Cardiac Glycosides in Heart Failure Treatment

Cardiac Glycosides

• Cardiac glycosides are plant sterol derivatives that affect myocardial contraction and atrioventricular conduction.
• They can be toxic in large doses, causing cardiac arrest in systole, but are important drugs in the treatment of congestive heart failure in lower doses.
• They have a diuretic activity, which improves circulation and relieves edema often associated with heart failure.

Properties of Cardiotonic Glycosides

• General properties:
  • Amorphous powders
  • Soluble in water
  • Bitter in taste
  • Insoluble in organic solvents
  • Odourless compounds
  • Generally toxic compounds
• Physical and chemical properties:
  • Soluble in H2O and EtOH
  • Aglycones are soluble in organic solvents
  • Increase in glycosides increases solubility
  • Enzyme & acid hydrolysis
  • Elevated temperature results in dehydration of the –OH at C14 with the production of an inactive anhydro-form

Cardiotonic Scaffold

• Two types of genin can be distinguished:
  • Five-membered lactone ring (cardenolides)
  • Six-membered lactone ring (bufanolides/bufadienolides)
• Sugar moieties are attached by a C3,β-linkage and composed of up to four sugar units, including glucose, rhamnose, and other deoxy-sugars.

Structural Diversity and Structure-Activity Relationship

• Naturally occurring deoxy-sugars (except rhamnose) are unique to cardiac glycosides and relevant to phytochemical testing.
• Deoxy sugars associated with cardiac glycosides include:
  • 6-deoxy hexose (methyl pentose): rhamnose, fucose, allomethylose
  • Methyl pentose-3-methyl-ether: digitalose
  • 2,6-deoxy hexose: digitoxose, boivinose
  • 2,6-deoxy hexose-3-methyl-ether: cymarose, sarmentose, oleandrose
• Cardioactivity is due to aglycone moiety, while pharmacokinetic behavior is influenced by glycone moiety.
• The α,β-unsaturated lactone ring is responsible for activity, but saturation decreases potency by 10-fold, and opening results in complete loss of activity.
• The cis junction of rings C/D and A/B is necessary for activity, with A/B cis fused rings being more potent than A/B trans.