How does digoxin facilitate Ca 2+ entry?

Digoxin facilitates Ca 2+ entry through VG-LT Ca 2+ channels. Increased iCa 2+ triggers CICR (Calcium-induced Calcium-release) from the SR (Sarcoplasmic Reticulum).

What is the result of increased iCa 2+ in the molecular mechanism of action?

Increased iCa 2+ facilitates excitation-contraction coupling (ECC). Increased Na + leads to increased Ca 2+ influx, resulting in increased Ca 2+ release from S.R producing contraction.

CVS - CHF. 94 good questions, nicely answered!

Q: What is the role of organic nitrates in C.H.F?

Organic nitrates, such as Nitroglycerine , are venodilators that produce decreased preload, resulting in decreased venous and pulmonary congestion, thereby relieving edema and dyspnea.

What interactions does spironolactone have that may lead to side effects?

Spironolactone interacts with androgen and progesterone receptors, which may lead to gynecomastia and other sexual side effects in some patients.

Why are adverse effects less frequent with eplerenone compared to spironolactone?

Such adverse effects are less frequent with eplerenone owing to its low affinity for the progesterone and androgen receptors.

What are the names of two aldosterone antagonists?

Spironolactone
Eplerenone

What is the role of beta-blockers in heart failure?

Beta-blockers counteract chronic sympathetic overactivity when the heart fails to maintain sufficient cardiac output. They inhibit arterial constriction and effects of noradrenaline and catecholamines on the heart.

How do spironolactone and eplerenone function as aldosterone antagonists?

Spironolactone and eplerenone are aldosterone antagonists that work by blocking the mineralocorticoid receptor, the target site for aldosterone.

How do beta-blockers affect the demands on the heart in heart failure?

These effects reduce demands on the heart, lessening structural and physiological changes that occur with chronic heart failure.

What is the role of organic nitrates in C.H.F?

Organic nitrates, such as Nitroglycerine, are venodilators that produce decreased preload, resulting in decreased venous and pulmonary congestion, thereby relieving edema and dyspnea.

What is the effect of aldosterone antagonists in the kidney?

In the kidney, aldosterone antagonists inhibit sodium reabsorption and potassium excretion.

How do aldosterone antagonists affect the heart?

In the heart, aldosterone antagonists inhibit cardiac extracellular matrix and collagen deposition, thereby attenuating cardiac fibrosis and ventricular remodeling.

What is one role of ACEIs in CHF therapy related to arteriolar dilatation?

ACEIs produce arteriolar dilatation, leading to decreased afterload and improved Cardiac Output, resulting in decreased fatigue.

How does Hydralazine function as a vasodilator in C.H.F?

Hydralazine is an arterial vasodilator that decreases afterload and increases cardiac output, thereby decreasing fatigue. It is effective in increasing renal blood flow.

What is necessary for safe beta-blocker therapy initiation?

Initiation at a low dose and careful upward titration of dose are necessary to institute beta-blocker therapy safely.

What is the role of loop diuretics in C.H.F therapy?

Reduce extracellular fluid volume (ECF) and ventricular filling pressure (Preload).
Effective in controlling congestive symptoms (dyspnea, edema) and improve exercise tolerance.

How do ACEIs affect renovascular resistance in CHF therapy?

ACEIs decrease renovascular resistance by decreasing renal vasoconstriction of AngT-II, which increases renal blood flow.

When is Hydralazine most effective in treating C.H.F?

Hydralazine is most effective when combined with organic nitrates, making it useful in patients who cannot tolerate ACEIs.

How is titration of beta-blockers usually carried out?

Titration is usually carried out over weeks or months, during which patients may suffer from an initial worsening of symptoms with each dose increment.

What are some adverse effects of Cardiac Glycosides?

N/V/D, abdominal pain
Fatigue, headache, drowsiness, colour vision disturbances
Sinus bradycardia, premature ventricular complexes, atrial tachycardia with AV-Block, ventricular fibrillation.

What effect do ACEIs have on Aldosterone secretion in CHF therapy?

ACEIs decrease Aldosterone secretion, leading to increased Renal blood flow and decreased Aldosterone secretion, resulting in Natriuresis.

What are thiazide diuretics useful for in C.H.F therapy?

Thiazide diuretics are useful for mild HF. They are part of the diuretic options in C.H.F therapy to manage heart failure symptoms.

What is the initial dosage for Digoxin therapy in congestive heart failure?

Begin with 0.125 – 0.25mg/day for initiating Digoxin therapy in congestive heart failure. It is reserved for patients with CHF presenting with atrial fibrillation or remain symptomatic despite therapy with ACEI.

How are loop diuretics used in C.H.F therapy?

Loop diuretics are useful for moderate and severe HF. An example is Frusemide 40mg tab. o.d used in therapy.

What are the contraindications (CI) for Cardiac Glycosides?

Partial heart block
Hypertrophic obstructive cardiomyopathy
Acute myocardial infarction
Rheumatic fever

Describe the role of ACEIs in venodilatation during CHF therapy.

ACEIs cause venodilatation, which decreases preload. Natriuresis and decreased preload filling pressures improve pulmonary and venous congestion.

How do ACEIs contribute to the reversal of ventricular remodeling in CHF therapy?

ACEIs reverse ventricular remodeling by:

Decreased preload and afterload
Preventing the trophic effects of AT-II on cardiac myocytes
Attenuating Aldosterone induced cardiac fibrosis

How does Digoxin help in atrial fibrillation with rapid ventricular response?

Digoxin blocks AV node, protecting the ventricle from rapid atrial rate. Loading dose is 1mg over 24 hours (i.e. 0.25mg/6hrs IV). Maintenance dose is 0.125mg daily.

What is the role of potassium-sparing diuretics in C.H.F therapy?

Diuresis not effective when used alone.
Combined with Loop diuretics.
Beneficial effects: Low dose Spironolactone improves survival in advanced HF.

What is the lipophilicity and absorption characteristic of Digoxin?

Digoxin is moderately lipophilic and well absorbed from the GIT. Acetylated and methylated forms have improved absorption.

What is the therapeutic use of cardiac glycosides in atrial flutter?

Cardiac glycosides convert atrial flutter to atrial fibrillation, shortening the Effective Refractory Period, which may return to normal rhythm on withdrawal of Digoxin.

What are the electrophysiological effects of cardiac glycosides at therapeutic doses?

At therapeutic doses, digoxin increases vagal tone and decreases sympathetic activity, resulting in:

Decreased HR
Decreased conduction in AV node
Decreased refractory period in atrial and ventricular tissues.

What is the bioavailability and plasma protein binding percentage of Digoxin?

Digoxin has a bioavailability of approximately 70% and plasma protein binding of around 30%.

What are the mechanical effects of cardiac glycosides?

Cardiac glycosides have positive inotropic effects. They increase myocardial force of contraction in patients with CHF. Increased force of contraction increases Cardiac Output, increasing blood flow to various organs and inhibiting compensatory Sympathetic and RAAS activation. This results in:

Decreased HR
Decreased preload (venous pressure) → improved cardiac performance and relief of pulmonary congestion
Decreased afterload increasing tissue perfusion
Decreased Na⁺ and water retention relieving oedema.

What happens at higher doses of cardiac glycosides?

At higher doses:

Increases automaticity by direct effect and sympathetic activation.
Decreases iK+

These effects predispose to arrhythmia.

How is Digoxin distributed in the body and what barriers does it cross?

Digoxin has a large V.d; it is widely distributed in all tissues including CNS and crosses the placenta.

Describe the effects of cardiac glycosides at toxic doses.

At toxic doses:

Overloading of iCa2+ leads to extra-systoles → pulsus bigeminy then trigeminy → ventricular tachycardia → ventricular fibrillation.
Simultaneous increase in automaticity and blockade of AV node conduction and Ca2+ overload produces all forms of arrhythmias.

How is Digoxin metabolized and what is its half-life?

Digoxin is metabolized in hepatic microsomal enzymes with a long t_1/2 of 36 - 48 hours.

What effect does digoxin have on the Na⁺/K⁺ ATPase pump?

Digoxin inhibits the membrane Na⁺/K⁺ ATPase pump, leading to increased iNa⁺ and consequently increases free iCa²⁺ through increasing Na⁺/Ca²⁺ exchange mechanism.

How is Digoxin excreted and what affects its excretion?

Digoxin can be excreted unchanged by kidneys. Renal impairment prolongs its t_1/2, requiring dose adjustments.

What are cardiac glycosides like Digoxin derived from?

Cardiac glycosides like Digoxin are derived from plant sources such as Digitalis purpurea and animal sources like toad toxin. They are potent and highly specific inhibitors of the intrinsic plasma membrane Na⁺/K⁺-ATPase, known as 'the Na⁺ pump'. They modulate electrophysiological properties of the heart and its contractile functions.

How does digoxin facilitate Ca²⁺ entry?

Digoxin facilitates Ca²⁺ entry through VG-LT Ca²⁺ channels. Increased iCa²⁺ triggers CICR (Calcium-induced Calcium-release) from the SR (Sarcoplasmic Reticulum).

What is the result of increased iCa²⁺ in the molecular mechanism of action?

Increased iCa²⁺ facilitates excitation-contraction coupling (ECC). Increased Na⁺ leads to increased Ca²⁺ influx, resulting in increased Ca²⁺ release from S.R producing contraction.

What is the safety margin and therapeutic serum level of Digoxin?

Digoxin has a narrow safety margin, TDM recommended. Therapeutic serum level of digoxin is 0.5-2.0 ng/ml.

What does Digoxin inhibit to increase contractility in heart muscle cells?

Digoxin inhibits the sodium pump, inducing an increase in intracellular sodium. This drives an influx of calcium in the myocardium cells, causing an increase in contractility.

What is the action of Digoxin in cardiac glycosides?

Digoxin inhibits cardiac Na⁺/K⁺ ATPase pump, leading to an increase in iCa²⁺ and increased force of contraction. Adverse effects include cardiac toxicity, arrhythmia, fatigue, malaise, confusion, blurred/yellow vision, etc.

What are the effects of Digoxin on cardiac output and ventricular filling pressure?

Effects of Digoxin include:

Increase in CO
Decrease in ventricular filling pressure
Inhibit the AV node conduction, improving abnormal heart rhythms (arrhythmias).

What is the first step in the CHF Treatment Algorithm?

The first step is to assess left ventricular function. If the ejection fraction is ≤ 40%, assess volume status. This determines the next steps in treatment.

Name the drug class and adverse effects of Milrinone.

Milrinone belongs to the phosphodiesterase (PDE₃) inhibitors class. It inhibits cardiac PDE₃, increasing cAMP and contractility. Adverse effects include nausea, vomiting, thrombocytopenia, and liver toxicity.

What are the types of parenteral drug therapy for managing hospitalized acute heart failure or refractory C.H.F (emergency)?

Loop Diuretics
Vasodilators: e.g. Sodium nitroprusside, Hydralazine, Diazoxide, etc
Sympathomimetics: e.g. Dobutamine, Dopamine
Phosphodiesterase inhibitors: e.g. Inamrinone, Amrinone

What should be done if there is evidence of fluid overload in CHF treatment?

If there is evidence of fluid overload (elevated jugular venous pressure, edema, rales), initiate diuretics and ACE inhibitors; add digoxin if symptoms persist; add β blocker when fluid overload is resolved.

What are the actions and adverse effects of Dobutamine?

Dobutamine increases cAMP, activating and stimulating myocardial contractility. Adverse effects include hypertension, angina, arrhythmia, dyspnea, headache, nausea & vomiting, and paraesthesia.

What is the treatment approach if there is no evidence of fluid overload?

If there is no evidence of fluid overload, initiate ACE inhibitors; add β blocker; add diuretics and digoxin as needed for persistent or new symptoms.

What is the management for Class I ambulatory heart failure?

Management for Class I ambulatory heart failure involves the use of Diuretics.

List the drugs under the inotropic sympathomimetics class.

The inotropic sympathomimetics class includes Dobutamine and Dopamine. They increase cAMP, activating and stimulating myocardial contractility. Adverse effects include hypertension, angina, arrhythmia, dyspnea, headache, nausea & vomiting, and paraesthesia.

When should spironolactone be considered in CHF treatment?

If the patient has marked limitation of physical activity or is unable to carry out physical activity without discomfort and symptoms of heart failure or angina are present, consider administering spironolactone.

Which medications are used for Class II ambulatory heart failure?

Class II ambulatory heart failure is managed with ACEIs or ARBs.

What are the key components involved in the regulation of inotropy in myocardial cells?

L-type calcium channels: Allow Ca²⁺ influx.
RyR: Releases Ca²⁺ from SR.
SERCA: Pumps Ca²⁺ back into SR.
Na⁺/K⁺-ATPase: Maintains ion balance.
Cardiac Glycosides: Affect Na⁺/K⁺-ATPase.
CCBs: Affect L-type calcium channels.
Myocin activators: Enhance myosin interaction.
Myofilament Sensitizers: Increase sensitivity to Ca²⁺.

What is the role of L-type calcium channels in myocardial cells?

L-type calcium channels allow the influx of Ca²⁺ into myocardial cells, initiating the process of inotropy regulation. This influx is crucial for subsequent steps in calcium handling and muscle contraction.

What combination of medications is used for Class III ambulatory heart failure?

Class III ambulatory heart failure is treated with Diuretics + ACEIs or ARBs.

What are PDE₃ inhibitors used for?

PDE₃ inhibitors such as Milrinone and Inamrinone are used in emergencies. They are classified as other positive inotropic agents.

How does the sarcoplasmic reticulum (SR) contribute to calcium regulation in myocardial cells?

The sarcoplasmic reticulum (SR) releases Ca²⁺ through RyR channels, contributing to calcium-induced calcium release. This process is essential for muscle contraction and inotropy regulation.

How is Class IV ambulatory heart failure managed?

Management for Class IV ambulatory heart failure includes Diuretics + ACEIs or ARBs + Digoxin.

Why are thiazides less effective in patients with reduced glomerular filtration?

Thiazides are less effective in patients with reduced glomerular filtration because they exert their diuretic effects from the luminal side of the nephron. Loop diuretics are a drug of choice in CHF.

What is the function of SERCA in myocardial cells?

SERCA pumps Ca²⁺ back into the sarcoplasmic reticulum, reducing cytosolic calcium levels and aiding muscle relaxation. Phospholamban regulates SERCA activity.

Name a cardiac myocin activator mentioned as a newer agent.

A cardiac myocin activator mentioned as a newer agent is Omecamtiv. It falls under the category of other positive inotropic agents.

What should be used for patients intolerant to ACEIs or ARBs?

For patients intolerant to ACEIs or ARBs, use Hydralazine or Nitrates.

What does dopamine stimulate at low doses and what is the effect?

At low doses, dopamine stimulates D1 and D2 in renal and vasculature causing vasodilation, increasing renal blood flow.

Describe the interaction between troponin C and calcium in myocardial cells.

Troponin C binds to Ca²⁺, leading to a conformational change that allows actin and myosin interaction, facilitating muscle contraction. This is a key step in inotropy regulation.

List some examples of myofilament calcium sensitizers.

Examples of myofilament calcium sensitizers include Levosimendan, pimobendan, and sulmazole. They are identified as newer agents in the category of other positive inotropic agents.

What does dopamine stimulate at intermediate doses?

At intermediate doses, it stimulates B1 on the heart.

Why are selective catecholamines preferred?

Selective catecholamines are preferred due to less adverse effects. Adrenaline/Dopamine are no longer in favour as first line agents. Dobutamine has superior pharmacodynamics properties as an agent for vasopressor therapy.

What role does Na⁺/K⁺-ATPase play in myocardial cells?

Na⁺/K⁺-ATPase helps maintain the electrochemical gradient by pumping Na⁺ out and K⁺ into the cell, indirectly influencing Ca²⁺ handling and inotropy.

What are the clinical uses of Dopamine, Dobutamine, and Adrenaline?

Low BP; hypotension
Low cardiac output
Reduced perfusion due to shock, trauma, and sepsis

In what types of shock is dopamine used?

Dopamine is used in septic and cardiogenic shock.

What is the effect of Dobutamine on a-2 receptors?

Dobutamine is selective B-Ino effect on a-2 receptors, less effect on the failing heart. Dobutamine increases myocardial contractility, the drug of choice among catecholamines for treatment of cardiogenic shock and refractory heart failure.

What are the types of diuretics mentioned as treatment options?

Loop diuretics (Frusemide)
Thiazides (Hydrochlorothiazide)
K+ sparing (Spironolactone)

Why is dobutamine preferred over dopamine in cardiogenic shock?

Dobutamine is preferred, dopamine increases the heart rate when treating cardiogenic shock.

Why is Adrenaline contraindicated in cardiogenic shock?

Adrenaline is contraindicated in cardiogenic shock due to organ injury and mortality. Dobutamine increases myocardial contractility, the drug of choice among catecholamines for treatment of cardiogenic shock and refractory heart failure.

What is one rationale for pharmacologic intervention in CHF related to haemodynamics?

One rationale is to improve haemodynamics and cardiac function by improving the cardiac output with positive inotropic agents and reducing the pre-load and afterload; e.g. Digoxin.

Name the ACEIs and AT II antagonists listed in the treatment options.

ACEIs (e.g. Enalapril, etc)
AT II antagonists (e.g. Lorsatan)

What is the drug of choice first line in hypovolemic shock and why?

Drug of choice first line in hypovolemic shock is epinephrine/Noradrenaline because dobutamine is associated with decreased cardiac output due to its vasodilator activity (inodilator).

What is the effect of positive inotropic drugs in the pathophysiology of CHF?

Positive inotropic drugs increase the force of contraction, counteracting the decreased force of contraction seen in CHF. This helps improve low cardiac output associated with heart failure.

What vasodilators are included in the treatment options?

Organic Nitrates (e.g. Nitroglycerine)
Nitroprusside, etc

What is the purpose of long-term treatment with ACEI and β-blockers in CHF?

Long-term treatment aims to improve survival with cardioprotective drugs that have intrinsic vasodilator activity, e.g. Carvedilol (blocks B-1 & α-1), Metoprolol (B-1 selective).

What is the rationale behind using β-blockers in CHF treatment?

The rationale is to reduce overstimulation of the heart by the compensatory mechanism (Sympathetic and RAAS system) preventing remodelling/fibrosis.

What are the dietary recommendations for non-pharmacological management of CHF?

Restrict water intake
Reduce salt intake
Take low fat foods
Take food rich in proteins in case of ascites

Which cardiac glycoside is mentioned in the treatment options?

Cardiac Glycosides (Digoxin)

How does low cardiac output affect renal blood flow and carotid sinus firing?

Low cardiac output leads to decreased renal blood flow and decreased carotid sinus firing. This triggers the activation of the renin-angiotensin-aldosterone system and sympathetic system.

What lifestyle change is suggested for non-pharmacological management of CHF?

Stop smoking.

What are the goals of therapy for CHF?

Relieve symptoms: Patients are uncomfortable, with low cardiac output and fluid accumulation causing breathlessness.
Decrease morbidity.
Slow progression (survival).
Ultimately prevent mortality.

What systems are activated due to decreased renal blood flow and carotid sinus firing?

Decreased renal blood flow activates the renin-angiotensin-aldosterone system, while decreased carotid sinus firing activates the sympathetic system, increasing sympathetic discharge.

List the sympathomimetics included in the treatment options.

Adrenaline
Dobutamine IV
Dopamine IV – for cardiac emergencies

What role do ACEIs and ARBs play in the pathophysiology of CHF?

ACEIs and ARBs inhibit the effects of the renin-angiotensin-aldosterone system, reducing vasoconstriction and the subsequent increase in preload and afterload.

How does vasoconstriction affect preload and afterload in CHF?

Vasoconstriction leads to increased preload through venous vasoconstriction and increased afterload through arterial vasoconstriction, exacerbating heart failure symptoms.

What is the effect of aldosterone in CHF?

Aldosterone causes salt and water retention, leading to volume expansion and increased preload, worsening the symptoms of heart failure.

What drugs target increased preload and afterload in CHF?

Diuretics target increased preload, venodilators target increased preload, and arterial vasodilators target increased afterload, helping to manage heart failure symptoms.

CVS - CHF

94 important questions on CVS - CHF