This page intentionally left blank r r e e t t p p a CChh 4.1 1.4 Cardiotonics Pharmacodynamics (Cardiac Glycosides) (Mode of Action of Drugs) Congestive heart failure (CHF) is a clinical syndrome with multiple causes and involve the right or left ventricle or both and in CHF, cardiac output is usually below the normal range This ventricular dysfunction may be systolic, which leads to inadequate force generation to eject blood normally and diastolic, which leads to inadequate relaxation to permit normal filling Systolic dysfunction, with decreased cardiac output and significantly reduced ejection fraction is typical of acute heart failure, especially that resulting from myocardial infarction CARDIAC GLYCOSIDES There are the drugs having cardiac inotropic property They increase myocardial contractility and cardiac output in a hypodynamic heart without increase in oxygen consumption and overall myocardial efficiency is increased The cardiac glycosides are mainly obtained from plants e.g digitalis, stropanthus and squill species and also present in certain other plants and animals In 1776, William Withering, a Birmingham physician and botanist identified digitalis and other ingredients, which was found useful in the treatment of dropsy In 1911, Mackenzie and Cushney studied the effect of digitalis on heart and its use in congestive heart failure The important cardiac glycosides are listed in table 4.1.1 Pharmacological Actions Effect on Heart Contractility: Digitalis increases the force of myocardial contraction without causing corresponding increase in the oxygen consumption This pharmacological action forms the basis of its use in treatment of CHF In a patient of CHF, force of contraction of the heart at a given fibre length is decreased, thus the stroke volume is decreased As digitalis increases the force of contraction of the heart and subsequently, it increases the cardiac output, increase in circulating velocity, residual volume is decreased, diastolic volume is decreased and size of heart is decreased but these effects are noticed secondary to increase in 170 Section 4/ Drugs Acting on Cardiovascular & Urinary System Table 4.1.1: Classification of cardiac glycosides I Natural glycosides Digitoxin (DIGITALIN) Digoxin (LANOXIN) Lanatoside-C (CEDILANID) Stropanthin-K (STROPHOSID) Stropanthin-G (OVABAIN) Proscillaridin-A Cavallotoxin Thevetin Bufotoxin II Semisynthetic Acetyl digoxin (ACYLANID) Desacetyl lanatoside-C (DESLANOSIDE) Acetyl stropanthidin (diagnostic use) 0.05-0.2 mg/day 0.125-0.5 mg/day oral 0.25-1.0 mg slow IV 0.25-1.0 mg/day 0.25-0.5 mg IV 0.25-0.5 mg IV 0.3-1.0 ml (Tr Scilla) 0.2-0.5 mg/day oral/IV 0.25-1 mg IV 0.25 mg IV contractility and are not the primary effects of digitalis sympathetic tone and thus reducing the heart rate Cardiac output: Digitalis increases the cardiac output in CHF patients by increasing the force of myocardial contraction It also increases the contractility of normal heart but cardiac output remains unchanged or is slightly decreased In normal individuals, it increases the tone of arteries as well as that of the veins Refractory period: It is a period after onset of depolarization during which a stimulus can not evoke a propagated action potential In atrium, refractory period is shortened by vagal action and increased by direct action Heart rate: In CHF patients, the heart rate is decreased Digitalis produce a decrease in heart rate by stimulation of vagus The ‘vagal effect’ is probably evoked by sensitization of carotid baroreceptors, and by direct stimulation of vagal centre The vagal action can be blocked by atropine but after full digitalising dose the effect can not be blocked by atropine and it is due to its direct cardiac action In CHF patients, the sympathetic activity is increased as a compensatory phenomenon which leads to tachycardia Digitalis decreases the SA node: Digitalis sensitizes the SA node to normal vagal impulse resulting in bradycardia In a patient suffering from paroxysmal supraventricular tachycardia, it decreases the heart rate due to vagal action on SA node which is associated with decrease in the slope of slow diastolic depolarisation and increase in the transmembrane negativity and, also lower the SA rate by antiadrenergic action Automaticity: It is the ability to generate propagated impulse Digitalis increases the ability of the Purkinje cell and the ventricular muscle to initiate impulses Conductivity: Conduction through AV node is depressed whereas conduction is slightly increased in the auricle and ventricles Cardiotonics (Cardiac Glycosides) 171 ECG changes: Digitalis, in therapeutic doses causes inversion of T wave, sagging of S-T segment and shortening of Q-T internal (shortening of systole) In toxic dose, it causes prolongation of P-R interval (slowing of AV conduction), atrial arrhythmias (atrial tachycardia and atrial fibrillation) with AV block and ventricular arrhythmias may probably explain reversal of toxic effects of digitalis by potassium Inhibition of the Na+ K+-ATPase leads to increase in intracellular sodium and decrease in potassium Extracardiac Actions Digitalis also exerts some indirect action on heart mainly by increase in vagal activity which ultimately influences activity of AV node, SA node and auricles • Digitalis produces diuresis in CHF patients, it increases excretion of sodium and water by the kidney which may be due to decrease in the venous pressure bringing about shifting of edema fluid into the circulation and also improves the renal circulation • Digitalis can produce nausea and vomiting which is probably due to the chemoreceptor trigger zone (CTZ) stimulation • Digitalis has mild vasoconstrictor action increasing the peripheral resistance But in CHF patients peripheral resistance decreases due to withdrawal of reflex sympathetic overactivity Venous tone improves in normal as well as CHF patients It has no significant effect on coronary circulation Mechanism of Action of Digitalis Digitalis acts by interfering with the sodium and potassium transport across the cell membrane and by increasing the amount of coupling calcium i.e making more calcium available for excitationcontraction coupling Cardiac glycosides inhibit Na + K + ATPase by competing with potassium and Calcium also forms a link between the electrical events in the membrane and contractile proteins Digitalis makes more calcium available for excitation-contraction coupling and increasing cardiac contractility Pharmacokinetics Among the cardiac glycosides, digitoxin is absorbed rapidly and completely from the gastrointestinal tract with oral absorption of approximately 90 to 100 percent with plasma protein binding of approx 95 percent with plasma half life of to days It enters the liver cells where it is metabolised to epidigitoxigenin and is excreted in bile and urine Adverse Effects It includes anorexia, vomiting which may be of central origin Headache, visual disturbance, xanthopsia (yellow vision), white vision, diplopia, drowsiness, disorientation, delirium and psychotic behaviour Cardiac related effects include cardiac arrhythmias e.g tachyarrhythmias, ventricular arrhythmias, supraventricular arrhythmia, AV block and bradycardia Treatment of Digitalis Induced Arrhythmias Tachyarrhythmias K+ tends to antagonise digitalis induced enhanced automaticity and decreases bind- 172 Section 4/ Drugs Acting on Cardiovascular & Urinary System ing of the cardiac glycosides to Na+ K+-ATPase Infuse KCl 20 mmol/hr intravenously or orally depending upon the case and is equal to the amount eliminated during the day Methods of Digitalization Supraventricular Arrhythmias Can be treated by beta blockers e.g propranolol 10-40 mg every hourly orally or 0.5-1 mg IV Ventricular Arrhythmias Lignocaine (1-2 mg/kg IV) is the drug of choice Phenytoin is also useful (250 mg IV) and has the added advantage of countering the depression of AV conduction by digitalis AV Block and Bradycardia Can be treated by atropine (0.6-1.2 mg IM) Therapeutic Uses Digitalis is used therapeutically in the treatment of: Congestive Heart Failure Digitalis increases stroke volume and cardiac output Digitalis by increasing the cardiac output, brings about more complete emptying of the ventricles during systole This reduces the pulmonary congestion and edema and decrease in systemic venous pressure The cardiac glycosides primarily correct systolic dysfunction Intravenous digitalization is done in emergency conditions of CHF or in atrial fibrillation Digoxin 0.25 mg followed by 0.1 mg hourly be given by slow IV route with close monitoring of cardiac function Oral digitalization: Digoxin 0.5-1.0 mg stat and followed by 0.25 mg hourly with monitoring of toxicity • Digitoxin 1.2 mg is administered as a single dose This can be given in divided dose also, in hours interval Maintenance dose method: Administration of a daily maintenance dose (0.5 mg) of digoxin will digitalise the patient within a week Atrial Fibrillation Digitalis is the drug of choice in atrial fibrillation for controlling ventricular rate Its effect is due to the prolongation of the refractory period of the conducting tissue The dose in so adjusted as to maintain the ventricular rate of 60 to 80 beats per minute at rest and approximately 100 beats per minute during light exercise Atrial Flutter The reversal to normal rhythm is because digitalis converts flutter into fibrillation Digitalis enhances the AV block and reduces the ventricular rate The dosing schedule is dependent on the desired speed of action and urgency Like other drugs having a longer duration of action the treatment is initiated with a loading dose which is followed by maintenance dose for achieving a rapid onset of action and to avoid cumulative toxicity Paroxysmal Supraventricular Tachycardia The maintenance dose is the amount required to maintain the therapeutic effect Its effects is due to vagomimetic activity, generally one fourth total IV digitalizing ... Contractility: Digitalis increases the force of myocardial contraction without causing corresponding increase in the oxygen consumption This pharmacological action forms the basis of its use in treatment... of CHF In a patient of CHF, force of contraction of the heart at a given fibre length is decreased, thus the stroke volume is decreased As digitalis increases the force of contraction of the... i.e making more calcium available for excitationcontraction coupling Cardiac glycosides inhibit Na + K + ATPase by competing with potassium and Calcium also forms a link between the electrical