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inotropism - physiology , various inotropes, use of inotropes in anaesthesia and critical care , newer inotropes

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  1. 1. INOTROPES AND NEWER AGENTS Dr Kiran Rajagopal DA DNB. Anaesthesiologist
  2. 2. OBJECTIVES • Define the term Inotrope • Discuss basic physiological principles • Discuss drug classification and pharmacology • Inotropes ,anaesthesiologists and intensivists • Newer agents
  3. 3. INOTROPES • Drugs that affect the force of contraction of myocardial muscle,independent of changes in heart rate and loading conditions • Positive or negative • Term “inotrope” generally used to describe positive effect
  4. 4. GOOD VS EVIL • Intravenous positive inotropic drugs are indicated when patients with acute systolic heart failure exhibit signs or symptoms of end-organ dysfunction due to hypoperfusion. • The use of positive inotropic drugs has concerns regarding increased morbidity and mortality.
  5. 5. • Problems include increased arrhythmia,Induced myocardial ischemia, and in some cases,hypotension • The largest database demonstrating increased mortality with inotropes is the ADHERE (Acute Decompensated Heart Failure National Registry), where short-term inotropic therapy was associated with increased in-hospital mortality.
  6. 6. WHAT DEFINES AN INOTROPIC INTERVENTION •Inotropic interventions comprise all means that increase contractile force of the myocardium
  7. 7. PHYSIOLOGY • can be explained at the level of the smallest force- producing unit, the actin-myosin cross-bridge using a simplified two-stage cross-bridge model • During a cross-bridge cycle, the myosin head attaches to actin, rotates to produce force, which is maintained during the so-called on-time. • Thereafter, the cross-bridge detaches again to enter its non-force-producing state for the duration of the off-time
  8. 8. EXCITATION CONTRACTION COUPLING • contractile force depends on the number of crossbridges attached per unit of time • The cross-bridges are activated by calcium binding to troponin C with the subsequent conformational changes of tropomyosin and troponin I to facilitate actomyosin interaction. • The muscle relaxes when calcium is pumped back into the sarcoplasmic reticulum (SR) by the sarcoplasmic reticulum calcium pump (SERCA) and eliminated outside the cell by the sodium–calcium exchanger (NCX)
  9. 9. Inotropy, i.e. the number of cross-bridges activated, depends upon: (i) amount of calcium available to bind to troponin C, (ii) the calcium affinity of troponin C, (iii) alterations at the level of the cross-bridge (iv) the ability of attached cross-bridges to increase calcium affinity of troponin C and activate neighbouring crossbridges (i.e. co-operativity)
  10. 10. • It is assumed that one molecule of ATP is hydrolysed during one individual cross-bridge cycle. • Accordingly, the most efficient way to increase contractile force would be to prolong cross-bridge attachment time
  12. 12. Endogenous inotropic mechanisms include • length-dependent activation of cross-bridges, • contraction frequency-dependent activation of contractile force, and • catecholamine-mediated inotropy. The most important mechanism is length-dependent activation of cross-bridges by increasing the length of the individual sarcomere (Frank-Starling mechanism) HOW DOES THE HEART REGULATE ITS INOTROPIC STATE?
  13. 13. • length-dependent activation occurs without an increase in calcium release • Frequency-dependent up-regulation of contractile force is calcium dependent. With increasing heart rate, more calcium enters the cardiomyocyte, is accumulated into the SR, and is available for release during the next contraction
  14. 14. • Catecholamines increase contractile force by the β- adrenoceptor-adenylyl cyclase system or by stimulation of α-receptors • Through protein kinase A, the β-adrenoceptor system phosphorylates L-type calcium channels to increase calcium influx and ryanodine receptors (RyRs) to increase SR calcium release resulting in activation of cross-bridges
  15. 15. • In addition, phosphorylation of phospholamban accelerates SR accumulation of calcium • relaxation by phosphorylation of troponin I due to reduced calcium sensitivity of troponin C (positive lusitropy) • At the cross-bridge level, cyclic AMP (cAMP)- mediated increase in contractility reduce the attachment time of the individual crossbridge. • Consequently, cAMP-mediated inotropy increases the rate of force development and rate of relaxation at the expense of a reduced economy of contraction
  16. 16. ALTERATIONS IN HEART FAILURE In heart failure, excitation–contraction coupling is significantly altered, largely by abnormal calcium accumulation of the SR • SR calcium uptake is abnormal due to SR calcium leak through RyR • decreased re-uptake of calcium secondary to decreased SERCA protein levels • increased calcium elimination outside the cell due to increased levels of the NCX.
  17. 17. • In the failing myocardium frequency-dependent up- regulation of SR calcium load is absent, which is associated with a decline of contractile force at higher heart rates
  18. 18. CONVENTIONAL INOTROPIC AGENTS •Sympathetic amines •Phosphodiesterase inhibitors •Cardiac glycosides •Calcium sensitizers
  19. 19. SYMPATHOMIMETICS • Epinephrine • Norepinephrine • Dopamine Naturally occuring •Dobutamine •Dopexamine •Phenylephrine •Metaraminol •Ephedrine Synthetic
  20. 20. SYMPATHOMIMETICS • Epinephrine • Norepinephrine • Dopamine Naturally occuring •Dobutamine •Dopexamine Synthetic
  21. 21. ADRENORECEPTORS •  receptors – 1 • Located in vascular smooth muscle • Mediate vasoconstriction Alpha1 receptor effects are mediated primarily by the coupling protein Gq. When Gq is activated, the alpha moiety of this protein activates the enzyme phospholipase C, resulting in the release of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from membrane lipids.
  22. 22. Calcium is released from stores in smooth muscle cells by IP3, and protein kinase is activated by DAG. Direct gating of calcium channels may also play a role in increasing intracellular calcium concentration
  23. 23. α2 RECEPTOR •2 --Located throughout the CNS, platelets –Mediate sedation, analgesia & platelet aggregation Alpha2 receptor activation results in inhibition of adenylyl cyclase via the coupling protein Gi.
  24. 24. β ADRENOCEPTOR •  receptors – 1 • Located in the heart • Mediate increased contractility & HR – ---3 In fat cells.mediate lipolysis
  25. 25. – 2 • Located mainly in the smooth muscle of bronchi and blood vessals Mediate bronchodilatation & vasodilatation β2-receptor population in human cardiac tissue accounts for 15% of β receptors in the ventricles and 30% to 40% in the atria β2 Receptors may help compensate for disease by maintaining response to catecholamine stimulation when β1 receptors are down-regulated during chronic catecholamine stimulation and in CHF • In addition to positive inotropic effects, β2 receptors in the human atria participate in regulation of the heart rate.
  26. 26. β ADRENOCEPTOR Beta receptors (β1, β2, and β3) stimulate adenylyl cyclase via the coupling protein Gs, which leads to an increase in cyclic adenosine monophosphate (cAMP) concentration in the cell
  27. 27. DOPAMINERGIC RECEPTORS DA1 • Renal and splanchinic,mesentric ,coronary blood vessals • Mediate vasodilatation • Vasodilatory effects maximum in renal Dopamine DA 1 receptors are post synaptic ,activate adenylyl cyclase via Gs and increase cAMP in neurons and vascular smooth muscle
  28. 28. DA 2 RECEPTORS • Found in presynaptic receptors in nerve terminals • These receptors reduce the synthesis of cAMP via Gi and inhibit release of norepinephrine • central DA2 receptors may mediate nausea and vomiting
  30. 30. EPINEPHRINE G - Protein Adenyl cyclase ATP cAMP Increased heart muscle contractility Adrenaline
  31. 31. • Prototype drug among sympathomimetics • Endogenous catecholamine produced in the adrenal medulla. • α 1 + α 2, β 1+ β 2 agonism . Weak β 3 action • Natural function includes • Regulation of Myocardial contractility Heart rate Vascular& bronchial muscle tone Glandular secretion Glycogenolysis & lipolysis
  32. 32. INDICATIONS • Cardiac arrest efficacy due to increased coronary perfusion pressure • Anaphylaxis • Cardiogenic shock • Bronchospasm • Low output after CPB • Hypotension with spinal/epidural can be treated with 1-4µg/min • Added to local anaesthetics to prolong action
  33. 33. DOSAGE • Shock/hypotension 0.03-0.2 µg/kg bolus iv 0.03-0.015 µg/kg/min 0.05-0.5 µg/kg/min in children • Cardiac arrest 0.5-1 mg iv bolus 0.01mg/kg iv in Pediatrics • Anaphylaxis/bronchospasm 10 µg/kg sc(max 400 µg)/300µg every20 min. 3 dose • Inhalation max daily dose -10-20 MDI
  34. 34. ABSORPTION • Most potent activator of alpha adrenergic receptor 2-10 times > norepinephrine 100 times > isoproterenol • Orally not effective as it is rapidly metabolized in gi mucosa and liver. • Slower after im and sc • Effectively absorbed from tracheal mucosa
  35. 35. CARDIOVASCULAR EFFECTS • Results from stimulation of α and β receptors 1-2µg/min iv stimulate β2 receptors 2-10 µg /mt stimulate β1 receptors 10-20 µg /mt stimulate both α+β receptors • Positive inotrope ,chronotrope • Increases heart rate by accelerating the rate of phase 4 depolarization • Heart rate initially increases and later decrease due to vagal reflex • Increase cardiac out put and MVO2 • Improves coronary blood flow
  36. 36. CVS as iv bolus • increase SVR ,systolic bloodpressure • minimal increase in diastolic blood pressure increases coronary blood flow in arrest Net effect is increase in pulse pressure and minimal change in MAP. as iv infusion • SVR and DBP decrease( β2)
  37. 37. RESPIRATORY SYSTEM • Respiratory stimulant • Increase both tidal volume and respiratory rate • Potent bronchodilator • Decrease the release of antigen induced bronchospastic subastances from mast cells • Increases the viscosity of bronchial secretions
  38. 38. CNS • Limited penetration due to poor lipid solubility • No effect on cerebral blood flow
  39. 39. AUTONOMIC SYSTEM • Decreases the intestinal tone and secretions • Splanchnic flow is increased
  40. 40. GIT • Decrease renal blood flow by 40% • GFR is unaltered • Bladder tone decreased spinchter tone increased
  41. 41. METABOLIC • Decrease insulin secretion • Increase glucagon and glycogenolysis • Elevated blood sugar • Initial increae in k+ de to release from liver f/b decrease due to skeletol muscle uptake
  42. 42. METABOLISM • COMT in liver to meta adrenaline ,nor meta adrenaline • MAO within adrenergic neurons • EXCRETION in urine as inactive metabolites
  43. 43. ADVANTAGES • Direct acting.not dependent on the release of nor epinephrine • Potent α+β gives maximum effects • Powerful inotrope with variable α effect • If BP rises tachycardia diminishes due to vagal effect • bronchodilator
  44. 44. DIASDVANTAGES • Initial tachycardia ,arrythmias • Organ ischemia esp kidney.U/O has to be monitored • Pumonary vasoconstriction may occur  pHTN and RV failure..a vasodilator may be added • Risk of myocardial ischemia • Extravasation from a peripheral line cause central line prefered • Elevation of plasma glucose
  45. 45. SPECIAL POINTS • Dose of adrenaline should be limited to 1micrograms/kg/30 min in presence of halothane 3 micrograms/kg/30 min in presence of isoflurane to prevent ventricular arrythmias • . In adults, the epinephrine dose required to produce three premature ventricular contractions in 50% of patients (ED50) at 1.25 minimum alveolar concentration (MAC) was 2.1 μg/kg for halothane, 6.7 μg/kg for isoflurane, and 10.9 μg/kg for enflurane. • Children tolerate larger doses than do adults • Hypocapnia potentiates this drug interaction.
  46. 46. SPECIAL POINTS • Halothane-epinephrine–induced arrhythmias are attenuated by pretreatment with sodium thiopental • The doses of epinephrine required to produce ventricular arrhythmias during desflurane or sevoflurane anesthesia are similar to, but significantly less than, those observed during administration of isoflurane and halothane.
  47. 47. SPECIAL POINTS • Preexisting α1 blockade can cause the paradoxical phenomenon of epinephrine reversal (a hypotensive and tachycardic response) as the β2-vasodilating effects are unmasked • Patients receiving nonselective β-blockers may demonstrate unopposed α responses. Cardioselective (β1) blockade does not have this • Infiltration of ADR containing solutions should be avoided in regions supplied by end arteries
  48. 48. NOR EPINEPHRINE • Endogenous neurotransmitter in post ganglionic sympathetic nerve endings • α1+α2+β1 limited β2 • Predominant at α receptors
  49. 49. DOSAGE • short half-life of 2.5 minutes, continuous infusion is preferred • starting infusion doses 0.015-0.030 µg/kg/min usual range 0.01-0.1 µg/kg/min
  50. 50. CVS • Increase in SVR decreases venous return to heart. • decreased venous return combined with baroreceptor mediated reflex decreases in heart rate due to marked increase in MAP tend to decrease CO despite β1 action of NE.
  51. 51. CVS • Increase PVR  increase SBP ,DBP • CO unchanged or decreases • Bradycardia • Increase coronary flow by coronary vasodilatation
  52. 52. RESPIRATORY • Slight increase in minute volume accompanied by a degree of bronchodilation
  53. 53. CNS • Decreases cerebral blood flow and oxygen consumption • Mydriasis
  54. 54. AUTONOMIC • Decreased hepatic and splanchnic blood flow • Decreased renal blood flow • GFR is maintained • Tone of bladder neck increased GIT
  55. 55. METABOLIC • Decrease insulin secretion  hyperglycemia
  56. 56. METABOLISM • oxidative deamination by mitochondrial MAO • Methylation by cytoplasmic COMT • EXCRETION by kidneys
  57. 57. INDICATIONS • Refractory hypotension • Sepsis • for treating RV failure associated with cardiac surgery. simultaneous infusion of NE into left atrium by a left atrial catheter plus inhaled NO/iv NTG. NE first reaches systemic circulation,metabolized peripherally before it reaches lung.if infused by a central vein it would have incresed PVR
  58. 58. ADVANTAGES • Equipotent to adrenaline at β1 receptors • Redistributes blood flow to brain and heart as all other vessals will be constricted • Reduced organ perfusion • Pulmonary vasoconstriction • Arrhythmias • Skin necrosis with extravasation DISADVANTAGES
  59. 59. SPECIAL POINTS • Mimimize the duration of use • Monitor U/O , lactic acidosis • Dose reduction with halothane • Hypertensive crisis if co administered with MAO Is or TCA • Incompatabile with barbiturates and sodium bicarbonate
  60. 60. DOPAMINE • endogenous central neurotransmitter • immediate precursor to norepinephrine in the catecholamine synthetic pathway Actions • Direct: α1 , β1 ,DA1 agonistic action • Indirect: induces release of stored neuronal norepinephrine.. •
  61. 61. • At low doses (<3 mcg/kg/min)--- dopamine activates dopaminergic (DA1) receptors vasodilation in various vascular beds, including the coronary and renal arteries and mesenteric arteries. • (3 to 10 mcg/kg/min)- activate β-adrenergic receptors that cause increased inotropy and heart rate and also promote release and inhibit reuptake of norepinephrine in presynaptic sympathetic nerve terminals • (10 to 20 mcg/kg/min), dopamine acts primarily as an α-adrenergic agonist resulting in peripheral vasoconstriction
  62. 62. USES • Increase cardiac output in patients with low systemic BP ,increased atrial filling pressure,&decreased urine output eg;CPB • Increase myocardial contractility,renal blood flow, , excretion of Na,urine output • Diuresis,natriuresis,independent of effect on renal blood flow
  63. 63. RENAL DOSE OF DOPAMINE • The benefits of “renal doses” of dopamine have remained controversial. Estimated glomerular filtration rate does not improve with use of low-dose dopamine infusions, and there is no apparent renal protective effect • The ROSE AHF (Renal Optimization Strategies Evaluation In Acute Heart Failure) trial recently found that low-dose dopamine was not better than placebo when added to standard care.
  64. 64. RENAL DOSE OF DOPAMINE • No randomized control trials have demonstrated a decrease in incidence of acute kidney injury when dopamine is administered to patients considered to be at risk for developing AKI. • In patients receiving dopamine before renal insult ,there is clear diuretic effect but no evidence that the creatinine clearance or need for HD is altered(Cottee and Saul,1996)
  65. 65. CVS EFFECTS • Increase cardiac out put (β1) • Low doses may decrease SBP AND DBP(β2) • increase in HR ,systolic BP,systemic vascular resistance • Positive inotropic effect partially due to release of stored norepinephrine. • Cardiac dysrrythmias may occur due to endogenous norepinephrine release
  66. 66. RESP.SYSTEM • Impairs the ventilatory response to arterial hypoxemia. • Depression of ventillation due to inhibitory action at carotid bodies,so watch ABG
  67. 67. CNS • Central neurotransmitter • Exogenous dopamine doesnot cross BBB except in its levo form • Causes nausea due to direct action on CTZ,which lies outside BBB
  68. 68. AUTONOMIC • Vasodilatation of splanchnic circulation due to action on dopaminergic receptors • Decreases gastroduodenal motility in critically ill
  69. 69. GIT • Decrease hepatic blood flow with epidural is reversed by dopamine 5mcg /kg/mt • Increase splanchnic oxygen requirement (in septic patients) • Reduces the release of aldosterone
  70. 70. METABOLISM • MAO ,COMT • 25% of administered dopamine is converted to noradrenaline within adrenergic nerve terminals • Renal excretion
  71. 71. ADVANTAGES • Increased renal perfsion and urine output • Blood flow shifts from skeletal muscles to splanchnic circulation • Easy to titrate
  72. 72. DISADVANTAGES • Arrythmias • Max inotropic effect less than epinephrine • Renal vasodilator effects overrided by alpha effects at high doses
  73. 73. SPECIAL POINTS • Correction of hypovolemia as with all inotropes • Reduced dose in patients on MAOIs • Inactivated by alkaline solutions
  74. 74. DOBUTAMINE • Synthetic catecholamine Actions • Direct β1 agonist,limited α1 & β2 action. • Positive inotropy via β1 .as dobutamine is metaboloised metabolite o methyl dobutamine is α1 antagonist any α1 agonist action of the drug diminishes over time.
  75. 75. CVS • Increase contractility • Sanode automaticity increasedchronotropic • On blood vessals it cause minimal vasodilation via β2 • Coronary blood flow may increase • LVEDP decreases
  76. 76. • HR  increased • Contractility increased • CO  increased • BP  increased or no change • LVEDP  decreased • LAP  decreased • SVR decreased • PVR decreased
  77. 77. CNS • Stimulation at higher doses • Urine output increases secondary to increase in cardiac otput GIT
  78. 78. METABOLIC • Decreases blood glucose
  79. 79. METABOLISM by redistribution Rapid metabolism by COMT Glucuronide conjugation in liver
  80. 80. INDICATION • Low CO states especially with increase in SVR ,PVR • Cardiac stress testing
  81. 81. DOSAGE 2-20 µg/kg/min • Diuresis function improves at 1-2 µg/kg/min. • Patients on chronic infusions show tachyphylaxis and need higher dose. • Little benefit for doses above 10 µg/kg/min.other therapies should be added or substituted when doses approaching 15 µg/kg/min needed
  82. 82. ADVANTAGES • At low doses,less tachycardia compared to dopamine • Increased CO with lesser increase in MVO2 and higher coronary blood flow compared to dopamine • After load reduction may improve RV and LV systolic function. • Renal blood flow may increase due to β2
  83. 83. DISADVANTAGES • Tachycardia and arrhythmia are dose related • Hypotension may occur,if reduction in SVR is not fully offset by increase in CO. • Tachyphylaxis > 72 hr use • Should not be used in patients with cardiac outflow obstruction
  84. 84. DOPEXAMINE • Synthetic analogue of dobutamine. • Activates β2 and dopaminergic receptors. • Mild inotropic action via β2 and • Potentiation of endogenous norepinephrine due to blockade of reuptake.So indirect β1 action. • In CHF there is down regulation of β1 but β2 is preserved.Here dopexamine has a theoretical advantage
  85. 85. ISOPROTERENOL • Synthetic catecholamine Actions • β1+β2 agonist with no α action • most potent activator of β1+β2
  86. 86. DOSAGE • 20-500ng/kg/min • 1-5 µg/min
  87. 87. DISADVANTAGES • Not a pressor so hypotension while CO increases • Pro arrhythmia • Tachycardia limits diastolic filing time • Dilates all vascular bed –shifts blood away from critical tissues • Coronary steal
  88. 88. INDICATIONS • Brady cardia unresponsive to atropine • Low CO esp when tachycardia is not detrimental • Pulmonary hypertension or right heart failure • Temporary therapy in AV block
  89. 89. ADRENOCEPTOR DYNAMICS • Desensitisation / down-regulation – Chronic heart failure – Prolonged use of inotrope / vasopressor – Sespis / acidosis
  90. 90. PHOSPHODIESTERASE INHIBITORS • Phosphodiesterase is responsible for the hydrolysis of cyclic 3,5 adenosine monophosphate (cAMP) and 3,5 cyclic guanosine monophosphate (cGMP) • Both cAMP, and to a lesser extent cGMP, have an important role in the regulation of inotropic mechanisms in the human myocardium
  91. 91. • The inotropic effect is mediated through release of calcium from the sarcoplasmic reticulum and other sub-sarcolemmal sites, and the interaction between released calcium ions and contractile proteins. • cAMP causes an increase in protein kinase A (PKA) activity which, in turn, promotes opening of the cell membrane L-type calcium channel resulting in calcium entry into the cell
  92. 92. • Calcium entry provides the stimulus for calcium release via the ryanodine receptor in the sarcoplasmic reticulum. This process has been called calcium-induced calcium release (CICR). • PKA may also increase contraction by promoting calcium uptake into the sarcoplasmic reticulum as a result of phosphorylation of the regulatory protein phospholamban, and the Calcium binding protein calmodulin.
  93. 93. Concentrations of cAMP can be increased by two mechanisms First, the concentration may be increased by active conversion of adenosine triphosphate (ATP) to cAMP via the enzyme adenylyl cyclase. Following G protein coupled receptor activation, stimulatory G-proteins activate adenyl cyclase leading to an increase in myocardial 3,5 catecholamines via β receptors
  94. 94. • The breakdown of cAMP is under the control of the enzyme phosphodiesterase, which catalyses the hydrolysis of phosphodiester bonds in cAMP leading to the production of a monophosphate and a free hydroxyl group • Currently, drugs which are available in clinical practice for improving cardiac performance are inhibitors of either phosphodiesterase III or IV. These compounds are the biguanides amrinone and milrinone, and the imidazolone derivative enoximone.
  95. 95. MILRINONE • Milrinone largely replaced amrinone in the 1980s. Amrinone is no longer widely available worldwide Actions • Inotropic action: inhibits phosphodiesterase 111 in heart and blood vessals.increased cAMP causes positive inotropy,lusitropy,chronotropy, dromotropy,and automaticity • Vasodilator: in vascular smooth muscles increased cAMP causes vasodilation
  96. 96. • Elimination half life is 2.5 hrs.Physiologic half life = 6 hrs.
  97. 97. DOSE • frequently used without bolus to avoid rapid initial effects • loading dose:50µg/kg over 1-10 min f/b 0.375-0.75 µg/kg/min • infusion can be started from 0.01µg/kg/min and titrated to a maximum 0.75µg/kg/min • oral form for chronic therapy • Excretion: Renal . Dose reduction in renal dysfunction which is common in CCF
  98. 98. ADVANTAGES • When used as a single agent ,it has favourable effects on myocardial oxygen supply-balance,due to reduction of preload,afterload & minimal tachycardia. • No tachyphylaxis • Retains efficacy in CCF where β1 receptor coupling is impaired.
  99. 99. • When compared to dobutamine at equipotent doses,milrinone produce greater decrease in PVR,greater augmentation of RV ejection fraction,less tachycardia ,fewer arrhythmias and lower MVO2 • Synergistic action with those which increase cAMP production(catecholamines)
  100. 100. DISADVANTAGES • Hypotension with bolus doses. • Arrhythmias • When milrinone is discontinued after several days,its physiologic half life may exceed 12-18 monitor the fluid balance and perfusion for atleast 48hrs after stopping.
  101. 101. INDICATIONS • Low CO syndrome, especially with increased LVEDP, pulmonary hypertension ,RV failure • To supplement /potentiate β agonists. • As a bridge to cardiac transplantation.
  102. 102. INAMRINONE • Bipyridine derivative • Same pharmacology as milrinone • Disadvantages Prolonged use ( > 24hrs) causes thrombocytopenia Produces photosensitivity Less potent than milrinone • Loading Dose: 0.75-1.5 mg/kg • Infusion Dose: 5-20 µg/kg/min
  103. 103. ENOXIMONE • A substituted imidazolone derivative .It acts by competitive inhibition of the sub-type PDE IV and possibly PDE III. loading infusion of 0.5–1.0 mg /kg over 10–30 min, followed by a maintenance infusion of 5–20 mcg /kg/ min.
  104. 104. CLINICAL PEARLS • Before staring a PDEI, hypovolemia must be corrected to prevent a further significant fall in blood pressure.. Volume loading should be undertaken with care in patients recently weaned from cardiopulmonary bypass since left ventricular compliance is usually abnormal, and rapid transfusion resulting in excessive left ventricular volume may cause a precipitate rise in left ventricular pressure, subendocardial compression, and myocardial ischaemia.
  105. 105. CLINICAL PEARLS • Vasopressors may be needed and should be prepared for use at the same time as PDEI administration. A norepinephrine infusion is commonly used; vasopressin has been described as an alternative. For those patients already on a vasopressor, an increase in dosage requirements should be expected. •
  106. 106. COMPARISON WITH CATECHOLAMINES • Catecholamines show a greater increase in heart rate and MAP, whereas the PDEI show a greater reduction in PCWP ,greater increase in stroke volume and hypotension . • In clinical practice, PDEI and catecholamines are frequently combined in order to maximize the inotropic effect, while at the same time limiting the vasodilator effects of PDI
  107. 107. LEVOSIMENDAN • Levosimendan is a pyridazinone-dinitrile derivative Calcium sensitizer that increases the affinity of troponin C (TnC) for calcium. Actions • binds to the N-terminal domain of cardiac TnC in a Ca2+ concentration-dependent manner, stabilizing the TnC-Ca 2+ complex • thereby accelerates the actin-myosin crossbridge formation rate.
  108. 108. • Its effects are maximum during systole when ca concentration is maximum and least during diastole when calcium concentration is minimum • Activates ATP-sensitive K+ channels in the vascular smooth muscle sarcolemma, leading to cell hyperpolarization and vasodilation and reducing peripheral vascular resistance. • Levosimendan relaxes both arterial and venous smooth muscle cells leading to decrease in preload and after load.
  109. 109. • It may protect the myocardium from ischemia as it dilates the coronary arteries and improves O2 supply. • It also opens myocardial mitochondrial ATPsensitive K+ channels, thereby protecting cardiomyocytes against apoptosis, ischemia-reperfusion injury and oxidative stress • Levosimendan selectively inhibits phosphodiesterase type 3, thus increasing intracellular cyclic adenosine monophosphate (cAMP) and ca, but these effects are minor at usual doses
  110. 110. ADVANTAGES • Doesnot increase intracellular calcium • Doesnot work via cAMP so no interaction with β agonists or PDIs • Renal blood flow and glomerular filtration rate are improved both acutely and chronically by levosimendan more than by dobutamine. • Levosimendan is renoprotective through activation of ATP-sensitive K + and potent vasodilation, which leads to increased renal perfusion
  111. 111. DISADVANTAGES • long-term effects on cardiac remodeling and cardiovascular mortality remain largely unknown. • Hypokalemia and Hypotension. The mechanism underlying hypokalemia is still unknown. Hypotension due to vasodilation and increased diuresis is more pronounced when a bolus is administered, and the new ESC guidelines on acute and chronic HF do not recommend bolus administration
  112. 112. LIDO /SURVIVE TRIAL • In the Levosimendan Infusion versus dobutamine (LIDO) trial, levosimendan led to greater improvement in hemodynamics and in secondary and post-hoc analyses it was associated with a lower risk of death at 31 and 180 days • In the SURVIVE trial no difference between levosimendan and dobutamine groups was found for survival during longterm follow-up despite evidence for an early reduction in plasma BNP levels with levosimendan
  113. 113. DOSE • 8-24 µg/kg/min iv Effects of levosimendan in cardiac surgery Most studies on levosimendan in cardiac surgery show a cardioprotective effect, with a decrease in the incidence of low CO syndromes and reduced cardiac troponin release and may reduce postoperative mortality
  114. 114. DIGOXIN NaK ATPase Na/Ca X-ch K N aN a Ca Inhibits (slows) NA/K ATPase Reduced Na gradient slows Ca removal K Na A cardiac glycoside derived from foxglove plant (digitalis purpura)
  115. 115. ACTIONS • Positive inotropism --> Inhibit Na K ATPase=>increase Na conc=>increase--- increased intracellular ca---increased ca release from ER =>positive inotropism • Decrease automaticity by decreasing transmembrane potential • Decrease the sympathetic activation of heart---due to sensitization of high pressure baroreceptors which reduces sympathetic outflow
  116. 116. It remains uncertain whether the sympatholytic or positive inotropic effects are responsible for relief of symptoms in heart failure • Contractility ---increased • Av conduction—decreased • Ventricular automaticity—inc rate of phase 4 depolarisation • Refractory period—decreasd in atria and ventricles ,increased in av node
  117. 117. ADVANTAGES • Supraventricular antiarrythmic actions • Reduced ventricular rate in atrial fibrillation/flutter. • Improves symptoms in CHF and reduce hospital stay
  118. 118. DISADVANTAGES • Low therapeutic index • Increased mvo2 and svr occur in patients withoutCHF • Long half life • Can cause any arrhythmia
  119. 119. INDICATIONS • CHF • Supraventricular arrhythmias
  120. 120. DOSAGE loading dose iv and im 0.25-0.5 mg increments (total of 1 to 1.25mg or 10-15 ug/kg) maintenance dose,0.125 to 0.250 mg/day
  121. 121. FACTORS POTENTIATING TOXICITY • Hypokalemia • Hypomagnesemia • Hypercalcemia • Alkalosis • Acidosis • Renal Insufficiency • Quinidine Therapy • Hypothyroidism
  122. 122. CAUTION • Administering calcium salts to digitalized patients.Malignant ventricular arrythmias may occur,even if the patient is off digoxin for more than 24 hrs
  123. 123. TREATMENT OF DIGOXIN TOXICITY • Increase serum potassium to upper limit of normal • Treat ventricular /atrial arrhythmias • Beta blockers are effective for digoxin induced arrhythmias, ventricular pacing if AV block develops • Beware of cardioversion—VF refractory to countershock may be induced.use low energy synchronized cardioversion and slowely increase the energy levels •
  124. 124. SERUM DIGOXIN LEVELS Digoxin levels >1.2 ng/ml may be harmful levels in the range of 0.5 to 0.9 ng/ml may be optimal. In general, digoxin levels below 1.0 ng/ml are safer and may even be more effective
  125. 125. DIG TRIAL Digoxin was once widely used to treat patients with systolic heart failure. However, in 1997, results from the DIG (Digitalis Investigation Group) study indicated that digoxin had a neutral effect on mortality, although reductions were seen in overall rates of hospitalization and heart failure progression
  126. 126. THE NEED FOR INOTROPIC DRUGS IN ANESTHESIOLOGY AND INTENSIVE CARE Perioperative heart failure is a major clinical problem, and perioperative cardiac morbidity is the leading cause of death following surgery and anesthesia. The number of Patients with extensive cardiovascular disease presenting for both cardiac and Noncardiac surgery has dramatically grown. An increasing number of sicker and older patients with ventricular dysfunction are now undergoing Cardiac surgery .
  127. 127. INOTROPIC DRUGS IN NONCARDIAC SURGERY • atrioventricular or sinoatrial blocks- use of chronotropic drugs (isoproterenol), when pacing not available or feasible • urgency/emergency surgery, or elective major surgery (hepatic, vascular), in patients with hemodynamic derangements determining an insult to a heart with an unknown reduced coronary reserve, or with preexisting valvular disease
  128. 128. • elective or urgent major vascular surgery (thoracic or abdominal aortic surgery) in patients with known chronic heart failure, in which aortic clamping procedures may pose an excessive afterload to the failing heart. • myocardial dysfunction in septic shock patients • perioperative pulmonary thromboembolic complications
  129. 129. ANAESTHETIC GOAL For Patients with reduced/depressed systolic heart function anesthetic goals are • monitoring of cardiac function • avoid sympathetic responses • optimisation of preload, afterload, • monitoring and maintaining heart rate and rhythm, • inotropic drugs • Postoperative management will also require monitoring in an intensive care unit. •
  130. 130. INOTROPIC DRUGS IN CARDIAC SURGERY POSTOPERATIVE MYOCARDIAL DYSFUNCTION • significant impairment in ventricular performance commonly occurs after cardiac surgery. • Both right and left ventricular ejection fractions (EF) may diminish to 35 to 75 percent of their pre-CPB levels, along with decreased cardiac index
  131. 131. • Postoperative ventricular dysfunction following cardiac surgery is similar to myocardial stunning: a myocardial dysfunction following a brief ischemic event, unassociated with morphologic injury (necrosis), and thus reversible after a period of convalescence. • The heart undergoing this type of surgery is subjected to ischemic and reperfusion injury resulting in various degrees of cytosolic calcium accumulation, free oxygen radicals generation, and myocytes and myocardial edema
  132. 132. • postsurgical stunning may involve both right and left ventricles • Weaning from CPB represents a critical phase in which the eventual ventricular dysfunction may fully appear, and inotropic drugs support may be required • A biphasic pattern of myocardial depression occurs - recovery from the initial compromise after separating from CPB is followed by a second period of low myocardial performance which reaches its nadir 3 to 6 hours after separation from CPB.
  133. 133. • The time to full recovery is usually 8 to 24 hours • return to baseline function is often delayed in patients with worse preoperative ventricular function • Postoperative ventricular dysfunction affects systolic and Diastolic function
  135. 135. Four main factors must anyway be taken into account when considering the use of an inotrope Prolonged, unappropriate or excessive treatment with inotropic medication may augment perioperative ischemic injury and adversely affect myocardial function and weaning from CPB.
  137. 137. CHOICE OF THE INOTROPE The ideal positive inotropic agent should • enhance contractility (both right and left ventricular) -without any significant increase in heart rate, preaload, afterload, and myocardial oxygen consumption. • enhance diastolic function -maintain diastolic coronary perfusion pressure and thus an adequate myocardial blood flow • have rapid onset, short half life and titrability
  139. 139. CABG • During CABG surgery, inotropes may be needed in case of preexisting ventricular dysfunction or unsuccessful revascularization if intra aortic balloon pump (IABP) alone is not enough. • In emergency revascularization of acute myocardial infarction, dobutamine and PDI may be the most beneficial inotropes, as they may better affect the oxygen delivery/consumption balance
  140. 140. CABG • If inotropic support is anticipated to be necessary for termination of CPB, it should be started five minutes before termination of CPB. • Starting the infusion of inotropic agents too soon increases myocardial oxygen consumption while the heart is being reperfused on CPB. This compromises the replenishmentof energy stores and serves no useful purpose.
  141. 141. CHRONIC HEART FAILURE myocardium presents unique features due to chronic catecholamine hyperstimulation: • β1 receptor downregulation with reduction in receptor density (proportional to the severity of systolic dysfunction), • a shift in proportion of β1 versus β2 receptors (from the • normal 80:20 to 60:40) • low intracellular levels of c AMP • acute changes in β-adrenergic receptors function can also occur during cardiac surgery .
  142. 142. • Catecholamine stimulation alone is submaximal, reaching a plateau effect on adenylyl cyclase and response to PDI alone could also be blunted (by a reduced intracellular AMPc pool) • Combination therapy (i.e. a PDI administered along with a β- adrenergic inotrope, dobutamine or epinephrine) may therefore be the treatment of choice .It minimizes side effects of the single drug • As depletion of myocardial stores of norepinephrine also occurs in chronic dysfunctional myocardium, indirect β- adrenergic agents (dopamine, dopexamine) would be poorly effective
  143. 143. • Choice of an inotropic agent, must take the problem of diastolic dysfunction into account. • When marked ventricular hypertrophy is present (severe aortic stenosis, hypertrophic obstructive cardiomyopathy) the use of β-adrenergic agents may worsen diastolic function with decrease in cardiac output. • No inotropes at all (or inotropes with a better effect on ventricular relaxation, such as PDI ) should be used. • Maintenance of adequate preload and perfusion pressures is also essential.
  144. 144. VALVULAR SURGERY • Aortic stenosis- the afterload has been markedly reduced, but left ventricular hypertrophy and diastolic dysfunction remain , inotropic support is rarely needed • Chronic aortic insufficiency-- ventricular dilation and dysfunction persist, requiring adequate preload and inotropes.
  145. 145. • Mitral stenosis, chronic mitral regurgitation, treatment with inotropes should be warranted • Acute aortic and mitral regurgitation both pose a great risk of severe ventricular dysfunction after surgical correction, requiring inotropic support, even preoperatively. • Tricuspid regurgitation is almost always associated with right ventricular dysfunction needing inotropic support.
  146. 146. HEART TRANSPLANTATION Transplanted heart has normal contractile function but it lacks the normal autonomic control of chronotropy and inotropy because of the interruption of autonomic innervation Routine inotropic support after ortothopic cardiac transplantation includes isoproterenol (to increase automaticity, inotropism and pulmonary vasodilation) and dopamine (to add further support with preservation of systemic perfusion pressures)
  147. 147. • The most frequent problems derive from sudden exposure of the unconditioned donor right ventricle to excessive afterload stress imposed by elevated pulmonary vascular resistance, with right heart failure ; prolonged graft ischemia or inadequate myocardial protection(excessive pre harvesting cathecolamine exposure) Both these situations require aggressive inotropic support and management of right ventricular failure
  148. 148. LUNG TRANSPLANTATION Several critical stages pose the usually hypertrophied right ventricle at high risk of failure • induction of anesthesia (hypotension), • commencement of positive-pressure ventilation (increase in RV afterload, hyperinflation with circulatory collapse), • institution of one lung ventilation (severe hypoxia), • clamping of the pulmonary artery (sudden increase in afterload), • unclamping of the pulmonary artery (profound hypotension)
  149. 149. • Norepinephrine, in addition to low dose epinephrine (or dobutamine) and cautious fluid loading, is the management
  151. 151. Cardiogenic Shock Complicating Acute Myocardial Infarction • Inotropes increase myocardial oxygen consumption and can cause ventricular arrhythmias, contraction band necrosis, and infarct expansion • Critical hypotension itself compromises myocardial perfusion, leading to elevated left ventricular (LV) filling pressures, increased myocardial oxygen requirements, and further reduction in the coronary perfusion gradient
  152. 152. • hemodynamic benefits usually outweigh specific risks of inotropic therapy when used as a bridge to more definitive treatment measures. • Inotropic agents may improve mitochondrial function in noninfarcted myocardium that has become deranged during AMI complicated by shock. • However, free cytosolic Calcium, which is significantly elevated in post ischemic cardiac myocytes, is further increased with the administration of inotropes, which leads to activation of proteolytic enzymes, proapoptotic signal cascades, mitochondrial damage, and eventual membrane disruption and necrosis
  153. 153. • lowest possible doses of inotropic agents should be used to adequately support vital tissue perfusion while limiting adverse consequences. • The American College of Cardiology/American Heart Association guidelines for management of hypotension complicating AMI suggest dobutamine as a first-line agent if systolic blood pressure ranges between 70 and 100 mm Hg in the absence of signs and symptoms of shock. Dopamine in patients who have the same systolic blood pressure in the presence of symptoms of shock.
  154. 154. • When response to a medium dose of dopamine or dopamine/ dobutamine in combination is inadequate, or the patient’s presenting systolic blood pressure is <70 mm Hg, the use of norepinephrine has been recommended
  155. 155. HEART FAILURE • The use of positive inotropes in chronic HF has been consistently demonstrated to increase mortality • A proposed central mechanism involves a chronic increase in intracellular Ca2, which contributes to altered gene expression and apoptosis and an increased likelihood of malignant ventricular arrhythmias.
  156. 156. • As a result, the current American College of Cardiology/ American Heart Association guidelines for diagnosis and management of chronic HF in the adult do not recommend the routine use of intravenous inotropic agents for patients with refractory end-stage HF but do state that they may be considered for palliation of symptoms in these patients
  157. 157. • Most commonly recommended initial inotropic therapies for refractory HF are-- Dobutamine, dopamine, and milrinone Used to improve CO and enhance diuresis by improving renal blood flow and decreasing SVR without exacerbating systemic hypotension • β-adrenergic receptor responses are often blunted in the failing human heart • PDIs such as milrinone, acting through a non–β adrenergic mechanism, are not associated with diminished efficacy or tolerance with prolonged use
  158. 158. • Several major clinical trials have evaluated the safety and efficacy of levosimendan in HF syndromes. (RUSSLAN [Randomized Study on Safety and Effectiveness of Levosimendan in Patients With Left Ventricular Failure due to an Acute Myocardial Infarct] • LIDO [Levosimendan Infusion versus Dobutamine in Severe Low-Output Heart Failure • Both demonstrated mortality benefit
  159. 159. • In some patients, complete inotropic dependence manifested by symptomatic hypotension, recurrent congestive symptoms, or worsening renal function may develop after discontinuation of parenteral therapy. • Inotropic support may become necessary until cardiac transplantation or implantation of an LV assist device can be instituted. Inotrope-dependent HF patients who do not go on to definitive therapy have a poor prognosis, with 1-year mortality ranging from 79% to 94%.
  160. 160. • Long-term inotropic therapy is associated with an increased risk of line sepsis, arrhythmias, accelerated functional decline due to worsening nutritional status, and direct acceleration of end organ dysfunction
  162. 162. NOR AD VS DOPAMINE
  163. 163. • Dobutamine is the first choice inotrope for patients with measured or suspected low cardiac output in the presence of adequate left ventricular filling pressure (or clinical assessment of adequate fluid resuscitation) and adequate MAP • If evidence of tissue hypoperfusion persists despite adequate intravascular volume and adequate MAP, a viable alternative (other than reversing underlying insult) is to add inotropic therapy. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012
  164. 164. INOTROPES IN PREGNANCY • Indications and use of digoxin is not altered • Same dose of digoxin will yield lower maternal values during pregnancy than in non pregnant • Fetal levels approximate those in mother • When iv inotropes are required the standard agents dopamine,dobutamine ,norepinephrine can be used
  165. 165. • Fetus is jeopardized as all agents increase resistance to uterine blood flow and can stimulate uterine contractions • Little information about efficacy of PDIs
  167. 167. ISTAROXIME • Istaroxime [(E,Z)-3-((2aminoethoxy)imino)androstane-6,17-dione] • newer inotropic agents acting at the Na+/K+ -ATPase • Istaroxime does not have a glycoside-like structure • in addition to its inhibitory effects on Na+/K+ -ATPase, it has been suggested to stimulate SERCA
  168. 168. • Inhibition of Na+/K+ -ATPase increases intracellular sodium, which reduces the driving force for the NCX, decreasing calcium elimination outside the cell. • increased sodium may stimulate the NCX to function in the reverse mode of transporting calcium intracellularly • Calcium influx into the cytosol may, be harmful in the failing heart with reduced SERCA activity and elevated diastolic calcium levels
  169. 169. CARDIAC MYOSIN ACTIVATORS • Directly influence the cross-bridge cycle. • These molecules accelerate the rate of actin- dependent phosphate release of the weakly bound actin-myosin cross-bridge • This promotes transition to the force producing on-state of the cross-bridge, more cross-bridges enter the force- producing state,more cross-bridges are activated per unit of time, and contractile force increases
  170. 170. OMECAMTIV MECARBIL Omecamtiv mecarbil has been under study. It is found to increase stroke volume and cardiac output, and decreased LV end-diastolic pressure and heart rate without increased myocardial oxygen consumption
  171. 171. GENE THERAPY • to increase sarcoplasmic reticulum calcium pump activity—by stimulating the calcium pumps • Most approaches are related to reduced SR calcium uptake, however, abnormal SR leak has also been considered • It has been shown in isolated myocytes that overexpression of the RyR-regulatory protein FKBP12.6 increases SR calcium content and fractional shortening
  172. 172. NITROXYL(HNO) • Nitric oxide s one-electron-reduced and protonated sibling. • HNO and NO are both gaseous signalling molecules and can be potent vasodilators, • HNO appears to have additional unique signalling pathways and mechanisms independent of NO. • HNO is a potent arterio- and venodilator in intact animal studies
  173. 173. • Mediated by guanylate cyclase increased circulating neuropeptide calcitonin gene related peptide levels and activation of vascular smooth muscle potassium channels • One characteristic that clearly differentiates HNO from traditional nitrovasodilators is the potential absence of tolerance or Tachyphylaxis.
  174. 174. • Early in vitro experiments suggested positive inotropic and lusitropic properties of HNO. • The mechanisms of these beneficial inotropic and lusitropic effects continue to be elucidated, • They appear to be independent of cAMP/protein kinase A (PKA) and cGMP/PKG signalling, with no modification of L-type calcium channel activity, • related to modification of specific cysteine residues on either phospholamban and/or SERCA2a, resulting in augmented SR calcium transients.
  175. 175. RYANODINE RECEPTOR STABILIZERS • Calcium leak through ryrs significantly contributes to abnormal calcium cycling in human heart failure. • A leak of calcium from the sr may not only decrease sr calcium load and availability for systolic contraction, but it may also promote diastolic dysfunction due to diastolic activation of contractile proteins.
  176. 176. • Jtv519, a 1,4-benzothiazepine, was one of the first compounds that restored abnormal RYR function and preserved contractile performance in heart failure models • jtv519 has inhibitor properties on l-type calcium channels, potassium channels, and possibly other transporters • Molecules that may specifically act on cardiac ryrs have been developed, including s44121.
  177. 177. ENERGETIC MODULATORS • Disturbed energetic metabolism is considered to play a major role in human heart failure • Administration of the glycolytic substrate pyruvate may result in profound inotropic effects under experimental conditions as well as in patients with heart failure
  178. 178. PYRUVATE • Pyruvate has numerous molecular effects that may contribute to its inotropic action. These include: an increase in phosphorylation potential, a reduction of inorganic phosphate, a decrease in hydrogen ion concentration, and a modulation of the cytosolic redox state. • The most important mechanism for its inotropic action may be an increase in the phosphorylation potential
  179. 179. • In isolated muscle strip preparations from patients with end-stage heart failure, pyruvate resulted in a concentration-dependent increase in developed force and a decrease in diastolic force. • When pyruvate was injected into the coronary circulation of patients with dilated cardiomyopathy, it exhibited a profile of an ideal inotropic agent with an increase in cardiac index and stroke volume index, a decrease in PCWP and heart rate. Mean aortic pressure and system vascular resistance did not change.
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inotropism - physiology , various inotropes, use of inotropes in anaesthesia and critical care , newer inotropes


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