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Questions and Answers
Which mechanism is primarily responsible for increasing preload?
Which mechanism is primarily responsible for increasing preload?
What effect do b-agonists primarily have in the context of cardiac function?
What effect do b-agonists primarily have in the context of cardiac function?
What is the primary factor affecting afterload in the cardiovascular system?
What is the primary factor affecting afterload in the cardiovascular system?
How does digoxin primarily affect cardiac contractility?
How does digoxin primarily affect cardiac contractility?
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Which statement accurately describes vasculature compared to cardiac selectivity of b-agonists?
Which statement accurately describes vasculature compared to cardiac selectivity of b-agonists?
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Which of the following is a characteristic of PDE3 inhibitors as compared to beta-agonists?
Which of the following is a characteristic of PDE3 inhibitors as compared to beta-agonists?
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What is the primary mechanism of action of digoxin in enhancing cardiac contractility?
What is the primary mechanism of action of digoxin in enhancing cardiac contractility?
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Which drug works primarily as a calcium sensitizer affecting the sarcomere?
Which drug works primarily as a calcium sensitizer affecting the sarcomere?
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What distinguishes norepinephrine from epinephrine in terms of hemodynamic effects?
What distinguishes norepinephrine from epinephrine in terms of hemodynamic effects?
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How do phosphodiesterase inhibitors like milrinone and amrinone affect cAMP levels?
How do phosphodiesterase inhibitors like milrinone and amrinone affect cAMP levels?
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Which statement is accurate regarding the therapeutic range of digoxin?
Which statement is accurate regarding the therapeutic range of digoxin?
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What is the effect of PDE3 inhibitors on vascular smooth muscle?
What is the effect of PDE3 inhibitors on vascular smooth muscle?
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Which phosphodiesterase subtype is highly expressed in the heart and primarily affects cAMP?
Which phosphodiesterase subtype is highly expressed in the heart and primarily affects cAMP?
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What is the primary effect of Levosimendan on vascular smooth muscle cells (VSMC)?
What is the primary effect of Levosimendan on vascular smooth muscle cells (VSMC)?
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Which statement accurately describes the mechanism of action of Omecamtiv Mecarbil?
Which statement accurately describes the mechanism of action of Omecamtiv Mecarbil?
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What is a significant drawback of Omecamtiv Mecarbil noted in clinical trials?
What is a significant drawback of Omecamtiv Mecarbil noted in clinical trials?
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Which determinants are essential for cardiac output (CO)?
Which determinants are essential for cardiac output (CO)?
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How do PDE3 inhibitors affect cardiac contractility?
How do PDE3 inhibitors affect cardiac contractility?
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What distinguishes the action of Digoxin from Levosimendan?
What distinguishes the action of Digoxin from Levosimendan?
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Which best describes the selectivity of adrenergic signaling in cardiac and vascular smooth muscle contraction?
Which best describes the selectivity of adrenergic signaling in cardiac and vascular smooth muscle contraction?
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What is a key difference between the mechanisms of cardiac and vascular contraction?
What is a key difference between the mechanisms of cardiac and vascular contraction?
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Study Notes
Introduction
- This document is a presentation on alpha and beta agonists and inotropes for blood pressure and cardiac function.
Outline
- Cardiac Physiology refresher
- Factors affecting cardiac output (stroke volume)
- Afterload
- Preload
- Contractility
- Factors affecting cardiac output (stroke volume)
- Molecular basis of cardiac and smooth muscle contraction
- alpha agonists and signaling
- Beta agonists and signaling
- Shock
- Acute Heart Failure/cardiogenic shock
- Other inotropes:
- Digoxin
- PDEIs
- Levosimendan
- Omecamtiv mecarbil
Cardiac Physiology: Cardiac Output
- Cardiac output (CO) = Heart rate (HR) x Stroke volume (SV)
- Stroke volume (SV) is determined by preload, afterload, and contractility
- Determinants of cardiac output:
- Afterload (decrease)
- Preload (increase)
- Contractility (increase)
- Heart rate (mostly increase)
Cardiac Cycle
- (Diagram)
- Shows the different stages of the cardiac cycle, including pressure and volume changes, and valve opening/closing.
Preload
- Pressure that fills the ventricle
- Increases in preload increase stroke volume (SV) and cardiac output (CO)
- Frank-Starling mechanism
- More force/pressure is produced the more the ventricle wall is stretched
- Intrinsic properties of the cardiac sarcomeres (stretch, tension), and Ca++ release machinery
Afterload
- Pressure and/or resistance that the heart has to actively work against
- Increases in afterload decrease SV and CO
- Blood pressure
- Vascular resistance
- Stiffness of the aorta and peripheral circulation
- High blood pressure = high afterload
- Intrinsic Factors of Ventricular Wall: remodeled LV/RV wall can increase afterload
Contractility
- Force generated for a given sarcomere/fiber length
- Can be modified by:
- Catecholamines
- Sympathetic and Parasympathetic Activity
- Inotropes
- Preload
- Afterload (Anrep Effect)
- Heart Rate (Bowditch Effect)
Preload and Afterload effects on cardiac output with LV dysfunction
- (Diagram)
- Shows the relationship between preload/afterload and cardiac index in different stages (normal, mild to moderate, severe) of LV dysfunction
Heart Rate
- Heart rate increases cause an increase in CO
- CO = HR*SV
- However, at too high a heart rate, filling is impaired, so preload decreases and SV drops affecting HR.
- A high heart rate can also adversely increase myocardial O2 demand and impair contractility
Summary
- 4 determinants of cardiac output: Preload, Afterload, Contractility, and Heart Rate
- Frank Starling mechanism: Heart responds to increased preload with increased ejection and CO.
- Heart is tuned to increase ejection with increased stretch
- Increased contractility increases CO – increases the amount of blood pushed out
- Increased afterload decreases CO – force the heart has to work against to eject blood
Molecular Basis of Contraction - Smooth Muscle
- Depolarization of smooth muscle and/or signaling causes release of Ca++ in intracellular stores through IP3 receptor on SR.
- Ca++ activates MLCK to phosphorylate MLC.
- Rho Kinase inactivates myosin phosphatase in parallel to MLCK to really drive MLC phosphorylation.
- MLC phosphorylation causes activation of myosin and subsequent vessel contractions.
Cardiac Contraction
- Cardiac contraction is all about Ca++
- Cardiac Troponin-Tropomyosin complex inhibits binding of myosin to actin.
- Increases in cytosolic Ca++ bind to cTnC allowing interaction of myosin and actin, and contraction to take place.
- When Ca++ levels fall every beat of the heart, relaxation occurs.
- This mechanism to contract is faster than MLC phosphorylation.
Calcium-induced calcium release
- Explains how depolarization triggers calcium release from the sarcoplasmic reticulum (SR).
- Calcium enters the cardiomyocyte via L-type calcium channels.
- Calcium activates ryanodine receptors, triggering more calcium release from SR.
- Calcium returns to SR via SERCA channels.
SR and T tubules in myocytes
- (Diagram)
- Shows the structure of the SR and T-tubules.
Excitation-Contraction (E-C) Coupling
- Action Potential - causes Ca++ influx due to depolarization- LTCC
- Ca++ releases more Ca++ from SR
- Ca++ binds cTnC – allows actin/myosin interaction
- Ca++ removed by SERCA- sarcoendoplasmic reticulum Ca++ ATPase
- SERCA (bound to phospholamban) which slows pump activity
- Other Ca++ removed by NCX (Na/Ca++ exchange)
- Na/K ATPase resets membrane potential (voltage)
Summary Cardiac Contraction
- Contraction is determined by the amount of Ca++
- Action potential depolarises cell and activates PM Ca++ channels.
- Increased Ca++ at PM causes large Ca++ release from SR.
- Released Ca++ binds TnC to allow myosin:actin interaction and contraction.
- SERCA activates to restore Ca++ to SR and NCX expels Ca++ from the plasma membrane.
- Phospholamban (PLN/PLB) is a protein that inhibits SERCA (slows).
- Cell repolarizes and cycle continues.
- Increases in Ca++ release within the cell will cause an increase in cardiac contractility.
Summary: VSM contraction
- VSM contraction is determined by the amount of MLC phosphorylation.
- Contractile agents cause increases in Ca++ from intracellular stores as well as Ca++ channels leading to depolarization.
- Ca++ causes activation of cascades leading to MLC phosphorylation.
- Additional signaling cascades (Rho kinase) sensitize the cell to Ca++ and promote MLC phosphorylation.
- PKA promotes dilation.
alpha and beta adrenergic receptors
- Alpha1, located in blood vessels; promotes constriction
- Alpha2, located on heart ; increases heart rate and contractility, increases coronary dilation.
- Beta1, located on heart; increases heart rate and contractility, increases coronary dilation.
- Beta2, promotes increased heart rate and vasodilation (including coronary)
Norepinephrine
- Has a1, and b1 (and sometimes b2) activation effects
- Increases afterload (↑ SVR), decreases CO
- Increases contractility, increases HR, increased CO
Epinephrine
- Has no alpha1 effects at low doses
- B1 and b2 (dilation) only
- At high doses will activate al receptors and the response will be similar to norepinephrine, with increased SVR and pressure, increase HR and contractility
Norepinephrine and Epinephrine
- Norepinephrine: major effect is a1 and b1 activation
- Increase SVR (and decreases CO)
- Increase CO via b1 effects to increase contractility and HR
- Epinephrine: No alpha1 effects at low doses. B1 and b2 (dilation) only, but at higher doses, a1 is strongly activated
α1-AR Agonists (sympathomimetics)
- Midodrine: prodrug enzymatically hydrolyzed to desglymidodrine (selective a1-receptor agonist). Peak concentration about 1 hr after administration. Treatment for orthostatic hypotension caused by impaired ANS function.
- Methoxamine: older al agonist, no longer marketed.
- Phenylephrine: Potent alpha1-adrenergic vasoconstrictor. May be considered when tachyarrhythmias preclude use of norepinephrine. Alternative vasopressor for patients with septic shock.
α1-AR Agonists Indications.
- Chronic orthostatic hypotension (midodrine).
- Raise blood pressure acutely (phenylephrine, norepinephrine).
- Non-systemic uses: Topical nasal or oral decongestant (phenylephrine); Used with local anesthetics (phenylephrine or with high concentration of epinephrine).
Other agents to elevate blood pressure
- Vasopressin (arginine vasopressin AVP, ADH): Hormone secreted from the pituitary (used in shock to increase blood pressure), stimulates vasoconstriction, increases blood volume via anti-diuretic effects on kidneys
Alpha-agonists Summary
- Alpha1 agonists are potent vasoconstrictors
- Activate PLC, increase Ca++ release, and enhance myosin light chain phosphorylation
- Most often used in shock or ICU settings
- Phenylephrine/norepinephrine are potent vasoconstrictors (also have less effect on beta-receptors)
Beta-agonists
- Used in settings of acute and severe cases of lowered CO.
- Not desirable for long-term treatment of CHF.
- Increased hypertrophy/fibrosis
- Desensitization of necessary βAR signaling
- Increased O2 demand
- Can make the heart ischemic
- Increased afterload (due to effects on αAR)
β1 Mechanism of action on the heart
- β1AR activates cAMP-dependent protein kinase.
- Has a coordinated response to modify numerous enzymes involved in Ca++ handling.
PKA Mechanism of modulating Ca++ release
- PKA can increase Ca++ release through direct and external modulation of Ca++ release channels.
- PKA phosphorylates and inhibits PLB; this allows for increased SERCA activity and leads to increased Ca++ in the SR stores.
- Other kinases are involved in this coordinated response.
PKA in vasculature (dilation)
- PKA functions very differently in the vasculature.
β1 and Cardiac Contraction Summary
- β1 adrenergic receptors cause:
- Activation of adenylate cyclase
- cAMP production
- Activation of PKA (cAMP dependent protein kinase)
- PKA phosphorylates multiple targets to increase Ca++ release
- Ryanodine receptor on SR - increase in Ca++ release
- PLB—which removes inhibition of SERCA—leads to increased Ca++ uptake in SR.
- LTCC-increased Ca++ influx
- Increased Ca++ increases contraction.
- Also results in multiple other effects on multiple systems necessary for the cardiac cycle (NCX, Na/K ATPase, K + and Na+ Channels).
Acute vs Chronic Heart Failure
- Acute: Acute stress/injury impacts ability of heart to contract.
- Can't maintain CO. Often treated with inotropes (beta agonists), vasodilators, and/or volume management. Emergency treatment, usually associated with ICU care.
- Chronic: Usually major myocardial remodeling, ischemia, hypertrophy, fibrosis.
- Reduced or preserved function. Often treated with beta-blockers, volume management, and vasodilators.
Uses of beta-agonists and other inotropes
- Chronic Heart Failure that has become acutely worse and patient can no longer maintain CO effectively.
- Acute decompensated heart failure
- Can happen in patients with either previous HFrEF or HFpEF
- Cardiogenic shock and low output syndrome
- Usually associated with an acute insult
- Cardiac Surgery
- Transplantation
- Other inflammatory insults (e.g., septic shock, COVID)
Myocardial stunning and cardiogenic shock associated with cardiac surgery
- Cardiopulmonary bypass and cardioplegic arrest—prolonged mild ischemic injury, myocyte hypoxia, acidosis, Oxidant Dependent Damage, Metabolic and Structural alterations, Inflammation.
- All of these insults cause reversible damage to heart muscle.
- ~10% of patients exhibit severe persistent stunning—signifies higher risk of mortality.
- Inotropes are frequently used to improve CO until normal heart function returns (hours to days)
Types of Acute Heart Failure
- Classified by sets of variables:
- Cold vs Warm (perfusion, thus cardiac index)
- Cold - poorly perfused
- Warm - well perfused
- Wet vs Dry (congestion and volume overload due to poor cardiac function)
- Dry - normal preload (PCWP)
- Wet - elevated preload (high PCWP)
- Cold vs Warm (perfusion, thus cardiac index)
Other Inotropes: cardiac contraction modulating agents
- PDE inhibitors: Milrinone, Amrinone (inamrinone), Drugs that affect the sarcomere (Levosimendan, Ca++ sensitizer), Omecamtiv Mecarbil
- Digoxin (Na+/K+ ATPase inhibitor): Indirectly increases intracellular Ca++.
Phosphodiesterase inhibitors
- Phosphodiesterases (PDE) degrade cAMP or cGMP.
- PDE3 is highly expressed in the heart.
- Milrinone, amrinone
- PDE3 inhibitors increase cardiac Ca++ and promote contraction through increased PKA signaling intracellularly.
- Similar to effects of beta-AR signalling (just downstream of them).
PDE3 inhibitors
- Inhibit PDE3, increasing CAMP levels to enhance PKA activity leading to Ca++ release and contraction
- PDE3Is similarly affect PKA in the vasculature aiding in dilation
- Very potent positive inotropes, often used in acute failure and low output syndrome
- Milrinone > amrinone
Digoxin
- Digoxin is a Na+/K+ ATPase inhibitor that indirectly increases intracellular Ca++
- Target: Inhibition of the Na+/K+-ATPase (sodium pump)
- Inhibition of the sodium pump increases intracellular sodium ion levels.
- Increases the net exchange of intracellular sodium for extracellular calcium ion through the sodium-calcium exchanger.
- Increases intracellular calcium levels enhances contractility of cardiac muscle.
Levosimendan
- Levosimendan is a cTnC Ca++ sensitizer
- Also has effects to open K+ channels on VSMC cells—hyperpolarizes VSMCs, promoting vasodilation by opposing depolarization and Ca++ release.
- Not approved in the US but is in clinical trials.
Omecamtiv Mecarbil
- Directly binds myosin and promotes cross-bridge cycling.
- Prolongs ejection time.
- Increases contractility and CO; Doesn't increase O2 consumption.
- Didn't improve survival, and there was some risk of more AF (in patients)
- Currently, denied approval by 2023.
Levosimendan and Omecamtiv Mecarbil
- New classes of inotropic agents that directly modify sarcomere function (independent of major needs to increase ATP production); PKA dependent mechanisms greatly increase energy demand.
- Still under investigation and clinical trials.
Summary of inotropic drugs
- All work on some part of cardiac contraction cycle.
- PDE3i increase cAMP to activate PKA.
- Levosimendan sensitizes TnC to Ca++.
- Omecamtiv mercarbil—allows easier myosin activation.
- Digoxin increases intracellular Ca++.
Things to know
- Determinants of CO: Preload, Afterload, Contractility
- Effects on Frank Starling Curves
- Mechanism of cardiac and VSM contraction and differences in effect of adrenergic signaling
- Uses and effects of β and α agonists.
- Different selectivity of drugs for receptors.
- Signaling mechanisms of digoxin and PDEi to increase cardiac contraction
Pressure Volume Loops
- (Diagram)
- Illustrates the pressure-volume relationship in the left ventricle across the cardiac cycle.
Factors that will affect preload
- Increased preload: Increased Venous Return, Increased Venous Blood Volume, Increased Venous Pressure, Decreased Venous Compliance, Atrial Inotropy, Increased Afterload, Increased Ventricular Compliance
Factors that will affect afterload
- Increased vascular resistance
- Hypertension
- Increased vasoconstriction
- Vascular anatomical remodeling/constriction
- Valve Disease (stenosis, regurgitation)
- Blood viscosity
- Pulmonary Hypertension (RV Afterload)
ESPVR (Ees) and contractility
- (Diagram)
- Illustrates the effects of contractility (inotropy) on the end-systolic pressure-volume relationship.
Preload, Afterload, and Contractility are Interdependent
- (Diagram)
- Shows how preload, afterload, and contractility affect the pressure-volume loop.
Multiple PV loops over time
- (Diagram)
- Shows a series of PV loops over time
β-agonists
- Increase contractility
- Promotes dilation (B2), decreases afterload
- But increased HR and CO likely result in increased afterload.
Example PV loops in cardiogenic shock
- CO is very low, low SV, decreased contractility, increased preload, and decreased afterload.
Beta-agonists and their selectivity
- Epinephrine: β₁ = β₂ > a₁ = α₂
- Norepinephrine: β₁ = a₁ > β₂ = α₂
- Dopamine: β₁ = β₂ > α₁
- Dobutamine: β₁ > β₂ > α₁
- Isoproterenol: β₁ = β₂
Beta agonists are used in specific situations depending on receptor affinity
- Epinephrine, dopamine, and dobutamine have higher affinity for Beta-AR than alpha, causing increased cardiac contractility and CO and vasodilation at higher doses
- Norepinephrine has similar affinity to Alpha-AR and Beta-AR receptors, causing vasoconstriction at higher doses but can be utilized in shock and hypotensive states when vasodilatory effect from other mechanisms is needed
Keep in mind specific differences in SVR/CO for different inotropes
- Phenylephrine - Increase SVR, decrease CO
- Norepinephrine/Epinephrine - Variable - SVR and CO effect varies at different doses
- Dopamine - variable at different doses
- Dobutamine - Decrease SVR, Increase CO
- Milrinone - Decrease SVR, Increase CO
Why use vasodilators before inotropes
- Vasodilators may allow for a sufficient blood pressure, perfusion, and oxygen delivery to the tissues without the need for additional inotropes.
- Fast acting, short half-life, may allow a larger effect before additional inotropes are needed.
Inotropes and Frank-Starling curves
- Inotropes are rarely used alone, other means to improve CO must be considered (vasodilators and diuretics).
- Using of diuretics and vasodilators to improve cardiac function allows the curve to shift up and to the left on the Frank-Starling curve.
Adverse effects of beta-agonists
- Ischemia (increased O2 demand)
- Hypertension
- Arrhythmias
- Tachycardia/Bradycardia
- Tissue ischemia (vasoconstriction, edema)
- Sudden Cardiac Death
- Major toxicity of prolonged inotrope support can lead to cardiac toxicity, inotrope-induced cardiogenic shock
- Mechanical circulatory support is needed if patients are unable to be stabilized without inotrope support
Summary
- Beta-agonists are used in emergency and acute settings of impaired cardiac function.
- Beta-agonists cause coordinated PKA activation resulting in increase of Ca++ release, increasing contractility
- Proper inotropes need to be selected to meet additional hemodynamic concerns (like blood pressure)
Other notes
- Diagrams are used to illustrate specific processes or mechanisms.
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Test your knowledge on key concepts in cardiac pharmacology, including mechanisms of preload, afterload, and the effects of various drugs such as digoxin and beta-agonists. This quiz will challenge your understanding of how different pharmacological agents influence cardiac function and hemodynamics.
