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Inotropes by elza

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inotropes

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Inotropes by elza

  1. 1. INOTROPES Dr. Elza Joy Munjely JR 1 Dpmt. of Pharmacology
  2. 2. • Cardiac glycosides: Digoxin • Catacholamines • Dopamine • Dobutamine • Epinephrine • Norepinephrene • Isoprenaline • Inotropic-vasodilator agents (inodilators) – Phosphodiesterase III inhibitors • Milrinone • Enoximone • Calcium sensitizers • Levosimendan
  3. 3. DIGOXIN • Unique combined inotropic-bradycardic action • Only inotrope approved in USA for oral use • MOA – Inhibition of Na-K ATPase Progressive accumulation of intracellular sod. Decrease in transmembrane Sod.gradient that drives the Sod. Calcium exchange less calcium is removed from the cell & more Ca is accumulated in the SR. Increased releasable calcium enhanced myocardial contractility. – Sinus slowing &AV nodal inhibition results from parasympathetic activation – Decreased renin release as digoxin decrease the activity of sodium pump with a natriuretic effect
  4. 4. PHARMACOKINETICS • Food delays absorption • oral Bioavailability – 70- 80 %,liquid filled capsules of digoxin has higher bioavailability than tabs • 10% of the population harbors the enteric bacterium Eubacterium lentum ,which inactivates digoxin which may account for drug tolerance • Also available for IV administration when oral dosing is inappropriate • 25% plasma protein bound • Lipid soluble & penetrates brain • Elimination t ½ :36 -48 hrs • Most of the drug is excreted unchanged by kidney,30% undergoes nonrenal clearance • Therapeutic serum digoxin level -0.5-1.4 nano gram/ml • Toxic serum digoxin level >2 nano grams/ml • Principal tissue reservoir is skeletal muscle & thus dosing should be based on estimated lean body mass
  5. 5. Drug interactions Phenobarbitone Phenytoin Enzyme induction Antacids Sucralfate neomycin absorption cholesteramine Enterohepatic circulation Digitalis effects
  6. 6. Drug interactions Diuretics steroids K+ levels Amiodarone Quinidine Verapamil Diltiazem captopril Displace binding From tissue protiens Ca2+ salts synergism Erythromycin Tetracycline omeprazole Digitalis toxicity Increase bioavailab ility Catecholamines Succinylcholine Increase arrhythmi as
  7. 7. USE • Chronic CHF with chronic atrial fibrillation • In chronic AF without heart failure, it is used- – Before cardioversion – In combination with verapamil,diltiazem & beta blocking drugs to ctl ventricular rate during exercise • In children as first line in CHF
  8. 8. DOSE • Initiated at .25mg daily • Loading dose of 0.5 mg three times daily sometimes in severely decompensated patients • Rapid digitalization now seldom used achieved by combination of intravenous digoxin 0.5 mg & oral digoxin 0.25mg to a total of 0.75 to 1mg.
  9. 9. Contraindication • Hypertrophic obstructive cardiomyopathy • WPW syndrome with AF • Significant AV nodal heart block • Diastolic dysfunction • Hypokalaemia • Renal failure • Thyrotoxicosis • Myxoedema • Severe myocarditis • Myocardial ischaemia • Ventricular tachycardia
  10. 10. ADRs • Narrow therapeutic index. • Therapeutic Plasma conc is 0.5 -1.4ng /ml • > 2ng/ml is toxic • Monitor plasma conc & ECG ,HR , Electrolytes
  11. 11. Cardiac ADRs • Bradycardia • C. Arrhythmia -↑automaticity partial or complete heart block atrial or ventricular extrasystole coupled beats( bigeminy) VF
  12. 12. Extra Cardiac ADR • GIT : Anorexia ,Nausea ,Vomiting, rarely diarrhoea • CNS :Head ache, Neuralgias Visual disturbance(yellow or green halos around lights), vertigo, Hallucinations, delusions • Misc : Gynaecomastia,fatigue,hypokalaemia
  13. 13. Management of Digoxin over dosage • Stop Digoxin • Stop Diuretics causing hypokalemia • Estimate serum K+: Mild to mod : Pot.salts 5g in div.dose, Oral Severe : Pot.chloride I/V 40mEq in 500ml of 5% glucose Pot.salts are CI if there is AV block
  14. 14. • V.arrhythmia : Lignocaine I/V • PSVT : Adenosine, Propranolol • AV block, Bradycardia : Atropine/ temporary pacemaker • Specific treatment : Digibind I/V antidote in severe cases
  15. 15. ACUTE INOTROPES SYMPATHOMIMETICS 1. Dopamine 2. Dobutamine 3. Dopexamine 4. Epinephrine (adrenaline) 5. Isoprenaline (isoproterenol) 6. Norepinephrine (noradrenaline)
  16. 16. ADRENERGIC RECEPTORS  Alpha1-adrenergic effects: • Vascular smooth muscle contraction- vasoconstriction  Alpha2-adrenergic effects: • Mediate sedation,analgesia & platelet aggregation
  17. 17. ALPHA ADRENORECEPTORS
  18. 18.  Beta1-adrenergic effects: o Direct cardiac effects • Inotropy (improved cardiac contractility) • Chronotropy (increased heart rate)  Beta2-adrenergic effects: • Vasodilation • Bronchodilation
  19. 19. BETA ADRENORECEPTORS β-1 adrenergic β-2 adrenergic
  20. 20. DOPAMINERGIC RECEPTORS • Present in renal ,splanchnic & coronary & cerebral vascular beds • Stimulation leads to vasodilatation • Second subtype of dopamine receptors causes vasoconstriction by norepinephrine release
  21. 21. Dopamine(DA)  Endogenous nonselective adrenergic and dopaminergic agonist  Clinical effects vary markedly with the dose. 1) Low dose: 2-5µg/kg/min  Activates dopaminergic receptors(specifically DA₁)  Vasodilation of renal vasculature and promotes diuresis and natriuresis
  22. 22. Contd… 2) Moderate dose: 5-10 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.
  23. 23. 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.
  24. 24. 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  ↓LV filling pressure, whereas ↑coronary blood flow(CBF)
  25. 25. Contd…  Favorable effects on myocardial O₂ balance makes dobutamine a choice for patients with the combination of CHF & CAD, particularly if PVR is elevated.  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
  26. 26. Contd… Dosing & Packing:  Infusion @ 2-15 µg/kg/min  Supplied in 5-ml (50 mg/ml) ampules containing 250 mg
  27. 27. Dopexamine  Structural analogue of DA  Because of ↓β-adrenergic effects & its specific effects on renal perfusion, it may advantage over dobutamine  Clinically available in many countries since 1990, but it has not gained widespread acceptance in practice
  28. 28. 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.
  29. 29. 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)  SBP rises  β₂- stimulation also relaxes bronchial smooth muscle
  30. 30. 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)
  31. 31. 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
  32. 32. 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
  33. 33. Contd… Common contraindication:  Hypertension.  Pheochromocytoma.  Caution with heart failure angina and hyperthyroidism.
  34. 34. 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, makes isoproterenol poor inotropic choice in most situations
  35. 35. Contd…  Causes inotropy, chronotropy, and systemic and pulmonary vasodilatation.  Indications: bradycardia, decreased CO, bronchospasm (bronchodilator).
  36. 36. 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  Supplied in 1-ml (2 mg/ml) ampules containing 2 mg
  37. 37. 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.
  38. 38. 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:  Dose infusion-0.01 -0.03;max.-0.1 mcg/kg/min  Ampules contain 2 mg of norepinephrine in 4 ml
  39. 39. INODILATORS PHOSPHODIESTERASE III INHIBITORS • MOA:inhibit the breakdown of cAMP in cardiac & vascular smooth muscle which leads to augmented myocardial contractility & periferal & venous vasodilatation • Amrinone • Milrinone • Enoximone • Piroximone
  40. 40. Milrinone • Approved for IV use in US & UK • Indications:Acute heart failure • Dose:Slow IV injection over 10 minutes diluted before use,50 mcg/kg,followed by IV infusion rate of 0.375- 0.750mcg/kg/min usually up to 12 hours following surgery or 48 hrs in acute heart failure , max dose:1.13mcg/kg • CI:Acute MI,hypertrophic obstructive subaortic stenosis, • No or few ADR
  41. 41. ENOXIMONE • Available for IV use in UK, • Dose:loading dose 90 mcg/kg/min over 10-30 min,then 5-20 mcg/kg/min • Indication A/c heart failure,patients awaiting transplantation • ADR:Nausea , Vomiting , Arrhythmias Thrombocytopenia Liver enzyme changes
  42. 42. 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.
  43. 43. 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.
  44. 44. 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
  45. 45. 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.
  46. 46. Contd… Adverse effects: Common adverse drug reactions (≥1% of patients) include:  Headache,  Hypotension,  Arrhythmias (AF, extrasystoles, atrial tachycardia, VT),  Myocardial ischaemia,  Hypokalaemia,  Nausea.
  47. 47. 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
  48. 48. THANKYOU

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