Cardiac glycosides and mechanism of action of digitalis

 Classification: Cardiac glycosides are naturally derived compounds that increase the force of heart contractions and are used primarily to treat heart failure and certain arrhythmias. They are classified based on their origin and structure:

1. C-23 Steroids (Cardenolides): Derived from plants, these include drugs like digitalis (from Digitalis purpurea) and ouabain.
2. C-24 Steroids (Bufadienolides): Found in animal sources such as the skin of toads (e.g., bufalin).

Chemistry:

• Cardiac glycosides are composed of two parts:
  1. Aglycone (genin) moiety: A steroid nucleus with an unsaturated lactone ring at the C-17 position. For example, digitoxigenin in digitalis.
  2. Sugar moiety: One or more sugar molecules (like glucose, rhamnose, or digitoxose) attached to the aglycone.

Digitalis, derived from the foxglove plant (Digitalis purpurea), primarily contains two potent glycosides: digoxin and digitoxin.

• Digoxin: Contains a steroid nucleus (digoxigenin) and three sugar molecules (digitoxose).
• Digitoxin: Similar to digoxin but differs slightly in its sugar composition and pharmacokinetics.

Mechanism of Action:

1. Inhibition of Na⁺/K⁺-ATPase:

   • Cardiac glycosides inhibit the Na⁺/K⁺-ATPase pump located on the cardiac cell membrane.
   • This inhibition leads to an increase in intracellular sodium (Na⁺) concentration.

2. Increase in Intracellular Calcium (Ca²⁺):

   • The increased intracellular Na⁺ reduces the activity of the Na⁺/Ca²⁺ exchanger, which normally expels Ca²⁺ from the cell in exchange for Na⁺.
   • As a result, intracellular Ca²⁺ levels rise, leading to enhanced calcium availability within the sarcoplasmic reticulum.

3. Increased Force of Contraction (Positive Inotropy):

   • The elevated intracellular Ca²⁺ enhances the interaction between actin and myosin filaments within the heart muscle, increasing the force of myocardial contraction.

4. Electrophysiological Effects:

   • Cardiac glycosides can increase vagal tone, leading to a decrease in heart rate (negative chronotropy) and slowed atrioventricular (AV) conduction (negative dromotropy).
   • They can also shorten the refractory period of the atrial and ventricular myocardium and AV node, which can be beneficial in controlling certain types of arrhythmias.

Clinical Applications:

• Heart Failure: Used to improve symptoms and exercise tolerance.
• Arrhythmias: Particularly useful in controlling ventricular response in atrial fibrillation and atrial flutter.

Toxicity and Side Effects:

• Narrow Therapeutic Index: Cardiac glycosides have a narrow margin between therapeutic and toxic doses, requiring careful monitoring.
• Toxic Effects: Can include gastrointestinal disturbances (nausea, vomiting), visual disturbances (blurred vision, yellow-green halos), and cardiac arrhythmias (e.g., ventricular tachycardia, AV block).

Cardiac glycosides, particularly digitalis, have a long history of use in cardiology, but due to their narrow therapeutic window, they require precise dosing and monitoring to avoid toxicity.