Basic Pharmacology of Heart Failure Treatment 2025 - VETM 5291 PDF

Basic Pharmacology of Heart Failure Management VETM 5291 Cardiovascular, Respiratory and Hemolymph Systems II Mandy Coleman, DVM, DACVIM (Cardiology) [email protected] ▪ Explain the rationale for the use of the following in the treatment of CHF: ▪...

Basic Pharmacology of Heart Failure Management VETM 5291 Cardiovascular, Respiratory and Hemolymph Systems II Mandy Coleman, DVM, DACVIM (Cardiology) [email protected] ▪ Explain the rationale for the use of the following in the treatment of CHF: ▪ Diuretics ▪ Positive inotropes ▪ Vasodilators Learning ▪ Relative to loop diuretics: Objectives ▪ Draw a diagram that illustrates normal solute movement in the loop of Henle By the end of this hour, ▪ Explain how a loop diuretic alters this movement to cause diuresis you will be able to… ▪ Describe these drugs’ effect on urinary excretion of electrolytes ▪ List 2 representative drugs and distinguishing characteristics ▪ Define and explain cardiac excitation-contraction coupling to a classmate ▪ Debate the relative advantages and disadvantages of sympathomimetic agents for acute inotropic support ▪ Discuss the two major mechanisms of action of pimobendan ▪ Defend the usefulness of pimobendan for chronic inotropic support in a dog with congestive heart failure General approach to CHF treatment Patients in congestive heart failure have … therefore, drugs that influence one or more of the following: these factors are often indicated: ▪ Excessive PRELOAD due to increased blood Diuretics and venodilators volume and systemic venoconstriction ▪ Excessive AFTERLOAD from vasoconstriction Arteriolar vasodilators ▪ Abnormal cardiac CONTRACTILITY Positive inotropes ▪ Abnormalities of heart rate and rhythm Antiarrhythmics MAP = CO x SVR First-line approach to acute left-sided CHF F O N S I First-line approach to acute left-sided CHF GOAL: F FUROSEMIDE (loop diuretic) Reduce blood volume/ preload Alleviate congestion O Supplemental OXYGEN Increase alveolar-capillary O2 gradient, reduce hypoxemia N Reduce preload NITROGLYCERIN (topical venodilator) Alleviate congestion S Alleviate anxiety caused by SEDATION with a cardio-friendly drug (e.g., butorphanol) respiratory distress I Support contractility INOTROPIC SUPPORT Improve cardiac output Additional considerations: mechanical ventilation, further afterload reduction in severe cases Diuretic Agents: Introduction ▪ “Di” = through; “uresis” = urination ▪ Diuretics promote urinary water loss by: ▪ Directly interfering with Na + reuptake from tubular filtrate (natriuresis), or ▪ Modifying the content of renal tubular filtrate (osmotic diuretics) ▪ Na+ controls dist’n of H2O among fluid compartments (“H2O follows Na+”) ▪ Renal glomerulus freely filters Na + and H2O ▪ Large amount of each must be reabsorbed daily to maintain blood volume ▪ Even small % decreases in reabsorption = large increases in Na +/H2O excretion  Rationale for Use: Trans-capillary Flow Dynamics/Net capillary filtration Starling Forces Average values: Pc = 18 mm Hg c = -25 mm Hg Pif = -7 mm Hg if = -1 mm Hg (Negative pressure sucks)  Rationale for Use: Trans-capillary Flow Dynamics/Net capillary filtration Small net gradient (1 mm Hg) favors outward movement of water (filtration > reabsorption) Starling Forces Net forces favoring reabsorption (in): Average values: Pc = 18 mm Hg c = -25 mm Hg TOTAL: 25 mmHg Pif = -7 mm Hg if = -1 mm Hg Net forces favoring filtration (out): (Negative pressure sucks) TOTAL: 26 mmHg  Rationale for Use: Trans-capillary Flow Dynamics/Net capillary filtration Small net gradient (1 mm Hg) favors outward movement of water (filtration > reabsorption) lymphatic vessel What normally happens to the excess interstitial fluid? How does tissue edema form in a patient with CHF? How would a diuretic affect Starling forces? How might these effects be helpful in a patient with interstitial edema?  Rationale for use of diuretics in Congestive Heart Failure (CHF) Frank-Starling Relationship ▪ Diuresis: heart failure Stroke volume/cardiac output ▪ Decreases blood volume (preload) ▪ Reduces atrial pressure/volume Normal heart ▪ Decreases capillary hydrostatic pressure ▪ Decreases edema formation (congestion) a normal tissue perfusion d ▪ Important: Diuresis DOES NOT improve cardiac ⋅ c ⋅ Heart disease output! Therefore, always use the lowest effective Hypotension/ b dose! ”forward” diuresis Venous congestion (“backward” heart failure) Left ventricular end-diastolic volume/pressure (PRELOAD) a = normal “operating point” b = operating point in diseased heart at normal preload c = compensated heart failure d = congestive heart failure Overview- Diuretics by site of action Add-on in cases refractory to loop diuretics alone Do not use in CHF! Osmotic diuretics Thiazides Weak; used extensively in CHF, but not for diuretic effects Loop diuretics K+-sparing diuretics Used extensively (first-line) in CHF treatment! Site : Thick Ascending Limb of the Loop of Henle Loop Diuretics (LD) Tubular epithelial cells 1. Na+/K+- ATPase sets up low intracellular [Na+] relative to interstitium and tubular fluid (IMPT) 2. Na+ moves out of tubule, into cell, through Na +/K+/2Cl- co-transporter (down concentration gradient) K+ and Cl- pulled along to maintain electroneutrality 3. Some K+ leaks back into tubule (down concentration gradient), taking + charge into lumen Positive charge repels Mg2+ and Ca2+, pushing them paracellularly into the interstitum TAL: impermeable to water, actively transports Na+  Site : Thick Ascending Limb of the Loop of Henle Loop Diuretics (LD; e.g. Furosemide) Tubular epithelial cells Loop diuretics Actively secreted into tubular fluid by proximal tubule Block Na+/K+/2Cl- co-transporter in LOH Water stays in tubule with Na+ (and K+ and Cl-)! Greater Na+ delivery downstream causes K+ and H+ loss in collecting duct Driving force for Mg2+, Ca2+ reabsorption decreases Net result: H2O, Na+, K+, Cl-, H+, Mg2+, Ca2+ loss TAL: impermeable to water, actively transports Na+  Site : Thick Ascending Limb of the Loop of Henle Loop Diuretics (LD) Tubular epithelial cells Loop diuretics Because LOH has large capacity for Na + absorption, LD have profound, “high ceiling” diuretic action Most powerful diuretics available! TAL: impermeable to water, actively transports Na+  Site : Thick Ascending Limb of the Loop of Henle Loop Diuretics (LD) Na+/K+/2Cl- transporter vital to macula densa (MD) Macula densa “detects” MD turns on RAAS in response to ↓Na in distal tubule decreased NaCl in tubular fluid Transporter blockade inhibits MD’s ability to detect tubular [Na+] Signal stimulating Result = activation of RAAS renin release Use of LD as sole agent worsens outcomes in CHF vs. Renin when given with a RAAS-blocking agent Always co-administer RAAS blocker in patients treated chronically with a loop diuretic! Renin-secreting cells of juxtaglomerular apparatus *RAAS = Renin-angiotensin-aldosterone system  Site : Thick Ascending Limb of the Loop of Henle Loop Diuretics Agents: Clinical indications: Furosemide (Lasix®) - most commonly Acute and chronic management of congestive prescribed loop diuretic heart failure* Wide dose range; IV, SQ or PO Tissue edema due to hypoalbuminemia IV: Rapid onset of action (5 min), time to peak Hypercalcemia effect (30 min). Duration of effect, 2-3 hours Oliguric renal failure (?) Torsemide – frequency of clinical use increasing; ~10 times more potent vs. furosemide Bumetanide, Ethacrynic acid  Inotropic Agents: Introduction Inotropic agents (“inotropes”) affect cardiac contractility Positive vs. negative Positive inotropes are prescribed in conditions/situations associated with compromised ventricular systolic function Most act by increasing cytosolic Ca 2+ Potential “costs” = pro-arrhythmia, ↑ myocardial energy demand and O2 consumption Newer agents (e.g., pimobendan) increase sarcomere sensitivity to Ca2+, avoiding these costs  Review: Excitation-contraction coupling (The process by which membrane depolarization leads to cell contraction) Increase in cytosolic Ca2+ is integral to myocyte contraction Two fluxes required: “Trigger Ca2+ ” in response to membrane depolarization (20%) Moves into cell through voltage-gated L-type Ca2+ channels (dihydropyridine receptors) during plateau of action potential Ca2+ from sarcoplasmic reticulum in response to trigger Ca2+ (80%) “Calcium-dependent calcium release” Moves through Ca2+release channels on sarcoplasmic reticulum Both Ca2+ fractions interact with troponin-C to allow contraction (Ryanodine receptor)  Review: Cardiomyocyte contraction (systole) Cardiomyocyte contraction is regulated by thin filaments (actin + tropomyosin + troponin) of the sarcomere Increase in cytosolic [Ca2+] is required for actin-myosin interaction TnI – inhibitory subunit* TnC – calcium-binding subunit TnT – tropomyosin-binding subunit  Review: Cardiomyocyte contraction (systole) At the sarcomere: 1. Cytosolic Ca2+ binds troponin C 2. Tropomyosin moves aside to uncover myosin-binding sites on actin 3. Cross-bridge cycling, contraction occur Elevated cytosolic [Ca] in response to action potential Ca2+ interaction with microfilaments Review: Regulation of cardiomyocte inotropy Force of myocyte contraction defined by # of actin- myosin cross-bridges, affected by: Concentration of Ca2+ in cytosol Affinity of troponin C for Ca2+ Whether proteins that regulate Ca2+ movement are phosphorylated Activation of sympathetic nervous system is primary way the body increases cardiac contractility! Important for heart’s response to exercise, emotional stress, pain, fear, hypotension, heart failure Mediated by stimulation of β1-adrenoreceptors Most positive inotropes mimic the effects of this system  Sympathetic Nervous System Activation: Cellular Mechanisms of Positive Inotropic Effect Norepinephrine or epinephrine β1-adrenergic receptor stimulation increases contractility Receptor binding = ↑ cAMP = ↑ activity of protein kinases “Trigger Ca2+” Protein kinases add phosphate groups to various proteins, modulating their effects: RyR Phosphorylated protein Effect SERCA Voltage-gated L-type More "trigger Ca2+” to interact with SR Ca2+ channels Actin-myosin SR Ca2+ release channels cross-bridging Increased Ca2+ release by SR (ryanodine receptors) Phospholamban Increased Ca2+ uptake by SERCA pump (regulatory protein) (more Ca2+ available for next beat) Augmented inotropy (This effect also allows the heart to relax more efficiently = “lusitropy”) Control/baseline (SR = sarcoplasmic reticulum)  Drugs Affecting Cardiac Inotropy Positive Inotropic Agents Negative Inotropic Agents β-adrenergic agonists (sympathomimetics) β-adrenergic blockers Phosphodiesterase (PDE) inhibitors Calcium channel blockers Calcium-sensitizing agents Cardiac glycosides  β1-adrenergic agonists (“Sympathomimetics”) Most potent class of myocardial stimulants available (↑ inotropy by 100% > baseline) Problem: only suitable for acute, short-term inotropic support under close supervision (i.e., IN-HOSPITAL USE) Substantial first-pass effect + short half-life (1-2 min) = IV constant rate infusion (CRI )only! Receptor desensitization occurs rapidly 50% reduction in inotropic response after 1-2 days Potential side effects (e.g., arrhythmia) necessitate close in-hospital monitoring Increase in intracellular Ca2+ favors arrhythmia development (Very) important consideration: most sympathomimetics aren’t “pure” inotropes Most also have vascular effects (i.e., cause vasoconstriction or vasodilation), depending on other adrenergic receptors stimulated and dose used  Receptors of the Sympathetic Nervous System ★ Norepinephrine (NE) – neurotransmitter released from sympathetic nerve terminals ★ Epinephrine (Epi; adrenaline) – hormone released into bloodstream in response to sympathetic stimulation  Clinically-relevant β-adrenergic agonists Relative Drug Receptor Affinity Physiological Effects Clinical Use Increased contractility Norepinephrine Circulatory collapse associated with Moderate/marked vasoconstriction (endogenous β1, α >> β2 profound peripheral vasodilation (i.e., catecholamine) Reflex bradycardia (baroreceptor- septic shock) mediated) Moderately increased contractility Epinephrine Mild net vasodilation (low-dose); Cardiac arrest (heart rate/inotropic (endogenous β1, β2> α vasoconstriction (high-dose) catecholamine) effects), anaphylaxis Moderately increased heart rate Markedly increased contractility β-adrenergic blocker overdose Isoproterenol β1> β2 Vasodilation (profound at high doses) (synthetic catecholamine) Rarely used for inotropic effect due to Markedly increased heart rate arrhythmia/tachycardia Moderately increased contractility Congestive heart failure (least Dobutamine β1 >> β2= α Net vascular effect = 0 vascular and heart rate effects) (synthetic catecholamine) Less effect on heart rate Cardiogenic shock  Clinically-relevant β-adrenergic agonists Relative Drug Receptor Affinity Physiological Effects Clinical Use Increased contractility Norepinephrine Circulatory collapse associated with Moderate/marked vasoconstriction (endogenous β1, α >> β2 profound peripheral vasodilation (i.e., catecholamine) Reflex bradycardia (baroreceptor- septic shock) mediated) Moderately increased contractility Epinephrine Mild net vasodilation (low-dose); Cardiac arrest (heart rate/inotropic Not used for inotropic effects in CHF patients (endogenous catecholamine) β1, β2> α vasoconstriction (high-dose) effects), anaphylaxis Moderately increased heart rate Markedly increased contractility β-adrenergic blocker overdose Isoproterenol β1> β2 Vasodilation (profound at high doses) (synthetic catecholamine) Rarely used for inotropic effect due to Markedly increased heart rate arrhythmia/tachycardia Moderately increased contractility Congestive heart failure (least Dobutamine β1 >> β2= α Net vascular effect = 0 vascular and heart rate effects) (synthetic catecholamine) Less effect on heart rate Cardiogenic shock  Pimobendan (Vetmedin®) ▪ Synthetic “inodilator” Actin filament ▪ In heart failure, primary mechanism by which pimobendan increases inotropy = Ca2+ sensitization ▪ ↑ affinity of troponin C (TnC) for Ca2+ ▪ ↑ degree of actin-myosin interaction Pimobendan + Improves efficiency of contraction without increasing intracellular [Ca2+]** ▪ Less arrhythmogenic ▪ Distinct advantage over other inotropes  Pimobendan (Vetmedin®) Secondary mechanism of ↑ inotropy = phosphodiesterase 3 (PDE-3) inhibition PDE-3 inactivates cAMP PDE-3 inhibition = ↑ cAMP and its downstream effects (positive inotropy, lusitropy) This effect is weak in the failing heart, but very important for the drug’s vascular ✕ effects (more about this later!) PDE-3 AMP (inactive) Pimobendan Myocardial cell  Pimobendan (Vetmedin®) - Clinical Use Most recently approved veterinary inotrope (2007) - oral formulation only Approved for use in dogs with congestive heart failure (CHF) due to dilated cardiomyopathy (DCM) or myxomatous mitral valve disease (MMVD) Use supported by results of randomized, double-blinded prospective clinical trials Additional clinical uses (not approved in US): Pre-clinical (e.g., prior to CHF onset) canine DCM and MMVD (Vetmedin–CA1) CHF due to DCM in cats CHF caused by other heart diseases (i.e., congenital heart disease)  Pimobendan (Vetmedin®) - Clinical Use Suitable for acute treatment of CHF (peak effect 1 hour after oral dose) Excellent for long-term inotropic support Good oral bioavailability Increases force of contraction without a significant ↑ in myocardial energy requirements or ↑ intracellular Ca2+* (less pro-arrhythmic) Favorable vascular effects (more next time!): decreases preload & afterload Wide margin of safety with few side effects No special monitoring required  Systemic Vasodilators Drugs causing relaxation of vascular smooth muscle (VSM) Type Cardiovascular Effects Drug(s) Venous dilators Relax capacitance vessels (veins) Organic nitrates Pooling in these vessels decreases volume of blood returning to the heart (REDUCE PRELOAD) Arterial/arteriolar Relax resistance vessels (small arteries/arterioles) Hydralazine dilators Decrease resistance against which heart must contract Ca2+ channel blockers (REDUCE AFTERLOAD) Combination Relax capacitance and resistance vessels Nitroprusside (balanced) dilators (REDUCE PRELOAD AND AFTERLOAD) Pimobendan RAAS inhibitors  Control of Vascular Smooth Muscle (VSM) Tone Signals causing vasoconstriction Signals causing vasodilation via VSM contraction: via VSM relaxation: Angiotensin II Nitric Norepi/Epi Oxide Norepi/Epi L-type α-adrenergic calcium channel β2-adrenergic or AT1 receptor receptor + Sarcoplasmic reticulum Ca2+ + IP3 − IP3 increases intracellular Ca2+ cAMP/cGMP decrease Ca2+ − intracellular Ca2+ VSM contraction Venodilators  Rationale for use of diuretics in Congestive Heart Failure (CHF) Frank-Starling Relationship ▪ Venodilation: heart failure Stroke volume/cardiac output ▪ Increases the capacity of the systemic veins ▪ Decreases volume of blood returning to the heart Normal (preload) heart ▪ Reduces atrial pressure/volume a normal tissue perfusion ▪ Decreases capillary hydrostatic pressure d ▪ Decreases edema formation (congestion) ⋅ c ⋅ Heart disease Hypotension/ b ”forward” venodilation Venous congestion (“backward” heart failure) Left ventricular end-diastolic volume/pressure (PRELOAD) a = normal “operating point” b = operating point in diseased heart at normal preload c = compensated heart failure d = congestive heart failure Venodilators - Nitrates Only clinically relevant dilators that predominantly affect veins Nitric oxide (NO) donors, vasodilate by ↑ cGMP NO: gas normally produced by vascular endothelium (AKA: “endothelial-derived relaxing factor”) Short t½: 1-3 min (rapidly converted to NO) Two types of nitrates: Organic nitrates*: nitroglycerin, isosorbide mono-/di-nitrate Nitroprusside - balanced (arterial and venous) vasodilator (discussed later)  Organic Nitrates Require activation within VSM cells Explosive! Nitroglycerin Administered topically due to poor oral bioavailability Conflicting experimental evidence for efficacy in vet med Used as ADJUNCT therapy in CHF – never as sole agent* Isosorbide mono- and di-nitrate Better oral bioavailability – available in tablet form Nitroglycerin paste Slower onset, longer duration of action Limited experience in veterinary patients Isosorbide tablets Organic Nitrates Potential side effects: Hypotension Headaches? (reported in human patients) Use limited by nitrate tolerance Develops within 18-24 h in people Avoid by intermittent administration (8-10 h nitrate-free interval/day) Arteriolar Dilators  Arterial/Arteriolar Vasodilation: Reduces peripheral vascular resistance (PVR) and afterload Greatest resistance to blood flow provided by small, muscular arteries and arterioles  Arterial/Arteriolar Vasodilation: Reduces peripheral vascular resistance (PVR) and afterload Greatest resistance to blood flow provided by small, muscular arteries and arterioles Major determinant of resistance = vessel radius (r) Muscular walls allow large changes in vessel radius Arterial dilators = ↑ vessel radius Benefit in hypertension: reduces/normalizes blood pressure Vascular 1 Benefit in CHF: decreased resistance against which heart must pump (AFTERLOAD) resistance r4  Arterial/Arteriolar Vasodilation: Reduces peripheral vascular resistance (PVR) Beneficial effect of afterload reduction in severe mitral insufficiency/CHF: PVR PVR LA Decreased PVR pressure Improved forward (systemic) flow Arteriolar dilator Decreased amount of blood traveling backward across MV Decreased left atrial pressure In CHF, decreased PVR ≠ decreased BP necessarily; the increase in cardiac output maintains BP! LV = left ventricle; LA = left atrium; Ao = aorta  Control of Vascular Smooth Muscle (VSM) Tone Signals causing vasoconstriction Signals causing vasodilation via VSM contraction: via VSM relaxation: Hydralazine L-type calcium channel + + Sarcoplasmic reticulum Ca2+ Ca-channel blockers (e.g., amlodipine) − cAMP/cGMP decrease Ca2+ − intracellular Ca2+ VSM contraction  Sodium Nitroprusside Potent, balanced venous and arterial dilator Used for acute treatment of CHF and life-threatening systemic arterial hypertension IV only – must be given as CRI due to short t1/2 Ultra-fast onset/offset of vasodilation Continuous BP monitoring required to avoid hypotension Unlike organic nitrates, tolerance DOESN’T develop… but cyanide toxicity can! Metabolized to free cyanide, buffered by methemoglobin in RBCs Dosing >24-36 h and at high dose rates predispose Balanced Vasodilators  Balanced Vasodilators Signals causing vasoconstriction: Signals causing vasodilation: + Nitroprusside Angiotensin II L-type Nitric Oxide − AT1 receptor calcium channel β2-adrenergic − receptor RAAS blockers + Sarcoplasmic reticulum e.g., ACEi and ARBs Ca2+ + + IP3 IP3 increases intracelluar Ca2+ Pimobendan − cAMP/cGMP decrease − intracellular Ca 2+ Sarcomere contraction  Sodium Nitroprusside Potent, balanced venous and arterial dilator Used for acute treatment of CHF and life-threatening systemic arterial hypertension IV only – must be given as CRI due to short t1/2 Ultra-fast onset/offset of vasodilation Continuous BP monitoring required to avoid hypotension Unlike organic nitrates, tolerance DOESN’T develop… but cyanide toxicity can! Metabolized to free cyanide, buffered by methemoglobin in RBCs Dosing >24-36 h and at high dose rates predispose  Bradykinin Angiotensinogen Angiotensin I Angiotensin II Vasodilation AT1 Receptor Anti-remodeling Aldosterone Direct release pathological effects Vasoconstriction, blood volume expansion, pro-inflammation, fibrosis Aldosterone release Blockers of the Renin-Angiotensin-Aldosterone (RAAS) System Adapted from: Zaman, et al. Nat Rev Drug Discov 2002  Bradykinin Angiotensinogen Angiotensin-Converting Enzyme Inhibitors (ACEi; “-pril”s) Angiotensin I Most well-studied class of RAAS blocker in heart disease/failure Block ACE to ↓angiotensin II production Angiotensin II Most common ACEi in veterinary medicine: Enalapril – 95% renal clearance Benazepril – 45% renal, 55% hepatic Vasodilation AT1 Receptor clearance (dog); 85% hepatic (cat) Anti-remodeling Well-tolerated with few side effects GI (anorexia, vomiting) Aldosterone Direct release pathological effects Hypotension (dogs > cats) Vasoconstriction, blood volume Azotemia (uncommon, greatest risk if expansion, pro-inflammation, fibrosis underlying renal disease) Hyperkalemia (uncommon, greatest risk of Aldosterone release used alongside potassium-sparing diuretic) Blockers of the Renin-Angiotensin-Aldosterone (RAAS) System Adapted from: Zaman, et al. Nat Rev Drug Discov 2002  Angiotensin II type-1 Receptor (AT1) Angiotensinogen Blockers (ARBs; “-sartan”s) Selective for AT1 receptor Angiotensin I – Block Ang II independent of source Preserve beneficial effects of AT2 receptor Angiotensin II – Ang II shunted to un-blocked AT2 Telmisartan approved in US AT1 Receptor AT2 Receptor Pathological effects Beneficial counter-effects Vasoconstriction, volume expansion Vasodilation, natriuresis Pro-inflammation, pro-fibrosis Anti-growth, -proliferation Tissue repair Aldosterone release Blockers of the Renin-Angiotensin-Aldosterone (RAAS) System Adapted from: Zaman, et al. Nat Rev Drug Discov 2002