Flashcards: Drug Therapy of Myocardial Ischemia (Angina Pectoris)

• Angina pectoris primary symptom

Ischemic heart disease.

• Angina pectoris definition

Chest pain, pressing substernal discomfort, or pain in the center of chest radiating to left shoulder, flexor aspect of left arm, jaw, or epigastrium.

• Angina pectoris atypical symptoms

Some patients have discomfort in different locations or of different characters.

• Angina pectoris patient demographics

Women, the elderly & diabetics are more likely to have ischemia with atypical symptoms.

• Pathophysiology of angina pectoris

Results from transient episodes of ischemia due to imbalance between myocardial oxygen demand and oxygen supply.

• Myocardial oxygen demand factors

Heart rate, ventricular wall tension & ventricular contractility.

• Oxygen supply factors

Determined by coronary blood flow.

• Factors increasing oxygen demand

Increased heart rate, increased ventricular wall tension (↑intracardiac pressure, ventricular radius & wall thickness), increased ventricular contractility.

• Factors decreasing oxygen supply

Fixed atherosclerotic narrowing of coronary artery, coronary spasm.

• Types of angina

Stable angina, Variant angina, Unstable angina.

• Typical stable angina (angina of effort)

Blood supply is decreased due to atherosclerotic narrowing of an epicardial coronary artery.

• Stable angina relief

Relieved by rest.

• Variant angina (vasospastic, Prinzmetal)

Coronary flow is decreased due to focal or diffuse reversible coronary spasm.

• Variant angina relief

Not relieved by rest.

• Unstable angina

Occurs in patients with atherosclerotic vessels.

• Unstable angina pathology

Coronary blood supply is decreased due to increased epicardial coronary spasm & formation of labile non-occlusive thrombi (resulting from rupture of atherosclerotic plaque).

• Unstable angina risk

There is increased risk of myocardial infarction in this type.

• Treatment of angina pectoris (general measures)

Avoid stress, exercise, heavy meal, decrease weight, control BP & stop smoking.

• Major anti-anginal drugs

Organic nitrates, β blockers, Ca channel blockers, metabolic modulators, antithrombotic & antiplatelet agents.

• Organic nitrates examples

Nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, erythrityl tetranitrate.

• Organic nitrates mechanism of action

Metabolized with release of NO, which involves an enzymatic step & possible a reaction with tissue SH groups.

• Nitric oxide (NO) action

Activates soluble guanylate cyclase, increasing formation of cGMP, which activates protein kinaseG.

• Nitrates effect on vasodilation

Causes vasodilation by inhibiting Ca entry or promoting Ca exit.

• Pharmacological actions of nitrates (smooth muscles)

Arterial smooth muscle (vasodilation at low concentration) & arteriolar V.D (at high concentration).

• Pharmacological actions of nitrates (nonvascular smooth muscle)

Relax bronchial muscle, urinary tract, esophageal, biliary muscles & biliary tract.

• Pharmacological actions of nitrates (CVS)

Nitrates increase the rate of relaxation of cardiac muscle (lusiotropic).

• Nitrates effect on cardiac function in impaired diastolic function

This effect is important in patients with impaired diastolic function (accompanied hypertension & heart failure).

• Nitrates effect on BP

Nitrates cause decreased BP, increased sympathetic discharge & reflex tachycardia.

• Antianginal effect of nitrates

Nitrates decrease myocardial O2 supply.

• Nitrates effect on coronary blood flow

Dilation of large epicardial coronary vessels, redistribution of coronary flow from normal to ischemic regions.

• Nitrates effect on myocardial O2 demand

Myocardial O2 demand is decreased by decreasing work done by heart.

• Nitrates effect on preload

Venodilation (decreased venous return & preload), which results in pooling of blood in capacitance vessels (veins) and decreased venous return.

• Nitrates effect on left ventricular end diastolic pressure & volume

Decreased.

• Nitrates effect on cardiac workload & O2 demand

Reduction in ventricular wall tension.

• Nitrates effect on afterload

Arterial dilation leads to decreased vascular resistance & afterload.

• Nitrates effect on coronary spasm

Relief of coronary spasm.

• Preload definition

Volume of blood filling ventricle during diastole, depends on venous return.

• Afterload definition

Resistance against which the ventricle ejects blood, in other words, the arterial pressure. It depends on vascular resistance.

• Nitrates pharmacokinetics

Nitrates are absorbed well orally & from skin.

• Nitroglycerin pharmacokinetics

Rapidly metabolized in the liver, so not given by swallowing but by sublingual, inhalation & transdermal patches.

• Isosorbide dinitrate pharmacokinetics

Slow onset of action & long duration of action.

• Mononitrates pharmacokinetics

Possess hepatic metabolism & have high bioavailability.

• Sublingual & transdermal routes for nitrates

Preferred because they can avoid first pass metabolism, provide rapid absorption, and can prevent the side effects (hypotension & reflex tachycardia) by removing the preparation when the pain is relieved.

• Nitrates therapeutic uses

Prevention & treatment of stable & variant angina, treatment of unstable angina (I.V nitroglycerin).

• Nitrates in acute heart failure

I.V glyceryltrinitrate.

• Nitrates in chronic heart failure

Isosorbide mononitrates with ACEI or hydralazine.

• Nitrates in acute myocardial infarction

Used in acute MI.

• Sodium cyanide as antidote

Sodium cyanide (NaNO2) I.V may be used to form methemoglobinemia that can remove cyanide from cytochrome oxidase.

• Cyanomethemoglobin detoxification

By sodium thiosulfate.

• Nitrates side effects

Flushing & throbbing headache (causes VD of skin, brain & retinal eye), postural hypotension, dizziness & syncope.

• Nitrates side effects (CVS)

Tachycardia, palpitation & worsening of angina (can be prevented by controlling the dose or combined with β blockers).

• Nitrates tolerance & dependence

Tolerance especially during chronic exposure or using long acting nitrates, mechanism is unknown, but it is partly due to depletion of free SH groups in tissues.

• Nitrates side effect (Methemoglobinemia)

Is seldom occurring, but it happens with amyl nitrite when used in cyanide poisoning.

• Nitrates side effect (Monday morning sickness)

Headache & dizziness occur in workers in explosive factories when they start their work, then the symptoms disappear because of tolerance.

• Nitrates drug interactions

PDE5 isoform inhibitors (e.g. sildenafil (Viagra)) (first line drug in erectile dysfunction), because this combination leads to a drastic decrease in BP & death.

• Nitrates precautions (storage)

Have very short shelf life, because active volatile substance evaporates, so they should not be put in sunlight or in opened bottles.

• Nitrates precautions (administration)

When taken rapidly acting nitroglycerine, instruct patient to sit or lie down, if syncope occurs the patient should remain supine.

• Nitrates precautions (tolerance)

Nitrates should not be abruptly stopped to avoid withdrawal symptoms, nitrates patches should be removed after 10 hours to avoid tolerance.

• Nitrates & β blockers combination

Very effective in treatment of exertional angina.

• Nitrates & β blockers additive effect

β blockers can block the reflex tachycardia & positive inotropic effects of nitrates.

• Nitrates & β blockers mechanism

Nitrates attenuate the increase in left ventricular end diastolic volume associated with β blockers by increased venous capacitance.

• β- blockers examples

Propranolol, timolol, metoprolol, atenolol, nadolol.

• β- blockers antianginal mechanism

Decrease heart rate, BP & contractility, which decrease myocardial O2 requirement at rest & during exercise.

• β- blockers effect on myocardial perfusion

Lower heart rate is associated with increased in diastolic perfusion time that may increase myocardial perfusion.

• β- blockers indications in angina

Angina of effort (used for prophylaxis), reduce severity & frequency of attacks, unstable angina (decrease incidence of MI).

• β- blockers contraindications in vasospastic angina

Because they block β2 receptors in the coronary artery, leading to unopposed α1 receptor action (vasoconstriction) and increased coronary spasm, which can precipitate MI.

• Combinations of β- blockers in angina (with nitrates)

Prevent tachycardia.

• Combinations of β- blockers in angina (with nifedipine)

Cause bradycardia that can prevent the tachycardia induced by nifedipine.

• Calcium channel blockers examples

Nifedipine, amlodipine, diltiazem, verapamil, nicardipine.

• Verapamil mechanism on CVS

Predominant effect on heart & least at BVs, decreases cardiac contractility & O2 consumption.

• Verapamil other CVS effects

Depression of SA node, inhibition of AV conduction, antiarrhythmic effect.

• Nifedipine mechanism on BVs

Predominant effect on BVs & less on heart, dilates coronary arteries (increased O2 supply), decreases peripheral resistance & BP & afterload, relieves focal coronary artery spasm (variant angina).

• Calcium channel blockers indications

Used in all types of angina.

• Nifedipine in variant angina

Used in variant angina, but should not be given with nitrates because of hypotension & reflex tachycardia.

• Verapamil in angina pectoris

Used in all types of angina pectoris, but not with β blockers because they produce AV block & heart failure.

• Useful combinations of Calcium channel blockers

Verapamil + nitrates (verapamil reduces afterload & nitrates reduces preload, net effect is additive reduction of O2 demand).

• Useful combinations of Calcium channel blockers (Nifedipine)

Nifedipine + β- blockers.

• Ranolazine

A new antianginal drug, metabolic modulator.

• Ranolazine mechanism

Inhibits fatty acid oxidation pathway in myocardium & reduces oxygen requirement.

• Antiplatelet agents in angina

Aspirin and clopidogrel, aspirin at doses 75-150 mg.