Cardiac Glycosides and Sugar Units

Cardiac Glycosides

• Combination of sugar with the aglycone increases both potency and toxicity of the active principle.
• The sugar affects physical properties such as water solubility and diffusion through semipermeable membranes, influencing the rate of absorption and transport of the compound to the site of action.

Structure-Activity Relationships

• Unsaturation of the β-oriented lactone is essential for activity.
• Opening of the lactone ring renders the glycosides inactive, and saturation results in a substantial decrease of activity.
• β-Orientation of the C-3 OH and lactone at C-17 is important; if it changes to α-orientation, the activity is weaker.
• Activity is stronger if A/B and C/D junctions are cis.
• The β-hydroxyl group at C-14 is important for activity; change to the α-position leads to loss of activity.

Toxicity

• Early symptoms of ingestion include nausea, vomiting, diarrhea, abdominal pain, mild hallucinations, delirium, and severe headache.
• Later symptoms may include irregular and slow pulse, tremors, convulsions, and various cerebral disturbances, especially of a visual nature.
• Digitalis poisoning can cause heart block or tachycardia, depending on the dose and the condition of one's heart.

Hydrolysis of Cardiac Glycosides

• Acid hydrolysis splits sugars from the aglycone, cleaving glycosidic linkages and giving aglycones and sugars.

Mechanism of Action of Cardiac Glycosides

• Cardiac glycosides inhibit Na+/K+-ATPase, the "sodium-potassium pump", causing more Na+ to remain inside myocardial cells.
• Increased intracellular Na+ stimulates Na+/Ca++ exchange, bringing more Ca++ inside heart cells to increase the force of contraction.
• This action indirectly increases the calcium concentration reaching the contractile proteins.

Effects of Administration of Electrolytes

• ↓K+, ↑Ca++, ↓Mg++ → toxicity
• Hypercalcemia increases the risk of digitalis-induced arrhythmia.
• Hypokalemia results in increased digoxin binding, increasing its therapeutic and toxic effects.
• Hypomagnesemia can sensitize the heart to digitalis-induced arrhythmias.

Occurrence

• Medicinally important glycosides are obtained from a limited number of plant families, including Scrophulariaceae, Apocyanaceae, Ranunculaceae, Liliaceae, and Ranunculaceae.
• Cardiac glycosides are classified into two types: cardenolides and bufadienolides, based on the type of lactone ring.

Cardio-Active Glycosides

• Definition: Cardiac glycosides are naturally occurring steroidal glycosides that act as cardiotonic agents.
• Cardiotonic drugs increase myocardial contractility without a corresponding increase in O2 consumption.
• They have a specific and powerful action on the cardiac muscle when administered into man or animal.

Congestive Heart Failure

• Definition: Contractile function is reduced below normal due to disease or lifestyle.
• Manifestation: Blood accumulates in the heart, lungs, abdomen, and lower extremities.

Medicinal Importance

• Cardiac glycosides are used to treat Congestive Heart Failure (CHF).
• They increase the force of contraction of cardiac muscles without increasing oxygen consumption.
• They also increase cardiac output and treat atrial arrhythmias, such as atrial fibrillation and atrial flutter.