therapeutics for coronary vascular disease nitrates

Therapeutics for Coronary Vascular

Disease

Nitrates

Nitrates

Nitroglycerin Glyceryl trinitrate(GTN)

Nitrates

Isosorbide dinitrate(ISDN)

Nitrates

Isosorbide-5-mononitrate(5-ISMN)

Nitrates

Amyl Nitrite

Nitrates

Sodium Nitroprusside

ACTION of NITRATES

•Dilate coronaryarteries

•Dilate Arterioles•Dilate venous

capacitancevessels

•Decrease arterialresistance

•Decrease pre-load

Angina pectoris

• Angina pectoris is the principle symptom of ischemic heart disease.

•The condition is characterized by sudden, severe substernal pain.

•The primary cause of angina is an imbalance between myocardial oxygen demand and oxygen supplied by coronary vessels.

Angina pectoris

•This imbalance may be due to a decrease in myocardial oxygen delivery, an increase in myocardial oxygen demand, or both

•Since the heart normally extracts about 75% of blood oxygen at rest, increasing oxygen supply primarily occurs through increasing coronary blood flow

Angina pectoris

•Stable angina (exertional angina, typical or classic angina, angina of effort, atheroscelorotic angina)

•The underlying pathology is usually atherosclerosis

•Anginal episodes can be precipitated by exercise, cold, stress, emotion, or eating

Stable Angina Pectoris

The Therapeutic Rationale:1. Decrease cardiac load (preload

and afterload) and 2. Increase myocardial blood flow

Vasospastic angina

•Variant angina, Prinzmetal's angina

•Caused by transient vasospasm of the coronary vessels

•Usually associated with underlying atheromas

•Chest pain may develop at rest

Vasospastic angina

•Variant angina, Prinzmetal's angina

•

• The Therapeutic Rationale:

•Decrease vasospasm of coronary vessels

Unstable angina

•Preinfarction angina, crescendo angina, angina at rest

•Caused by recurrent episodes of small platelet clots at the site of a ruptured atherosclerotic plaque which can also precipitate local vasospasm

•Associated with a change in the character, frequency, and duration of angina in patients with stable angina and when there are prolonged episodes of angina at rest

Unstable angina

• Preinfarction angina, crescendo angina, angina at rest

• Unstable angina requires vigorous therapy as it signals the imminent occurrence of a myocardial infarction

•The Therapeutic Rationale: Inhibit platelet aggregation and thrombus formation, decrease cardiac load, and vasodilate coronary arteries

Factors that Affect

Myocardial Oxygen Demand •The major determinants of

myocardial oxygen consumption include:

•Ventricular wall stress, heart rate, and inotropic state (contractility)

•Both preload and afterload affect the stress on the ventricular wall

Factors that Affect Myocardial Oxygen Demand

•TRIPLE PRODUCT

•aortic pressure

•heart rate

•ejection time

KNOW

Factors that Affect Myocardial Oxygen Supply

• Coronary artery blood flow is the

primary determinant of myocardial oxygen supply since myocardial oxygen extraction from the blood is nearly complete, even at rest

Factors that Affect Myocardial Oxygen Supply

• Coronary blood flow is essentially

negligible during systole and is therefore determined by perfusion pressure (aortic diastolic pressure), duration of diastole, and coronary resistance

Factors that Affect Myocardial Oxygen Supply

•Coronary Perfusion Pressure

(CPP)

•CPP = Aortic diastolic pressure - LVEDP

•Normal > 50 mmHg

Factors that Affect Myocardial Oxygen Supply

•Coronary vascular resistance is determined by numerous factors including:

•Metabolic products that vasodilate coronary arterioles

•Autonomic activity

•Extravascular mechanical compression

•Atherosclerosis

•Intracoronary thrombi

Categories of pharmacological agents are

used in the treatment of angina

•Organic nitrates

•Calcium channel blockers

•Beta-adrenergic antagonists

Categories of pharmacological agents are

used in the treatment of angina

Organic nitrates

•reduce preload,

•reduce afterload,

•vasodilate coronary arteries,

•inhibit platelet aggregation

Categories of pharmacological agents are

used in the treatment of angina

•Calcium channel blockers

•reduce afterload,

•vasodilate coronary arteries,

•may inhibit platelet aggregation;

•some also decrease heart rate, decrease contractility)

Categories of pharmacological agents are

used in the treatment of angina

•Beta-adrenergic antagonists

•decrease heart rate,

•decrease contractility,

•decrease afterload due to decrease in cardiac output,

•may inhibit platelet aggregation

Organic Nitrates (Nitrovasodilators)

•All organic nitrates lead to the

formation of the reactive free radical, nitric oxide (NO) Most of these agents are simple nitric and nitrous acid esters of polyalcohols

Organic Nitrates (Nitrovasodilators)

•Glyceryl trinitrate (GTN,

nitroglycerin, Nitro-Bid)

•Isosorbide dinitrate (ISDN, Isordil)

•Isosorbide-5-mononitrate (5-ISMN, Ismo)

•Amyl nitrate (highly volatile liquid which is administered by inhalation)

Mechanism of Action

•Veins and large arteries appear to have greater enzymatic capacity than resistance vessels, resulting in greater effects of organic nitrates on these vessels

•Why?

Mechanism of Action

• NO is an important endogenous diffusible mediator of smooth muscle contraction and neuronal transmission

•NO is very short-lived (half-life of a few seconds)

•Endogenous NO produced by vascular endothelium in response to acetylcholine is known as EDRF (endothelium-derived relaxing factor)

Mechanism of Action

• NO activates a cytosolic form of soluable guanylate cyclase (sGC)by binding to iron in the heme prosthetic group of the enzyme

•Activated guanylate cyclase catalyzes the formation of cyclic GMP (cGMP), which subsequently activates cGMP-dependent protein kinase

Mechanism of Action •Activation of cGMP-dependent protein kinase

in smooth muscle results in relaxation through several possible mechanisms, all of which involve protein phosphorylation:

• Activation of Ca2+-ATPases which increases Ca2+ efflux

• Inhibition of Ca2+ channels which decreases Ca2+ influx

• Hyperpolarization of the sarcolemmal•membrane by stimulation of Ca2+-activated K+

channels

Routes of Administration

•Amyl nitrate, a gas at room

temperatures, can be administered by inhalation and has a very rapid onset and very short duration of action (3 - 5 min)

Routes of Administration

•The sublingual route of administration

is rapid (onset of action 1-3 min) and effective for the treatment of acute attacks of angina pectoris and avoids first-pass effects

•The short duration of action (20-30 min) is not suitable for maintenance therapy

Routes of Administration

•Intravenous nitroglycerin may be

useful in the treatment of severe recurrent unstable angina because the onset of action is also rapid

Tolerance and Dependence

•Continuous or frequent exposure to

organic nitrates may lead to the development of complete tolerance (tachyphylaxis)

•Transdermal administration of GTN may provide therapeutic blood levels for 24 hours or more, but efficacy does not persist for more than 8-10 hours

Tolerance and Dependence

•The mechanism of tolerance remains uncertain but several theories have been suggested:

•Diminished ability to convert nitrate to NO (no cross-tolerance with acetylcholine)

•Diminished release of NO because of depletion of endogenous sulfhydryl compounds (sulfhydryl-regenerating agents can partially reverse tolerance)

•Alterations in guanylate cyclase activation

Tolerance and Dependence

Adverse Effects

•The major acute adverse effects of nitrovasodilators are due to excessive vasodilation: –Orthostatic hypotension

–Tachycardia

–Severe throbbing headache

–Dizziness

–Flushing

–Syncope (fainting)

Continuous Rx for Stable Angina

Combination therapy may be more effective than monotherapy in many patients

•A beta-blocker with a dihydropyridine calcium channel blocker (e.g. propanolol and nifedipine)

Continuous Rx for VariantAngina

• Beta-blockers may worsen angina due to increased coronary resistance secondary to the unopposed effects of catecholamines acting at alpha-adrenergic receptors

Continuous Rx for Unstable Angina

• Verapamil has been found to be more effective than propanolol in controlling unstable angina

•Nifedipine alone is no more effective than nitrates or beta-blockers in reducing the frequency of rest angina

Continuous Rx for Unstable Angina

• Adding nifedipine to beta-

blocker and nitrate therapy can decrease the frequency of rest angina, the incidence of myocardial infarction, and the necessity for emergency revascularization

Continuous Rx for Unstable Angina

• Aspirin has been shown to

reduce the incidence of cardiac events in these patients

•IV heparin or thrombolytic agents may also be indicated in some patients

Hemodynamic Effects

Nitrate Alone•Heart Rate Reflex Increase

•Afterload Decrease

•Preload Decrease

•Contractility Reflex Increase

•Ejection Time Decrease

Hemodynamic Effects

Channel Blockers Alone•Heart Rate Decrease

•Afterload Decrease

•Preload Increase

•Contractility Decrease

•Ejection Time Increase

Hemodynamic Effects

Combined Ca++ or -blocker with Nitrates

Heart Rate Decrease

Afterload Decrease Preload None or Decrease Contractility None Ejection Time None

Action of Anti-anginals

PHCL 554

•Remember there will be an examination on Mar 4th.