Cardiac Glycosides - BioPharma Notes

Cardiac glycosides are often called digitalis or digitalis glycosides as most of them are obtained from digitalis or foxglove plant. Cardiac glycosides are also obtained from various other plants.
William Withering, a master physician and botanist, was first to identify digitalis as active ingredient in a mixture used to treat dropsy (old term for edema) in 1776. He described about therapeutic usefulness of digitalis in 1785.
The most widely used agent is digoxin. Digitoxin is rarely used.

Mechanism of action of Cardiac Glycosides

Figure 1- Mechanism of action of digitalis (Source- Lippincott’s Illustrated Reviews)

Digoxin is potent inhibitor of cellular Na⁺/K⁺-ATPase enzyme. This ion transport system brings potassium ions inside the cell and move sodium ions outside the cell.
This decreases the Na⁺ concentration gradient and the ability of Na⁺/Ca²⁺exchanger to move calcium out of the cell. The increased intracellular calcium in the heart causes more calcium to be released by sarcoplasmic reticulum.
Thus, it results in small but physiologically important increase in free Ca²⁺ which is available at next contraction cycle of cardiac muscle. Increase in intracellular calcium activates the light chain of myosin, which combines with actin to form actomyosin, and the muscle contracts thus increasing cardiac contractility.
It also enhances vagal tone and decrease myocardial oxygen demand and heart rate.

Pharmacological Action Cardiac Glycosides

Cardiovascular Actions

In patients with CHF (Congestive Heart Failure), it increases force of contraction and increase stroke output. It decreases the heart rate.
It increases ability of purkunje cells and ventricular muscles to initiate impulse.
In small doses, in increase conduction velocity in atria and ventricles (vagal action) and in therapeutic doses, depress the conduction velocity (direct action).
In small dose, it shortens atrial refractory period (RP) and prolong it with larger doses.
IV injection of digitalis in normal human increases arterial BP, whereas no such increase is observed in case of CHF.
The characteristic change occurring in ECG are prolonged P-R interval, shortening of Q-T interval and changes in T wave and S-T segment.

Extra-cardiac actions

It stimulates CTZ (Chemoreceptor Trigger Zone) which causes nausea and vomiting.
It increases urinary output by inhibiting renin release from kidney, improving renal circulation, increasing sodium excretion and decreasing venous pressure.

Pharmacokinetics of Cardiac Glycosides

Administered through oral or IV route.
Absorption occurs mostly from small intestine. Absorption after SC or IM administration is unreliable. Digoxin’s absorption decreases in presence of food and malabsorption syndrome.
Excreted by kidney so require dosage adjustment in renal patient.

Properties	Digoxin	Digitoxin
Absorption	70–80%	90–100%
Plasma Protein binding	25%	90% or more
Disposal	Renal excretion of unchanged drug 50-75%	Metabolized in liver
Enterohepatic recycling	6-8%	Extensive
Plasma half-life	24-48 hours	5-7 days
Time for max. effect of a single dose	4-6 hours	6-12 hours
Persistence of effect after stopping drug	3-6 days	18 days
Time for digitalization without loading dose	5–7 days	25–30 days

Table 1- Pharmacokinetics of oral digoxin and digitoxin (source- Pharmacology and Pharmacotherapeutics)

Therapeutic Uses

Used to treat severe CHF after initiation of ACE inhibitors, beta-blocker and diuretic therapy. Patients with mild to moderate heart failure respond to ACE inhibitors, beta-blockers, aldosterone antagonist and diuretics and may not requires digitalis. Digoxin is not recommended for treating acute heart failure associated with acute MI (Myocardial Infarction).

Helpful in treatment of chronic, pure, left ventricular failure in patients with hypertensive or ischemic heart disease.
Used in patients with atrial fibrillation with rapid ventricular rate.
It is drug of choice in treating paroxysmal atrial tachycardia (PAT) associated with heart failure.

Note- The use of digoxin has lessened in recent years due to its narrow therapuetic index and development of other safer alternatives. However, it remains an important second- or third-line treatment option for different cardiac problems.

Adverse Effects

Both digoxin and digitoxin has narrow therapeutic index. There is only a small difference between therapeutic dose and dose that may be fatal.

Digoxin toxicity is the most common adverse effect observed. Nausea, vomiting and anorexia may occur in initial stage of toxicity. Patient may also experience blurred vision, visual disturbance, headache and vertigo. Lassitude, confusion, delirium and psychotic behavior may appear.

It can be managed by discontinuing digoxin, determining serum potassium level and administration of potassium salts (if required)

Digoxin causes cardiac arrhythmia which may be more likely in case of digoxin toxicity.
It causes skin rashes and gynecomastia.

Drug-Interaction

Drugs which increase serum digoxin level include quinidine, verapamil, methyldopa, indomethacin and amiodarone.
Drug which decrease serum digoxin level include rifampicin, antacids, neomycin, diuretics and IV calcium.
Diuretics (thiazide and loop diuretics) can indirectly interact with digoxin as they decrease plasma potassium level (produce hypokalemia). Hypokalemia results in increased digoxin binding to Na⁺/K⁺ -ATPase and increase its therapeutic and toxic effects.
Hypercalcemia enhances digitalis-induced increases in intracellular calcium, which can lead to calcium overload and increased susceptibility to digitalis-induced arrhythmias. Hypomagnesemia also sensitizes the heart to digitalis-induced arrhythmias.

Contraindications

Contraindicated in patients who are hypokalemic. It should be used with caution in patients with hypercalcemia and hypomagnesemia.
It is contraindicated in Wolff-Parkinson-White (WPW) syndrome.
Should be avoided in heart block due to increased risk of conduction abnormalities.
Its dosage should be adjusted in renal patients as it excreted mainly through kidneys.

References

https://www.cvpharmacology.com/cardiostimulatory/digitalis
https://pharmafactz.com/digoxin-pharmacology/
Patocka J, Nepovimova E, Wu w, Kuca K. Digoxin: Pharmacology and toxicology-A Review. Environ Toxicol Pharmacol. 2020; 79: 103400.
Hatcher RA. The Pharmacology of Digitalis. JAMA. 1906; XLVII (25): 2059-2061.
The American Journal of the Medical Sciences. 2009; 337 (5): 355-359.
Whayne Jr TF. Clinical Use of Digitalis: A State of the Art Review. Am J Cardiovasc Drugs. 2018; 18(6): 427-440.
Pharmacology and Pharmacotherapeutics. 24th edition.
Lippincott Illustrated Reviews Pharmacology. 6th edition.