VETM 5291: Pharmacology of Heart Failure

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Questions and Answers

What is the primary mechanism by which diuretics help reduce edema in patients with CHF?

Improve capillary permeability

Enhance renal blood flow

Increase cardiac output

Decrease blood volume (preload) (correct)

In congestive heart failure, what is the effect of diuretics on Starling forces?

Increase capillary hydrostatic pressure

Reduce myocardial contractility

Decrease atrial pressure/volume (correct)

Increase interstitial fluid pressure

How do diuretics affect the formation of interstitial edema?

They reduce capillary hydrostatic pressure (correct)

They increase venous return

They enhance lymphatic drainage

They promote increased plasma proteins

What is a critical consideration when prescribing diuretics to CHF patients?

Use the lowest effective dose Signup and view all the answers

What role does diuresis play in the overall management of CHF?

It decreases congestion and edema formation Signup and view all the answers

Why is it important to monitor diuretic use in patients with CHF?

To manage excessive urine output and dehydration Signup and view all the answers

What is the effect of diuretics on tissue perfusion in CHF patients?

They can reduce tissue perfusion by decreasing preload Signup and view all the answers

What is a limitation of diuretic therapy in the context of CHF?

They may require careful dosing to avoid fluid depletion Signup and view all the answers

What therapeutic benefit do Angiotensin II type-1 Receptor (AT1) Blockers provide regarding the AT2 receptor?

They preserve beneficial effects by shunting Ang II to the un-blocked AT2 receptor. Signup and view all the answers

Which of the following is a characteristic effect of the Angiotensin II type-1 receptor (AT1)?

Causes vasoconstriction and volume expansion. Signup and view all the answers

What is the primary outcome of Angiotensin II's action at the AT2 receptor?

Natriuresis and vasodilation. Signup and view all the answers

Which statement about Angiotensin II type-1 receptor blockers is accurate?

They block Ang II independently of its source. Signup and view all the answers

Which of the following effects is NOT associated with the AT1 receptor?

Vasodilation. Signup and view all the answers

What is the primary action of positive inotropes on ventricular systolic function?

Increase cytosolic Ca2+ concentration Signup and view all the answers

What is one of the potential drawbacks of using positive inotropes?

Pro-arrhythmia Signup and view all the answers

How does pimobendan differ from traditional positive inotropes?

It increases sensitivity of sarcomeres to Ca2+ Signup and view all the answers

During cardiomyocyte contraction, what is the role of 'trigger Ca2+'?

It enters through voltage-gated L-type Ca2+ channels Signup and view all the answers

Which component of the sarcomere interacts with calcium to facilitate contraction?

Troponin-C Signup and view all the answers

What is the primary mechanism through which calcium is released from the sarcoplasmic reticulum?

Calcium-induced calcium release Signup and view all the answers

Which subunit of troponin is specifically responsible for binding calcium?

TnC Signup and view all the answers

What effect does an increase in cytosolic Ca2+ have on the interaction between actin and myosin?

It enhances the interaction. Signup and view all the answers

What metabolizes to free cyanide in the context of sodium nitroprusside?

Sodium Nitroprusside Signup and view all the answers

What are the primary vasodilatory signals involved with balanced vasodilators?

IP3 and Nitric Oxide Signup and view all the answers

Which vasodilator is classified as a potent, balanced venous and arterial dilator?

Sodium Nitroprusside Signup and view all the answers

In what situations is sodium nitroprusside commonly used?

Acute treatment of CHF and life-threatening systemic arterial hypertension Signup and view all the answers

What is required due to the short half-life of sodium nitroprusside?

Continuous intravenous infusion (CRI) Signup and view all the answers

What differentiates sodium nitroprusside from organic nitrates in terms of tolerance?

There is no tolerance development with sodium nitroprusside Signup and view all the answers

What potential toxicity is associated with sodium nitroprusside?

Cyanide toxicity Signup and view all the answers

Why is continuous blood pressure monitoring required during the administration of sodium nitroprusside?

To avoid hypotension Signup and view all the answers

What primarily defines the force of myocyte contraction?

Number of actin-myosin cross-bridges Signup and view all the answers

What is the primary way the body increases cardiac contractility?

Activation of the sympathetic nervous system Signup and view all the answers

What effect does β1-adrenergic receptor stimulation have on contractility?

Increases inotropy Signup and view all the answers

Which protein is specifically phosphorylated to increase calcium uptake by SERCA?

Phospholamban Signup and view all the answers

Positive inotropic agents include which of the following?

Cardiac glycosides Signup and view all the answers

What effect does phosphorylation of actin-myosin cross-bridging have?

Increases calcium release from SR Signup and view all the answers

What is a major limitation of β1-adrenergic agonists?

They have a high first-pass effect and short half-life Signup and view all the answers

Which of the following drugs is classified as a negative inotropic agent?

β-adrenergic blockers Signup and view all the answers

Which mechanism is primarily responsible for increased levels of 'trigger Ca2+' during sympathetic activation?

Phosphorylation of voltage-gated L-type calcium channels Signup and view all the answers

What occurs when K+ leaks back into the tubule?

It repels Mg2+ and Ca2+, pushing them into the interstitum. Signup and view all the answers

Which of the following describes the action of loop diuretics?

They block Na+/K+/2Cl- co-transporter in the Loop of Henle. Signup and view all the answers

What is the net result of using loop diuretics?

Loss of H2O, Na+, K+, Cl-, H+, Mg2+, and Ca2+. Signup and view all the answers

Why do loop diuretics have a profound diuretic action?

The Loop of Henle has a large capacity for Na+ absorption. Signup and view all the answers

What role does the Na+/K+/2Cl- transporter play in the macula densa?

It activates the renin-angiotensin-aldosterone system (RAAS) in response to NaCl levels. Signup and view all the answers

What happens to the ability of the macula densa to detect tubular [Na+] when the transporter is blocked?

It inhibits the macula densa’s ability to detect Na+. Signup and view all the answers

What is the effect of using loop diuretics as a sole agent in patients with congestive heart failure?

It may worsen outcomes compared to combined therapies. Signup and view all the answers

What happens to water in the TAL when loop diuretics are used?

Water remains in the tubular fluid with Na+, K+, and Cl-. Signup and view all the answers

Study Notes

Basic Pharmacology of Heart Failure Management

This presentation covers pharmacology for congestive heart failure (CHF) management
The course is VETM 5291, Cardiovascular, Respiratory and Hemolymph Systems II
Instructor: Mandy Coleman, DVM, DACVIM (Cardiology), [email protected]

Learning Objectives

Explain drug rationales for CHF treatment
Understand how loop diuretics function
Describe cardiac excitation-contraction coupling
Discuss the advantages and disadvantages of inotropic drugs
Explain pimobendan's mechanisms of action
Understand the usefulness of pimobendan in CHF

General Approach to CHF Treatment

CHF patients often exhibit one or more of these issues:
- Excessive preload due to increased blood volume and systemic venoconstriction
- Excessive afterload from vasoconstriction
- Abnormal cardiac contractility
- Abnormalities in heart rate and rhythm
Drugs like diuretics and venodilators target these issues

First-Line Approach to Acute Left-Sided CHF

Furosamide (loop diuretic): reduces blood volume
Oxygen: increases alveolar-capillary oxygen gradient, reducing hypoxia
Nitroglycerin (venodilator): reduces preload and congestion
Sedation (cardio-friendly drug): alleviates anxiety
Inotropic support: improves cardiac output
Additional considerations: mechanical ventilation and afterload reduction may be necessary in severe cases.

Diuretic Agents: Introduction

Diuretics promote urination (loss of water and salts).
They work by altering sodium re-uptake in the kidneys.
Na+ affects water distribution and controls the fluid compartments. This is also affected by re-absorption, where even slight decreases can lead to significant water/salt excretion.
The goal of diuretics is to reduce blood volume through salt and water excretion.

Rationale for Use: Trans-capillary Flow Dynamics

Starling forces govern fluid movement across capillaries – capillary pressure and interstitial fluid pressure vs. plasma and interstitial osmotic pressures
Normally, filtration (outward fluid movement) is slightly greater than reabsorption.
Diuretics can affect fluid balance in the body by impacting these forces.

Rationale for Use of Diuretics in CHF

Diuresis decreases blood volume (preload) and capillary pressure reducing edema.
Diuretics do not improve cardiac output alone, therefore the lowest effective dose should be used.
The Frank-Starling Diagram demonstrates the relationship between blood volume and cardiac output.

Overview - Diuretics by Site of Action

Diuretics target specific areas in the nephron for altering fluid balance. Osmotic diuretics, thiazides, loop diuretics, and K+-sparing diuretics are used.
Avoid using osmotic diuretics in CHF cases

Site 2: Thick Ascending Limb of the Loop of Henle - Loop Diuretics

Loop diuretics block Na+/K+/2Cl− cotransporters.
This prevents re-absorption, leading to increased urine output and reducing fluid volume.
Furosemide is a commonly prescribed loop diuretic.
Loop diuretics are the first line treatment in severe CHF cases
Torsemide is often used in the place of furosemide.

Inotropic Agents: Introduction

Positive inotropes enhance cardiac contractility by impacting cytoplasmic calcium concentrations.
Positive inotropes are used when ventricular systolic function is compromised.
Potential downsides to using inotropes include pro-arrhythmias and increased energy/oxygen demand.
Newer inotropic agents like pimobendan avoid such costs

Review: Excitation-Contraction Coupling

An increase in cytosolic calcium is needed for myocyte contraction.
Two fluxes initiate cardiac contraction: a trigger release from voltage-gated L-type calcium channels, and a greater release from sarcoplasmic reticulum calcium channels
Trigger calcium response to membrane depolarization is followed by calcium release from sarcoplasmic reticulum.
Both fractions interact with troponin to allow contraction

Review: Cardiomyocyte Contraction (Systole)

Cardiomyocyte contraction depends on regulated interaction of thin filaments (actin + tropomyosin + troponin) in the sarcomere.
Increase in cytosolic [Ca2+] enables actin-myosin interaction.
The Troponin Complex includes 3 subunits that regulate myosin binding sites on actin to initiate cross-bridge cycles with myosin.

Review: Regulation of Cardiomyocyte Inotropy

The force of myocyte contraction depends on the concentration of calcium in the cytosol, affinity of troponin for calcium, and protein movements (phosphorylated or not)
The sympathetic nervous system is crucial for increasing cardiac contractility.

Sympathetic Nervous System Activation and Inotropic Effects

Norepinephrine and epinephrine stimulate β₁-adrenergic receptors.
This triggers a cascade of events leading to increased cAMP, which activates protein kinases.
Phosphorylation of proteins involved in calcium handling enhances calcium release and myosin binding, leading to increased contractility.

Drugs Affecting Cardiac Inotropy

Positive inotropes include β₁-adrenergic agonists, phosphodiesterase inhibitors, calcium-sensitizing agents, and cardiac glycosides.
Negative inotropes include β₁-adrenergic blockers or calcium channel blockers.

β₁-Adrenergic Agonists ("Sympathomimetics")

Very potent inotropic agents but have severe side effects
Only appropriate for short-term, intensive, hospital-level use
Rapid receptor desensitization requires frequent IV dosing (intravenous constant rate)
Potential side effects include arrhythmias and need for continual monitoring
Not a good chronic treatment for CHF

Receptors of the Sympathetic Nervous System

Norepinephrine and epinephrine can stimulate various receptors on different cells. This can result in vasoconstriction or vasodilation depending on the receptor subtypes involved.

Clinically-relevant β-adrenergic agonists and their uses

Each agent has varying effects on cardiac contractility and vascular tone
Uses for each drug vary

Pimobendan (Vetmedin®) - Overview

Synthetic "inodilator"
Primary mechanism in heart failure involves calcium sensitization and increasing the affinity of troponin-C for calcium
Improves contractile efficiency, without increasing intracellular calcium concentration

Pimobendan (Vetmedin®) - Clinical Use

Primarily used for treating CHF in dogs (can also be used for pre-clinical conditions like DCM).
Oral administration with a peak effect in 1 hour

Systemic Vasodilators

Drugs causing relaxation of vascular smooth muscle impacting blood flow.

Venodilators

Cause relaxation in veins, decreasing preload (amount of blood in the heart).
Organic nitrates (nitroglycerin, isosorbide) are examples of these, and are important in decreasing blood pressure.
Nitroprusside is a potent, balanced venous and arterial dilator useful in acute cases. Has a very short half-life and demands continuous blood pressure monitoring.

Arteriolar Dilators

Cause relaxation in small arteries to decrease afterload (resistance against which the heart pumps).
These include hydralazine, calcium channel blockers (e.g., amlodipine).

Balanced Vasodilators, e.g., Sodium Nitroprusside

These drugs affect both the venous and arterial side of the circulation (e.g., Sodium nitroprusside, discussed above).

Blockers of the Renin-Angiotensin-Aldosterone (RAAS) System

Ace inhibitors block the formation of angiotensin II.
Angiotensin II receptor blockers only target angiotensin II receptors (e.g., Telmisartan)
These drugs are beneficial in hypertension, cardiac failure, and some heart diseases.

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Description

This quiz explores the pharmacological management of congestive heart failure (CHF) as part of the VETM 5291 course. You'll learn about drug rationales, mechanisms of action for loop diuretics, and the use of inotropic drugs. Understand the principles behind CHF treatment and the role of various medications.