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 Bipyridine s 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: To increase to cardiac output To distribute the blood flow appropriately 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)

10. Pharmacokinetics Oral bioavailability of most digoxin tablets is 70-80% Large aVd (4-7 L/kg) and mainly distributed into skeletal muscles Elimination t 1/2 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)

11. 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

12. Pharmacokinetics Parameters Digitoxin 1 Digoxin 1 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) Excretion Mainly bile, also urine Urine (unchanged) Urine (unchanged) Doses 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 8 th hourly for total 3 doses 0.25-0.5mg per day 0.2-0.5mg IV in case of acute heart failure

13. 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 )

14. 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

15. 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

16. Therapeutic uses Congestive heart failure Paroxysmal supraventricular tachycardia Atrial flutter and atrial fibrillation Dilated heart

17. Adverse effects and toxicity Cardiac side effects Arrhythmias GI side effects – anorexia, nausea, vomiting, diarrhea, abdominal cramps CNS – headache, fatigue, neuralgia, blurred vision, loss of colour perception Endocrinal - gynecomastia

18. Contraindications Hypokalemia Children <10 years and elderly Myocardial infarction Hypothyroidism Myocarditis WPW syndrome

19. Drug interactions Decreased digitalis effects Decreased absorption – antacids, sucralfate , neomycin Increased metabolism – enzyme inducers, phenytoin, phenobarbitone Hyperthyroidism increases renal clearance Cholestyramine decreases enterohepatic circulation Enhanced toxicity Decreased serum potassium – loop diuretics, thiazides, corticosteroids Displace digitalis from protein binding sites – amiodarone , quinidine, verapamil, tetracycline, erythromycin Calcium salts by synergistic action Catecholamines and succinylcholine cause arrhythmias

20. β adrenergic agonists Dobutamine Dopamine D opexamine

21. Dobutamine Used clinically as a racemic mixture of 2 enantiomers l form – potent agonist at α 1 d form – potent α 1 antagonist, agonist at β 1 Net effect is β 1 agonistic action Structurally similar to dopamine, but doesn’t have actions on dopamine receptors

22. Pharmacokinetics Inactive when given orally, usually given IV t 1/2 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

23. Pharmacological actions

24. Therapeutic uses Short term management of cardiac failure following surgery or MI Cardiac stress testing (Noninvasive assessment of coronary artery disease along with ECHO)

25. 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

26. 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

27. Cardiovascular effects At low therapeutic dose (2-5 μ g/kg/min IV), it reacts with vascular D 1 receptors, especially in renal, mesenteric and coronary vasculature and produce increase in GFR, renal blood flow and Na excretion At 5-10 μ g/kg/min, it also stimulates β 1 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 μ g/kg/min ) it can cause vasoconstriction by α 1 receptors

28. Therapeutic uses Conditions with low CO with compromised renal functions P atient should be under intensive care with monitoring of arterial and venous pressures and ECG and also urine output. I t is given intravenously, preferably into a large vein T he 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

29. 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)

30. Dopexamine Synthetic analog related to dopamine with intrinsic activity at D 1 and D 2 receptors and also at β 2 receptors Favourable hemodynamic effects in severe CHF

31. Phosphodiesterase inhibitors ( Bipyridine ) Non-glycoside, non-sympathomimetic inotropic agent Non-selective ------- aminophylline, theophylline Selective PDE-3 inhibitors ------- inamrinone , milrinone , enoximone , inamrinone milrinone

32. 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

33. 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 )

34. 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 μ g/kg/minute Milrinone 50 μ g/kg followed by maintenance dose of 0.25-1 μ g/kg/minute Patients awaiting cardiac transplant

35. 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

36. 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

37. 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

38. 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

39. Istaroxime Investigational drug which is a steroid derivative Increases the contractility by inhibiting Na + -K + -ATPase I n addition also facilitates sequestration of calcium by SR, hence having lesser arrhythmogenic potential than digoxin I n phase 2 trials

40. 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

41. 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

42. 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)

43. 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