inotropes

• Inotropes


  Agents that alter the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular contraction.
• Inotropes


  • Used to support the failing heart
  • The heart may fail in several circumstances, and a variety of drugs may be used to support it
• Heart failure


  A condition that develops when the heart's muscle becomes weakened after it is injured from something like a heart attack or high blood pressure, and loses its ability to pump enough blood to supply the body's needs
• Risk factors for heart failure

  • Heart attack
  • High blood pressure
  • High cholesterol
  • Damage to heart valves
  • Diabetes
  • Obesity
  • Advancing age
• Failing heart


  Unable to pump enough blood to meet the body's demands due to a decrease in the contractility of the left ventricular heart muscle
• Failing heart


  Seen in the Frank Starling curve as a decrease in cardiac output relative to ventricular filling
• Mechanisms responsible for heart failure

  • Decreased energy production
  • Increased energy utilisation
  • Abnormal calcium homeostasis
  • Altered gene expression

  
• Cardiac output


  Fundamental issue in heart failure is that cardiac output is insufficient, resulting in decreased blood supply to organs
• Cardiac output


  MAP = HR x SV
• Compensatory mechanisms in heart failure

  • Frank Starling
  • Neuroendocrine response (increased sympathetic output, increased RAAS activity, increased ADH)
  • Myocardial hypertrophy

  
• Muscle cell: cardiac or vascular


  • Voltage gated calcium channels
  • Actin + myosin filaments
  • Calcium in sarcoplasmic reticulum

  
• Muscle contraction


  1. Depolarisation

  2. Increase in cytoplasmic calcium

  3. Contraction

  
• Classes of inotropes


  • Cardiac glycosides
  • Catecholamines
  • Phosphodiesterase inhibitors
  • Calcium entry promoters
  • Calcium
  • Calcium sensitizers
• Inotrope action


  • Involves calcium handling in the cardiac myocyte
  • Rationale is to increase calcium available for activation of contractile proteins

  
• Increasing calcium influx


  1. Beta-adrenergic activation

  2. Phosphodiesterase inhibition
• Beta-adrenergic activation


  Activation of beta1 receptors leads via adenylate cyclase and cAMP to activation of protein kinase A, which phosphorylates L-type calcium channels to favour mode 2 gating, increasing calcium entry during depolarisation
• Beta1 receptors


  • Predominant adrenergic receptors in the heart
  • Stimulation causes increased rate and force of cardiac contraction, mediated by cAMP

  
• Beta1 receptor activation


  • Also increases sensitivity of contractile machinery, probably via troponin C phosphorylation
  • Increases cytosolic calcium for uptake into sarcoplasmic reticulum, for release during action potential
• Beta2 receptors


  • In vasculature mediate vasodilation
• Alpha1 receptors


  • In the heart cause a significant increase in contractility without an increase in rate, mediated by IP3-calcium release, more pronounced at low heart rates, with slower onset and longer duration than beta1 receptor mediated response

  
• Inotropes used in acute severe heart failure, infarction, cardiac surgery, cardiomyopathies, septic shock, cardiogenic shock, and during positive end expiratory pressure ventilation


  • Adrenaline/Epinephrine
  • Dobutamine

  
• Phosphodiesterase inhibitors


  In cardiac muscle, PDE III catalyses breakdown of cAMP. Inhibiting PDE III leads to increased levels of cAMP, increased activation of PKA, and increased phosphorylation of L-type calcium channels, leading to more calcium entry on depolarisation and an inotropic effect.

  
• Phosphodiesterase inhibitors


  • Increase calcium influx, increasing rate and force of myocardial contraction
  • Also affect diastolic heart function through enhanced calcium re-sequestration rate and improved diastolic relaxation
  • Cause vasodilation without significantly increasing myocardial oxygen consumption or heart rate
  • Tolerance is not a feature
  • May inhibit platelet aggregation and reduce post-ischaemic reperfusion injury

  
• Phosphodiesterase inhibitors


  • Enoximone, milrinone
• Decreasing calcium efflux


  Inhibition of the Na+/K+ ATPase, which maintains the sodium gradient that drives the Na+/Ca2+ exchanger to extrude calcium
• Cardiac glycosides


  Inhibit the Na+/K+ ATPase, increasing intracellular sodium, which reduces the driving force for calcium efflux and thereby increases calcium loading in the sarcoplasmic reticulum, producing a positive inotropic effect

  
• Cardiac glycosides


  • Also have parasympathetic effects, increasing contractility (positive inotrope) but decreasing heart rate (negative chronotrope)

  
• Digoxin


  Inhibits Na/K ATPase, increasing intracellular sodium and decreasing intracellular potassium, leading to increased calcium loading and positive inotropy, as well as decreased heart rate
• Inotropes increase cardiac force and are used for heart support in conditions like failure, shock, and post-cardiac surgery