Drugs Used in Heart Failure Flashcards
What is heart failure and its symptoms?
Heart failure -When cardiac output is inadequate to provide O needed by the body
Symptoms:
Tachycardia, decreased exercise tolerance, dyspnea, peripheral & pulmonary edema, cardiomegaly
What are the risk factors associated with Heart Failure?
Hypertension • Coronary artery disease • Myocardial infarction • Diabetes mellitus • Family history of cardiomyopathy • Use of cardiotoxins • Obesity
HFrEFvs HFpEF?
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)
what is Congestive Heart Failure (CHF)
Abnormal increases in blood volume & interstitial fluid. Symptoms include dyspnea from pulmonary congestion in left HF, and peripheral edema in right HF
what are the Physiologic Compensatory Mechanisms in HF
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
What are the 4 primary factors that function to have Cardiac performance
(1) Preload
(2) Afterload
(3) Contractility
(4) Heart rate
what is preload?
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
What is Afterload?
Force against which ventricles must act.
• Dependent on vascular resistance (aortic BP)
What is Cardiac Muscle Contraction?
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
Effects of Factors on Cardia Performace?
Drugs used to treat HFrEF (Systolic HF)
- Diuretics
- Spironolactone
- Inhibitors of angiotensin (ACE-inhibitors / ARBs)
- Direct vasodilators
- b-adrenoceptor antagonists (b-blockers)
- Inotropic agents
Drugs used to treat HFpEF (Diastolic HF)
- Diuretics
- ACEI /ARBs
- b-adrenoceptor antagonists (b-blockers)
- Calcium-channel antagonists
What are the recommended therpay by stage of CHF
What are diuretics?
- 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)
What are the clinical applications of diuretics
• 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)
What is the mechanism of the inhibitors of Angiotensin?
What are the ACE inhibitors and what is their effects?
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
What are the clinical applications of ACE inhibitors in HF
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
What are the adverse effects of ACE inhibitors?
- Hypotension,
- Persistent dry cough
- Hyperkalemia
- Angioedema
- Acute renal failure (patients with bilateral renal artery stenosis)
- Teratogenic
What are the ARBS and what is their effect?
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
What are direct vasodilators and what is their effect?
• Concurrent use of hydralazine & isosorbide dinitrate recommended for what types of patients:
- who cannot tolerate ACEI or ARB or,
- in African American patients with advanced heart failure as an adjunct to standard therapy
What are the adverse effect of direct vasodilators?
- Hydralazine & isosorbide dinitrate = Headache, dizziness
- Hydralazine =Tachycardia, peripheral neuritis, lupus-like syndrome
- Contraindications =Sildenafil
What are the B-Blocksers and their mechanism of action?
- 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)
What are the clinical apllications of B-Blockers in Heart Failure?
- 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
What are the adversde effects of b-blockers?
- 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
Sprionolactone effets?
- 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
What are the clinical applications and adverse effects of Spironolactone in HR?
- 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)
What is Digoxin?
- 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
What are the disadvantages of Digoxin?
• Narrow therapeutic margin • Unfavourable, complicated pharmacokinetics • Drug sensitivity varies between patients • Drug sensitivity may change during therapy • Severe, potentially lethal adverse effects
What is DIgoxin Mechniams of Action?
- Po sitively inotropic - Increases force of heart contraction
- Negatively chronotropic - Decreases heart rate
What is the mechanism of action of the Inotropic action of Digoxin?
• 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
DIGOXIN mechanism of action for Ca2+ effects?
Digoxin Summary?
What are the clinical application of DIgoxin?
• 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
Digxon PK?
• 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)
What are the adverse effects of DIgoxin?
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
Digxoin Interactions:
What are the PDE III inhibitors?
- 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
Dopamine
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.
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)
