Cardiac glycosides, toxicities and therapeutic options in modern medicine.

Glycosides are composed of the interaction of nucleotides like glucose (sugar) in our nature. Sometimes they are called O-glycosides, S-glycosides. C-glycosides, N-glycoside,s and so on on the basis of their principle molecule. O-glycosides are the most common glycosides found in our nature. There is a linkage called Glycosidic Linkage between glycone and aglycone. Basically, polysaccharides are the broad-based definition of glycosides. Glycosides are found in Aloe, Rhubarb, Senna, poplar, willow and so on. There are different types of glycosides like phenol glycosides, aldehyde glycoside, isothiocynate steroidal glycoside, etc. Steroidal glycosides are called cardiac glycosides. They are used as cardiotonic. There are some drugs that use as therapeutic medicine such as Digitalis, Ouabain, Thevatia, Indian Squill, etc. But they have toxicities. They have some separate activities such as electrophysiological and mechanical on the the heart. Again they inhibit sodium-potassium adenosine in heart. If sodium potassium ATPase concentration decreased, there will be a chance of human the heart failure. This is the adverse effect of cardiac glycosides.

 

Cardiac Glycosides:

Cardiac glycosides are called steroid glycosides. There are some plants that contain C₂₃ or C₂₄ they are steroidal glycosides that show the effect of slow or fast heart rating. There are lots of plants but Digitalis purpuria is the most successful plant to treat cardiac disease. Basically, Glycosides are confined in nature. There are two types of genin here which use as cardiotonic. They are Cardenolide and Bufadienolide.

                                        

                 Image: Cardenolides                                                      Image: Bufadienolide

Cardenolides are five-membered rings and bufadienolides are six-membered rings. Cardenolides are found numerously than bufadienoli. Again, there are different types of sugar found in cardiac glycosides. They are fucose, rhamnose, digitalose, cymarose, glucose, thevetose, and so on.

There are some characteristics of cardiac glycosides. They are:

1. Generally they found originally in a plant but some of them result from removal of one sugar molecule from another primary glycoside such as Digitalis.

2. Cardiac glycosides are non-volatile.

3.They are soluble in water and organic solvent.

4. They are generally bitter in taste.

5. They are solid either crystalline or amorphous.

Not only Digitalis purpurea but also different types of the plant contain cardenolide derivatives. There are some constituents of plants and their parts.

 

1. Digitalis Leaf: In this portion purpurea glycosides A and purpurea glycosides B are found and they possess the C₃ genin in digitoxoses sugar moieties. The most active components in Digitalis leaf are gitoxin and digitoxin.

                                                                   Image: Digitalis Leaf

 

2. Digitalis seeds: The seeds of Digitalis purpurea have more different types of glycosides linkage from Digitalis leaves. After extraction from seeds, they are called Digitalin. They are composed of gitonin, saponins digitonin, and digitalium verum which is water-soluble.

                                                                   Image: Digitalis seeds

 

3. Digitalis Lanata Leaf: They are identical to Digitalis purpurea but the main different thing is that they are acetylated at digitoxose moiety to the last glucose moiety. They are crystalline.

Image: Digitalis Lanata Leaf

 

 4. Squill: Squill is collected from the dried slice of Drimia maritima. Stoll was isolated a crystalline glycoside scillaren A and amorphous scillaren B from Drimia maritima in 1923. Though scillaren A is the most important active constituent in a squill. They have a short action duration.

 Image: Squill

 

 5.Nerium: Nerium is collected mostly from Nerium oleander. They have two glycosides. They are neriin and oleandrin which have a cardio stimulatory effect. Its lymph is rich in Alpha trocoferol and mineral. The seeds and bark contain glucosides.

 

  

Image: Nerium

Cardiac Glycosides Toxicities:

Cardiac glycosides basically reversibly inhibit sodium-potassium ATPase exchanger and increased intracellular calcium and inotropy. But the thing is cardiac glycosides have a low level of the therapeutic effect. Cardiac glycosides are used as medicine for treating cardiac disease. Sometimes it became poisonous or toxicity because of overdose by accidental or intentional ingestion. The symptoms of overdose are nausea, vomiting, and abdominal pain. But the main life-threatening condition is cardiac toxicities. There are a different types of cardiac glycosides which have different variation of their pharmacological and pharmacokinetic properties in their structure. Nerium oleander seeds composed of cardiac glycosides including thevetin A, thevetin B, and neriifolin. If anyone takes about five to fifteen nerium leaves it would result in fatal poisoning. Even one leaf of Nerium oleander could be created toxicity in children. Not only leaves but also extract, flowers, and root extract can cause more nonfatal cases. In the case of taking of eight to ten leaves of Thevetia peruviana seeds can be fatal to but the seeds have not been shown to correlate with the degree of toxicity of glycosides.

 

The main mechanism of cardiac glycoside toxicities is that cardiac glycosides bind to inactive the sodium-potassium ATPase that emits sodium and implies potassium into cardiomyocytes or myocardiocytes which are the cells that made make up the heart muscle. The inhibition causes a build-up of intracellular sodium that helps to increase intracellular calcium in this channel. It turns persuades further calcium ion release from the sarcoplasmic reticulum (SR) which main function is to store calcium ion. After then, it increased the force of contraction of the heart. When intracellular calcium ions increase then it also raises the membrane potential of the cell and conducting increasing rates of spontaneous cellular depolarization. The myocardium becomes irritable and increased vagal tone that causes bradycardia. This inhibition of the sodium-potassium ATPase also causes of hyperkalemia. In the case of acute poisoning by these alkaloids, the degree of hyperkalemia can cause severe toxicity.

Therapeutic Options in Modern Medicine:

There are different types of drugs that have a therapeutic effect on cardiac disease.

Name of the drug	Biological Source	Active Constituents	Uses
Digitalis	Dried leaves of Digitalis purpurea	Purpurea glycoside A and B.	Cardiotonic.
European Squill	Dried sliced bulb of Urginea maratima	Scillaren A & B	Cardiotonic.
Ouabain	Dried seeds of Strophanthus gratus	Ouabin	Cardiotonic.
Thevetia	Dried seeds of Thevetia nerifolia	Thevetin	Cardiotonic.
Indian Squill	Dried sliced bulb of Urginea indica	Scillaren A & B	Cardiotonic.

 

 

Digitalis (Digitalis purpurea) components have different uses in medical science. They are used in the treatment of chronic heart failure because they have the most successful cardiotonic effect than other glycoside plants. At present there are various modern and more efficacious treatments for heart failure disease are available. This digitalis compounds are very convenient and widely used. In the case of heart failure patients, they have shown a great result for digoxin in clinical studies. They are used in conjunction with vasodilators and diuretics that improves the cardiac output and ejection fraction that reduces pulmonary capillary pressure. It helps to reduce pulmonary congestion and edema (swelling). For this reason, heart rate changes very little. These drugs help to increases the inotropy rate. Another main important function of digitalis of digoxin is it works on blood vessels is vasoconstriction (narrow of the blood vessel), given to heart failure patients and the systemic vascular resistance falls. This mechanism helps to development of cardiac output that leads to withdrawal of compensatory vasoconstrictor mechanisms. The Digitalis compounds have a small direct diuretic effect on the kidneys that is beneficial to heart failure patients.

 

References:

1. https://www.tandfonline.com/doi/abs/10.1081/CLT-120022006

2. https://www.cancertherapyadvisor.com/home/decision-support-in-medicine/critical-care-medicine/digoxin-overdose-cardiac-glycoside-toxicity-digoxin-toxicity-digoxin-poisoning/

3. https://www.researchgate.net/publication/257254501_Cardiac_Glycoside_Toxicity_More_Than_200_Years_and_Counting

4. https://www.uspharmacist.com/article/digoxin-use-in-modern-medicine

5. https://www.researchgate.net/publication/308548495_CARDIAC_GLYCOSIDES_USES_IN_HEART