Cardiac Glycosides and Plant Toxins Quiz

Cardiac Glycosides

• Cardiac glycosides are a class of naturally occurring drugs, impacting the heart with both beneficial and toxic effects. They are plant-derived, acting specifically on the heart.

Historical Use

• Traditionally used as arrow poisons in Eastern Africa for hunting and warfare.
• Used to assassinate people.

Modern Use

• Treating congestive heart failure (dropsy/edema).
• Treating atrial fibrillation and irregular heartbeats (HR).
• Diuretic agent.

Sources (examples)

• Digitalis lanata: (Total glycosides, 1.5%), primary glycosides are Lanatosides A-E and digoxin.
• Digitalis purpurea: (Total 0.5%), primary glycosides are Purpural glycosides A, B & E, digitoxin, gitoxin and gitraloxin.

Pharmacology and Mode of Action

• Act directly or indirectly on the failing heart.
• Increase contractility (positive inotropic effect) of heart muscle.
• Slow heart rate (antiarrhythmic effect) by affecting atrioventricular conduction.
• Have a diuretic effect on the kidney.

Mechanism of Action

• Inhibit the sodium pump (Na+/K+ adenosine triphosphatase).
• Accumulate intracellular sodium, triggering sodium/calcium exchange.
• Increase calcium levels in heart cells, enhancing contractile force.
• Also stimulate the vagus nerve, so decreasing the heart rate.

Chemical Structure - Aglycone Moiety

• Steroidal nucleus.
• Unsaturated lactone ring attached to C-17.
• A tertiary β-hydroxyl group attached to C-14.
• Cis-junction of rings C/D and A/B is essential for cardiac activity.
• A/B cis fused rings, are more potent than A/B trans.

SAR-Aglycone Moiety

• Oxygen substitution in the steroidal nucleus influences distribution and metabolism (e.g., more -OH groups cause quicker action and removal from the body.)
• Replacing -OH groups at C-3 or C-14 with Hydrogen atoms reduces potency.
• β orientation of C-17 is necessary for activity. 17 α-cardenolides are inactive.

Structure-Activity Relationship (SAR)

• Cardioactivity depends on the aglycone moiety.
• Pharmacokinetic behavior is influenced by the glycone moiety (sugar). This affects aspects such as polarity, onset of action and excretion.

SAR-Sugar Moiety

• The sugar moiety is generally inactive but when attached to the steroid moiety, it affects the activity and pharmacokinetic behavior.
• Free aglycones are less potent than their glycosides.
• Sugar type and number influence potency.
• Digoxin, with 6-deoxy sugars is usually more potent than its 6-CH2OH counterpart.

Digitalis Glycosides - Source (examples)

• D lanata: Primary glycosides are Lanatosides A-E and digoxin.
• D purpurea: Major glycosides are A, B, E, digitoxin, gitoxin and gitaloxin.

Cardiac Glycosides from Oleander

• Nerium oleander's active part are its leaves, sourced from the Apocynaceae family.
• Contains cardioactive compounds like Thevetioside, and Oleandrin.
• These are highly toxic and even small amounts produce symptoms like skin rash, blurred vision, nausea, abdominal pain, etc.
• Yellow oleander (Thevetia peruviana) is rich in Thevetin A.

Bufadinolides

• Less widely distributed in nature than cardenolides.
• These are found in Liliaceae and Ranunculaceae
• Rarely used therapeutically as cardioactive drugs.

Squill

• Dried sliced bulbs (used part) of Urginea maritima.
• Liliaceae family.
• Contains scillarins (like scillaren A and proscillaridin A).

Toad Venom Posioning

• Similar to digitalis toxicity, carrying high mortality.
• Venom gland of cane toads contains significant amounts of cardiac glycosides.

Comparison between Digoxin/Digitoxin

• Digoxin:
  • Usually administered orally.
  • Shorter onset of action.
  • Shorter half-life in the bloodstream.
  • Eliminated via kidney.
• Digitoxin:
  • Usually administered orally.
  • Longer onset of action.
  • Longer half-life in the bloodstream.
  • Eliminated via liver.

Digoxin Toxicity and Antidote

• Digoxin immune fab (digoxin antibody) binds to and removes digoxin from the body.

Mechanism of Action and Side Effects (general)

• Cardiac glycosides inhibit the Na+/K+ ATPase enzyme.
• Side effects are variable, but some common ones are visual disturbances, nausea, vomiting, anxiety, and potentially fatal arrhythmias.
• Preferred treatments: ACE inhibitors, beta blockers.
• Contraindications: Ventricular fibrillation.

Xanthopsia (Yellow Vision)

• Possible symptom of digoxin intoxication.