Antianginal therapy

Amirhossein Azhari

Electrophysiologist

Coronary AtherosclerosisDiseases of the coronary arteries is almost always due to plaque and its complications , particularly thrombosis.Atherosclerosis is a progressive inflammatory disorder of arterial wall that is characterized by focal lipid rich deposits of atheroma that remain clinically silent until they become large enough to impair tissue perfusion

Goal of therapy

The goal of therapy with antianginal agents is to restore the balance between oxygen supply and demand in the ischemic region of the myocardium.

High oxygen demandLow oxygen supply

Pharmacology of Antianginal Agents

Three major classes of agents are used individually or in combination to treat angina:Organic nitrates–Vasodilate coronary arteries–Reduce preload and aferload

Calcium channel blockers–Vasodilate coronary arteries–Reduce afterload–The non-dihydropyridines (verapamil

and diltiazem) also decrease heart rate and contractility

Beta-adrenergic blockers–Decrease heart rate and contractility–Decrease afterload 2° to a decrease in

cardiac output– Improve myocardial perfusion 2° to a

decrease in heart rateA new class of drugs, are in the final stages of approval for chronic angina–Reduce myocardial oxygen

consumption by shifting metabolism from fatty acid to glucose metabolism

–No hemodynamic effects

Nitrates

The action of these agents is to relax vascular smooth muscle. The vasodilator effects of nitrates are evident in systemic (including coronary) arteries and veins

they appear to be predominant in the venous circulation.

The venodilator effect reduces ventricular preload, which in turn reduces myocardial wall tension and O2 requirements.

Nitrates

All of these agents are enzymatically converted to nitric oxide (NO) in the target tissues–NO is a very short-lived endogenous

mediator of smooth muscle contraction and neurotransmission

Veins and larger arteries appear to have greater enzymatic capacity than resistance vessels, resulting in greater effects in these vessels

NO activates a cytosolic form of guanylate cyclase in smooth muscle

–Activated guanylate cyclase catalyzes the formation of cGMP which activates cGMP-dependent protein kinase

–Activation of this kinase results in phosphorylation of several proteins that reduce intracellular calcium and hyperpolarize the plasma membrane causing relaxation

Mechanism of Action of Nitrovasodilators

Nitric Oxide

activates

converts

Guanylate Cyclase*

GTPcGMP

activates

cGMP-dependent protein kinase

Activation of PKG results in phosphorylation of several proteins that reduce intracellular calcium

causing smooth muscle relaxation

Nitrates become denitrated by glutathione S-transferase

to release

Increased coronary blood flow:–Large epicardial coronary arteries

are dilated without impairing autoregulation in small coronary vessels

–Collateral flow may be increased–Decreased preload improves

subendocardial perfusion–Dilation of coronary arteries can

paradoxically result in aggravation of angina - a phenomenon known as “coronary steal”

Pharmacokinetic Properties ofOrganic Nitrates

Hepatic first-pass metabolism is high and oral bioavailability is low for nitroglycerin (GTN) and isosorbide dinitrate (ISDN)–Sublingual or transdermal administration

of these agents avoids the first-pass effect

Isosorbide mononitrate (5-ISMN) is not subject to first-pass metabolism and is 100% available after oral administration

GTN ISDN 5-ISMN

Half-life (min) 3 10 280

Plasma clearance (L/min) 50 4 0.1

Apparent volume of distribution (L/kg) 3 4 0.6

Oral bioavailability)%( <1 20 100

Property

Amyl nitrate is a gas at room temperatures and can be administered by inhalation– Rapid onset, short duration (3-5 min)

GTN and ISDN have a rapid onset of action (1-3 min) when administered sublingually, but the short duration of action (20-30 min) is not suitable for maintenance therapy

IV nitrogylcerin can be used to treat severe recurrent unstable angina

Slowly absorbed preparations of nitrovasodilators (oral, buccal, transdermal) can be used to provide prolonged prophylaxis against angina (3-10 hrs), but can lead to tolerance (tachyphylaxis

Ointment. Nitroglycerin ointment (15 mg/inch) is efficacious when applied (most commonly to the chest) in strips of 0.5 to 2.0 inches. The delay in onset of action is approximately 30 minutes.

Because this form of the drug is effective for 4 to 6 hours, it is particularly useful for patients with severe angina or unstable angina who are confined to bed and chair. absorption is also enhanced if the paste is covered with plastic, with the edges taped to the skin.

Tolerance and Dependence with Nitrovasodilators

Continuous or frequent exposure to nitrovasodilators can lead to the development of complete tolerance–Transdermal GTN may provide

therapeutic levels of drug for 24 hours or more, but efficacy only lasts 8-10 hrs

–Nitrate-free periods of at least 12 hrs (e.g.- overnight) are recommended to avoid or reduce tachyphylaxis

The mechanism of tolerance is not completely understood but appears to relate to the enzymes involved in converting the nitrates to NO, or to the enzyme that produces cGMP

Adverse Effects of Nitrovasodilators

The major acute adverse effects of nitrovasodilators are due to excessive vasodilation

–Orthostatic hypotension–Tachycardia–Severe throbbing headache–Dizziness–Flushing–Syncope

Sildenafil (Viagra) and for erectile dysfunction can potentiate the actions of nitrovasodilators because they inhibit the breakdown of cGMP (they should not be taken within 6 hours of taking a nitrovasodilator

Ca Channel Blockers

Chemistry of Ca++ Channel Blockers

Dihydropyridines: Nicardipine, nifedipine, nimodipine, amlodipine, and many others

Nondihydropyridines: Diltiazem, verapamil

Effects on Vascular Smooth Muscle

Ca++ channel blockers inhibit L-type and/or T-type voltage-dependent Ca++ channels

Little or no effect on receptor-operated channels or on release of Ca++ from SR

“Vascular selectivity” is seen with the Ca++ channel blockers–Decreased intracellular Ca++ in arterial

smooth muscle results in relaxation (vasodilatation) -> decreased cardiac afterload (aortic pressure)

–Little or no effect of Ca++-channel blockers on venous beds -> no effect on cardiac preload (ventricular filling pressure)

–Specific dihydropyridines may exhibit greater potencies in some vascular beds (e.g.- nimodipine more selective for cerebral blood vessels, nicardipine for coronary vessels)

–Little or no effect on nonvascular smooth muscle

Relative Cardiovascular Effects of Calcium Channel Blockers

(adapted from Goodman & Gilman, 9th ed.)

Verapamil ++++ ++++ +++++ +++++Diltiazem +++ ++ +++++ ++++Nifedipine +++++ + + 0Nicardipine +++++ 0 + 0

Compound

Coronary vasodilatio

n

Suppression of cardiac

contractility

Suppression of

SA node

Suppression of

AV node

Desired Therapeutic Effects of Calcium Channel Blockers for Angina

Improve oxygen delivery to ischemic myocardium–Vasodilate coronary arteries–May inhibit platelet aggregation–Particularly useful in treating

vasospastic angina

Reduce myocardial oxygen consumption

Decrease afterload (no effect on preload

Non-dihydropyridines also lower heart rate and decrease contractility

Dihydropyridines may aggravate angina in some patients due to reflex increases in heart rate and contractility

Nifedipine

Nifedipine, a dihydropyridine, is a particularly effective dilator of vascular smooth muscle and is a more potent vasodilator than diltiazem or verapamil

Thus, in clinical practice, the potential negative chronotropic, inotropic, and dromotropic (on AV conduction) effects of nifedipine are seldom a problem

The beneficial effects of nifedipine in the treatment of angina result from its ability to reduce myocardial O2 requirements because of its afterload-reducing effect and to increase myocardial O2 delivery as a result of its dilating action on the coronary vascular bed .

This immediate-release formulation is no longer recommended because of concerns regarding adverse events.

An extended-release formulation using the gastrointestinal therapeutic system of drug delivery is designed to deliver 30, 60, or 90 mg of nifedipine in a single daily dose at a relatively constant rate over a 24-hour period and is useful for the treatment of chronic stable angina, Prinzmetal angina, and hypertension.

Adverse effects

These occur in 15% to 20% of patients and require discontinuation of medication in about 5%. Most adverse effects are related to systemic vasodilation and include headache, dizziness, palpitations, flushing, hypotension, and leg edema (unrelated to heart failure). Gastrointestinal side effects, including nausea, epigastric pressure, and vomiting, are noted in approximately 5% of patients

Long-acting nifedipine should be considered as an effective and safe antianginal drug for the treatment of symptomatic patients with chronic CAD who are already receiving beta blockers, with or without nitrates. Short-acting nifedipine should ordinarily be avoided.

Because of its potent vasodilator effects, nifedipine is contraindicated for patients who are hypotensive or have severe aortic valve stenosis and for patients with unstable angina who are not simultaneously receiving a beta blocker in whom reflex-mediated increases in the heart rate may be harmful

Short-acting nifedipine may cause an increase in mortality.

Verapamil

Verapamil dilates systemic and coronary resistance vessels and large coronary conductance vessels. It slows the heart rate and reduces myocardial contractility. This combination of actions results in a reduction in myocardial O2 requirement, which is the basis for the drug's efficacy in the management of chronic stable angina.

Intravenous verapamil should generally not be used together with a beta blocker (given intravenously or orally), nor should a beta blocker be administered intravenously in patients receiving oral verapamil.

Both drugs can be administered orally but with caution in view of the potential for the development of bradyarrhythmias and negative inotropic effects

Adverse effects

Adverse effects of verapamil are noted in approximately 10% of patients and relate to systemic vasodilation (hypotension and facial flushing), gastrointestinal symptoms (constipation and nausea), and central nervous system reactions, such as headache and dizziness. A rare side effect is gingival hyperplasia, which appears after 1 to 9 months of therapy

DiltiazemDiltiazem's actions are intermediate between those of nifedipine and verapamil. In clinically useful doses, its vasodilator effects are less profound than those of nifedipine, and its cardiac depressant action, on the sinoatrial and AV nodes and myocardium, is less than that of verapamil.

This profile may explain the remarkably low incidence of adverse effects of diltiazem

Several sustained-release formulations of diltiazem are available for once-daily treatment of systemic hypertension and angina pectoris.

The usual starting dosage of sustained-release formulations is 120 mg once daily up to a typical maintenance dosage of 180 to 360 mg once daily.

The maximum effect on blood pressure may not be observed until 14 days after starting therapy.

Second-Generation Calcium Antagonists

The second-generation calcium antagonists (e.g., nicardipine, isradipine, amlodipine, felodipine) are mainly dihydropyridine derivatives, with nifedipine being the prototypical agent.

Amlodipine

It causes marked coronary and peripheral dilation and may be useful in the treatment of patients with angina accompanied by hypertension. It may be used as a once-daily hypotensive or antianginal agent. Amlodipine has little, if any, negative inotropic action and may be especially useful for patients with chronic angina and LV dysfunction

The usual dosage of amlodipine is 5 to 10 mg once daily.

Downward adjustment of the starting dose is appropriate for patients with liver disease and older patients.

Significant changes in blood pressure are typically not evident until 24 to 48 hours after initiation. Steady-state serum levels are achieved at 7 to 8 days.

Beta-Adrenergic Blocking AgentsBeta blockers constitute a cornerstone of therapy for angina. In addition to their antiischemic properties

are effective antihypertensives

antiarrhythmics

reduce mortality and reinfarction in patients after MI

reduce mortality in patients with heart failure.

This combination of actions makes them extremely useful in the management of stable IHD.

Abrupt withdrawal of beta-adrenergic blocking agents after prolonged administration can result in increased total ischemic activity in patients with chronic stable angina. Occasionally, such withdrawal can precipitate unstable angina and may, in rare cases, even provoke MI.

This increased ischemia may be caused by a return to the previously high levels of myocardial O2 demand while the underlying atherosclerotic process has progressed, but a rebound phenomenon resulting in increased beta-adrenergic sensitivity probably occurs in some patients.

Chronic beta blocker therapy can be safely discontinued by slowly withdrawing the drug in a stepwise manner over the course of 2 to 3 weeks. If abrupt withdrawal of beta blockers is required, patients should be instructed to reduce exertion and manage angina episodes with sublingual nitroglycerin and/or substitute a calcium antagonist

Characteristics of Different

Beta Blockers

Two major subtypes of beta receptors, designated beta1 and beta2, are present in different proportions in different tissues.

Beta1 receptors predominate in the heart, and stimulation of these receptors leads to

increase in heart rate

atrioventricular (AV) conduction

contractility

release of renin from juxtaglomerular cells in the kidneys

lipolysis in adipocytes

Beta2 stimulation causes

Bronchodilation

Vasodilation

glycogenolysis

Nonselective beta-blocking drugs propranolol, nadolol, penbutolol, pindolol, sotalol, timolol, carteolol) block both beta1 and beta2 receptors

cardioselective beta blockers

acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol, nebivolol) block beta1 receptors while having less effect on beta2 receptors

However, as the doses of these drugs are increased, this cardioselectivity diminishes.

Because cardioselectivity is only relative, the use of cardioselective beta blockers in doses sufficient to control angina may still cause bronchoconstriction in some susceptible patients.

Some beta blockers also cause vasodilation. Such drugs include

labetalol (an alpha-adrenergic blocking agent and beta2 agonist)

carvedilol (with alpha- and beta1-blocking activity)

bucindolol (a nonselective beta blocker that causes direct [non–alpha-adrenergic mediated] vasodilation)

Effects on Serum Lipid LevelsBeta blocker therapy usually causes no significant changes in total or LDL cholesterol levels but increases triglyceride and reduces HDL cholesterol levels.

propranolol, which can increase plasma triglyceride concentrations by 20% to 50% and reduce HDL cholesterol levels by 10% to 20%

Increasing beta1 selectivity is associated with lesser effects on lipid levels. Adverse effects on the lipid profile may be more frequent with nonselective than with beta1-selective blockers. The effects of these changes in serum lipid levels by long-term administration of beta blockers must be considered when this therapy is begun or maintained for hypertension or angina.

Beginning therapy with a very low dose metoprolol succinate extended release, 25 mg daily, for 2 weeks in patients with NYHA functional Class II) and then gradually increasing the dose over the course of several weeks has been shown to be well tolerated and beneficial in patients with idiopathic dilated cardiomyopathy and those with heart failure caused by IHD

In patients who already have impaired LV function, heart failure may be intensified, an effect that can be counteracted in part by the use of digitalis or diuretics.

Use of more than one class of antianginal agent can reduce specific undesirable effects of single agent therapy

Nitrates Alone

Reflex Increase

Decrease

Decrease

Reflex increase

Decrease

Beta-Blockers or Channel Blockers

Alone

Decrease*

Decrease

Increase

Decrease*

Increase

Nitrates Plus Beta-Blockers or

Channel Blockers

Decrease

Decrease

None or decrease

None

None

Undesireable effects are shown in italics

*Dihydropyridines may cause the opposite effect due to a reflex increase in sympathetic tone

Heart Rate

Afterload

Preload

Contractility

Ejection time

Effect

Combination Therapy of Angina

Investigational AgentsNicorandil is a nicotinamide ester that dilates peripheral and coronary resistance vessels via action on ATP-sensitive potassium channels and possesses a nitrate moiety that promotes systemic venous and coronary vasodilation.[

As a result of these dual actions, nicorandil reduces preload and afterload and results in an increase in coronary blood flow.

Nicorandil has antianginal efficacy similar to those of beta blockers, nitrates, and calcium channel blockers

Nicorandil has been associated with ulcerations of the gastrointestinal tract

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