VETM 5291: Pharmacology of Heart Failure

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.