21.Inotropic Drugs

• Inotropic drugs

Dr S A Jayaratne Dept of Pharmacology

Inotropes• Cardiac glycosides (steroid inotropes)

• Was first discovered by Sir William Withering

• Crude digitalis is the extract of dried leaf of the foxglove plant (Digitalis purpurea)

• Digitalis has several active glycosides which include digoxin & lanatosides

• Digoxin is the most important therapeutically

• Yellow oleander (thevetia peruviana) &

Nerium oleander

• All parts(leaves,flowers,stems & woody

trunks) of these plants are poisonous

• They contain cardiac toxins (cardiac

glycosides)

Mechanism of action

• Direct

• Indirect

Mechanism of action-direct

Inhibits membrane bound enzyme sodium-potassium

adenosine triphosphatase (Na+/K+ATPase). This

enzyme supply energy for the system that pumps Na+

+ out & K+into contracting& conducting tissues

Increase con: of Na,+ slow the rate of extrusion of

Ca++via Na+/Ca++ Reduce the exchange of extraellular

Na+ with intracellular ca++

Mechanism of action-direct contd--

Increases the intracellular concentration of Ca+

+

Increased Ca++ facilitates myocardial

contraction resulting in a positive inotropic

effect

Mechanism of action-indirect

• Enhances vagal activity via an action on the

central nervous system and diminishes

sympathetic activity

• Slows discharge at the SA node and delays

conduction through the AV node

Digoxin- Pharmacokinetics

Administered orally – variable absorption (iv infusion –rarely)

Plasma half life of 36-48 hours (normal renal function prolonged in renal

failure & elderly)Maintenance dose administered once daily

85% is eliminated unchanged by the kidney15% is metabolised by the liver

Clinical indications

1) Treatment of heart failure• increase contractility• Is useful in heart failure associated with sinus

rhythm • Also useful in heart failure associated with

atrial fibrillation

Clinical indications contd--

2) Treatment of atrial fibrillation Slow AV conduction by increasing vagal

activity. Increasing the refractory period of the AV

node increase the interval between impulses & reduce the ventricular rate Atrial dysarrhythmia is uneffected

Clinical indications contd--

3) Converts atrial flutter to atrial fibrillation

Increase vagal activity shorten the refractory

period of the atrial muscle so that flutter is

converted to fibrillation

Adverse effects

Adverse effects related to –

• Plasma concentration

• Sensitivity of myocardium & conducting

system to digoxin

Adverse effects contd--• GIT - anorexia, nausea, vomiting, diarrhoea Nausea precedes vomiting and is a warning that

dosage is excessive• Abnormal cardiac rhythm ventricular ectopic beats, ventricular

tachyarrythmias, paroxysmal supraventricular tachycardia

• Visual effects-disturbances of colour vision(yellow red or green colour)

Adverse effects contd--

• Gynaecomastia in men & breast enlargement

in females (long term use)

• Mental effects-confusion, restlessness,

agitation & nightmares, acute psychosis

Digoxin Toxicity

• Potential for development of toxic effects is increased in-

• In renal failure dose should be reduced• Elderly

• Hypothyroidism-intolerant of digoxin• Hypokalaemia• Hypomagnesaemia

Acute digoxin toxicity

Symptoms:- nausea & vomiting hyperkalaemia sinus arrhythmia, bradycardia ectopic rhythms

Treatment of digoxin overdose

• Immediately discontinue digoxin• Monitor & maintain the serum potassium level

• Administration of digoxin specific binding (Fab) digoxin specific binding fragment

• IV phenytoin for ventricular arrhythmias• IV atropine for bradycardia

Other inotropic drugs (non steroid inotropes) (cardiac stimulants)

• Sympathomimetics: Beta-1 adrenoceptor

stimulants such as dobutamine and dopamine

• since they increase cardiac contractility and

cause some vasodilation.

• .

Mechanism of action

• Acts on 1 adrenoceptor in the myocardium– increases myocardial contractility and heart

rate Activation of adrenoceptors

results in vasoconstriction

Clinical uses

• Used in the treatment of Cardiogenic shock –post myocardial infarction or – following cardiac surgery

Phosphodiesterase inhibitors• These drugs cause an increase in cylic AMP by

inhibiting cardiac phosphodiesterase.

• The increase in cAMP results in an increase in transmembrane calcium flux

• a secondary increase in cardiac contractility.

• Amrinone, milrinone -withdrawn in certain countries

• Not used in Sri-lanka