Inotropic agents

Dr Kirtan BhattKIMS

Bangalore

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

What are inotropic agents?• Inotropic agents are the drugs that increase cardiac contractility by

increasing the force of contraction and also velocity of contraction.

Mechanism of cardiac contractility

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

Cardiac glycosides (cardenolides)• Sir William Withering, 1785(English botanist and physician)• Purple foxglove plant (Digitalis purpurea)

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

• 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

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)

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)

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

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

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)

• 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

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

Therapeutic uses1. Congestive heart failure2. Paroxysmal supraventricular tachycardia3. Atrial flutter and atrial fibrillation4. Dilated heart

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

Contraindications 1. Hypokalemia2. Children <10 years and elderly3. Myocardial infarction4. Hypothyroidism5. Myocarditis 6. WPW syndrome

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

β adrenergic agonists

• Dobutamine• Dopamine• Dopexamine

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

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

Pharmacological actions

Therapeutic uses• Short term management of cardiac failure following surgery or MI• Cardiac stress testing (Noninvasive assessment of coronary artery

disease along with ECHO)

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

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

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

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

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)

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

Phosphodiesterase inhibitors (Bipyridine )

• Non-glycoside, non-sympathomimetic inotropic agent• Non-selective ------- aminophylline, theophylline Selective PDE-3 inhibitors ------- inamrinone, milrinone, enoximone,

inamrinone milrinone

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

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)

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

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

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

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

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

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

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

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

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)

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