vasoconstrictors such as angiotensin II (AngII), serotonin, and phenylephrine

Administration of nitroglycerin is associated with plasma volume expansion, which may be reflected by a decrease in hematocrit. Although diuretic therapy with hydrochlorothiazide can improve a patient's exercise duration, appropriately designed crossover trials have failed to demonstrate an effect of diuretics on nitrate tolerance

A more effective approach to restoring responsiveness is to interrupt therapy for 8-12 hours each day, which allows the return of efficacy. It is usually most convenient to omit dosing at night in patients with exertional angina either by adjusting dosing intervals of oral or buccal preparations or by removing cutaneousnitroglycerin

However, patients whose anginal pattern suggests its precipitation by increased left ventricular filling pressures (i.e., occurring in association with orthopnea or paroxysmal nocturnal dyspnea) may benefit from continuing nitrates at night and omitting them during a quiet period of the day

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Tolerance also has been seen with isosorbide-5-mononitrate; an eccentric twice-daily dosing schedule appears to maintain efficacy

While these approaches appear to be effective, some patients develop an increased frequency of nocturnal angina when a nitrate-free interval is employed using nitroglycerin patches; such patients may require another class of anti-anginal agent during this period

Tolerance is not universal, and some patients develop only partial tolerance. The problem of anginal rebound during nitrate-free intervals is especially problematic in the treatment of unstable angina with intravenous nitroglycerin. As tolerance develops, increasing doses are required to achieve the same therapeutic effects; eventually, despite dose escalation, the drug loses efficacy

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Toxicity and Untoward Responses Headache is common and can be severe. It usually decreases over a few days if

treatment is continued and often can be controlled by decreasing the dose. Transient episodes of dizziness, weakness manifestations associated with postural hypotension may develop Interaction of Nitrates with PDE5 Inhibitors sildenafil, tadalafil, and vardenafil all have a significant and potentially

dangerous interaction with organic nitrates, the therapeutic actions of which are mediated via their conversion to NO with resulting increases in cyclic GMP. In the presence of a PDE5 inhibitor, nitrates cause profound increases in cyclic GMP and can produce dramatic reductions in blood pressure.

Compared with controls, healthy male subjects pretreated with sildenafil or the other PDE5 inhibitors exhibit a much greater decrease in systolic blood pressure when treated with sublingual glyceryl trinitrate, and in many subjects a fall of more than 25 mm Hg was detected. This drug class toxicity is the basis for the warning that PDE5 inhibitors should not be prescribed

to patients receiving any form of nitrate and dictates that patients should be questioned about the use of PDE5 inhibitors within 24 hours before nitrates are administered. A period of longer than 24 hours may be needed following administration of a PDE5 inhibitor for safe use of nitrates, especially with tadalafil because of its prolonged t1/2.

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In the event that patients develop significant hypotension following combined administration of sildenafil and a nitrate, fluids and -adrenergic receptor agonists, if needed, should be used for support

These same hemodynamic responses to PDE5 inhibition also may underlie the efficacy of sildenafil in the treatment of patients with primary pulmonary hypertension, in whom chronic treatment with the drug appears to result in enhanced exercise capacity associated with a decrease in pulmonary vascular resistance

PDE5 inhibitors also are being studied in patients with congestive heart failure and cardiac hypertrophy

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Therapeutic Uses ANGINA Sublingual Administration Because of its rapid action, long-established efficacy, and low cost,

nitroglycerin is the most useful drug of the organic nitrates given sublingually The onset of action is within 1-2 minutes, but the effects are undetectable by

1 hour after administration Absorption may be limited in patients with dentures or with dry mouths Nitroglycerin tablets are stable but should be dispensed in glass containers

and protected from moisture, light, and extremes of temperature Active tablets usually produce a burning sensation under the tongue, but the

absence of this sensation does not reliably predict loss of activity; elderly patients especially may be unable to detect the burning sensation

Anginal pain may be prevented when the drug is used prophylactically immediately prior to exercise or stress

The smallest effective dose should be prescribed Patients should be instructed to seek medical attention immediately if three

tablets taken over a 15-minute period do not relieve a sustained attack because this situation may be indicative of myocardial infarction (MI) ,unstable angina, or another cause of the pain

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Other nitrates that can be taken sublingually do not appear to be longer acting than nitroglycerin because their half-lives depend only on the rate at which they are delivered to the liver. They are no more effective than nitroglycerin and often are more expensive.

Oral Administration Oral nitrates often are used to provide prophylaxis against anginal

episodes in patients who have more than occasional angina. They must be given in sufficient dosage to provide effective plasma levels after first-pass hepatic degradation.

Cutaneous Administration Application of nitroglycerin ointment can relieve angina, prolong exercise

capacity, and reduce ischemic ST-segment depression with exercise for 4 hours or more.

The ointment is particularly useful for controlling nocturnal angina, which commonly develops within 3 hours after the patient goes to sleep.

To avoid tolerance, therapy should be interrupted for at least 8 hours each day. With this regimen, long-term prophylaxis of ischemic episodes often can be attained

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Transmucosal or Buccal Nitroglycerin This formulation is inserted under the upper lip above the incisors, where

it adheres to the gingiva and dissolves gradually in a uniform manner. Hemodynamic effects are seen within 2-5 minutes it is therefore useful for short-term prophylaxis of angina Nitroglycerin continues to be released into the circulation for a prolonged

period, and exercise tolerance may be enhanced for up to 5 hours. CONGESTIVE HEART FAILURE nitrovasodilators relieve pulmonary congestion and to increase cardiac

output in congestive heart failure.

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UNSTABLE ANGINA PECTORIS AND NON-ST-SEGMENT–ELEVATION MYOCARDIAL INFARCTION

unstable angina pectoris has been used to describe a broad spectrum of clinical entities characterized by an acute or subacute worsening in a patient's anginal symptoms.

efforts have been directed toward identifying patients with unstable angina on the basis of their risks for subsequent adverse outcomes such as MI or death

The term acute coronary syndrome has been useful in this context: Common to most clinical presentations of acute coronary syndrome is disruption of a coronary plaque, leading to local platelet aggregation and thrombosis at the arterial wall, with subsequent partial or total occlusion of the vessel

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There is some variability in the pathogenesis of unstable angina, with gradually progressive atherosclerosis accounting for some cases of new-onset exertional angina

Less commonly, vasospasm in minimally atherosclerotic coronary vessels may account for some cases where rest angina has not been preceded by symptoms of exertional angina.

For the most part, the pathophysiological principles that underlie therapy for exertional angina—which are directed at decreasing myocardial oxygen demand—have limited efficacy in the treatment of acute coronary syndromes characterized by an insufficiency of myocardial oxygen (blood) supply.

the degree of coronary stenosis correlates poorly with the likelihood of plaque rupture Drugs that reduce myocardial O2 consumption by reducing ventricular preload (nitrates)

or by reducing heart rate and ventricular contractility (using adrenergic receptor antagonists) are efficacious, but additional therapies are directed at the atherosclerotic plaque itself and the consequences (or prevention) of its rupture

these therapies include combinations of: anti-platelet agents, including aspirin and thioenopyridines such as clopidogrel or

prasugrel anti-thrombin agents such as heparin and the thrombolytics anti-integrin therapies that directly inhibit platelet aggregation mediated by glycoprotein

(GP)IIb/IIIa mechano-pharmacological approaches with percutaneously deployed intracoronary stents coronary bypass surgery for selected patients

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ACUTE MYOCARDIAL INFARCTION Therapeutic maneuvers in MI are directed at reducing the size of the infarct, preserving

or retrieving viable tissue by reducing the O2 demand of the myocardium, and preventing ventricular remodeling that could lead to heart failure.

Nitroglycerin is commonly administered to relieve ischemic pain in patients presenting with MI, but evidence that nitrates improve mortality in MI is sparse (faint).

A decreased ventricular preload should be avoided in patients with right ventricular infarction because higher right-sided heart filling pressures are needed in this clinical context.

Because the proximate cause of MI is intracoronary thrombosis, reperfusion therapies are critically important, employing, when possible, direct percutaneous coronary interventions (PCIs) for acute MI, usually using drug-eluting intracoronary stents

Thrombolytic agents are administered at hospitals where emergency PCI is not performed, but outcomes are better with direct PCI than with thrombolytic therapy

VARIANT (PRINZMETAL) ANGINA Multiple mechanisms have been proposed to initiate vasospasm, including endothelial cell

injury Whereas long-acting nitrates alone are occasionally efficacious in abolishing episodes of

variant angina additional therapy with Ca2+ channel blockers usually is required. Ca2+ channel blockers, but not nitrates, have been shown to influence mortality and the

incidence of MI favorably in variant angina Morphine ?

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CA2+ CHANNEL ANTAGONISTS Ca2+ channel antagonists, also called Ca2+ entry blockers, inhibit Ca2+ channel function.

In vascular smooth muscle, this leads to relaxation, especially in arterial beds. These drugs also may produce negative inotropic and chronotropic effects in the heart.

Mechanisms of Action The Ca2+ channel antagonists produce their effects by binding to the 1 subunit of the L-

type Ca2+ channels and reducing Ca2+ flux through the channel. Actions in Cardiac Cells In the SA and AV nodes, depolarization largely depends on the movement of Ca2+

through the slow channel. The effect of a Ca2+ channel blocker on AV conduction and on the rate of the sinus node pacemaker depends on whether or not the agent delays the recovery of the slow channel

Although nifedipine reduces the slow inward current in a dose-dependent manner, it does not affect the rate of recovery of the slow Ca2+ channel

The channel blockade caused by nifedipine and related dihydropyridines also shows little dependence on the frequency of stimulation

At doses used clinically, nifedipine does not affect conduction through the AV node. In contrast, verapamil not only reduces the magnitude of the Ca2+ current through the

slow channel but also decreases the rate of recovery of the channel. In addition, channel blockade caused by verapamil (and to a lesser extent by diltiazem)

is enhanced as the frequency of stimulation increases, a phenomenon known as frequency dependence or use dependence

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Verapamil and diltiazem depress the rate of the sinus node pacemaker and slow AV conduction; the latter effect is the basis for their use in the treatment of supraventricular tachyarrhythmias

Bepridil, like verapamil, inhibits both slow inward Ca2+ current and fast inward Na+ current. It has a direct negative inotropic effect. Its electrophysiological properties lead to slowing of the heart rate, prolongation of the AV nodal effective refractory period, and importantly, prolongation of the QTc interval.

Hemodynamic Effects All the Ca2+ channel blockers approved for clinical use decrease coronary

vascular resistance and can lead to an increase in coronary blood flow. The dihydropyridines are more potent vasodilators in vivo and in vitro than verapamil, which is more potent than diltiazem. The hemodynamic effects of these agents vary depending on the route of administration and the extent of left ventricular dysfunction.

Nifedipine given intravenously increases forearm blood flow with little effect on venous pooling; this indicates a selective dilation of arterial resistance vessels.

The decrease in arterial blood pressure elicits sympathetic reflexes, with resulting tachycardia and positive inotropy

nifedipine relaxes vascular smooth muscle at significantly lower concentrations than those required for prominent direct effects on the heart

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Thus, arteriolar resistance and blood pressure are lowered, contractility and segmental ventricular function are improved, and heart rate and cardiac output are increased modestly.

After oral administration of nifedipine, arterial dilation increases peripheral blood flow; venous tone does not change.

The other dihydropyridines—amlodipine, felodipine, isradipine, nicardipine, nisoldipine, nimodipine, and clevidipine— share many of the cardiovascular effects of nifedipine.

Amlodipine is a dihydropyridine that has a slow absorption and a prolonged effect Amlodipine produces both peripheral arterial vasodilation and coronary dilation,

with a hemodynamic profile similar to that of nifedipine However, there is less reflex tachycardia with amlodipine, possibly because the

long t1/2 produces minimal peaks and troughs in plasma concentrations Felodipine may have even greater vascular specificity than does nifedipine or

amlodipine. At concentrations producing vasodilation, there is no negative inotropic effect

Like nifedipine, felodipine indirectly activates the sympathetic nervous system, leading to an increase in heart rate. Nicardipine has anti-anginal properties similar to those of nifedipine and may have selectivity for coronary vessels. Isradipine also produces the typical peripheral vasodilation seen with other dihydropyridines, but because of its inhibitory effect on the SA node, little or no rise in heart rate is seen

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This inhibitory effect does not extend to the cardiac myocytes, however, because no cardiodepressant effect is seen.

Despite the negative chronotropic effect, isradipine appears to have little effect on the AV node, so it may be used in patients with AV block or combined with a adrenergic receptor antagonist

In general, because of their lack of myocardial depression and, to a greater or lesser extent, lack of negative chronotropic effect, dihydropyridines are less effective as monotherapy in stable angina than are verapamil, diltiazem, or a adrenergic receptor antagonist

Nisoldipine is more than 1000 times more potent in preventing contraction of human vascular smooth muscle than in preventing contraction of human cardiac muscle in vitro, suggesting a high degree of vascular selectivity

Although nisoldipine has a short elimination t1/2, a sustained-release preparation that is efficacious as an anti-anginal agent has been developed. Nimodipine has high lipid solubility and was developed as an agent to relax the cerebral vasculature. It is effective in inhibiting cerebral vasospasm and has been used primarily to treat patients with neurological defects associated with cerebral vasospasm after subarachnoid hemorrhage.

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Clevidipine is a novel dihydropyridine L-type Ca2+ channel blocker—available for intravenous administration—that has a very rapid (t1/2 ~2 minutes) onset and offset of action.

It may be useful in controlling blood pressure in severe or perioperative hypertension when oral therapy is not possible or desirable.

Verapamil is a less potent vasodilator in vivo than are the dihydropyridines. Like dihydropyridines, verapamil causes little effect on venous resistance

vessels at concentrations that produce arteriolar dilation With doses of verapamil sufficient to produce peripheral arterial

vasodilation, there are more direct negative chronotropic , inotropic effects than with the dihydropyridines

Intravenous verapamil causes a decrease in arterial blood pressure owing to a decrease in vascular resistance, but the reflex tachycardia is blunted or abolished by the direct negative chronotropic effect of the drug.

This intrinsic negative inotropic effect is partially offset by both a decrease in afterload and the reflex increase in adrenergic tone. Thus, in patients without congestive heart failure, ventricular performance is not impaired and actually may improve, especially if ischemia limits performance.

In contrast, in patients with congestive heart failure, intravenous verapamil can cause a marked decrease in contractility and left ventricular function.

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Oral administration of verapamil reduces peripheral vascular resistance and blood pressure, often with minimal changes in heart rate. The relief of pacing-induced angina seen with verapamil is due primarily to a reduction in myocardial oxygen demand

Intravenous administration of diltiazem can result initially in a marked decrease in peripheral vascular resistance and arterial blood pressure, which elicits a reflex increase in heart rate and cardiac output.

Heart rate then falls below initial levels because of the direct negative chronotropic effect of the agent. Oral administration of diltiazem decreases both heart rate and mean arterial blood pressure

While diltiazem and verapamil produce similar effects on the SA and AV nodes, the negative inotropic effect of diltiazem is more modest.

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Toxicity and Untoward Responses Patients receiving immediate-release capsules of nifedipine develop headache, flushing,

dizziness, and peripheral edema. However, short-acting formulations of nifedipine are not appropriate in the long-term

treatment of angina or hypertension. Dizziness and flushing are much less of a problem with the sustained-release formulations and with the dihydropyridines having a long t1/2 and relatively constant concentrations of drug in plasma

Peripheral edema may occur in some patients with Ca2+ channel blockers but is not the result of generalized fluid retention; it most likely results from increased hydrostatic pressure in the lower extremities owing to precapillary dilation and reflex postcapillary constriction

Contraction of the lower esophageal sphincter is inhibited by the Ca2+ channel blockers. For example, Ca2+ channel blockers can cause or aggravate gastroesophageal reflux

Constipation is a common side effect of verapamil, but it occurs less frequently with other Ca2+ channel blockers

Urinary retention is a rare adverse effect Uncommon adverse effects include rash and elevations of liver enzymes. Worsened myocardial ischemia has been observed with nifedipine Worsening of angina was observed in patients with an angiographically demonstrable

coronary collateral circulation. The worsening of angina may have resulted from excessive hypotension and decreased coronary perfusion, selective coronary vasodilation in nonischemic regions of the myocardium in a setting where vessels perfusing ischemic regions were already maximally dilated (i.e., coronary steal), or an increase in O2 demand owing to increased sympathetic tone and excessive tachycardia

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Although bradycardia, transient asystole, and exacerbation of heart failure have been reported with verapamil, these responses usually have occurred after intravenous administration of verapamil in patients with disease of the SA node or AV nodal conduction disturbances or in the presence of blockade

The use of intravenous verapamil with an intravenous adrenergic receptor antagonist is contraindicated because of the increased propensity for AV block and/or severe depression of ventricular function.

Patients with ventricular dysfunction, SA or AV nodal conduction disturbances, and systolic blood pressures below 90 mm Hg should not be treated with verapamil or diltiazem, particularly intravenously

The use of verapamil to treat digitalis toxicity thus is contraindicated; AV nodal conduction disturbances may be exacerbated.

Important drug–drug interactions may be encountered with Ca2+ channel blockers. Verapamil blocks the P-glycoprotein drug transporter. Both the renal and hepatic disposition of digoxin occurs via this transporter. Accordingly, verapamil inhibits the elimination of digoxin and other drugs that are cleared from the body by the P-glycoprotein.

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Therapeutic UsesVariant Angina

Variant angina results from reduced blood flow (a consequence of transient localized vasoconstriction) rather than increased oxygen demand

Controlled clinical trials have demonstrated efficacy of the Ca2+ channel blocking agents for the treatment of variant angina

protection in variant angina is due to coronary dilation rather than to alterations in peripheral hemodynamics

Exertional Angina Ca2+ channel antagonists also are effective in the treatment of exertional,

or exercise-induced, angina Their utility may result from an increase in blood flow owing to coronary

arterial dilation, from a decrease in myocardial oxygen demand (secondary to a decrease in arterial blood pressure, heart rate, or contractility), or both. Numerous double-blind, placebo-controlled studies have shown that these drugs decrease the number of anginal attacks and attenuate exercise-induced ST-segment depression

As described earlier, Ca2+ channel antagonists, particularly the dihydropyridines, may aggravate anginal symptoms in some patients when used without a adrenergic receptor antagonist

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This adverse effect is not prominent with verapamil or diltiazem because of their limited ability to induce marked peripheral vasodilation and reflex tachycardia.

Concurrent therapy with nifedipine and the receptor antagonist propranolol or with amlodipine and any of several receptor antagonists has proven more effective than either agent given alone in exertional angina, presumably because the antagonist suppresses reflex tachycardia

This concurrent drug therapy is particularly attractive because the dihydropyridines, unlike verapamil and diltiazem, do not delay AV conduction and will not enhance the negative dromotropic effects associated with receptor blockade

Although concurrent administration of verapamil or diltiazem with a receptor antagonist also may reduce angina, the potential for AV block, severe bradycardia, and decreased left ventricular function requires that these combinations be used judiciously, especially if left ventricular function is compromised prior to therapy

Amlodipine produces less reflex tachycardia than does nifedipine probably because of a flatter plasma concentration profile

Isradipine, approximately equivalent to nifedipine in enhancing exercise tolerance, also produces less rise in heart rate, possibly because of its slower onset of action.

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Myocardial Infarction

There is no evidence that Ca2+ channel antagonists are of benefit in the early treatment or secondary prevention of acute MI.

Diltiazem and verapamil may reduce the incidence of reinfarction in patients with myocardial infarction who are not candidates for a adrenergic receptor antagonist

but adrenergic receptor antagonists remain the drugs of first choice. administration of statins can lead to improvements in the rate of adverse

cardiac events, apparently independent of changes in serum lipid levels.

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. Other Uses antiarrhythmic agents Hypertension amlodipine in the treatment of heart failure Clinical trials are under way to evaluate the capacity of Ca2+

channel blockers to slow the progression of renal failure and to protect the transplanted kidney

Verapamil has been demonstrated to improve left ventricular outflow obstruction and symptoms in patients with hypertrophic cardiomyopathy

Verapamil also has been used in the prophylaxis of migraine headaches

While several studies suggest that dihydropyridines may suppress the progression of mild atherosclerosis, there is no evidence that this alters mortality or reduces the incidence of ischemic events

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Unstable Angina

Medical therapy for unstable angina involves the administration of aspirin, which reduces mortality

Nitrates B adrenergic receptor blocking agents heparin, which are effective in controlling ischemic episodes and angina Because vasospasm occurs in some patients with unstable angina Ca2+

channel blockers may offer an additional approach to the treatment of unstable angina

However, there is insufficient evidence to assess whether such treatment decreases mortality except when the underlying mechanism is vasospasm.

In a randomized, double-blind clinical trial, the short-acting dihydropyridine nifedipine was found to be less effective than metoprolol, and there are no studies supporting the administration of a dihydropyridine to patients with unstable angina

In contrast, therapy directed toward reduction of platelet function and thrombotic episodes clearly decreases morbidity and mortality in patients with unstable angina

and administration of statins also can reduce adverse cardiac events.

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Nimodipine has been approved for use in patients with neurological deficits secondary to cerebral vasospasm after the rupture of a congenital intracranial aneurysm

Nifedipine, diltiazem, amlodipine, and felodipine appear to provide symptomatic relief in Raynaud's disease.

The Ca2+ channel antagonists cause relaxation of the myometrium in vitro and may be effective in stopping preterm uterine contractions in preterm labor

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ADRENERGIC RECEPTOR ANTAGONISTS Adrenergic receptor antagonists are effective in reducing the severity and frequency of

attacks of exertional angina and in improving survival in patients who have had an MI. these agents are not useful for vasospastic angina and, if used in isolation, may worsen

the condition Most adrenergic receptor antagonists apparently are equally effective in the treatment

of exertional angina Timolol, metoprolol, atenolol, and propranolol have been shown to exert

cardioprotective effects. The effectiveness of adrenergic receptor antagonists in the treatment of exertional

angina is attributable primarily to a fall in myocardial O2 consumption at rest and during exertion, although there also is some tendency for increased flow toward ischemic regions

The decrease in myocardial O2 consumption is due to a negative chronotropic effect (particularly during exercise), a negative inotropic effect, and a reduction in arterial blood pressure (particularly systolic pressure) during exercise. Not all actions of adrenergic receptor antagonists are beneficial in all patients

The decreases in heart rate and contractility cause increases in the systolic ejection period and left ventricular end-diastolic volume; these alterations tend to increase O2 consumption

However, the net effect of receptor blockade usually is to decrease myocardial O2 consumption, particularly during exercise.

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Nevertheless, in patients with limited cardiac reserve who are critically dependent on adrenergic stimulation, receptor blockade can result in profound decreases in left ventricular function.

Despite this, several adrenergic receptor antagonists have been shown to reduce mortality in patients with congestive heart failure, and treatment of patients with heart failure with adrenergic antagonist drugs has become standard therapy for many such patients

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Therapeutic Uses

UNSTABLE ANGINA Adrenergic receptor antagonists are effective in reducing recurrent episodes of

ischemia and the risk of progression to acute Clinical trials have lacked sufficient statistical power to demonstrate beneficial

effects of receptor antagonists on mortality. On the other hand, if the underlying pathophysiology is coronary vasospasm, nitrates and Ca2+ channel blockers may be effective, and receptor antagonists should be used with caution

In some patients, there is a combination of severe fixed disease and superimposed vasospasm; if adequate anti-platelet therapy and vasodilation have been provided by other agents and angina continues, the addition of a receptor antagonist may be helpful.

MYOCARDIAL INFARCTION Adrenergic receptor antagonists that do not have intrinsic sympathomimetic

activity improve mortality in MI. They should be given early and continued indefinitely in patients who can

tolerate them

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COMPARISON OF ANTI-ANGINAL THERAPEUTIC STRATEGIES

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COMBINATION THERAPY AND NEW ANTI-ANGINAL DRUGS Nitrates and Adrenergic Receptor Antagonists effective in the treatment of typical exertional angina The additive efficacy primarily is a result of the blockade by one drug of a reflex

effect elicited by the other Adrenergic receptor antagonists can block the baroreceptor-mediated reflex

tachycardia whereas nitrates, by increasing venous capacitance, can attenuate the increase in

left ventricular end-diastolic volume associated with receptor blockade Concurrent administration of nitrates also can alleviate the increase in coronary

vascular resistance associated with blockade of adrenergic receptors Ca2+ Channel Blockers and Receptor Antagonists if there is a component of coronary vasospasm in patients treated with a dihydropyridine such as nifedipine or with nitrates,

substantial reflex tachycardia often limits the effectiveness of these agents. A receptor antagonist may be a helpful addition in this situation

The efficacy of amlodipine is improved by combination with a adrenergic receptor antagonist

Relative contraindications to the use of receptor antagonists for treatment of angina—bronchospasm, Raynaud's syndrome, or Prinzmetal angina—may lead to a choice to initiate therapy with a Ca2+ channel blocker

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coronary vasodilators (nitrates and/or Ca2+ channel blockers) are an important part of the therapeutic program in the majority of patients with ischemic heart disease.

Ca2+ Channel Blockers and Nitrates In severe exertional or vasospastic angina The concurrent administration of a nitrate and nifedipine has been advocated

in particular for patients with exertional angina with heart failure, the sick-sinus syndrome, or AV nodal conduction disturbances, but excessive tachycardia may be seen.

Ca2+ Channel Blockers, Receptor Antagonists, and Nitrates the use of all three may provide improvement The dihydropyridines and nitrates dilate epicardial coronary arteries, the

dihydropyridines decrease afterload, the nitrates decrease preload, and the receptor antagonists decrease heart rate and myocardial contractility

ANTI-PLATELET, ANTI-INTEGRIN, AND ANTI-THROMBOTIC AGENTS Aspirin reduces the incidence of MI and death in patients with unstable angina low doses of aspirin appear to reduce the incidence of MI in patients with

chronic stable angina. Aspirin, given in doses of 160-325 mg at the onset of treatment of MI, reduces

mortality in patients presenting with unstable angina

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. The addition of the clopidogrel to aspirin therapy reduces mortality in

patients with acute coronary syndromes a related thioenopyridine, prasugrel, has been approved for treatment of

acute coronary syndromes Heparin, in its unfractionated form and as low-molecular-weight heparin,

also reduces symptoms and prevents infarction in unstable angina Thrombin inhibitors, such as hirudin or bivalirudin, directly inhibit even

clot-bound thrombin, are not affected by circulating inhibitors, and function independently of antithrombin III

Thrombolytic agents, on the other hand, are of no benefit in unstable angina

Intravenous inhibitors of the platelet GPIIb/IIIa receptor (abciximab, tirofiban, and eptifibatide) are effective in preventing the complications of PCIs and in the treatment of some patients presenting with acute coronary syndromes

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MECHANO-PHARMACOLOGICAL THERAPY: DRUG-ELUTING ENDOVASCULAR STENTS Intracoronary stents can ameliorate angina and reduce adverse events in

patients with acute coronary syndromes limited by subacute luminal restenosis within the stent smooth muscle proliferation within the lumen of the stented artery is a

common pathological finding the development of drug-eluting stents has had an important impact on

clinical practice