Drugs Used in Heart Failure

Question 1

What is heart failure and its symptoms?

Answer 1

Heart failure -When cardiac output is inadequate to provide O needed by the body

Symptoms:
Tachycardia, decreased exercise tolerance, dyspnea, peripheral & pulmonary edema, cardiomegaly

Question 2

What are the risk factors associated with Heart Failure?

Answer 2

Hypertension • Coronary artery disease • Myocardial infarction • Diabetes mellitus • Family history of cardiomyopathy • Use of cardiotoxins • Obesity

Question 3

HFrEFvs HFpEF?

Answer 3

HFrEF - heart failure with reduced ejection fraction = systolic heart failure. Mechanical pumping action (contractility) and the ejection fraction of the heart are reduced

HFpEF - Heart failure with preserved ejection fraction = diastolic heart failure/ Stiffening and loss of adequate relaxation leads tp abnormal ventricular filling, resulting in a reduction in cardiac output (ejection fraction may be normal)

Question 4

what is Congestive Heart Failure (CHF)

Answer 4

Abnormal increases in blood volume & interstitial fluid. Symptoms include dyspnea from pulmonary congestion in left HF, and peripheral edema in right HF

Question 5

what are the Physiologic Compensatory Mechanisms in HF

Answer 5

Chronic activation of SNS & renin-angiotensin- aldosterone pathway is associated with cardiac tissue remodeling. This prompts additional neurohumoral activation leads to vicious cycle which leads to death

Question 6

What are the 4 primary factors that function to have Cardiac performance

Answer 6

(1) Preload
(2) Afterload
(3) Contractility
(4) Heart rate

Question 7

what is preload?

Answer 7

Force stretching the ventricles
• Force of contraction of myocardial cells depends on length they are stretched (Frank-Starling phenomenon)

an increase in ventricle ‘stretching’

increase in force contraction

However, preload can be too high!
• Due to volume overload, poor myocardial
contractility etc.

congestive heart failure

Question 8

What is Afterload?

Answer 8

Force against which ventricles must act.
• Dependent on vascular resistance (aortic BP)

Question 9

What is Cardiac Muscle Contraction?

Answer 9

Force of cardiac muscle contraction is directly related to [Ca2+]i

Sources of [Ca2+]i
• Voltage-sensitive Ca2+ channels

• Exchange with Na+
• Released from sarcoplasmic reticulum

Removal of [Ca2+]i
• Na+/Ca2+ exchange

• Uptake by sarcoplasmic reticulum

Question 10

Effects of Factors on Cardia Performace?

Answer 10

Question 11

Drugs used to treat HFrEF (Systolic HF)

Answer 11

• Diuretics
• Spironolactone
• Inhibitors of angiotensin (ACE-inhibitors / ARBs)
• Direct vasodilators
• b-adrenoceptor antagonists (b-blockers)
• Inotropic agents

Question 12

Drugs used to treat HFpEF (Diastolic HF)

Answer 12

• Diuretics
• ACEI /ARBs
• b-adrenoceptor antagonists (b-blockers)
• Calcium-channel antagonists

Question 13

What are the recommended therpay by stage of CHF

Answer 13

Question 14

What are diuretics?

Answer 14

• Relieve pulmonary congestion & peripheral edema • Reduce symptoms of volume overload (eg, orthopnea)
• decreasedplasma volume which leads to decreased venous return to the heart (preload)
• decreased cardiac workload & O2 demand
• Also decreased afterload (reducing plasma volume which leads to BP)

Question 15

What are the clinical applications of diuretics

Answer 15

• Integral component of treatment for congestive symptoms
and/or intravascular volume overload

• No evidence of a mortality benefit with thiazide or loop diuretics alone
• Thiazide diuretics : patients with hypertensive heart disease (with congestive symptoms). Often ineffective as monotherapy due to weak diuretic effect
• Loop diuretics : more effective diuretics than thiazides (useful if edema present)

Question 16

What is the mechanism of the inhibitors of Angiotensin?

Answer 16

Question 17

What are the ACE inhibitors and what is their effects?

Answer 17

Captopril / Enalapril / Lisinopril
• Agents of choice in HF
•decreases vascular resistance & BP which leads to increased cardiac output ( afterload)
•decreases salt & H20 retention (preload)
•decreases long-term remodeling of the heart

•ACE inhibitors improve symptoms in patients with HF, decrease incidence of hospitalization & MI, and prolong survival

Question 18

What are the clinical applications of ACE inhibitors in HF

Answer 18

Recommended for all patients with:
• symptomatic heart failure • asymptomatic patients with decreased LVEF or history of MI

Suggested for patients:
• at high risk of developing heart failure due to
atherosclerotic disease, obesity, diabetes
mellitus or hypertension

Question 19

What are the adverse effects of ACE inhibitors?

Answer 19

• Hypotension,
• Persistent dry cough
• Hyperkalemia
• Angioedema
• Acute renal failure (patients with bilateral renal artery stenosis)
• Teratogenic

Question 20

What are the ARBS and what is their effect?

Answer 20

Candesartan / Valsartan

• Potent competitive antagonists of angiotensin type I receptor
• DO NOT affect bradykinin levels
• Clinical Application In HF: Substitute for patients who can’t tolerate ACE inhibitors (severe cough or angioedema)
• Adverse Effects :Similar to ACE inhibitors (no cough) Teratogenic

Question 21

What are direct vasodilators and what is their effect?

Answer 21

Question 22

• Concurrent use of hydralazine & isosorbide dinitrate recommended for what types of patients:

Answer 22

• who cannot tolerate ACEI or ARB or,
• in African American patients with advanced heart failure as an adjunct to standard therapy

Question 23

What are the adverse effect of direct vasodilators?

Answer 23

• Hydralazine & isosorbide dinitrate = Headache, dizziness
• Hydralazine =Tachycardia, peripheral neuritis, lupus-like syndrome
• Contraindications =Sildenafil

Question 24

What are the B-Blocksers and their mechanism of action?

Answer 24

• Studies demonstrate reverse cardiac remodeling & reduction in mortality & hospitalization (30-40% in patients with NYHA II-IV HF)
• decrease HR and decrease contractility & inhibition of renin release (b1 receptors)
• Prevent deleterious effects of norepinephrine on cardiac
• muscle fibers which leads to decreased remodeling, hypertrophy etc
• Can get initial exacerbation of symptoms (start at low
  dose & gradually increase over several weeks)

Question 25

What are the clinical apllications of B-Blockers in Heart Failure?

Answer 25

* Recommended in addition to an ACEI for patients with: - symptomatic heart failure - asymptomatic patients with a decreased LVEF or history of MI * N B. USE CAUTIOUSLY in decompensated HF and are contraindicated in cardiogenic shock

Question 26

What are the adversde effects of b-blockers?

Answer 26

* Same as all b-blockers * Use cautiously in asthmatics and patients with severe bradycardia * Fluid retention (upon initial treatment) – an increasing dose of concurrent diuretic may help

Question 27

Sprionolactone effets?

Answer 27

* Patients with advanced heart disease have elevated aldosterone levels due to: • angiotensin stimulation • reduced hepatic clearance * MOA Aldosterone antagonist which prevents Na+ retention, myocardial hypertrophy & hypokalemia

Question 28

What are the clinical applications and adverse effects of Spironolactone in HR?

Answer 28

* + ACE inhibitors are shown to decrease morbidity & mortality in patients with severe heart failure * Adverse Effects **Hyperkalemia** (esp. in patients taking ACEIs/ARBs, K+ supplements or who have renal failure) GI disturbances (gastritis, peptic ulcer) CNS effects (lethargy, confusion) Endocrine abnormalities (gynecomastia, decreased libido, menstrual irregularities)

Question 29

What is Digoxin?

Answer 29

* Inotropic Agent * • Cardiac glycoside * • Derived from digitalis (foxglove) plant * • Widely used in treatment of HF * • Digoxin can decrease the symptoms of heart failure, increase exercise tolerance and decrease rate of hospitalization, but DOES NOT increase survival

Question 30

What are the disadvantages of Digoxin?

Answer 30

• Narrow therapeutic margin • Unfavourable, complicated pharmacokinetics • Drug sensitivity varies between patients • Drug sensitivity may change during therapy • Severe, potentially lethal adverse effects

Question 31

What is DIgoxin Mechniams of Action?

Answer 31

* Po sitively inotropic - Increases force of heart contraction * Negatively chronotropic - Decreases heart rate

Question 32

What is the mechanism of action of the Inotropic action of Digoxin?

Answer 32

• Inotropic action : increase cytoplasmic Ca2+ concentration that enhances contractility of cardiac muscle and leads to increases cardiac output * also * enhances vagal tone which leads to decreased HR • reduces sympathetic activity • reduces peripheral resistance which leads to myocardial O2 demand

Question 33

DIGOXIN mechanism of action for Ca2+ effects?

Answer 33

Question 34

Digoxin Summary?

Answer 34

Question 35

What are the clinical application of DIgoxin?

Answer 35

• HF with atrial fibrillation (main application) • Can be used (in addition to ACEI & b-blocker) to decrease symptoms, increase exercise tolerance & decrease rate of hospitalization

Question 36

*Digxon PK?*

Answer 36

• Very potent (narrow safety margin) • Widely distributed (including CSF) • t ½ = ~36-40 h • Accumulates in muscle which leads to a large Vd (loading dose required)

Question 37

What are the adverse effects of DIgoxin?

Answer 37

Digoxin toxicity = one of most common ADRs • Cardiac effects: arrhythmias, characterized by slowing of AV conduction (atrial arrhythmias) • GI effects: anorexia, nausea & vomiting • CNS effects: headache, fatigue, confusion, blurred vision, alteration of color perception, halos on dark objects • Hypokalemia • Drug accumulation / relative overdose • Hypomagnesemia or hypercalcemia • Hyperthyreosis • Abnormal renal function • Respiratory disease • Acid-base imbalances • …. age above 65, low body weight, fever etc

Question 38

Digxoin Interactions:

Answer 38

Question 39

What are the PDE III inhibitors?

Answer 39

* Inhibit myocardial cAMP PDE activity which leads to increased cAMP levels (+ve inotropic effect and increased cardiac output) * Possess systemic & pulmonary vasodilator effects (reduce both preload and afterload) * Shown to increase AV conduction slightly * Used for short-term therapy in patients with intractable heart failure

Question 40

Dopamine

Answer 40

Stimulates both adrenergic & dopaminergic receptors • Lower doses = mainly dopaminergic stimulating (produce renal and mesenteric vasodilation) • Higher doses = both dopaminergic & b1 stimulating (produce cardiac stimulation & renal vasodilation) • Large doses = stimulate alpha receptors (vasoconstriction) • Used in the treatment of shock (eg, MI, open heart surgery, renal failure, cardiac decompensation) which persists after adequate fluid volume replacement. Dopamine also promotes diuresis.

Answer 41

Dobutamine is administered as a racemic mixture 1 1 • (-) isomer is an a agonist • (+) isomer is an a and a mild b -receptor agonist and a weak b 1 1 2 -antagonist, a potent b agonist agonist -receptors 1 -receptors) 2 • At therapeutic levels the stimulation of b predominate, leading to a potent inotropic effect (with little change in heart rate). Net vascular effect is mild vasodilation (b • Used to increase cardiac output in acute management of heart failure (eg, MI)