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

24. Pharmacological actions

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