BPS 337 Alpha & Beta Agonist Inotropes 2023 PDF

𝛼 + 𝛽 Agonists and inotropes for BP and Cardiac Function Richard T Clements PhD BPS 337 12/06/2023 Richard T. Clements PhD Assistant Professor Biomedical and Pharmaceutical Sciences Office 495P/ Lab 470 [email protected] ...

𝛼 + 𝛽 Agonists and inotropes for BP and Cardiac Function Richard T Clements PhD BPS 337 12/06/2023 Richard T. Clements PhD Assistant Professor Biomedical and Pharmaceutical Sciences Office 495P/ Lab 470 [email protected]  Outline Refresher: Cardiac Physiology Factors Affecting Cardiac output (stroke volume) Afterload, Preload Contractility Molecular basis of cardiac and smooth muscle contraction a agonists and signaling Shock b agonists and signaling Acute Heart Failure/cardiogenic shock Other Inotropes: digoxin, PDEi Levosimendan, omecamtiv mecarbil  Cardiac Physiology: Cardiac Output CO = Heart Rate * Stroke volume SV determined by preload, afterload, and contractility Determinants of Cardiac Output: Afterload (decrease) Preload (increase) Contractility (increase) Heart Rate (mostly increase) Cardiac Cycle  Preload Frank-Starling Mechanism Pressure that fills the ventricle. Increases in preload increase SV and CO Increases End-systolic pressure and volume Why does the amount of blood filling the heart increase the SV? Frank-Starling mechanism More force is produced the more the ventricle wall is stretched Intrinsic properties of the cardiac sarcomeres (stretch, tension) and Ca++ release machinery Preload = EDV, EDP = SV and CO  Frank-Starling Curve: Summary 1. The heart automatically matches cardiac output during systole (blood out) to variations in ventricular filling pressure during diastole (blood in). 2. An increase in diastolic ventricular volume (venous return) is matched by a rapid increase in cardiac output. A decrease in venous return is matched by a rapid decrease in cardiac output. 3. A failing heart produces a depressed Frank-Starling curve, with diminished cardiac output even at elevated diastolic pressures. 4. This is done through the mechanical properties of the ventricular wall and contraction force being matched with stretch and tension of the wall/sarcomere  Afterload Afterload is the 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 Afterload = ESV, ESP = SV and CO Contractility Contractility is the force generated for a given sarcomere/fiber length Can be modified by Catecholamines * Sympathetic and Parasympathetic Activity * Inotropes * Preload Afterload (Anrep Effect) HR (Bowditch Effect) Preload and Afterload effects on cardiac output with 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 effecting 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 HR 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 which phosphorylates and inactivates myosin phosphatase often activated in parallel to MLCK to really drive MLC phosphorylation MLC phosphorylation causes activation of myosin and subsequent vessel 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 myosin and actin to interact and contraction to take place. When Ca++ levels fall every beat of the heart, relaxation occurs. This mechanism to contract is much FASTER than MLC phosphorylation SR and T tubules in myocytes  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) Bers 2002 Most of these steps require large amounts of ATP  Summary Cardiac Contraction Contraction is determined by the amount of Ca++ 1. Action potential depolarizes cell and activates PM Ca++ channels (l-type calcium channel) 2. Increased Ca++ at PM causes large Ca++ release from the SR 3. Released Ca++ binds TnC to allow myosin:actin interaction and contraction 4. SERCA activates to restore Ca++ to SR and NCX expels Ca++ from the plasma membrane - Phospholamban (PLN/PLB) is a protein that inhibits (slows) SERCA 5. Cell repolarizes and cycle continues. Increases in Ca++ release within the cell will cause an increase in cardiac contractility.  Summary: VSM contraction VSM contraction: 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.  a and b adrenergic receptors Receptor Tissue expression Actions Type Alpha1: – located in the Alpha1 Most vascular smooth Contracts (increases vascular blood vessels and muscle resistance) promotes constriction Pupillary dilator (radial) Contracts (mydriasis) muscle Pilomotor (piloerector) Contracts (erects hair) Beta1: muscle Located on the heart Alpha2 Adrenergic, and some Inhibits neurotransmitter release and promotes other nerve terminals increases in heart rate and contractility Most vascular smooth Contracts Increases coronary muscle dilation Pancreatic beta cells Inhibits insulin release Fat cells Inhibits lipolysis Beta2 :promotes Beta1 Heart Increases heart rate and increased heart rate and contractility (chronotropy, vasodilation (including ionotropy, lusitropy) coronary) Juxtaglomerular cells Stimulates Renin release Fat cells Stimulates lipolysis Beta2 Respiratory, uterine and Relaxes  Increase Increase Decrease Afterload Contractility Afterload Decrease CO Increase CO Increase CO  aAR and mechanism of action in blood vessels Alpha-adrenergic receptors increase vessel contraction: Increase Ca++ influx Increase phospholipase C (PLC) activation. PLC cleaves PIP2 into IP3 and Diacylglycerol (DAG). IP3 increases Ca++ release. Increases MLC phosphorylation Also modulates other contractile pathways including Rho-kinase and inhibition of myosin phosphatase.  a adrenergic agonists Alpha1 – agonists promote vascular constriction – and increases in blood pressure: Generally used to combat hypotension Alpha2 agonists- Centrally acting agonist that can reduce blood pressure. Not first line for HTN (clonidine)  Uses of a1-agonists/pressors: Shock Shock is caused by excessively low blood pressure and poor perfusion. Types of Shock Hypovolemic Shock Hemorrhage/dehydration: Usually just fluids. Distributive Shock: Caused by inappropriate vasodilation Sepsis Anaphylaxis Neurogenic (spinal cord injury) Vasoplegic syndrome (associated with excessive dilation post- surgery) Often treated with vasoconstrictors (a-agonists/pressors as necessary) Cardiogenic Shock: Impaired function of the heart to maintain blood pressure and cardiac output – will discuss later slides Obstructive Shock – mechanical block of flow  a1-AR Agonists (sympathomimetics) Midodrine: Midodrine is a prodrug that is enzymatically hydrolyzed to desglymidodrine: selective α 1 -receptor agonist. Peak concentration of desglymidodrine is achieved about 1 hr after midodrine is administered. Treatment of orthostatic hypotension, typically due to impaired ANS function. Methoxamine Older a1 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 who: (1) develop tachyarrhythmias on norepinephrine, epinephrine, or dopamine (2) have persistent shock despite use of two or more vasopressor/inotropic agents including vasopressin (salvage therapy) (3) have high cardiac output with persistent hypotension. Dosing initial:0.5 to 2 mcg/kg/minute maintenance: 0.25 to 5 mcg/kg/minute May decrease stroke volume and cardiac output in patients with cardiac dysfunction  a1-AR Agonists Phenylephrine, Midodrine, Methoxamine Indications Chronic orthostatic hypotension (midodrine). Raise blood pressure acutely (phenylephrine, norepinephrine) used in a hypotensive emergency:shock. Non-systemic uses: Topical nasal or oral Decongestant ( phenylephrine) Used with local anesthetics (phenylephrine or with high concentration of epinephrine)  Norepinephrine and Epinephrine Norepinephrine: major effect is a1 and b1 activation Increase SVR Increase CO via b1 effects to increase contractility and HR Epinephrine: No alpha1 effects at low doses. B1 and b2 (dilation) only. At high doses will activate a1 receptors and response will be more similar to norepinephrine with pronounced increase in SVR and pressure, increase HR and contractility. Norepinephrine Norepinephrine is considered a first line agent in septic shock. Strong a1 activation to promote vasoconstriction Increases MAP and SVR via constriction in peripheral beds less b1 activity compared to epinephrine and less stroke volume/contractility changes compared to dopamine Norepinephrine (Levophed) dosing: titrate to lowest effective dose MAP>65. This is delivered IV initial dosing 8-12 mcg/minute: 2-4 mcg/min thereafter Weight-based dosing:.01 to.15 mcg/kg/min Rapid onset, duration a few minutes  Epinephrine Strong a1 and b1 activation to promote vasoconstriction and increase HR and cardiac contractility Increases MAP and SVR via constriction in peripheral beds epinephrine dosing: titrate to lowest effective dose MAP>65. IV infusion: 0.01 to 0.7 mcg/kg/minute Can be used in conjunction with NE, if NE insufficient Inotropic actions predominate at lower doses with vasoconstrictive actions at higher doses May be considered especially when inotropic support is required Cardiovascular Effects of Relatively Pure Alpha1-AR Agonist Increases peripheral arterial resistance and decreases venous capacitance that increases blood pressure. In the presence of a normal cardiovascular reflexes, the rise in blood pressure elicits a baroreceptor mediated increase in vagal/parasympathetic tone with a fairly marked slowing of the heart rate. Specific alpha1 agonists will not affect heart rate/contractility on their own  a1-AR Agonists with some a2 Activity Xylometazoline, Oxymetazoline (Afrin) Have in addition, partial agonism at a2-AR. May be used topically as nasal decongestant and for nose bleeds. Constricts nasal blood vessels and decreases blood flow to the epithelium. May cause hypotension at large doses. paradoxical hypotension is caused by high permeability of these drugs across the BBB. In the brain they activate a2-AR to produce a central suppression of sympathetic output to the cardiovascular system.  a2-AR Agonists Clonidine Treating hypertension through central effects lowering sympathetic outflow will also produce bradycardia via both central and peripheral effects can produce sedation Dexmedetomidine is adjunct agent in anesthesia: Highly specific Alpha 2 agonist. Apraclonidine, Brimonidine Treat glaucoma reduce intra-ocular pressure neuroprotective effect on optic nerves (unknown mechanism)  Adverse Effects of α Receptor Agonists Effect Rationale Hypertensio Overdose-induced systemic n vasoconstriction by activation of α receptors on arteriolar smooth muscle. Myocardial Extreme α-mediated necrosis or vasoconstriction of coronary infarction arteries. Cerebrovasc α-mediated constriction of ular cerebral blood vessels. accident Urinary α-mediated internal sphincter retention/ constriction Other agents to elevate blood pressure: Vasopressin (arginine vasopressin AVP, ADH) Hormone secreted from pituitary Used in settings of septic shock to help increase blood pressure Directly stimulates vasoconstriction V1 receptors Increases blood volume through anti-diuretic effects on kidney V2 receptors Side effects include bronchoconstriction, and adverse effects in coronary circulation in SIHD patients.  a-agonists summary Alpha1 agonists are potent vasoconstrictors Stimulate a1-AR to activate PLC, increase Ca++ release, and enhance myosin light chain phosphorylation to constrict blood vessels Most often used in the treatment of shock to quickly elevate blood pressure (emergency and ICU settings) Phenylephrine, norepinephrine are potent vasoconstrictors with less effect on b-ARs Epinephrine, dopamine, dobutamine – less potent/minimal a activity and less constriction and/or vasodilatory effect on vessels Vasopressin has similar effects to a-agonists on vessels and blood pressure. Alpha2 agonists generally cause vasodilation and/or sedation (pure a2 agonists) This is due to effects on a2 receptors in the brain which greatly reduce SNS activity and tone.  b-agonists Used in settings of acute and severe cases of lowered CO. Severe hypotension Cardiac arrest Cardiogenic shock Myocardial stunning and post-cardiac surgery low output syndrome Not desirable for long term treatment of CHF Increased hypertrophy/fibrosis Desensitization of necessary bAR signaling Increased O2 demand Can make the heart ischemic Increased afterload due to effects on aAR  b1 mechanism of action on the heart bAR activates cAMP- dependent protein kinase. Has a coordinated response to modify numerous enzymes involved in Ca++ handling hninger, Principles of Biochemistry -7th-Edition.pdf  PKA mechanism of modulating Ca+ + release PKA can increase Ca++ release through direct modulation of Ca++ release through RyR, and external Ca++ channels. However, Ca++ stores need to be replenished and increased so PKA phosphorylates and inhibits PLB PLB normally inhibits SERCA. pPLB no longer inhibits SERCA and SR Ca++ stores increase Subsequent Ca++ release from SR is increased. Other kinases are involved in this coordinated response: ex CamKII, but PKA is major player. PKA works completely differently in the vasculature (dilation) Cardiac VSMC This is why B2-receptors cause dilation even though a similar mechanism  b1 and Cardiac Contraction Summary B1 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 : increased Ca++ release PLB – which now removes inhibition of SERCA: Increased Ca++ uptake in SR LTCC – increased Ca++ influx Increased Ca++ increases contraction Also multiple effects on systems to assist in cardiac cycle : NCX, Na/K ATPase , K+ and Na+ channels.  Acute vs Chronic Heart Failure Acute Chronic Acute stress or injury impacts ability of heart to contract Usually major myocardial Cannot maintain CO remodeling / ischemia Often treated acutely with: Hypertrophy Inotropes Fibrosis ß-agonists CAD Vasodilators/volume management Reduced or Preserved Provide support until underlying cause resolves function Emergency treatment usually Often treated chronically associated with ICU level care. with ß-blockers, volume management, vasodilators  Uses of b-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: 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 which requires extended ICU stays, significant inotropic support, and greatly increases the risk of mortality. Inotropes are often used to improve CO until normal heart function returns (hours-days)  Types of Acute Heart Failure Classified in two different sets of variables Cold vs Warm: Refers to perfusion and thus cardiac index (CO) Cold – poorly perfused Warm - well perfused Wet vs Dry: refers to congestion and volume overload due to poor cardiac function Dry: normal preload as shown by PCWP Wet: elevated preload as shown by high PCWP  Don’t worry about the details here. Appreciate that inotropes are used sparingly and in very specific contexts  Why use vasodilators before inotropes during acute heart failure? Vasodilators used in acute heart failure include IV nitroglycerin and sodium nitroprusside. These compounds are NO donors Very fast acting and short half lives. Vessel dilation causes a large drop in afterload which should increase CO and may provide sufficient perfusion to the tissue without the need for inotropes Impaired heart function may be sufficient with less work. Inotropes have significant drawbacks and are used only when other means to increase CO – modulating preload and afterload – are/will be insufficient. b-agonists and their selectivity  Beta agonists are used in specific situations depending on receptor affinity. Epinephrine, dopamine and dobutamine Have much higher affinity for Beta-AR than alpha Therefore, can increase cardiac contractility and CO without having major constriction (or increase dilation via B2) vasoconstriction at high doses. Norepinephrine Similar affinity to Alpha and Beta1 receptors Cause significant vasoconstriction Used in shock and hypotension when the vessels are too dilated to maintain CO and tissue perfusion. Keep in mind specific differences in SVR/CO for different inotropes  Inotropes and Frank-Starling curves Inotropes are rarely used alone Use of diuretics and vasodilators to try and shift function up and to the left on Frank-Starling curves V= vasodilator, I = inotrope, D=diuretic  Adverse effects of b-agonists Major adverse effects: Ischemia (increased O2 demand) Hypertension Arrythmia Tachycardia/Bradycardia depending on drug Tissue ischemia (vasoconstriction and edema) Sudden Cardiac Death Major toxicity of prolonged inotrope support can lead to cardiac toxicity and inotrope induced cardiogenic shock If patients are unable to be stabilized without inotrope support or cannot be weaned from support, will need mechanical circulatory support ECMO, L/RVAD, intravenous pumps (IABP, impella)  Summary B-agonists are primarily used in emergency and acute settings of impaired cardiac function. B-agonists activate PKA which produces a coordinated response to increase Ca++ release and increase contractility Proper inotrope needs to be selected to meet additional hemodynamic concerns (blood pressure) Example epinephrine (moderate constriction/dilation) vs norepinephrine (significant constriction) Other Inotropes : cardiac contraction modulating agents. PDE inhibitors: Milrinone Amrinone (inamrinone) Digoxin (Na/K ATPase inhibitor) Drugs that affect the sarcomere Levosimendan (Ca++ sensitizer) Omecamtiv Mecarbil  Phosphodiesterase inhibitors Phosphodiesterases (PDE) degrade cAMP or cGMP. There are many different ones: PDE 1-7 Have different specificities to cAMP, cGMP, or both PDE3 is highly expressed in the heart. Acts on cAMP Milrinone, amrinone PDE3 inhibitors increase cardiac Ca++ and promote contraction This is through increasing PKA signaling intracellularly Similar to effects of beta-AR signaling ( just downstream) Phosphodiesterase Inhibitors Phosphodiesterases degrade cyclic nucleotides. PDE3 – turns cAMP to AMP Inhibition of PDE3 increases cAMP levels to promote increased PKA activity and subsequent Ca++ and contraction. PDE3i has similar effects on PKA in the vasculature which promote dilation Very potent inotropic effects: used similarly to b-agonists for acute failure, low output syndrome Milrinone>>amrinone PDE3 inhibitors work similarly to b- AR stimulation just further downstream PDE3 PDE3 They also have effects to dilate smooth muscle through PKA Digoxin is a Na+/K+ ATPase inhibitor that indirectly increases intracellular Ca++  Summary of Digoxin Mechanism Mechanism: 1. Target: Inhibition of the Na+-K+-ATPase (sodium pump). 2. Inhibition of the sodium pump begins to increase intracellular sodium ion levels. 3. This increases the net exchange of intracellular sodium for extracellular calcium ion through the sodium-calcium exchanger. 4. An increase in intracellular calcium levels enhances contractility of cardiac muscle. Digoxin has a very narrow effective therapeutic range with toxicity at high doses and requires monitoring Effect is slow : mainly used in CHF patients, and limited if any use in acute heart failure. Levosimendan Levosimendan is a cTnC Ca++ sensitizer Also has effects to open K+ channels on VSMC cells. Hyperpolarizes VSMC and promotes vasodilation by opposing depolarization and Ca++ release NOT approved in the United States, but is elsewhere. In clinical trials. Levosimendan Mechanism  Omecamti v Mecarbil Directly binds myosin and promotes cross bridge cycling Prolongs ejection time, Increases contractility Increases CO Doesn’t increase O2 consumption Didn’t improve survival or symptoms – some increased risk in AF patients Denied approval 2023 Levosimendan and Omecamtiv Mecarbil Increase contractility and CO 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 intracelleular Ca++ OM  Things to know Determinants of CO: Preload, Afterload, Contractility Effects on Frank Starling Curves Do not worry about PV loops in major detail Mechanism of cardiac and VSM contraction and differences Effect of adrenergic signaling on contraction in vascular smooth muscle and cardiac muscle Uses and effects of b and a agonists Different selectivity of drugs for receptors. How AR modulate cardiac contraction and dilation Signaling mechanisms of digoxin and PDEi to increase cardiac contraction  Things to know Determinants of CO: Preload, Afterload, Contractility Effects on Frank Starling Curves Mechanism of cardiac and VSM contraction and differences Effect of adrenergic signaling on contraction in vascular smooth muscle and cardiac muscle Uses and effects of b and a agonists Different selectivity of drugs for receptors. Signaling mechanisms of digoxin and PDEi Pressure Volume Loops  Factors that will affect preload Increase 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 Preload, Afterload and Contractility are interdependent.  Multiple PV loops over time LVP LVV  b-agonists Promotes dilation (B2- decrease afterload) Increase contractility But increased HR and CO would likely result in net increased afterload (also still somea activity)  Example PV loops in cardiogenic shock CO very low SV low Contractility decreased Preload increased Afterload decreased b-agonists and their selectivity