Inotropic agents
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Inotropic agents
Dr Kirtan BhattKIMS
Bangalore
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Protocol • Introduction• Mechanism of cardiac contractility• General indications of inotropic agents• Inotropic agents
Cardiac glycosidesβ adrenergic agonists BipyridinesCalcium sensitizer
• Other drugs• Future prospects• Summary
• Sources and chemistry• Mechanism of action• Pharmacokinetics• Pharmacological effects• Uses• Adverse effects• Contraindications• Drug interactions
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What are inotropic agents?• Inotropic agents are the drugs that increase cardiac contractility by
increasing the force of contraction and also velocity of contraction.
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Mechanism of cardiac contractility
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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 output2. To distribute the blood flow appropriately3. To maintain blood pressure
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Cardiac glycosides (cardenolides)• Sir William Withering, 1785(English botanist and physician)• Purple foxglove plant (Digitalis purpurea)
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Sources and chemistry
Important cardiac glycosides
Source Glycoside Aglycone or genin
Digitalis purpurea(purple foxglove)
DigitoxinGitoxinGitalin
DigitoxigeninGitoxigeninGitaligenin
Digitalis lanata(white foxglove)
DigitoxinGitoxinDigoxin
DigitoxigeninGitoxigeninDigoxigenin
Strophanthus gratus Strophanthus-GOuabain
Strophanthus kombe Strophanthin-K
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• 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
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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)
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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)
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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
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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)
Dosesa) Digitalising dose
b) Maintenance dose
1mg in 24 hours or 0.4mg every 12 hours for total 3 doses orally0.1mg 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
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Pharmacological actions
Cardiac effectsIn a normal heart
increases the force of contractionConstriction of blood vesselsHR and CO unchanged
In heart failureIncreases the contractility and COSystole is shortened so that there is more time for ventricular fillingHR is reduced Decreases conduction velocity of AV node and His-Purkinje system and
prolongs their ERP (protection of ventricle from AF and AFl)
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• Sensitivity of different parts of heart to digitalisAV node > Atrial muscles > Purkinje fibres > Ventricles
• ECG changesProlongation of PR interval (delayed AV conduction)Shortening of QT interval (shorter ventricular systole)Depression of ST segmentInversion or disappearance of T wave
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Extracardiac effects• Blood vessels
In normal persons – direct vasoconstrictorIn heart failure – opposes compensatory sympathetic overactivity, decreases
HR, PVR and venous toneEffect on BP is secondary to improvement in circulation
• KidneyDiuresis due to improvement in renal perfusionDiuresis also due to decreased activity of RAAS
• GIT – anorexia, nausea, vomiting, diarrhea• CNS – disorientation, hallucinations, visual disturbances and
aberration in colour perception
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Therapeutic uses1. Congestive heart failure2. Paroxysmal supraventricular tachycardia3. Atrial flutter and atrial fibrillation4. Dilated heart
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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
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Contraindications 1. Hypokalemia2. Children <10 years and elderly3. Myocardial infarction4. Hypothyroidism5. Myocarditis 6. WPW syndrome
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Drug interactions• Decreased digitalis effects
a. Decreased absorption – antacids, sucralfate, neomycinb. Increased metabolism – enzyme inducers, phenytoin, phenobarbitonec. Hyperthyroidism increases renal clearanced. Cholestyramine decreases enterohepatic circulation
• Enhanced toxicitya. Decreased serum potassium – loop diuretics, thiazides, corticosteroidsb. Displace digitalis from protein binding sites – amiodarone, quinidine,
verapamil, tetracycline, erythromycinc. Calcium salts by synergistic actiond. Catecholamines and succinylcholine cause arrhythmias
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β adrenergic agonists
• Dobutamine• Dopamine• Dopexamine
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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
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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
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Pharmacological actions
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Therapeutic uses• Short term management of cardiac failure following surgery or MI• Cardiac stress testing (Noninvasive assessment of coronary artery
disease along with ECHO)
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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
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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
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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
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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 veinThe 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
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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)
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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
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Phosphodiesterase inhibitors (Bipyridine )
• Non-glycoside, non-sympathomimetic inotropic agent• Non-selective ------- aminophylline, theophylline Selective PDE-3 inhibitors ------- inamrinone, milrinone, enoximone,
inamrinone milrinone
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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
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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)
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Uses • Used only intravenously for acute heart failure or for acute
exacerbation of chronic heart failureInamrinone 0.75 mg/kg bolus given over 2-3 minutes followed by 2-20
μg/kg/minuteMilrinone 50 μg/kg followed by maintenance dose of 0.25-1 μg/kg/minute
• Patients awaiting cardiac transplant
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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• ArrhythmiasPrecautions• Severe aortic or pulmonary valve disease• HOCM• Monitor BP and HR during use• Platelet count and liver functions monitoring
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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
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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
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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
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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
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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
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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
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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)
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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