α and β agonists and inotropes for BP and Cardiac Function

Introduction

• The presentation discusses α and β agonists and inotropes for blood pressure (BP) and cardiac function.

Outline

• Cardiac Physiology refresher including factors affecting cardiac output (stroke volume), afterload, and preload.
• Molecular basis of cardiac and smooth muscle contraction.
• α and β agonists and signaling pathways.
• Shock types and their associated mechanisms
• Inotropes: digoxin, PDEIs, levosimendan, and omecamtiv mecarbil and their roles in acute heart failure/cardiogenic shock

Cardiac Physiology: Cardiac Output

• Cardiac output (CO) is calculated as heart rate (HR) multiplied by stroke volume (SV).
• Stroke volume (SV) is determined by preload, afterload, and contractility.
• Determinants of cardiac output include decreasing afterload, increasing preload, increasing contractility, and increasing HR.

Cardiac Cycle

• A detailed diagram of the cardiac cycle is presented.
• The cycle shows the different phases of contraction and relaxation in the heart, including isovolumetric contraction, ejection, isovolumetric relaxation, and rapid inflow.
• Valve opening and closing are shown in relation to the phases, and the pressure and volume of the chambers.
• Electrocardiogram (ECG) and phonocardiogram are noted, which can track cardiac activity.

Preload

• Preload is the pressure that fills the ventricle.
• Increases in preload increase both stroke volume (SV) and cardiac output (CO).
• Frank-Starling mechanism describes how more force is produced the more the ventricle wall is stretched, via tension and release of Ca++.

Afterload

• Afterload is the pressure and/or resistance the heart must overcome to actively work against.
• Increased afterload decreases stroke volume (SV) and cardiac output (CO).
• Factors contributing to increased afterload include heightened blood pressure, stiff aorta, and peripheral circulation stiffness.
• Remodeled LV/RV muscle can raise afterload.

Contractility

• Contractility is the force generated during a given sarcomere/fiber length.
• Mechanisms for modifying contractility include catecholamines and sympathetic/parasympathetic activity. - Important inotropes also modify contractility.
• Preload, afterload, and heart rate (HR) can also modify contractility.

Preload and Afterload effects on cardiac output with LV dysfunction

• Diagrams show cardiac index versus pulmonary capillary wedge pressure (PCWP) and systemic vascular resistance (SVR).
• LV dysfunction shows a depression and shift in the Frank Starling curves with decreasing cardiac output under various levels of preload and afterload pressures.

Heart Rate

• Increased heart rate increases cardiac output but too high HR leads to reduced preload which lowers SV and cardiac output.

Summary

• Four major determinants of cardiac output include preload, afterload, contractility and HR.
• The Frank-Starling mechanism describes how the heart adjusts its output to changes in filling volume.

Molecular Basis of Smooth Muscle Contraction

• Depolarization of smooth muscle is mediated by Ca++ release from internal stores via IP3 receptors.
• Calcium activates myosin light chain kinase (MLCK).
• MLCK phosphorylates myosin light chains (MLC), initiating contraction followed by vessel contraction. Rho kinase inactivates myosin phosphatase, thereby promoting MLC phosphorylation

Cardiac Contraction

• Cardiac contraction is driven by calcium.
• Troponin-tropomyosin complex regulates actin and myosin interactions.
• When calcium levels rise, the troponin-tropomyosin complex moves, allowing myosin to bind to actin and initiate contraction.
• Relaxation occurs when calcium levels fall, and the complex returns to its resting conformation.
• The mechanism for contraction is faster than MLC phosphorylation.

Calcium-Induced Calcium Release

• Depolarization opens L-type calcium channels.
• Calcium activates ryanodine receptors in the sarcoplasmic reticulum (SR), releasing even more calcium.
• This leads to contraction.
• Calcium returning to the SR via SERCA stops active contraction.

SR and T tubules in myocytes

• These structures are critical for cardiac contraction.
• They have a intricate and interconnected relationship to ensure calcium regulation during contraction and relaxation.

Excitation-Contraction (E-C) Coupling

• Action potential initiates calcium influx, stimulating calcium release from SR stores.
• Calcium binds to troponin C, allowing for myosin-actin interaction.
• SERCA actively removes calcium.
• NCX (Na/Ca exchanger and Na/K ATPase) helps restore ionic balance across cell membranes.

Summary Cardiac Contraction

• Cardiac contraction is directly proportional to Ca++ concentration within the cell.
• Action potential triggers calcium influx from extracellular fluid and internal stores.
• Calcium binds to cTnC, initiating contraction.
• Regulatory mechanisms (like SERCA and NCX) restore low calcium levels, allowing the relaxation of the heart.

Summary: VSM Contraction

• Smooth muscle contraction regulation is via the amount of MLC phosphorylation.
• Ca++ release and channel activation trigger cascades that result in MLCK-mediated MLC phosphorylation.
• Signaling cascades like Rho-kinase sensitize the cell to the increased Ca++ release and promotes active MLC phosphorylation
• PKA promotes dilation.

α and β Adrenergic Receptors

• Alpha1 receptors are located in blood vessels and promote constriction.
• Beta1 receptors are located in the heart and promote increased heart rate and contractility.
• Beta2 receptors promote increased heart rate and vasodilation, including coronary vasodilation.
• Alpha receptors have higher affinity to norepinephrine than beta receptors but beta receptors have higher affinity to epinephrine and related compounds at lower concentrations.

Adrenoceptors

• Norepinephrine activates alpha1 and beta1 receptors.
• Epinephrine activates both alpha and beta receptors.
• Different levels of α / ß receptor activation can result in vasoconstriction/vasodilation/changes in heart rate/contractility.

α AR and mechanism of action in blood vessels

• Alpha-adrenergic receptors increase vessel contraction via calcium influx.
• Phospholipase C (PLC) activation leads to increased intracellular calcium, initiating the contractile response.
• Various downstream signaling pathways (Rho-kinase and myosin phosphatase inhibition) impact the mechanism of action.

α adrenergic agonists

• Alpha1 agonists promote vasoconstriction and raise blood pressure.
• Alpha2 agonists can reduce blood pressure via central action.
• Specific examples of these agonists include phenylephrine, methoxamine, clonidine, and methylnorepinephrine.

Uses of α1-agonists/pressors: Shock

• Shock is diagnosed by low blood pressure.
• Types of shock include hypovolemic (lack of blood volume), distributive (widespread vasodilation), cardiogenic (pump problem with the heart), and obstructive (blockage of blood flow through the vessels).
• Alpha1-agonists are commonly used to treat hypotension associated with various forms of shock.

α1-AR Agonists (sympathomimetics)

• Midodrine is a prodrug that converts to desglymidodrine.
• Methoxamine is an older alpha1 agonist that is no longer in use in modern medicine.

Phenylephrine

• A potent alpha1-adrenergic vasoconstrictor.
• Used to treat hypotension.
• It is an alternative when tachyarrhythmias make norepinephrine unsuitable.
• Also used in topical nasal decongestants.

α1-AR Agonists Indications

• Used in chronic orthostatic hypotension.
• Also used as decongestants and with local anaesthetics.

Norepinephrine and Epinephrine

• Norepinephrine primarily activates alpha1 and beta1 receptors. At higher concentrations, it activates alpha2, thereby promoting vasoconstriction.
• Epinephrine activates both alpha and beta1 and beta2 receptors.
• Effects include increased cardiac output, contractility, and heart rate (with pronounced increases at higher concentrations).

Norepinephrine

• A first-line agent for septic shock.
• Strong activation on alpha1 receptors promotes vasoconstriction.
• Less beta1 activity compared to epinephrine.
• Dosing is titrated to lowest effective dose.

Epinephrine

• Strong alpha1 and beta1 activation promotes vasoconstriction, thus increases cardiac contractility and increases in heart rate.
• Used in situations where cardiac function must be enhanced, and at lower doses to avoid excessive systemic vasoconstriction.

Cardiovascular Effects of Relatively Pure Alpha1-AR Agonist

• Increase blood pressure and peripheral arterial resistance.
• Decrease in venous blood capacitance that increases blood pressure.

α1-AR Agonists with some α2 Activity

• Xylometazoline and oxymetazoline are used topically as nasal decongestants and vasoconstrictors for nosebleeds.
• These drugs can cause paradoxical hypotension at high doses by affecting central α2 receptors.

α2-AR Agonists

• Clonidine is primarily used to treat hypertension by modulating central sympathetic outflow.
• Dexmedetomidine is an α2 agonist adjunct in anesthesia, particularly useful in managing chronic symptoms.
• Other α2 agonists are used to treat glaucoma (optic nerve protection effects).

Adverse Effects of α Receptor Agonists

• Potential for overdose causing systemic vasoconstriction and cardiovascular issues such as hypertension, myocardial necrosis, cerebral vascular accidents, and acute urinary retention.

Other agents to elevate blood pressure

• Vasopressin is a hormone that directly increases the contraction of blood vessels, thus raising blood pressure.
• It also has a significant effect on reducing urine volume.

β-agonists

• Used in acute and severe cases of lowered cardiac output.
• These include settings like severe hypotension, cardiac arrest, cardiogenic shock, myocardial stunning post-cardiac surgeries and low-output syndrome.

β1 Mechanism of Action on the Heart

• β1-adrenergic receptors activate cAMP.
• cAMP activates protein kinase A (PKA).
• PKA phosphorylates multiple targets to regulate calcium release and increase contractility.
• This has impacts on numerous enzymes involved in calcium handling during contraction and relaxation.

PKA Mechanism of Modulating Ca++ Release

• PKA can increase Ca++ release to affect contractility response in cardiac cells.
• It can phosphorylate and inhibit Phospholamban (PLB), which normally inhibits SERCA, to increase calcium uptake in the SR stores.

PKA works completely differently in the vasculature (dilation)

• The influence of PKA varies in cardiac and smooth muscle.
• In vessels, PKA activation promotes vasodilation, due to stimulation of different targets than those in the heart.

β1 and Cardiac Contraction Summary

• The mechanism of β1-adrenergic receptor activation in cardiac tissue involves cAMP production followed by PKA activation, thereby increasing Ca++ release from internal stores.
• Ca++ release leads to contractility and ultimately cardiac output.
• Multiple targets are phosphorylated during this mechanism, acting synergistically to raise cardiac contractility and subsequent CO.

Acute vs Chronic Heart Failure

• Acute heart failure is often caused by acute stress or injury and involves impaired myocardial contractility and decreased cardiac output.
• Chronic heart failure has more permanent changes and exhibits myocardial remodeling, hypertrophy, and fibrosis. These conditions are more resistant to treatment than acute heart failure.
• Acute heart failure is often treated with inotropes and vasoconstrictors and may require ICU-level care.
• Chronic heart failure is often treated with beta-blockers, volume management, and vasodilators.
• Each of these can have effects on specific receptor subtypes (and not all).

Uses of β-agonists and other inotropes

• β-agonists and other inotropes are used to treat acutely worsening chronic heart failure (CHF).
• Also used in cases of cardiogenic shock, and low-output syndrome.
• Often used in conjunction with other support systems.

Myocardial stunning and cardiogenic shock associated with cardiac surgery

• Prolonged mild ischemic injury to the heart muscle, acidosis, and oxidative stress can cause reversible damage to myocardial tissue.
• Following extensive procedures like cardiac surgery, there is a high risk of myocardial stunning.
• Damaged heart cells often require supplementary inotropic support to restore normal CO.

Types of Acute Heart Failure

• Acute heart failure can be classified as "wet" (congestive) or "dry" (non-congestive) and "warm" (preserved cardiac index) or "cold" (reduced cardiac index).
• These classifications assist in determining the patient's volume status and treatment options.

Inotropes and Frank-Starling curves

• Inotropes alone are rarely used; diuretics and vasodilators are typically used along with inotropes to assist the failing heart.
• Their use helps shift the function and improve cardiac output, according to the Frank-Starling curve.

Adverse Effects of β-Agonists

• Adverse effects of beta agonists include ischemia, hypertension, arrhythmias, and tissue ischemia.
• It can cause sudden cardiac death (SCD), due to overuse or toxicity.
• Mechanical circulatory support may be needed if inotropes fail to restore normal cardiac function.

Summary

• Beta agonists are primarily used in emergency situations to promote increased cardiac contractility; they are not suitable for long-term treatment.
• Inotropes must be used in tandem with appropriate volume management as needed.

Other Inotropes: Cardiac Contraction Modulating Agents

• PDE inhibitors, specifically milrinone and amrinone, increase cAMP levels.
• Digoxin is an inhibitor of the sodium pump resulting in increased intracellular calcium.
• Levosimendan is a calcium sensitizer.
• Omecamtiv mecarbil directly binds myosin to improve the cycling of cross bridges over time.

Phosphodiesterase inhibitors

• Phosphodiesterase inhibitors increase cAMP levels.
• Milrinone and amrinone are examples.
• This mechanism is functionally similar to beta-agonists.

Digoxin

• Digoxin is a sodium pump inhibitor.
• This mechanism indirectly increases intracellular calcium.
• Digoxin raises contractility but has a narrow therapeutic window, resulting in potential toxicity.

Levosimendan

• Levosimendan is a calcium sensitizer.
• It opens K+ channels, leading to hyperpolarization and promoting vasodilation.

Omecamtiv Mecarbil

• Omecamtiv mecarbil directly binds to myosin, facilitating more efficient cross-bridge cycling in cardiac cells.
• It improves ejection time and raises CO without increasing oxygen consumption.

Levosimendan and Omecamtiv Mecarbil

• Levosimendan and omecamtiv mecarbil are newer inotropic agents that focus on modifying sarcomere function in the heart muscle.
• They do not rely on direct augmentation of energy production like prior inotropes.

Summary of inotropic drugs

• All of these inotropic drugs target either the Ca2+ signaling pathway, or myosin activation, to improve cardiac contraction.

Things to know

• Important determinants of cardiac output include preload, afterload, and contractility.
• Adrenergic signaling impacts both cardiac and smooth muscle contraction.
• β and α agonists have distinct receptor selectivities.
• Signaling mechanisms of digoxin (Na/K ATPase inhibition), PDE3 inhibitors (increasing intracellular cAMP), and other inotropic agents (such as calcium sensitization and direct myosin binding) should be understood.

Pressure Volume Loops

• Pressure-volume loops graphically depict cardiac function.
• These curves can diagnose and assess damage to the heart, by charting the relationship between pressure and ventricular volume.

Factors that will affect preload

• Increased preload is related to increased venous return, venous blood volume, and blood pressure with decreased venous compliance, as well as atrial inotropy.

Factors that will affect afterload

• Increased afterload is related to increased vascular resistance, elevated systemic vascular resistance/hypertension, alterations in vascular anatomy and blood viscosity, as well as valve diseases such as stenosis or regurgitation, and pulmonary hypertension.

ESPVR (Ees) and contractility

• Contractility, directly impacts the shape of different pressure volume loops
• A change in contractility causes a shift in the shape and position of the pressure-volume curves

Preload, Afterload and Contractility are interdependent

• These parameters work together to impact cardiac function, as changes in one factor influence others.
• Pressure-volume loops visually illustrate this interplay by demonstrating how altered parameters impact the overall form of the plot.

Multiple PV loops over time

• Demonstrates changes in cardiac function over time by showing pressure/volume loops, that together, can show how the heart is reacting to different conditions over time.

β-agonists

• Beta agonists are used to increase myocardial contractility and CO.
• Stimulation of beta receptors increase Ca2+ release, and promotes dilation to decrease afterload.

Example PV loops in cardiogenic shock

• Examples presented shows that with cardiogenic shock, the preload (and afterload are increased) while contractility goes down.
• The PV loop demonstrates the effects of the different cardiac pathologies of altered preload, afterload, and contractility.

β-agonists and their selectivity

• Specific agonists activate distinct beta receptor subtypes.
• β-agonists can either enhance contractility, or have a significant impact on blood vessel dilation.
• Their selectivity is crucial in clinical use and dictates their specific targets, and potential side effects.

Beta agonists are used in specific situations depending on receptor affinity

• Epinephrine, dopamine and dobutamine have much stronger affinity for β receptors than α.
• Conversely, norepinephrine has approximately the same affinity for both receptors. As such, norepinephrine can be used when the vessels are too dilated to maintain CO and tissue perfusion.

Keep in mind specific differences in SVR/CO for different inotropes

• Different inotropes have varying impacts on systemic vascular resistance (SVR) and cardiac output (CO).
• Their selectivity and targeted mechanisms of action vary significantly; a major point to consider during patient treatment.