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Inotropes and their choice


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inotropes and their choice

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Inotropes and their choice

  1. 1. Inotropes and their choice Moderator: Speaker: Dr. R. K. Verma Dr. Dharmraj Singh
  2. 2. Inotropes  Drugs that affect the strength of contraction of heart muscle (myocardial contractility).  Positively inotropic agents ↑strength of muscular contraction.  Negatively inotropic agents weaken the force of muscular contractions.  Term “inotrope” generally used to describe positive effect
  3. 3. Contd…  Both positive and negative inotropes are used in the management of various cardiovascular conditions.  The choice of agent depends largely on specific pharmacological effects of individual agents with respect to the condition.  One of the most important factor affecting inotropic state is the level of calcium in the cytoplasm of the muscle cell.  Positive inotropes usually increase this level, while negative inotropes decrease it.
  4. 4. Positive inotropic agents:  ↑Myocardial contractility  Used to support cardiac function in conditions such as: a) Decompensated CHF, b) Cardiogenic shock, c) Septic shock, d) Myocardial infarction, e) Cardiomyopathy, etc.
  5. 5. Contd… Positive inotropic agents include: 1) Calcium 2) Calcium sensitizers: Levosimendan 3) Cardiac myosin activators: Omecamtiv 4) Catecholamines: • Dopamine • Dobutamine • Dopexamine • Epinephrine (adrenaline) • Isoprenaline (isoproterenol) • Norepinephrine (noradrenaline)
  6. 6. Contd… 5) Cardiac glycosides: Digoxin 6) Phosphodiesterase (PDEIII) inhibitors: • Enoximone, Piroximone • Milrinone • Amrinone 7) Prostaglandins: PGE₂ 8) Glucagon
  7. 7. Negative inotropic agents  ↓Myocardial contractility, and are used to ↓cardiac workload in conditions such as angina.  While negative inotropism may precipitate or exacerbate heart failure,  Certain beta blockers (e.g. carvedilol, bisoprolol and metoprolol) have been believed to reduce morbidity and mortality in congestive heart failure.
  8. 8. Contd… 1) Beta blockers 2) Calcium channel blockers:  Diltiazem  Verapamil  Clevidipine 3) Class IA antiarrhythmics such as:  Quinidine  Procainamide  Disopyramide 4) Class IC antiarrhythmics such as:  Flecainide
  9. 9. Adrenergic Agents  Alpha1-adrenergic effects: • Vascular smooth muscle contraction  Alpha2-adrenergic effects: • Vascular smooth muscle relaxation
  10. 10. Beta-Adrenergic Agents  Beta1-adrenergic effects: o Direct cardiac effects • Inotropy (improved cardiac contractility) • Chronotropy (increased heart rate)  Beta2-adrenergic effects: • Vasodilation • Bronchodilation
  11. 11. Dopaminergic Agents  Dopaminergic Agents classified as D1 &D2 • D1-receptors mediates vasodilation in kidney, intestine, & heart • D2-antiemetic action of droperidol
  12. 12. Recepter selectivity of adrenergic agonists.1 Drugs α₁ α₂ β₁ β₂ DA₁ DA₂ Epinephrine 2 ++ ++ +++ ++ 0 0 Ephedrine 3 ++ ? ++ + 0 0 Norepinephrine2 ++ ++ ++ 0 0 0 Dopamine2 ++ ++ ++ + ++ +++ Dopexamine 0 0 +++ ++ ++ +++ Dobutamine 0/+ 0 +++ + 0 0 1 0,no effect; +, agonist effect (mild, moderate, marked) 2 the α₁- effects of epi, norepi, & dopamine became more prominent at higher dose 3 primary MOA of ephedrine is indirect stimulation
  13. 13. Effect of adrenergic agonists on organs sysyems.1 Drugs HR MAP CO PVR Bronchodilation RBF Epinephrine ↑↑ ↑ ↑↑ ↑/↓ ↑↑ ↓↓ Ephedrine ↑↑ ↑↑ ↑↑ ↑ ↑↑ ↓↓ Norepinephrine ↓ ↑↑↑ ↓/↑ ↑↑↑ 0 ↓↓↓ Dopamine ↑/↑↑ ↑ ↑↑↑ ↑ 0 ↑↑↑ Dopexamine ↑/↑↑ ↓/↑ ↑↑ ↑ 0 ↑ Isoproterenol ↑↑↑ ↓ ↑↑↑ ↓↓ ↑↑↑ ↓/↑ Dobutamine ↑ ↑ ↑↑↑ ↓ 0 ↑ 1 0, no effect; ↑,(mild, moderate marked); ↓, (mild, moderate marked); ↓/↑, variable effect; ↑/↑↑mild-to-moderate increase.
  14. 14. Effects of Agents  Pressors: ↑SVR & ↑BP  Inotropes: affect myocardial contractility and enhance stroke volume  Chronotropic agents: affect heart rate  Lusotropic agents: improve relaxation during diastole and ↓EDP in the ventricles  Dromotropic agents: Affects conduction speed through AV node; ↑HR  Bathmotropic agents: affect degree of excitability
  15. 15. calcium  When injected IV, produce intense positive inotropic effect lasting 10-20 minutes & manifesting as ↑SV & LVEDP, ↓HR & SVR  Inotropic effects of Ca are enhanced in presence of preexisting hypocalcaemia  Risk of cardiac dysrhythmias when Ca is administered IV to patients receiving digitalis should be considered, especially if hypokalemia is also present. Dose: CaCl₂, 5-10 mg/kg to adults, may administered to improve myocardial contractility & SV at the conclusion of CPB
  16. 16. Contd…  Myocardial contractility at conclusion of CPB may be ↓by hypocalcemia because of a) Use of K+ containing cardioplegia solutions b) Administration of citrated stored whole blood c) T/t of metabolic acidosis with NaHCO₃  10% solution of CaCl₂ contains more Ca than Ca gluconate solution
  17. 17. calcium sensitizers  Pimobendan sulmazole, levosimendan are positive inotropic drugs that improve myocardial contractility independent of ↑in intracellular cAMP or Ca concentration  As a results, interaction b/w actin & myosin filaments is prolonged, & ↑myocardial contractility occurs.
  18. 18. Contd…  Desensitization of myofilaments to activating effects of Ca may occur during myocardial ischemia & stunning & these drugs may be particularly useful in these circumstances.  The PDE III inhibiting properties of myofilament Ca sensitizers produces arterial & venous dilation that likely also contribute to the positive inotropic effects of these drugs.
  19. 19. Levosimendan  Pyridazone-dinitrile derivative Calcium channel sensitizer Mode of action:  ↑the sensitivity of the heart to Ca, thus ↑cardiac contractility without a rise in intracellular Ca.  Positive inotropic effect by ↑Ca sensitivity of myocytes by binding to cardiac troponin C in a Ca-dependent manner.  Vasodilatory effect, by opening ATP-sensitive K channels in vascular smooth muscle to cause smooth muscle relaxation.
  20. 20. Contd…  Combined inotropic and vasodilatory actions result in an ↑force of contraction, ↓preload & afterload.  By opening mitochondrial (ATP)-sensitive K-channels in cardiomyocytes, the drug exerts a cardioprotective effect.  ↑Myocardial contractility without ↑myocardial O₂ demand, and as a consequence appears to be free of serious arrhythmogenic effects in patients with cardiac failure.
  21. 21. Mechanism of action of levosimendan on cardiovascular functions Bollen Pinto et al., Current Opinion in Anesthesiology 2008, 21:168–177
  22. 22. Contd… Loading dose: 6 to 12 μg/kg iv over 10 min F/B Continuous infusion: 0.05-0.2 μg/kg /min for 24 hours  Hemodynamic responses are generally observed within 5 minutes of commencement of infusion of the loading dose.  Peak effects are observed within 10 to 30 minutes of infusion; the duration of action is about 75-78 hours to 1 week.  No dosage adjustments required with mild to moderate renal failure.  Loading doses do not require adjustment with mild to moderate hepatic impairment
  23. 23. Contd…  Indicated for inotropic support in acutely decompensated severe CHF, refractory cardiac failure, refractory pulmonary hypertension and dilated cardiomyopathy..  Contraindicated in patients with: a. Moderate-to-severe renal impairment, b. Severe hepatic impairment, c. Severe ventricular filling or outflow obstruction, d. Severe hypotension and tachycardia, e. History of torsades de pointes.
  24. 24. Contd… Adverse effects: Common adverse drug reactions (≥1% of patients) include:  Headache,  Hypotension,  Arrhythmias (AF, extrasystoles, atrial tachycardia, VT),  Myocardial ischaemia,  Hypokalaemia,  Nausea.
  25. 25. Contd… CLINICAL BENEFITS:  Enhances cardiac contractility without ↑myocardial oxygen demand, and causes vasodilation  Significantly reduces the incidence of worsening CHF or death in patients with decompensated CHF  No evidence of arrhythmogenesis to date POTENTIAL LIMITATIONS :  Vasodilatory properties can cause adverse effects (headache, hypotension)  Must be administered intravenously  Limited clinical experience at present
  26. 26. Catecholamines  Dopamine, epinephrine and norepinephrine are endogenous  Dobutamine and isoproterenol are synthetic  Sustained use or antecedent CHF can lead to down-regulation of β-receptors and decrease efficacy
  27. 27. Relative receptor activity of most commonly used inotropes α1 α2 β1 β2 DA Norepinephrine +++ +++ + - - Epinephrine +++ ++ +++ ++ - Dopamine ++ + ++ +++ +++ Dobutamine + - +++ + - Isoproterenol - - ++ ++ -
  28. 28. Dopamine(DA)  Endogenous nonselective direct and indirect adrenergic and dopaminergic agonist  Clinical effects vary markedly with the dose. 1) Low dose: 0.5-3μg/kg/min  Activates dopaminergic receptors(specifically DA₁)  Vasodilation of renal vasculature and promotes diuresis and natriuresis  Use of this “renal dose” does not impart any beneficial effect on renal function.
  29. 29. Contd… 2) Moderate dose: 3-10 μg/kg/min  β₁ - stimulation ↑ myocardial contractility, HR, SBP, and CO  Myocardial O₂ demand typiaclly↑ more than supply 3) High dose: 10-20 μg/kg/min  α₁ - effects became prominent  ↑PVR & ↓renal blood flow(RBF)  Indirect effects of DA are due to release of norepinephrine from postsynaptic sympathetic nerve ganglion.
  30. 30. Dose Dependent effect of Dopamine <3 mcg 3 - 10 mcg > 10 mcg ↑Contractility Minimal change in HR and SVR ↑ Renal BF ↑ Splanchnic BF Modest ↑ CO ↑ Renal BF ↓Proximal Tub. Na Absorbtion ↑ Splanchnic BF ↑ HR, Vasoconstriction ↑/ ↓ Renal BF ↓/↑ Splanchnic BF
  31. 31. Contd… Uses:  T/t of shock to improve CO, BP, & maintain renal function  Often used in combination with a vaodilator (eg. Nitroglycerin or nitroprusside), which reduce afterload & further improve CO Chronotropic & proarrhythmic effects of DA limit its usefulness in some patients.
  32. 32. Contd… Dosing & Packing:  Continuous infusion 1-20 μg/kg/min  Most commonly supplied in 5 ml (40mg/ml) ampules containing 200 mg of DA
  33. 33. Dobutamine  Racemic mixture of two isomers with affinity for both β₁ & β₂ receptors, with relatively higher selectivity for β₁ receptors  Primary cardiovascular effect - ↑CO as a result of ↑myocardial contractility  ↓ PVR caused due to β₂- activation usually prevents much of ↑arterial BP  ↓LV filling pressure, whereas ↑coronary blood flow(CBF)
  34. 34. Contd…  Favorable effects on myocardial O₂ balance are believed to make dobutamine a choice for patients with the combination of CHF & CAD, particularly if PVR is elevated.  It has been shown to ↑myocardial O₂ consumption, such as during stress testing (rationale for its use in perfusion imaging), some concern remain regarding its use in patients with myocardial ischaemia.  Its should not be routinely used without specific indications to facilitate separation from CPB
  35. 35. Contd…  Used in low CO states and CHF e.g. myocarditis, cardiomyopathy, MI  If BP adequate, can be combined with afterload reducer (Nitroprusside or ACE inhibitor)  In combination with Epinephrine/Norepinephrine in profound shock states to improve CO and provide some peripheral vasodilatation Dosing & Packing:  Infusion @ 2-20 μg/kg/min  Supplied in 5-ml (50 mg/ml) ampules containing 250 mg
  36. 36. Dopexamine  Structural analogue of DA  Potentail advantage over DA because it has less β₁- adrenergic(arrhythmogenic) & α- adrenergic effects  Because of ↓β-adrenergic effects & its specific effects on renal perfusion, it may advantage over dobutamine  Clinically avialable in many country since 1990, but it has not gained widespread acceptance in practice
  37. 37. Contd… Dosing & Packing:  Infusion should be started @0.5μg/kg/min, ↑ to 1μg/kg/min at interval of 10-15 min to maximum infusion rate 6μg/kg/min.
  38. 38. Epinephrine(adrenaline)  Endogenous catecholamine synthesized in the adrenal medulla  Direct stimulation of β₁- receptors of the myocardium cause ↑BP, CO & myocardial O₂ demand by ↑contractility & HR  α₁- stimultion ↓splanchnic & RBF but ↑coronary perfusion pressure(CPP) by ↑aortic DP  SBP rises, although β₂- mediated vasodilation in skeletal muscle may ↓DP  β₂- stimulation also relaxes bronchial smooth muscle
  39. 39. EPINEPHRINE α1 predominantly Vasoconstriction ↓ Renal BF ↓ Splanchnic BF ↑ Glucose β1 predominantly ↑HR ↓ Duration of Systole ↑ Myocardial contract Periph. arteriolar dil. ↑/ ↓ Renal BF ↑ Renin secretion ↑/ ↓ Splanchnic BF ↑ Glucose Hypokalemia Epinephrine Low Dose (<0.05-0.1 mcg/kg/min) High Dose (> 0.1 μg/kg/min)
  40. 40. Contd… Uses:  T/t for anaphylaxis & ventricular fibrillation Complications:  Cerebral hemorrhage  Coronary ischaemia  Ventricular dysrhythmias  Volatile anesthetics, particularly halothane, potentiate the dysrhthmic effects of epinephrine(10μg/kg)
  41. 41. Contd… Dosing & Packing:  Emergency situation (eg, cardiac arrest & shock), iv bolus 0.05-1 mg, depending on the severity of cardiovascular compromise  Major anaphylactic reactions 100-500μg (repeated, if necessary) followed by infusion  To improve myocardial contractility or HR, a continuous infusion is prepared (1 mg in 250 ml [4μg/ml]) & run @ 2-20μg/min
  42. 42. Contd…  Reduce bleeding from operative sites  Local anesthetics solutions containing 1:200,000 (5μg/ml) or 1:400,000 (2.5μg/ml)- less systemic absorption & longer duration of action  Epinephrine is available in vials & prefilled syringes containing: a) 1:1000 (1mg/ml) b) 1:10,000 (0.1mg/ml [100μg/ml]) c) 1:100,000 (10μg/ml)- for pediatric use
  43. 43. Contd… Common contraindication:  Hypertension.  Pheochromocytoma.  Caution with heart failure angina and hyperthyroidism.
  44. 44. Isoprenaline (Isoproterenol)  Synthetic catecholamine  Non-specific pure β- agonist with minimal alpha-adrenergic effects.  β₁- effects ↑HR, contractility , CO  SBP may ↑ or remain unchanged, but β₂- stimulation ↓PVR & DBP  ↑Myocardial O₂ demand while ↓O₂ supply, making isoproterenol or any pure β- agonist a poor inotropic choice in most situations
  45. 45. Contd…  Causes inotropy, chronotropy, and systemic and pulmonary vasodilatation.  Indications: bradycardia, decreased CO, bronchospasm (bronchodilator).
  46. 46. Contd… Dosing & Packing:  Occasionally used to maintain HR following heart transplantation.  Dose starts at 0.01 mcg/kg/min and is increased to 2.0 mcg/kg/min for desired effect.  Avoid in patients with subaortic stenosis, and hypertrophic cardiomyopathy or TOF lesions because increases the outflow gradient  Supplied in 1-ml (2 mg/ml) ampules containing 2 mg
  47. 47. Norepinephrine (Noradrenaline)  Direct α₁- stimulation with little β₂- activity induces intense vasoconstriction of arterial & venous vessels  ↑Myocardial contractility from β₁- effects, along with peripheral vasoconstriction contributes to ↑arterial BP  ↑SBP & DBP both, but ↑afterload & reflex bradycardia prevent any ↑CO  ↓Renal & splanchnic blood flow & ↑myocardial O₂ requirements limit the outcome benefits of norepinephrine in management of refractory shock.
  48. 48. Contd…  Norepinephrine has been used with an α- blocker (eg, phentolamine) in an attempt to take advantage of its β- activity without the profound vasoconstriction caused by α- stimulation  Extravasation of norepinephrine at the site of IV administration can cause tissue necrosis Dosing & Packing:  Bolus 0.1μg/kg or  Continuous infusion @ 2-20μg/kg/min (due to its short half life)  Ampules contain 2 mg of norepinephrine in 4 ml
  49. 49. prostaglandins  The effects of prostaglandins on cardiac function are complex & depend on direct inotropic effects, the activity of the SNS relative to PNS, & the metabolic status of heart  PGE₂ produces an ↑in HR & myocardial contractility by direct inotropic effects as well as by ↑reflex SNS activity  PGE₂(Dinoprostone) produces ↑ in HR &CO
  50. 50. CADIAC GLYCOSIDES  Purified cardiac glycoside (clinically useful; Digoxin, digitoxin, & ouabain) extracted from the foxglove plant, Digitalis lanata.  Widely used in the treatment of various heart conditions, namely AF, atrial flutter and sometimes heart failure that cannot be controlled by other medication. Mechanism of Action: Positive inotropic effect include direct on heart that modify its electrical & mechanical activity & indirect effects evoked by reflex alteration in ANS
  51. 51. CONTD…  Selectively & reversibly inhibit Na-K ATP ion transport system (Na pump) located in the sarcolemma of cardiac cell membranes→  ↑Na+ concentration in the cardiac cells leads to ↓extrusion of Ca2+ by Na+ pump mechanism  ↑intracellular concentration of Ca2+ is responsible for positive inotropic effect of cardiac glycosides  Positive inotropic effects produced by cardiac glycosides occur without change in HR & associated with ↓LV preload, afterload, wall tension, & O₂ consumption in the failing heart.
  52. 52. Contd… • ↑PNS activity due to sensitization of arterial baroreceptors (carotid sinus) & activation of vagal nuclei & nodose ganglion in the CNS • ↓activity of SA node & prolongs the effective refractory period, & thus the time for conduction of cardiac cardiac impuse through AV node • Slowed HR especially in presence of AF
  53. 53. Digoxin Digitoxin Avg digitalization dose Oral 0.75-1.50 mg 0.8-1.2 mg Intravenous 0.5-1.0 mg 0.8-1.2 mg Avg daily maintenance dose Oral 0.125-0.500 mg 0.05-0.20 mg Intravenous 0.25 mg 0.1 mg Onset of effect Oral 1.5-6.0 hrs 3-6 hrs Intravenous 50-30 mins 30-120 mins Absorption from the GIT 75% 90-100% Plasma protein binding 25% 95% Route of elimination Renal Hepatic Enterohepatic circulation Minimal Marked Elimination half-time 31-33 hrs 5-7 days Therapeutic plasma 0.5-2.0 ng/ml 10-35 ng/ml concentration
  54. 54. Ouabain Dose: 1.5-3.0 mcg/kg iv to provide rapid increases in myocardial contractility or to decrease the heart ratein rapid ventricular response AF
  55. 55. Selective Phosphodiesterase inhibitors (noncatecholamine, nonglycoside cardiac inotropic agents) Selective PDE exert competitive inhibitory action on an isoenzyme fraction of PDE (PDE III) ↓hydrolysis of cAMP & cGMP ↑intracellular concnof cAMP & cGMP in myocardium & vascular smooth muscle Stimulation of protein kinases C Phosphorylate substance & inward movement of Ca2+
  56. 56. Contd…  Positive inotropic effect with vascular & airway smooth muscle relaxation  Positive inotropic effect due to inhibition of cardiac PDE III, leading to ↑myocardial cAMP  Selective PDE inhibitors act independently of β- adrenergic receptors & ↑myocardial contractility in patients with myocardial depression from β-receptor blockade & those who have become refractory to catecholamine therapy
  57. 57. Contd…  Selective PDE III inhibitors exceeds cardiac glycosides & is complementary & synergistic to the action of catecholamines.  These drugs can be used in conjuction with digitalis without provoking digitalis toxicity  Mx of Ac cardiac failure (as after MI) in Pts who would benefit from combined inotropic & vasodilator therapy  Amrinone, Milrinone, Enoximone, Piroximone
  58. 58. Amrinone  Bipyridines derivative, selective PDE III inhibitor & produces dose dependent positive inotropic & vasodilator effects  Non-receptor mediated activity based on selective inhibition of Phosphodiesterase Type III enzyme resulting in cAMP accumulation in myocardium  cAMP increases force of contraction and rate and extent of relaxation of myocardium  Inotropic, vasodilator and lusotropic effect  ↑CO & ↓LVEDP,  HR & SBP may↑
  59. 59. CONTD… Advantage over catecholamines:  Independent action from β-receptor activation, particularly when these receptors are downregulated (CHF and chronic catecholamine use)  Oral/ IV  Initial injection single dose: 0.5-1.5 mg/kg IV, ↑CO with in 5 min, with detectable positive inotropic effect persisting for approx 2 hrs  Continuous infusion: after initial injection 2-10 μg/kg/min  Recommended maximum daily dose 10 μg/kg including the initial dose
  60. 60. Contd…  Patients who have failed to respond to catecholamine may respond to amrinone  Vasodilating effects of amrinone can accelerate the cooling rate of core temperature during deliberate mild hypothermia for neurosurgical procedure. Side effects:  Occasional hypotension  Thrombocytopenia
  61. 61. Milrinone  Like amrinone positive inotropic & vasodilator effects  Minimal effects on HR & myocardial O₂ consumption  ↑CO by improving contractility, ↓SVR, PVR, lusotropic effect; ↓preload due to vasodilatation  Unique in beneficial effects on RV function  Protein binding: 70%  Half-life is 1-4 hours  Elimination: primarily renally excreted  Load with 50 μg/kg over 30 mins followed by 0.25 to 0.75 μg/kg/min
  62. 62. Milrinone Minimal ↑ HR ↑ CO Minimal ↑ in O2 demand ↓ SVR ↓ PVR Diastolic Relaxation
  63. 63. Enoximone & piroximone  Imidazole derivatives that act as highly selective PDE III inhibition to ↑myocardial contractility  Half-life 4.3 hrs  Metabolized mainly by liver Dose: 0.5 mg/kg IV f/b 5-20 μg/kg/min continuous infusion
  64. 64. COMPARISON BETWEEN LEVOSIMENDAN, MILRINONE AND DOBUTAMINE Feature Levosimendan Milrinone Dobutamine Class Calcium channel sensitizer Phosphodiesterase-III inhibitor Catecholamine(β- adrenergic agent) ↑intracellular Ca concentrations No Yes Yes Vasodilator Coronary and systemic Peripheral Mild peripheral ↑Myocardial O₂ demand No No Yes Arrhythmogenic potential Rare and may be due to QTc prolongation Ventricular and supraventricular arrhythmias Ventricular ectopic activity; less arrhythmogenic than milrinone Adverse events Headache, hypotension Ventricular irregularities, hypotension, headache Tachycardia and increased SBP on overdosage
  65. 65. glucagon  Polypeptide hormone produced by α- cell of pancreas  Enhances formation of cAMP  Evoke the release of catecholamine Principal cardiac indication: to ↑myocardial contractility & HR in the presence of β-adrenergic blockade.  Because glucagon is peptide, it must be administered IV or IM
  66. 66. Contd… Cardiovascular effects:  Rapid injection (1-5 mg IV to adults) or a continuous infusion (20 mg/hr), reliabily ↑SV & HR independent of adrenergic stimulation  Tachycardia may sufficienlty with augmented CO  Abrupt ↑in HR can occur when administered to patients in atrial fibrillation  MAP may ↑modestly, whereas SVR is unchanged or ↓  Enhance automaticity in the SA & AV nodes without ↑automaicity of ventricles
  67. 67. Contd… Renal effect: similar to dopamine, but less potent Chronic administration is not effective in evoking sustained positive inotropic & chronotropic effects. Side effects:  Nausea & vominting  Hyperglycemia & paradoxical hypoglycemia  Hypokalemia  Systemic hypertension in patients unrecognized pheochromocytoma
  68. 68. Beta blockers  β-Receptor blockers have variable degree of selectivity for the β₁- receptors  More selective β₁- receptor blockers has less influence on bronchopulmonary & vascular β₂- receptors.  Theoretically, a selective β₁ -blockers would have less of an inhibitory effect on β₂-receptors & therefore , might be preferred in patients with COPD or PVD
  69. 69. Pharmacology of β₁-blockers* Selectivity for β₁- Receptors ISA α-Blockade Hepatic Metabolism T1/2 Atenolol + 0 0 0 6-7 Esmolol + 0 0 0 -1/4 Labetalol 0 + + 4 Metoprolol + 0 0 + 3-4 Propranolol 0 0 + 4-6 *IAS, Intrinsic sympathomimetic activity; +, mild effect; 0, no effect
  70. 70. Contd…  Patients with PVD could potentially have a ↓in blood flow if β₂-receptors, which dilate the arterioles, are blocked.  Many of β-blockers have some agonist activity; although they would not produce effects similar to full agonist(such as epinephrine)  Β-blockers with ISA may not be beneficial as β- blockers without ISA in treating patients with cardiovascular disease.
  71. 71. Esmolol  Ultrashort-acting selective β₁-antagonist that ↓HR, & to a lesser extent, BP  Successfully used to prevent tachycardia & hypertension in response to perioperative stimuli, such as intubation, surgical stimulation, & emergence.  For example, esmolol (0.5-1 mg/kg) attenuates the rise in BP & HR that usually accompanies ECT without significantly affecting seizure duration.
  72. 72. Contd…  Although esmolol is considered to be cardioselective, at higher doses it inhibits β₂-receptors in bronchial and vascular smooth muscle.  The short DOA is due to rapid redistribution (distribution half-life 2 min) & hydrolysis by RBC esterase (elimination half-life 9 min)  S/E can be reversed with in minutes by discontinuing its infusion  As with all β₁-antagonist, esmolol should be avoided in patients with sinus bradycardia, heart block >1⁰, cardiogenic shock, overt heart failure.
  73. 73. Contd… Dosing & Packing:  Short term therapy: Bolus (0.2-0.5 mg/kg), such as attenuating the cardiovascular response to laryngoscopy & intubation.  Long-term treatment: typically initiated with a loading dose of 0.5mg/kg administered over 1 min f/b a continuous infusion of 50μg/kg/min to maintain therapeutic effect.
  74. 74. Contd…  If this fail to produce sufficient response within 5 min, the loading dose may be repeated and the infusion ↑by increments of 50μg/kg/min every 5 min to a maximum 200μg/kg/min.  Multidose vials for bolus administration containing 10 ml of drug (10mg/ml)  Ampules for continuous infusion (2.5g in 10ml) also available but must be diluted prior to administration to a concentration of 10mg/ml.
  75. 75. Choice of inotrope Guided :  The expected need for inotropes  clinical evidence of depressed myocardial function  Empirical drug choice and titration, with careful hemodynamic monitoring
  76. 76. Predictive factors of inotropic support, as highlighted by several studies.  Low ejection fraction (< 45%)  History of congestive heart failure  Cardiomegaly  High LVEDP following ventriculogram  MI within 30 days of operation*  Older age (> 70 years)  Longer duration of aortic cross-clamping  Prolonged cardiopulmonary bypass*  Urgent operation  Re-operation*  Female gender*  Diabetes mellitus LVEDP = left ventricular end-diastolic pressure; MI = myocardial infarction. * statistical significance for coronary artery bypass surgery only.
  77. 77. Ideal positive inotrope  Enhance contractility without any significant increase in heart rate preload, afterload, and myocardial oxygen consumption.  Enhance the diastolic function  Maintain the diastolic coronary perfusion pressure and thus an adequate myocardial blood flow.  It finally should have rapid titration times and onset of action and a short half-life
  78. 78. Contd…  Catecholamines are the mainstay of current inotropic treatment  they can be divided into  more potent (epinephrine, isoproterenol, noradrenaline) and  milder (dopamine, dopexamine, dobutamine
  79. 79. Indications in specific settings Coronary artery bypass graft surgery:  In most cases, no or only mild inotrope requirement.  Inotropes may be needed in case of preexisting ventricular dysfunction or in case of unsuccessful revascularization if the intra-aortic balloon pump alone is not enough.  Emergency revascularization of acute myocardial infarction, dobutamine and PDE inhibitors.  Off-pump coronary artery bypass graft surgery (dopamine, dobutamine)
  80. 80. Contd… Chronic heart failure:  Combination therapy (i.e. a PDE inhibitor administered along with a beta-adrenergic inotrope, dobutamine or epinephrine) may therefore be the treatment of choice in these patients Diastolic dysfunction:  No inotropes at all (or inotropes with a better effect on ventricular relaxation, such as PDE inhibitors, if systolic dysfunction coexists)
  81. 81. Contd… Valvular surgery  Moderately severe aortic stenosis- Inotropic support is rarely needed  Chronic aortic insufficiency- Requiring adequate preload and inotropes  Mitral stenosis, chronic mitral regurgitation- Treatment with inotropes is warranted.  Acute aortic and mitral regurgitation- require aggressive inotropic support even preoperatively  Tricuspid regurgitation-Inotropes are beneficial
  82. 82. Contd… Orthotopic cardiac transplantation:  Routine inotropic support includes isoproterenol (to increase the automaticity, inotropism and pulmonary vasodilation) and dopamine (to add further support whilst maintaining the systemic perfusion pressures). Right ventricular dysfunction:  heart transplantation,  lung transplantation  pulmonary thromboendoarterectomy  left ventricular assist device implantation,  inadequate myocardial protection
  83. 83. Successful management Right ventricular afterload The contractile strength maintenance of the aortic blood pressure Pulmonary vasodilators inotropes : • dobutamine, •isoproterenol, • epinephrine, •PDE inhibitors Vasoconstrictors
  84. 84. Clinical Application 1st Line Agent 2nd Line Agent Septic Shock Norepinephrine Vasopressin Phenylephrine Epinephrine (Adrenalin) Heart Failure Dopamine Milrinone Dobutamine Cardiogenic Shock Norepinephrine Dobutamine Anaphylactic Shock Epinephrine (Adrenalin) Vasopressin Neurogenic Shock Phenylephrine Hypotension Anesthesia -induced Phenylephrine Following CABG Epinephrine
  85. 85. Summary  Understand appropriate clinical application of vasopressors and inotropic agents.  In hyperdynamic septic shock, norepinephrine or phenylephrine is first-line agent. Vasopressin as second-line agent to reduce need for other pressors.  In cardiogenic shock, norepinephrine is preferred initial agent. After establishing adequate perfusion, Dobutamine added.
  86. 86. Contd…  In anaphylactic shock, 1st line agent is Epinephrine followed by Vasopressin as second line agent.  Epinephrine is the 1st line agent in hypotension after CABG.  In both neurogenic shock and anesthesia-induced hypotension, Phenylephrine is the 1st line agent.
  87. 87. Thank You