1. Coronary Artery Disease
2. Systemic arterial hypertension: (pressure loading)
3. Valvular heart disease: (volume loading from mitral regurgitation, or aortic regurgitation, pressure loading from aortic stenosis)
4. Extrinsic cardiomyopathy: (ischemic, HTN, valvular, alcoholic, diabetic)
5. Intrinsic cardiomyopathy: [dilated (familial), hypertrophic, restrictive (stiff without hypertrophic)]

Abnormalities of left ventricular

impaired relaxation -> increase LV diastolic pressure -> increase atrial and pulmonary capillary pressure -> fluid overload in lungs

Causes of diastolic heart failure:

Acute myocardial ischemia

Positively Inotropic Drugs

Positively Inotropic Drugs

Digitalis Glycosides

MOA

1. Inhibits Na+/K+ ATPase
2. [Na+]i increases
3. Ca2+ influx increases
4. Contractility increases

Positively Inotropic Drugs

Digitalis Glycosides

Adverse Effects

1. Consequences of [Ca²⁺]_i overload: increased automaticity, tachycardia, ventricular ectopic beats
2. Consequences of increased vagal activity: atrial tachycardia (due to increased automaticity) with 2:1 AV block
3. GI Disturbances: anorexia, nausea, vomiting diarrhea
4. Neuronal disturbances: fatigue, confusion, vertigo, color vision
5. Gynecomastia or breast enlargement: estrogenic activity

Positively Inotropic Drugs

Digitalis Glycosides

Other Considerations

Positively Inotropic Drugs

Digitalis Glycosides

Drug Interactions

1. Antacids and cholestyramine: reduce the absorption of digoxin
2. Diltiazem, quinidine, verapamil: reduce digoxin clearance, can cause digitalis toxicity
3. Diuretics: hypokalemia can precipitate digitalis toxicity
4. Antidote for serious digoxin toxicity: Digoxin Immune Fab

Positively Inotropic Drugs

Digitalis Glycosides

Indications

1. HF
2. Atrial Fibrillation
3. Atrial flutter

Positively Inotropic Drugs

Adrenergic Beta-Receptor Agonists

Adverse Effects

Predicted from agonist actions at adrenoceptors

1. excessive cardiac stimulation, tachycardia, palpitations, arrhythmias

Positively Inotropic Drug

Adrenergic Beta-Receptor Agonist

• a synthetic dopamine analogue
• racemic mixture (alpha1 agonist effect by one isomer is cancelled out by the other beta2 agonist isomer)
• has beta1 adrenergic agonist effect

Positively Inotropic Drug

Adrenergic Beta-Receptor Agonist

• a non-selective beta adrenergic agonist
• increase both myocardial contractility (beta1) and heart rate (beta1)
• produces peripheral arterial vasodilation (beta2)

Positively Inotropic Drug

Phosphodiesterase Inhibitor

Positively Inotropic Drug

• At LOW doses: causes vasodilation by stimulating dopaminergic receptors on smooth muscle and stimulating presynaptic D2 receptors (decrease NE release)
• At INTERMEDIATE doses: stimulates beta1 receptors in the heart
• At HIGH doses: stimulates alpha1 receptors

Positively Inotropic Drugs

• Inhibit type III phosphodiesterase (convert cAMP to 5'-AMP)
• Increas [cAMP] in cardiac tissue and smooth muscle
• Increase cardiac contractility and relax vascular smooth muscle
• Desensitization does not occur
• Additive effects with beta-adrenoceptor agonists

1. Tachycardia
2. Palpitation
3. Potentially Serious Arrhythmias

• Cause venous and arterial dilation
• Decrease the secretion of aldosterone and ADH
• Reduce the plasma volume, venous pressure, and level of edema
• Increase CO by reducing arterial pressure and cardiac afterload
• Counteracts the adverse effects of angiotensin II on cardiac (ventricular) remodeling in patients with heart failure

• Selectively reduce the binding of angiotensin II to AT1 receptors
• Have pharmacological and clinical effects that are similar to those of the ACEI
• ARB do not induce chronic cough
• ARB appear to be as effective as ACEI in treating HF

• Isosorbide dinitrate primarily relaxes venous smooth muscle, whereas hydralazine preferentially relaxes arterial smooth muscle
• The combined use of these two drugs reduces cardiac preload and afterload, leading to reduced venous pressure and edema and to increased CO, respectively
• This drug combination decreased mortality more than placebo but less than enalapril
• This drug combination is sometimes used to treat patients with HF who cannot tolerate an ACEI

• Compete with aldosterone for the mineralocorticoid receptor in renal tubules and other tissues
• Increase Na+ excretion, decrease K+ excretion, and exert a moderate diuretic effect
• Prevent the adverse effects of excessive aldosterone levels
• Additive effects with ACEI and Beta-Blockers

Alpha and Beta Blocker

• Used to be contraindicated in HF b/c of their negative inotropic effect
• Emerged as one of the newer treatments for HF
• The benefits of therapy with beta-blockers are caused by the ability of these drugs to reduce excessive sympathetic stimulation of the heart and circulation in patients with HF
• Several clinical trials have shown that some beta-blockers benefit patients with mild to moderate HF caused by Left Ventricular Systolic Dysfunction

• Diuretics are used to reduce plasma volume and edema
• Loop diuretics have more natriuretic activity than other types of diuretics
• Diuretics must be used carefully to avoid excessive diuresis, dehydration, and electrolyte imbalances
• Hypokalemia predisposes patients to digoxin toxicity and patients with HF should be closely monitored for this condition
• Thiazide diuretics can be used when a lesser degree of diuresis is required in the treatment of HF

Atrial Natriuretic Peptide (ANP): released from atria

Brain Natriuretic Peptide (BNP): released from brain and ventricles; plasma level of BNP goes up in patients with HF

C-type Natriuretic Peptide (CNP): released from vasculature endothelial cells; no effect on nitriuresis (binds to NPRB)

Natriuretic Peptide

• Aterial and venous dilation
• Increases CO and stroke volume without increasing HR
• Causes natriuresis and diuresis
• Binds to NP receptors, increases intracellular levels of cGMP, and causes smooth muscle relaxation
• No effect on cardiac contractility or cardiac electrophysiology

1. Hypotension
2. Ventricular tachycardia
3. Headache
4. Nausea

1. Acutely Decompensated Congestive Heart Failure