Josephus P. Sibal, MD

Anti Anginal Drugs & Heart Failure

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Objectives• Explain the pathophysiology of angina and

congestive heart failure • Discuss the kinetics, pharmacologic

actions, dosage, and interactions of – Anti anginal drugs – Heart failure drugs

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Types of Heart Failure:

Left-sided HF vs Right-sided HF

Systolic HF vs Diastolic HF (Heart failure with low EF vs Heart failure with preserved EF)

Acute HF vs Chronic heart failure

Low-output HF vs High-output HF

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Etiologies of Left-sided and Right-sided Heart Failure

Left-sided Heart Failure Right-sided Failure

LV end diastolic pressure (MI, CAD, dilated cardiomyopathy, valvular heart disease, AI, AS, hypertension) ↑ LA pressure (MS) Fluid overload (renal failure, iatrogenic)

Left-sided heart failure RV systolic overload (cor pulmonale, 1° PHPN, congenital HD with shunt anomaly) ↑ RA pressure (TS, TR)

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Differentiation of Systolic and Diastolic Heart FailureParameters Systolic Diastolic I. History: CAD ++++ + DM +++ + Valvular Heart Dse ++++ - II. Physical Examination: HPN ++ ++++ Jugular distention +++ + Cardiomegaly +++ + Soft Heart Sounds ++++ + S3 Gallop +++ + S4 Gallop + +++ Edema +++ +

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Differentiation of Systolic and Diastolic Heart FailureParameters Systolic Diastolic III. Chest X-ray: Cardiomegaly +++ + Pulm. Congestion +++ +++ IV. ECG: LVH ++ ++++ Q Waves ++ + V. Echocardiogram: Low ejection fraction ++++ - LV Dilatation ++ - LVH ++ ++++

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Pump failure = low CO

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CO = SV x HR

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Stroke Volume Preload Contractility Afterload

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Preload

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Afterload

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BP = SV x TPR

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Contractility Preload Afterload

Heart Rate Stroke Volume

Cardiac Output Total Peripheral Resistance

Blood Pressure

+ +

x

x

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Compensatory Mechanisms

•Cardiac •Neurohumoral

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Boyle’s Law

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Frank Starling

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LAPLACE LAWPressure x Radius 2 (Wall Thickness)Wall Stress =

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Model of Wall Stress

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SV

Ventricular end-diastolic volume

Ventricular massLaPlace

Frank-Starling

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Decreased BP

Sympa NS R-A system ADH

Contractility HR Vasoconstriction Circulating vol

Arteriolar Venous

Maintain BP

C.O.

S.V.

Venous return to heart ( preload)

(+)(+)

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Heart Failure

Failure of compensatory mechanisms

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Car

diac

Out

put

Left Ventricular End-Diastolic Volume!27

Left

Vent

ricul

ar E

nd-D

iast

olic

Pre

ssur

e

Left Ventricular End-Diastolic Volume

hype

rtrop

hy

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SV

Ventricular end-diastolic

volume

Ventricular mass

La Place

Frank-Starlin

g

CHFAtrial Pressur

e

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Decreased BP

Sympa NS R-A system ADH

Contractility HR Vasoconstriction Circulating vol

Arteriolar Venous

Maintain BP

C.O.

S.V.

Venous return to heart ( preload)

(+)(+)

(-) Pulmonary congestion

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NYHA Classification of CHF:Functional

ClassDescription General Guide

I Dyspnea occurs with greater than ordinary physical activity.

Climbs ≥ 2 flights of stairs with ease

II Dyspnea occurs with ordinary physical activity.

Can climb 2 flights of stairs but with difficulty

III Dyspnea occurs with less than ordinary physical activity.

Can climb ≤ 1 flight of stairs

IV Dyspnea may be present even at rest.

Dyspnea at rest

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Signs and symptoms of Left-sided and Right-sided Heart Failure:

Symptoms of Left HF: Easy fatigability Exertional dyspnea Confusion Orthopnea PND Cough Signs of Left HF: Tachypnea Tachycardia Rales S3/4 Gallop Wheezes

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Signs and symptoms of Left-sided and Right-sided Heart Failure:

Symptoms of Right HF: Easy fatigability Early satiety RUQ discomfort Signs of Right HF: Elevated JVP Hepatomegaly Ascites Lower extremity edema

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Diagnostic Tests:

1. Chest X-ray 2. ECG 3. 2-D Echo

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What to do?

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  Cardiac Drugs for HF, Classified According to Hemodynamic I Effects.

Mainly Preload Unloaders

(Venous Dilators)

Contractility Mainly Afterload Unloaders

(Arterial Dilators)

Diuretics Nitrates

Digoxin

Dobutamine

Dopamine

Ace-inhibitors Angiotensin-II Antagonists Hydralazine

Nitroprusside

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Congestive Heart Failure

Compensatory Responses

↑ Systemic vascular resistance (afterload) ↑ Blood volume (preload)

↓ Cardiac output ↑ LV end diastolic pressure

↑ Renin-angiotensin aldosterone system ↑ Sympathetic tone

↑ ADH release

• Vasodilators • Afterload unloader • Preload unloader

• Inotropic agents

• ACE inhibitors • ß blockers • Diuretics

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2. Treat all precipitating causes of CHF. Cardiac causes: • Non-compliance with medicines • Arrhythmia • Ischemia or infarction • Uncontrolled hypertension • RHD, myocarditis, valvular dse, MR • Endocarditis Non-cardiac causes: • Renal Failure (fluid overload) • Anemia • Pulmonary embolism • Infection • Delivery after pregnancy • Lifestyle

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3. Assess which of the following contributes to a decrease in cardiac output and must be corrected:

a. Increase in afterload b. Increase in preload c. Decrease in contractility d. Increase in heart rate

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4. If poor response to medical treatment:

a. Maximize medical treatment.

b. Consider a surgical option

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Diseases causing High Output HF:

• Anemia • Febrile disorders • Pregnancy • Beri-beri • Renal shunts • Arteriovenous fistulas • Thyrotoxicosis

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Usual Progression of Symptoms in Left-sided HF

• Dyspnea upon exertion • PND – Cardiac type: occurs 2-4 hrs after sleep – Pulmonary type: variable onset

• Orthopnea – Cardiac type: occurs after 5 mins – Pulmonary type: immediate onset

• Dyspnea at rest • Lower extremity edema

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Clinical Manifestations Based on Severity of Heart Failure:

• Early CHF (NYHA Class I): – May be asymptomatic

• Mild to Moderate CHF (NYHA Class II-III): – Mild, non-specific symptoms – PE may be normal

• Severe CHF (NYHA Class IV): – Signs and symptoms are obvious – Patients in marked distress: (orthopneic with distended

neck veins)

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Usual Cause of Death in Patients with CHF:

• Fatal ventricular arrhythmia (sudden cardiac death)

• Refractory heart failure

• Pulmonary embolism

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Precipitating Causes of Acute HF

Cardiac causes: • Non-compliance with medicines • Arrhythmia • Ischemia or infarction (superimposed) • Uncontrolled hypertension • RHD, myocarditis, valvular dse, MR • Endocarditis

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Treatment Options in Acute HF:

• Removal of precipitating cause • Morphine sulphate IV • Oxygen • Potent diuretics IV • Rapid digitalization • Rapid preload and afterload reduction • Intravenous titratable inotropic therapy • Rotating tourniquets • Intra-aortic counterpulsation • Cardiac surgery

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Precipitating Causes of Acute HF

Non-cardiac causes: • Renal Failure (fluid overload) • Anemia • Pulmonary embolism • Infection • Delivery after pregnancy • Lifestyle (stress)

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Basic Pharmacology of Drugs used in Heart Failure

• Digitalis – Purple foxglove (Digitalis purpurea) – Digoxin is the prototype – 65-80% absorbed after oral administration –Widely distributed in tissues – 2/3 is excreted unexchanged in the kidneys – Half life is 36-40 hours

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Digitalis• Inhibits Na+, K+, ATPase pump, or the

sodium pump • Increases contraction of the sarcomere by

increasing free calcium concentration • Done by: increase of intracellular sodium

via Na+, K+, ATPase inhibition, second, relative reduction in calcium expulsion

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Digitalis• Net effect is a distinctive increase in

cardiac contractility • Useful in dilated cardiomyopathy • Given at a slow loading dose of 0.125

-0.25 mg per day or rapid loading of 0.5 mg-0.75 mg q 8 hours for three doses

• Digoxin has no net effect on mortality but reduces hospitalization

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Effects of Digoxin of other Cardiac Tissues

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Effects in other organs• Since cardiac glycosides affect all

excitable tissues, smooth muscle and CNS effects are notable. – Nausea, vomiting, diarrhea, anorexia – Disorientation, hallucinations, visual

disturbances

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Interactions with K+, Ca++, Mg++

• Potassium and digitalis inhibit each other’s binding to Na+, K+, ATPase; therefore hyperkalemia reduces the enzyme binding of cardiac glycosides, where are hypokalemia reduces its actions.

• Hyperkalemia can precipitate bradycardia and hypokalemia can limit the effects of digitalis

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Interactions with K+, Ca++, Mg++

• Ca facilitates the effects of digitalis by overloading of intracellular calcium stores.

• Digitalis-induced abnormal automaticity

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Positive Inotropics• Bipyridines –Milrinone is a phosphodiestarase isoenzyme 3

inhibitor (PDE 3 inhibitor) – Increase myocardial contractility by increasing

calcium influx in the cardiac muscle during the action potential.

– Compared to inamrinone, milrinone is less likely to cause arrhythmias and can be used in acute heart failure or severe exacerbation of chronic heart failure.

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Positive Inotropics• Beta adrenoceptor stimulants – Dobutamine – Selective B1 agonist – Increases cardiac output by decreasing

ventricular filling pressure – Produce angina or arrhythmia – Given in mcg/kg BW –Maximum dose is 20 mcg/kg BW

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Positive Inotropics• Dopamine –May also be used in acute heart failure where

there is a need to increase the BP – It stimulates dopaminergic, beta, alpha effects

at different doses – Given in mcg/kg BW, max 20 mcg/Kg BW

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Drugs Without Positive Inotropic Effects

• Diuretics • ACE inhibitors • ARBs • Aldosterone antagonist • Beta blockers • Vasodilators

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Diuretics• Prototype: Furosemide • Mainstay of heart failure • No direct effect on cardiac contractility • Major action is to reduce venous pressure

and ventricular preload • Reduction in salt and water retention • Concomitant hypokalemia may develop • Usual dose: 40 mg IV or PO dose,

increased until signs of heart failure improve

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Diuretics• Thiazide type diuretics – Hydrochlorothiazide –May result to hyponatremia secondary to

potassium excretion – Usual dose 12.5 mg to 25 mg OD, in

combination with ARBs or ACEi • K+ sparing diuretics – Spironolactone or eplerenone – Aldosterone antagonist – Usual dose: 25-50 mg OD PO

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ACE Inhibitors• Blockade of RAAs • Given to patients with LV dysfunction • Reduction of preload (reduce salt & water

retention) and afterload (reduce peripheral resistance)

• Slow the progression of ventricular dilatation • Decrease long term remodeling of the heart

and vessels

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ACE Inhibitors• Prototype: captopril • Most commonly used: enalapril • Patient may benefit from asymptomatic to

severe heart failure • Usual dose: captopril 25 mg q 6, enalapril

10 mg OD,

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Angiotensin Receptor Blockers• Produce similar benefits as ACEi • Given to patients who are incessant to

cough. • Prototype: losartan • Usual dose: losartan 50 mg OD, eposartan

600 mg OD, candesartan 8 mg OD, irbesartan 150 mg OD, telmisartan 40 mg OD, olmesartan 20 mg OD

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Vasodilators• Nesiritide • Endogenous peptide (brain natriuretic

peptide) or BNP • Increases cGMP in smooth muscle cells

and reduces venous & arteriolar tone • Causes diuresis • Preload reducing agent

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Beta Blockers• Bisoprolol, carvedilol & metoprolol • Attenuate the high concentrations of

circulating cathecolamines • Decreasing heart rate, decrease

remodeling by reduction of the mitogenic activity of cathecolamines

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Antianginal drugs

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Pathophysiology of Angina

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Determinants of Coronary Blood Flow & Myocardial Oxygen Supply

• Coronary blood flow is directly related to: – perfusion pressure (aortic diastolic pressure) – Duration of diastole (vs tachycardia)

• Coronary blood flow is inversely proportional to the coronary vascular bed resistance

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Determinants of Vascular Tone• Increasing cGMP (dephosphorylation of

myosin light chains) – Nitric oxide

• Decreasing intracellular Ca2+ (calcium channel blockers which cause vasodilatation, decrease heart rate)

• Stabilizing or preventing depolarization of vascular smooth muscle cell membrane (increase the permeability of K+ channels

• Increasing cAMP (inactivation of myosin light chain kinase which causes vasodilatation) this mechanism is caused by beta blockers.

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• Vasodilate • Reduce rate

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Nitrates & Nitrites• Nitroglycerin – Prototype – Causes activation of guanylyl cyclase and an

increase in cGMP, the first step in smooth muscle relaxation

– Oral bioavailability is low – Sublingual dose eliminated first pass effect

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Nitrates• No effect on skeletal muscles • Direct effect of NTG is increased venous

capacitance and decreased ventricular preload

• Decreases platelet aggregation • Oral controlled release tablets, sublingual

tablets, buccal spray, transdermal patch & IV • Must NOT be taken with ED meds

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Nitrates• IV may be started at 0.5 mg/hr up to 5 mg/

hr • Oral preparations can be given 30 mg to

60 mg OD

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Calcium Channel Blockers• L-type calcium channel blocker • Dihydropyridines vs non dihydrophyridines • Reduces the frequency of opening in

smooth muscle content this gives decreased transmembrane content

• Decreased heart rate via dec sinus node pacemaker rate

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Calcium Channel Blockers• Tachyarrhythmias – Diltiazem & verapamil

HPN Amlodipine & nifedipine

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Beta blockers• Effects are due to dec HR, dec BP, dec

contractility • Effect would be decreased oxygen

demand at rest and exercise • Longer diastolic perfusion time

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Beta blockers• Contraindicated with: – Asthma – Severe bradycardia, AV dysfunction – Severe LV dysfunction – CHF NYHA IV

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Partial Fatty acid Oxidation (pFOX)

• Trimetazidine • metabolic mediators, inhibit the fatty

oxidation pathway in the myocardium

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Ivabradine• Activation of the If channel or the funny

bone channel • Decreases the heart rate without the effect

of hypotension

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Other Drugs• Sulfonylureas • thiazolidinediones

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