Inotropic agents
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Inotropic agents work by increasing the force and velocity of cardiac muscle contraction. They are used to improve myocardial function and support circulation in heart failure. Common inotropic agents include cardiac glycosides like digoxin which inhibit Na+-K+-ATPase, beta-adrenergic agonists like dobutamine which stimulate beta-1 receptors, and phosphodiesterase inhibitors like milrinone which increase cAMP levels. While inotropes can provide short-term hemodynamic support, long-term use does not improve survival and may increase mortality in heart failure patients.
Inotropic agents
- 1. Inotropic agents Dr Kirtan Bhatt KIMS Bangalore
- 2. Protocol • Introduction • Mechanism of cardiac contractility • General indications of inotropic agents • Inotropic agents Cardiac glycosides β adrenergic agonists Bipyridines Calcium sensitizer • Other drugs • Future prospects • Summary • Sources and chemistry • Mechanism of action • Pharmacokinetics • Pharmacological effects • Uses • Adverse effects • Contraindications • Drug interactions
- 3. What are inotropic agents? • Inotropic agents are the drugs that increase cardiac contractility by increasing the force of contraction and also velocity of contraction.
- 4. Mechanism of cardiac contractility
- 5. General indications of inotropic agents • As positive inotropic agents increase myocardial contractility, they are used when myocardial function needs to be improved and/or, to support a failing circulation. • The objectives of management in a patient with poor tissue perfusion: 1. To increase to cardiac output 2. To distribute the blood flow appropriately 3. To maintain blood pressure
- 6. Cardiac glycosides (cardenolides) • Sir William Withering, 1785(English botanist and physician) • Purple foxglove plant (Digitalis purpurea)
- 7. Sources and chemistry Important cardiac glycosides Source Glycoside Aglycone or genin Digitalis purpurea (purple foxglove) Digitoxin Gitoxin Gitalin Digitoxigenin Gitoxigenin Gitaligenin Digitalis lanata (white foxglove) Digitoxin Gitoxin Digoxin Digitoxigenin Gitoxigenin Digoxigenin Strophanthus gratus Strophanthus-G Ouabain Strophanthus kombe Strophanthin-K
- 8. • A sugar molecule joined together with a non-sugar molecule by an ether linkage is called a glycoside. • In a cardiac glycoside, the sugar part is 1-4 molecules of digitoxose and non-sugar part is a steroidal lactone • Non-sugar part ------- pharmacological activity sugar part ------------- pharmacokinetic activity
- 9. Mechanism of action Binds reversibly to Na+-K+-ATPase and inhibits it. Progressive accumulation of Na inside the cell and loss of intracellular K Influx of Ca and efflux of Na through NCX (there is also increase in Ca permeability through voltage sensitive L-type Ca channels during plateau phase)
- 11. Pharmacokinetics • Oral bioavailability of most digoxin tablets is 70-80% • Large aVd (4-7 L/kg) and mainly distributed into skeletal muscles • Elimination t1/2 is 36-48 hours (once daily dosing) and steady state plasma concentration is reached in 7 days • Excreted by kidney (increase in CO and renal blood flow may increase its clearance)
- 12. Pharmacokinetics (cont.) • aVd and clearance are reduced in the elderly • Liquid filled capsules (Lanoxicaps) have a higher BA than tablets (Lanoxin) • 10% population have Eubacterium lentum in the intestine, which inactivates digoxin tolerance • IM/SC absorption – severe irritation and poor absorption • Maximal increase in contractility is seen at serum levels of 1.4 ng/mL; higher serum concentration are reported to increase mortality rates
- 13. Pharmacokinetics Parameters Digitoxin1 Digoxin1 Ouabain Oral absorption 95-100% 75-90% Nil Administration Oral Oral IV aVd (L/kg) 0.6 6-7 18 Protein binding 90 30 Nil Plasma half-life 6-7 days 38-40 hours 18-20 hours Onset of action 2 hours ½ hour Very rapid (given IV) Duration of action Very long Intermediate Short Metabolised (%) 80 (liver) 2 20 (liver) 0 Excretion Mainly bile, also urine Urine (unchanged) Urine (unchanged) Doses a) Digitalising dose b) Maintenance dose 1mg in 24 hours or 0.4mg every 12 hours for total 3 doses orally 0.1mg once daily 0.5-0.75mg 8th hourly for total 3 doses 0.25-0.5mg per day 0.2-0.5mg IV in case of acute heart failure
- 14. Pharmacological actions Cardiac effects In a normal heart increases the force of contraction Constriction of blood vessels HR and CO unchanged In heart failure Increases the contractility and CO Systole is shortened so that there is more time for ventricular filling HR is reduced Decreases conduction velocity of AV node and His-Purkinje system and prolongs their ERP (protection of ventricle from AF and AFl)
- 15. • Sensitivity of different parts of heart to digitalis AV node > Atrial muscles > Purkinje fibres > Ventricles • ECG changes Prolongation of PR interval (delayed AV conduction) Shortening of QT interval (shorter ventricular systole) Depression of ST segment Inversion or disappearance of T wave
- 16. Extracardiac effects • Blood vessels In normal persons – direct vasoconstrictor In heart failure – opposes compensatory sympathetic overactivity, decreases HR, PVR and venous tone Effect on BP is secondary to improvement in circulation • Kidney Diuresis due to improvement in renal perfusion Diuresis also due to decreased activity of RAAS • GIT – anorexia, nausea, vomiting, diarrhea • CNS – disorientation, hallucinations, visual disturbances and aberration in colour perception
- 17. Therapeutic uses 1. Congestive heart failure 2. Paroxysmal supraventricular tachycardia 3. Atrial flutter and atrial fibrillation 4. Dilated heart
- 18. Adverse effects and toxicity • Cardiac side effects 1. Arrhythmias • GI side effects – anorexia, nausea, vomiting, diarrhea, abdominal cramps • CNS – headache, fatigue, neuralgia, blurred vision, loss of colour perception • Endocrinal - gynecomastia
- 19. Contraindications 1. Hypokalemia 2. Children <10 years and elderly 3. Myocardial infarction 4. Hypothyroidism 5. Myocarditis 6. WPW syndrome
- 20. Drug interactions • Decreased digitalis effects a. Decreased absorption – antacids, sucralfate, neomycin b. Increased metabolism – enzyme inducers, phenytoin, phenobarbitone c. Hyperthyroidism increases renal clearance d. Cholestyramine decreases enterohepatic circulation • Enhanced toxicity a. Decreased serum potassium – loop diuretics, thiazides, corticosteroids b. Displace digitalis from protein binding sites – amiodarone, quinidine, verapamil, tetracycline, erythromycin c. Calcium salts by synergistic action d. Catecholamines and succinylcholine cause arrhythmias
- 21. β adrenergic agonists • Dobutamine • Dopamine • Dopexamine
- 22. Dobutamine • Used clinically as a racemic mixture of 2 enantiomers • l form – potent agonist at α1 d form – potent α1 antagonist, agonist at β1 • Net effect is β1 agonistic action • Structurally similar to dopamine, but doesn’t have actions on dopamine receptors
- 23. Pharmacokinetics • Inactive when given orally, usually given IV • t1/2 is 2 minutes and the steady state plasma concentration is achieved in 10-12 minutes • Conjugates of dobutamine and its major metabolized 3-O- methyldobutamine are excreted primarily in urine and small amounts in faeces
- 25. Therapeutic uses • Short term management of cardiac failure following surgery or MI • Cardiac stress testing (Noninvasive assessment of coronary artery disease along with ECHO)
- 26. Adverse effects • Sharp rise in BP and heart rate in some patients, especially in those with history of hypertension • Increase in oxygen demand and precipitation of angina or aggravation of myocardial infarction • Ventricular ectopic activity • Tolerance on prolonged use
- 27. Dopamine • 3,4-dihydroxyphenylethylamine • Endogenous catecholamine and immediate precursor of norepinephrine and epinephrine • It differs from NE and E by absence of –OH group at β carbon atom side chain • Important neurotransmitter, doesn’t cross BBB
- 28. Cardiovascular effects • At low therapeutic dose (2-5 μg/kg/min IV), it reacts with vascular D1 receptors, especially in renal, mesenteric and coronary vasculature and produce increase in GFR, renal blood flow and Na excretion • At 5-10 μg/kg/min, it also stimulates β1 receptors causing increasing cardiac output but the PVR and MAP are unchanged due to simultaneous dilation of renal and splanchnic vessels • At still higher doses (>10 μg/kg/min) it can cause vasoconstriction by α1 receptors
- 29. Therapeutic uses • Conditions with low CO with compromised renal functions Patient should be under intensive care with monitoring of arterial and venous pressures and ECG and also urine output. It is given intravenously, preferably into a large vein The use of a calibrated infusion pump is necessary to control the rate of flow. Indications for slowing down the infusion or terminating – reduction in urine output, tachycardia, arrhythmias
- 30. Adverse effects • Ischemic necrosis and sloughing of surrounding tissue if it extravasates (rarely, gangrene of fingers or toes on prolonged administration) • Overdosage – excessive sympathomimetic activity • Nausea, vomiting, tachycardia, ectopic beats, hypertension (in high doses) • Arrhythmias (rarely)
- 31. Dopexamine • Synthetic analog related to dopamine with intrinsic activity at D1 and D2 receptors and also at β2 receptors • Favourable hemodynamic effects in severe CHF
- 32. Phosphodiesterase inhibitors (Bipyridine) • Non-glycoside, non-sympathomimetic inotropic agent • Non-selective ------- aminophylline, theophylline Selective PDE-3 inhibitors ------- inamrinone, milrinone, enoximone, inamrinone milrinone
- 33. Mechanism of action • Inhibit of phosphodiesterase-3 enzyme and prevent degradation of cAMP increased calcium influx increased contractility • Also a balanced arterial and venous dilation (hence called inodilators) causing fall in PVR and left and right ventricular filling pressures • Levosimendan, in addition to above mechanisms, is also a calcium sensitizer for cardiac smooth muscle
- 34. Pharmacokinetics Parameter Inamrinone Milrinone Bioavailability ---- 100% (as IV bolus, infusion) aVd (L/kg) 1.3 0.4-0.5 Protein binding 10-49% 70-80% Metabolism Hepatic Hepatic (12%) Half-life 2-4 hours 2-3 hours Excretion Renal (63%) and faeces (18%) Urine (85% unchanged in 24 hours)
- 35. Uses • Used only intravenously for acute heart failure or for acute exacerbation of chronic heart failure Inamrinone 0.75 mg/kg bolus given over 2-3 minutes followed by 2-20 μg/kg/minute Milrinone 50 μg/kg followed by maintenance dose of 0.25-1 μg/kg/minute • Patients awaiting cardiac transplant
- 36. Adverse effects of inamrinone • Nausea, vomiting • Dose dependent thrombocytopenia • Hepatotoxicity, especially with long term oral administration • Headache, fever, chest pain, nail discoloration, decreased tear production • Local pain and burning at site of IV injection • Arrhythmias Precautions • Severe aortic or pulmonary valve disease • HOCM • Monitor BP and HR during use • Platelet count and liver functions monitoring
- 37. Adverse effects of milrinone • Can potentiate arrhythmias occurring in heart failure • Headache, tremors • Angina like chest pain • Prolonged oral use is associated with increased mortality
- 38. Levosimendan • Levosimendan is a calcium sensitizer (may also inhibit PDE-3 at higher doses) • It enhances myofilament responsiveness to calcium by binding to cardiac troponin C, thus prolonging the duration of actin-myosin overlap without increasing the intracellular calcium concentration • This binding to troponin C depends on Ca concentration • It also causes vasodilation by activation of ATP dependent potassium channels in smooth muscles of blood vessels • No increase in myocardial oxygen demand
- 39. Glucagon • Glucagon exerts inotropic effects through cAMP • It increases myocardial contractility, thereby increasing CO and BP and reducing PVR • Can be used when digitalization is dangerous (following MI when giving digitalis can lead to arrhythmias) • Can be used in combination with other more potent inotropes, thereby reducing their dose and reducing their side effects
- 41. Istaroxime • Investigational drug which is a steroid derivative • Increases the contractility by inhibiting Na+-K+-ATPase • In addition also facilitates sequestration of calcium by SR, hence having lesser arrhythmogenic potential than digoxin • In phase 2 trials
- 42. Omecantiv mecarbil • Selective cardiac myosin activator • It stimulates myosin-ATPase and increase fractional shortening of myocytes without increasing intracellular calcium • The increase in myocyte shortening is associated with an increase in time-to-peak contraction with unaltered velocity of contraction. • Clinical trials are on after it proved to be useful in preclinical studies
- 43. Nitroxyl (HNO) • Protonated analogoue of NO • Mechanism of action independent of cAMP/protein kinase A (PKA) signalling, with no modification of L-type calcium channel activity, and related to modification of specific cysteine residues on either phospholamban and/or SERCA2a, resulting in augmented SR calcium uptake. • Early in vitro experiments suggested positive inotropic and lusitropic properties of HNO, while subsequent studies in healthy and heart failure dog models demonstrated significant improvements in load- independent LV contractility, associated with reductions in pre-load volume and diastolic pressure
- 44. Ryanodine receptor stabilizers • Abnormal leak of calcium through RyR not only increases the availability of Ca for contraction, but also affects the diastolic function • Moreover, it can also trigger arrhythmias • JTV519, a 1,4-benzothiazepine, was one of the first compounds that restored abnormal RyR function and preserved contractile performance in heart failure models. • In addition, JTV519 improved diastolic and systolic function in isolated myocardium from failing human hearts. • Subsequently, agents that specifically act on cardiac RyRs have been developed, including S44121. (in phase 2 trials)
- 45. Summary • Although inotropic agents improve functional status in CHF, long term benefit on mortality is questionable • In fact, some drugs have shown to increase mortality • At present digoxin remains the only oral inotropic agent available for management of CHF
Editor's Notes
- #5: SERCA maintains free cytosolic Ca at low levels during diastole SERCA is normally inhibited by phospholamban
- #6: Primarily to cerebral and coronary blood vessels, and also to mesenteric and renal To maintain adequate perfusion to cerebral and coronary arteries.
- #7: He noticed that a person with dropsy (swelling from congestive heart failure) improved remarkably after taking a traditional herbal remedy
- #8: Also from toad skin - Bufotoxin
- #9: Steroid nucleus linked to a lactone ring at 17 position and a series of sugars at carbon 3. They lack an easily ionizable group, hence their solubility is not pH dependent
- #14: These digitalis preparations have a cumulative effects Undergoes entero-hepatic circulation which increases the t1/2 10% population has enteric bacteria that inactivates digoxin
- #17: Vomiting due to CTZ stimulation
- #18: Should be given slow IV in patient in whom oral administration is not feasible. Avoid extravasation
- #19: Any arrhythmia during digoxin therapy should be assumed to be due to drug until proved otherwise
- #26: It augments myocardial contractility and promotes coronary and systemic vasodil.this causes increased HR and myocardial work and can reveal ischemia in myocardium
- #29: D1 receptor is associated with stimulation of adenylyl cyclase and produce smooth muscle relaxation by cAMP accumulation in smooth muscle.
- #30: Correct hypovolemia before giving dopamine It improves perfusion to kidneys in case of oliguria
- #31: Dose adjustments required if the patient is on MAO inhibitors or TCAs.
- #36: These drugs are unstable in dextrose so have to be given with NS
- #39: It binds to troponin C depending on the actual calcium concentration. This may result in drug binding only during high systolic calcium levels but not during diastole when calcium is low. By this on–off mechanism, levosimendan may increase calcium sensitivity only during systole without impairing diastolic relaxation
- #43: Alters the rate of transition of myosin from a low-actin-binding state to a strongly actin-bound force generating state.
- #45: In addition to RyR stabilization, JTV519 has inhibitor properties on L-type calcium channels, potassium channels, and possibly other transporters.