Cardiac glycosides or Digitalis

Synonyms- Cardiac glycosides / Digitalis / Cardiac inotrope

The main source of cardiac glycosides is from the foxglove family. Their effectiveness in cardiac failure was, described by William Withering in 1775. He published his classic monograph ‘An account of the foxglove and some of its medicinal uses: with practical remarks on dropsy on used by an old woman of Shorpshireand other diseases’ in 1785.

Initially kidney was thought to be the target organ. The cardiac glycosides are unique in that they not only improve the contractility of the myocardium, but also reduce the heart’s demand for energy and oxygen.

These drugs also decease the conduction of certain impulses within the heart and therefore decrease the heart rate.

Source of glycosides

1. Digitalis purpurea or Purple foxglve (leaf) – Digitoxin, Gitoxin, Gitalin
2. Digitalis lanata or White foxglove (leaf) – Digitoxin, Gitoxin, Digoxin
3. Strophanthus kombe (seed) – Strophanthin K
4. Strophanthus gratus (seed) – Strophanthin G (Ouabain)
5. Thevetia neriifolia (nut) – Thevetin
6. Convallaria majalis – Convallotoxin
7. Bufo vulgaris (Toad skin) – Bufotoxin

Chemistry of cardiac glycosides

Cardiac are glycosides that contain an aglycone (genine) and a sugar moiety. The sugar moiety consists of one to four sugar residues. The pharmacological activity rests with the aglycone and the sugar helps in the pharmacokinetic properties. The aglycone consists of a cyclopentanoperhydrophenantherene ring structure attached to a 5 or 6 membered unsaturated lactone ring.

Mechanism of action of cardiac glycosides

1. Cardiac glycosides produce their action by inhibition of Na⁺, K⁺ transport system (Na⁺, K⁺ -ATPase)
2. Inhibition of this sodium pump results in increased intracellular Na⁺ concentration
3. Normally sodium is brought into the cell in exchange for Calcium during the plateau phase
4. Because of the elevated intracellular Na⁺, sodium – calcium exchanger is not functional, leading to elevated intracellular Ca⁺⁺ levels
5. Ca⁺⁺ forms a complex with troponin and tropomyosin allowing actin and myosin filaments to come together
6. Muscle contracts
7. Altered Na⁺, K⁺ and Ca⁺⁺ levels are the basis for both the therapeutic and toxic effects of the cardiac glycosides.

Pharmacological effects of cardiac glycosides

Positive inotropic effect is noticed by improved emptying and reduction in size of the dilated failing heart.

The muscle contracts more quickly and more powerfully for the same filling stimulus and for the same oxygen consumption. So venous pressure is reduced, edema fluid is reabsorbed and blood pressure increases.

Negative chronotropic effects by direct stimulation of the vagal centre and by slowing the rate of passage of impulses through the conducting system. Diuretic effect due to increased blood flow and increased glomerular filtration rate.

Pharmacokinetics of cardiac glycosides

Absorption differs among the digoxin preparations. Prepared digitalis causes local irritation and vomiting in pig and dog and for these species digitalis glycoside should be given.

In ruminants, oral administration of glycosides leads to destruction of the drug and hence it is preferable to give the drug parenterally.

Plasma protein binding is high with digitoxin.

Excretion of the drug is by the kidneys. Enterohepatic recycling increases the duration of action of the drug. The use of these drugs in dogs and cats is not uncommon.

However, the absorption of digoxin from the gastrointestinal tract though adequate may differ somewhat among animals and can be influenced by feeding times.

Therapeutic uses of cardiac glycosides

1. Congestive heart failure
2. Arrhythmias by depressing the AV nodal conductivity and increasing refractoriness

Digitalization

Administration or dosing of digitalis or digoxin is known as Digitalization. Digitalis glycosides have a narrow margin of safety. Initial administration of large dose in divided doses. (24-48 hrs.)followed by maintenance dose.

1. Loading dose in dogs
   • Slow method- 5 equal parts for 48hrs
   • Rapid method- 3 equal parts @ 6hr interval.
   • Intensive method- half dose initially, one fourth after 6hrs and one eighth each after 4 hr. intervals
   • Digitoxin- 0.11 – 0.22mg/kg total loading dose
2. Maintenance dose-0.011mg/kg @12hr intervals in dogs

There is a considerable, individual variation in response to these glycosides.

Adverse reactions of cardiac glycoside

1. Risk of toxicity is greater in patients with advanced heart disease,in high dosage, renal disease, age and hypothyroidism
2. Factors that increase myocardial sensitivity to digitalis toxicity include myocardial disease or ischemia, hypokalemia, high serum calcium and low serum magnesium
3. Symptoms of toxicity can be grouped as cardiac symptoms and non-cardiac symptoms
4. Cardiac symptoms of toxicity
   • Sinus bradycardia,
   • S-A block,
   • A-V block, tachycardia,
   • premature ventricular contraction
5. Non-cardiac symptoms of toxicity
6. gastrointestinal disturbances like anorexia, nausea, vomiting fatigue and muscle weakness
7. CNS effects like confusion, hallucination, restlessness, insomnia, drowsiness and occasionally overt psychoses
8. Visual effects like hazy vision, difficulty in reading, photophobia, chromatopsia (yellow or green colour appearance)
9. gynaecomastia (antiadrenergic effect)

Treatment of cardiac glycoside Toxicity

1. Withhold cardiac glycosides immediately if this cause toxicity
2. Withhold potassium depleting diuretics
3. Administer potassium salts
4. Administer antiarrhythmics if arrhythmias appear to be life threatening
5. Administer agents like activated charcoal to bind digoxin in the gastrointestinal tract.

Precautions and Contraindications of Cardiac Glycoside

• Hypokalemia will lead to increased digitalis toxicity
• In elderly patients and in patients with renal and severe hepatic disease the toxicity will be higher
• Thyrotoxicosis reduces the responsiveness to digitalis
• Myxoedema increases the responsiveness to digitalis
• Partial A-V block may be converted to complete A-V block

Drug interactions for cardiac glycoside

1. Diuretics – potassium depleting diuretics precipitate digitalis toxicity while potassium sparing diuretics reduce the renal excretion of digitalis
2. Calcium precipitates digitalis toxicity
3. Quinidine reduces binding to proteins and thereby increase the concentration and toxicity of digitalis
4. Verapamil and diltiazem increase plasma concentrations of digoxin
5. Antacids and neomycin reduce absorption of digitalis