Drugs Acting on Cardiac Glycosides | Veterinary Pharmacology

These are the glycosides naturally obtained from certain plants and contain active principles which act specifically on the failing heart and make them normal. That’s why, they are called cardiac glycosides. All the cardiac glycosides have cardio tonic property.

Differences Between Cardiac Glycosides and Other Cardiac Stimulants (Adrenaline, Theophylline, etc.).

Cardiac Glycosides:

(i) They increase force of myocardial con­traction, but not heart rate.

(ii) Increase the myocardial efficiency be­cause the total myocardial oxygen con­sumption is not altered.

(iii) They inhibit Na⁺ – K⁺ – ATPase en­zyme and thereby slowly increase the cardiac contractility. Their duration of action is long.

(iv) In congestive heart failure (CHF) patient, they reduce the heart size by increasing the cardiac tone.

(v) They are mainly used to treat CHF.

Other Cardiac Stimulants:

(i) They increase both force of myocardial contraction and heart rate.

(ii) They decrease the myocardial efficiency because the total myocardial oxygen consumption is increased disproportionately (more) with the increase in contractility.

(iii) They act on their specific receptors to increase heart rate and force of contrac­tion quickly. Their duration of action is short.

(iv) They have no effect on cardiac tone and size.

(v) They are mainly used to treat heart block.

Digitoxin, Digoxin, Ouabain and desacetyllanatoside are used clinically. The term “digitalis” is frequently used to refer to the entire group of cardiac glycosides.

Chemistry and SAR:

Cardiac glycosides are the combination of an aglycone (or genin) and 1 to 4 sugars.

(i) The aglycone is chemically similar to steroids (i.e., adrenocortical and sex hormones) and to bile acids. It is the pharmacologically active portion of the glycosides. It contains cyclopentano-per-hydro-phena-thrine ring’ to which an unsatu­rated lactone ring is attached at C₇ position and -OH at C₁₄ po­sition. Pharmacological action of cardiac glycosides remains in the aglycone part.

(ii) The sugars modify the water and lipid solubility of the glycoside molecule and, thus affect its potency and duration of action.

SAR:

(a) The unsaturated lactone ring at C₁₇ is absolutely essential for pharmacologi­cal action.

(b) Saturation of lactone ring decreases the cardio tonic effect.

(c) Opening of lactone ring completely abolishes the action.

(d) —OH group at C₁₄ is must for pharmacological action.

(e) Presence of sugar at C₃ increases the potency and duration of cardio tonic action by increasing the solubility and thereby helping in penetration and fixation on cardiac cells.

Mechanism of Action:

During the trans membrane action potential, there is a net entry of Na⁺ and Ca²⁺ and a net loss of K⁺. The resting intracellular concentration of Na⁺ {[Na⁺]_i) and K⁺ ([K⁺]_i)} are maintained by the activity of the Na⁺ – K⁺ pump (or Na⁺ – K⁺– AT Pase).

The intracellular concentration of Ca²⁺([Ca ²⁺]_i) is in part regulated by exchange for Na⁺ wherein 1 molecule of Ca²⁺ comes out in exchange of 3 molecules of Na⁺ entry. This exchange process is bidirectional and ionic exchange depends on the concentra­tion gradients of ions.

Digitalis acts on Na⁺, K⁺– AT Pase (Na⁺– K⁺ pump) and inhibits its function. It binds at the external site (at the K⁺ binding site) of the pump. Due to inhibition of this pump Na⁺ conc. inside the cell is increased which make the Na⁺ – Ca²⁺ exchange process in reverse direction (as it is thereby bidirectional and depends on the concen­tration gradient) and Ca²⁺ concentration inside the cell is increased.

This increased [Ca²⁺]_i further increases the slow inward Ca²⁺ current during plateau phase of AP and also causes the release of additional Ca²⁺ from the sarcoplasmic reticulum into the cytosol (even in normal cells) which leads to activation of actin-myosin complex and thereby contraction of the cell.

Rise in [Ca²⁺]_i → fall in intracellular pH → H⁺ is exchanged for extracellular Na⁺ through Na⁺ – H⁺ exchange process to compensate. → increase [Na⁺]_i → increase [Ca²⁺]_i > contraction.

Pharmacokinetics:

Cardiac glycosides are well absorbed from the GI tract. Nearly 60 to 75% of digoxin and 90-100% of digitoxin are absorbed after oral administration. The plasma protein binding ability of digitoxin (97%) is much more higher than digoxin (about 25%).

Biological half life of digoxin and digitoxin are 1½ and 5-7 days respectively. Digoxin is mainly excreted in urine as its unchanged form, while the metabolite of digitoxin is excreted in faeces. The later drug undergoes enterohepatic circulation.

Pharmacological Actions:

(i) Cardiac glycosides have the positive ionotropic effect on heart. They in­crease the force (not duration) of contraction of myocardium in a dose- dependent manner. In a congestive heart failure (CHF) patient, digitalis increases cardiac output and decreases the cardiac filling pressures, heart size and venous and capillary pressures. It increases the cardiac work at reduced metabolic cost.

(ii) In purkinje fibres, they decrease the resting membrane Potential (Vm) or maximal diastolic potential (MDP), the rate of phase 0 depolarization, con­duction velocity, amplitude of AP and the APD. The fibres become more responsive to external stimuli. They increase the rate (slope) of phase 4 depolarization and thereby produce delayed after depolarization resulting in increase in automaticity.

(iii) Cardiac glycosides have no effect on S.A. node. On A.V. node, they in­crease ERP and decrease MDP, rate of phase O depolarization, conduction velocity and amplitude of A.V. nodal AP.

(iv) The indirect effects of cardiac glycosides are increased vagal activity and decreased sympathetic tone (due to decrease in sensitivity to catecholamines) of the heart. In congestive heart failure patients, the increase in vagal activity causes a decrease in the rate of impulse generation in the S.A. node (negative chronotropic effect).

(v) Tachycardia may be found with the excessive dose of digitalis (a positive chronotropic effect). In normal individuals, they have little effect on heart rate.

(vi) They affect ECG with the changes of P wave in atria, increased P-R interval in A-V node, and decreased Q-T segment and depression of T wave in ventricle.

(vii) In CHF patients, digitalis decrease peripheral vascular resistance (PVR) and vasomotor tone by increasing cardiac output. Whereas in normal indi­vidual, it constricts venous and arterial blood vessels. The systolic blood pressure may rise in CHF patients because digitalis increases the stroke volume. Diastolic blood pressure may fall due to improved circulation and increased tissue oxygenation.

(viii) They also have a diuretic effect.

Therapeutic Uses:

(i) Low-output cardiac failure

(ii) Atrial fibrillation and flutter

(iii) Paroxysmal atrial techycardia

Contraindications:

(i) High output CHF

(ii) Cardiac tamponade

(iii) Constrictive pericarditis

(iv) Circulatory shock

(v) Renal failure

(vi) Hepatic failure

(vii) Ventricular premature contractions, ventricular tachycardia or heart block unless the abnormality is associated with CHF.

Adverse Effects:

Cardiac glycosides have ‘low margin of safety’ with a lethal dose much closure (only 5-10 times) to the minimal effective dose. Most of the time, large doses of the drug are associated with the intoxication due to depletion of serum K⁺ ions. Toxic signs produced by digitalis are anorexia, nausea, vomition, diarrhoea, headache, fatique, neuralgias, malaise, dellirium, changes in vision, etc.

Cardiac adverse effects are atrial and ventricular extra systoles, tachycardia, ven­tricular fibrillation, A-V depression or block, sinus arrhythmia and S.A. block, etc.

Digitalization:

(i) The dosing schedule of digitalis and the route depend on the desired speed of action and the factors which govern individual susceptability.

(ii) A basic procedure followed in the past by many clinicians involves initial administration of a large amount (digitalization or loadings dose) of digitalis in several divided doses over a relatively short period (24-48 hrs.) to quickly achieve the desired therapeutic effect. Treatment is then continued daily with smaller doses (maintenance doses) to maintain therapeutic efficacy.

(iii) Techniques used for achieving oral digitalization can be placed into three general time courses: slow, rapid and intensive.

(a) Slow digitalization:

When mild failure of heart is presented, the total estimated loading dose is administered in 5 equal parts over 48 hrs. (until salutary effects are gained or toxicity supervenes). This is fol­lowed by daily maintenance doses.

(b) Rapid digitalization:

When the effect must be produced within few hours, the loading dose is divided into 3 equal parts given at intervals of 6 hrs., which is followed by daily maintenance doses.

(c) The extensive schedule is usually not selected unless an emergency exists: 1/2 of the loading dose is given initially, 1/4th given 6 hrs. later and 1/8th is given 4-6 intervals. This is followed by daily maintenance doses.

In Medical Practice: For slow digitalization, a maintenance dose (e.g., digoxin 0.25 mg/day) is given daily orally from the beginning. Full response takes 5-7 days to develop; the procedure is much safer.

For rapid digitalization, digoxin 0.5 to 1 mg stat; followed by 0.25 mg, orally every 6 hrs., generally take 6-24 hrs. This is seldom practiced now.

For intensive/emergent digitalization , digoxin 0.25 mg slow i.v. inj followed by 0.1 mg, i.v. inj hourly. It is rarely practiced now.

Doses:

Prepared digitalis causes local irritation and vomition in those species capable of emesis (pig, dog and cat; less common by parenteral route) and for this reason the glycoside should be used. In ruminants, the glycosides are largely destroyed in the rumen and parenteral administration is obligatory. The i.v. route is preferred for all parenteral dosing.