Cardiac glycoside

Last updated
Cardiac glycoside
Drug class
Cardiac glycoside general structure.svg
The general structure of a cardiac glycoside molecule.
Class identifiers
Use Congestive heart failure
ATC code C01A
Biological target Na+
/K+
-ATPase
External links
MeSH D002301
Legal status
In Wikidata

Cardiac glycosides are a class of organic compounds that increase the output force of the heart and decrease its rate of contractions by inhibiting the cellular sodium-potassium ATPase pump. [1] Their beneficial medical uses include treatments for congestive heart failure and cardiac arrhythmias; however, their relative toxicity prevents them from being widely used. [2] Most commonly found as secondary metabolites in several plants such as foxglove plants and milkweed plants, these compounds nevertheless have a diverse range of biochemical effects regarding cardiac cell function and have also been suggested for use in cancer treatment. [3]

Contents

Classification

General structure

The general structure of a cardiac glycoside consists of a steroid molecule attached to a sugar (glycoside) and an R group. [4] The steroid nucleus consists of four fused rings to which other functional groups such as methyl, hydroxyl, and aldehyde groups can be attached to influence the overall molecule's biological activity. [4] Cardiac glycosides also vary in the groups attached at either end of the steroid. Specifically, different sugar groups attached at the sugar end of the steroid can alter the molecule's solubility and kinetics; however, the lactone moiety at the R group end only serves a structural function. [5]

In particular, the structure of the ring attached at the R end of the molecule allows it to be classified as either a cardenolide or bufadienolide. Cardenolides differ from bufadienolides due to the presence of an "enolide," a five-membered ring with a single double bond, at the lactone end. Bufadienolides, on the other hand, contain a "dienolide," a six-membered ring with two double bonds, at the lactone end. [5] While compounds of both groups can be used to influence the cardiac output of the heart, cardenolides are more commonly used medicinally, primarily due to the widespread availability of the plants from which they are derived.

Classification

Example of the chemical structure of oleandrin, a potent toxic cardiac glycoside extracted from the Oleander bush. Oleandrin.svg
Example of the chemical structure of oleandrin, a potent toxic cardiac glycoside extracted from the Oleander bush.

Cardiac glycosides can be more specifically categorized based on the plant they are derived from, as in the following list. For example, cardenolides have been primarily derived from the foxglove plants Digitalis purpurea and Digitalis lanata , while bufadienolides have been derived from the venom of the cane toad Rhinella marina (formerly known as Bufo marinus), from which they receive the "bufo" portion of their name. [6] Below is a list of organisms from which cardiac glycosides can be derived.

Plant cardenolides

Other cardenolides

  • some species of Chrysolina beetles, including Chrysolina coerulans, have cardiac glycosides (including Xylose) in their defensive glands. [9]

Bufadienolides

Mechanism of action

Cardiac glycosides affect the sodium-potassium ATPase pump in cardiac muscle cells to alter their function. [1] Normally, these sodium-potassium pumps move potassium ions in and sodium ions out. Cardiac glycosides, however, inhibit this pump by stabilizing it in the E2-P transition state, so that sodium cannot be extruded: intracellular sodium concentration therefore increases. With regard to potassium ion movement, because both cardiac glycosides and potassium compete for binding to the ATPase pump, changes in extracellular potassium concentration can potentially lead to altered drug efficacy. [11] Nevertheless, by carefully controlling the dosage, such adverse effects can be avoided. Continuing on with the mechanism, raised intracellular sodium levels inhibit the function of a second membrane ion exchanger, NCX, which is responsible for pumping calcium ions out of the cell and sodium ions in at a ratio of 3Na+
/Ca2+
. Thus, calcium ions are also not extruded and will begin to build up inside the cell as well. [12] [13]

The disrupted calcium homeostasis and increased cytoplasmic calcium concentrations cause increased calcium uptake into the sarcoplasmic reticulum (SR) via the SERCA2 transporter. Raised calcium stores in the SR allow for greater calcium release on stimulation, so the myocyte can achieve faster and more powerful contraction by cross-bridge cycling. [1] The refractory period of the AV node is increased, so cardiac glycosides also function to decrease heart rate. For example, the ingestion of digoxin leads to increased cardiac output and decreased heart rate without significant changes in blood pressure; this quality allows it to be widely used medicinally in the treatment of cardiac arrhythmias. [1]

Non-cardiac uses

Cardiac glycosides were identified as senolytics: they can selectively eliminate senescent cells which are more sensitive to the ATPase-inhibiting action due to cell membrane changes. [14] [15] [16]

Clinical significance

Cardiac glycosides have long served as the main medical treatment to congestive heart failure and cardiac arrhythmia, due to their effects of increasing the force of muscle contraction while reducing heart rate. Heart failure is characterized by an inability to pump enough blood to support the body, possibly due to a decrease in the volume of the blood or its contractile force. [17] Treatments for the condition thus focus on lowering blood pressure, so that the heart does not have to exert as much force to pump the blood, or directly increasing the heart's contractile force, so that the heart can overcome the higher blood pressure. Cardiac glycosides, such as the commonly used digoxin and digitoxin, deal with the latter, due to their positive inotropic activity. On the other hand, cardiac arrhythmia are changes in heart rate, whether faster (tachycardia) or slower (bradycardia). Medicinal treatments for this condition work primarily to counteract tachycardia or atrial fibrillation by slowing down heart rate, as done by cardiac glycosides. [11]

Nevertheless, due to questions of toxicity and dosage, cardiac glycosides have been replaced with synthetic drugs such as ACE inhibitors and beta blockers and are no longer used as the primary medical treatment for such conditions. Depending on the severity of the condition, though, they may still be used in conjunction with other treatments. [11]

Toxicity

From ancient times, humans have used cardiac-glycoside-containing plants and their crude extracts as arrow coatings, homicidal or suicidal aids, rat poisons, heart tonics, diuretics and emetics, primarily due to the toxic nature of these compounds. [6] Thus, though cardiac glycosides have been used for their medicinal function, their toxicity must also be recognized. For example, in 2008 US poison centers reported 2,632 cases of digoxin toxicity, and 17 cases of digoxin-related deaths. [18] Because cardiac glycosides affect the cardiovascular, neurologic, and gastrointestinal systems, these three systems can be used to determine the effects of toxicity. The effect of these compounds on the cardiovascular system presents a reason for concern, as they can directly affect the function of the heart through their inotropic and chronotropic effects. In terms of inotropic activity, excessive cardiac glycoside dosage results in cardiac contractions with greater force, as further calcium is released from the SR of cardiac muscle cells. Toxicity also results in changes to heart chronotropic activity, resulting in multiple kinds of dysrhythmia and potentially fatal ventricular tachycardia. These dysrhythmias are an effect of an influx of sodium and decrease of resting membrane potential threshold in cardiac muscle cells. When taken beyond a narrow dosage range specific to each particular cardiac glycoside, these compounds can rapidly become dangerous. In sum, they interfere with fundamental processes that regulate membrane potential. They are toxic to the heart, the brain, and the gut at doses that are not difficult to reach. In the heart, the most common negative effect is premature ventricular contraction. [6] [19]

Related Research Articles

<i>Digitalis</i> Genus of flowering plants in the family Plantaginaceae

Digitalis is a genus of about 20 species of herbaceous perennial plants, shrubs, and biennials, commonly called foxgloves.

<span class="mw-page-title-main">Sodium–potassium pump</span> Enzyme found in the membrane of all animal cells

The sodium–potassium pump is an enzyme found in the membrane of all animal cells. It performs several functions in cell physiology.

<span class="mw-page-title-main">Digoxin</span> Plant-derived medication

Digoxin, sold under the brand name Lanoxin among others, is a medication used to treat various heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. Digoxin is one of the oldest medications used in the field of cardiology. It works by increasing myocardial contractility, increasing stroke volume and blood pressure, reducing heart rate, and somewhat extending the time frame of the contraction. Digoxin is taken by mouth or by injection into a vein. Digoxin has a half life of approximately 36 hours given at average doses in patients with normal renal function. It is excreted mostly unchanged in the urine.

<span class="mw-page-title-main">Digitoxin</span> Chemical compound

Digitoxin is a cardiac glycoside used for the treatment of heart failure and certain kinds of heart arrhythmia. It is a phytosteroid and is similar in structure and effects to digoxin, though the effects are longer-lasting. Unlike digoxin, which is eliminated from the body via the kidneys, it is eliminated via the liver, and so can be used in patients with poor or erratic kidney function. While several controlled trials have shown digoxin to be effective in a proportion of patients treated for heart failure, the evidence base for digitoxin is not as strong, although it is presumed to be similarly effective.

<span class="mw-page-title-main">Ouabain</span> Chemical substance

Ouabain or also known as g-strophanthin, is a plant derived toxic substance that was traditionally used as an arrow poison in eastern Africa for both hunting and warfare. Ouabain is a cardiac glycoside and in lower doses, can be used medically to treat hypotension and some arrhythmias. It acts by inhibiting the Na/K-ATPase, also known as the sodium–potassium ion pump. However, adaptations to the alpha-subunit of the Na+/K+-ATPase via amino acid substitutions, have been observed in certain species, namely some herbivore- insect species, that have resulted in toxin resistance.

<span class="mw-page-title-main">Cerberin</span> Chemical compound

Cerberin is a type of cardiac glycoside, found in the seeds of the dicotyledonous angiosperm genus Cerbera; including the suicide tree and the sea mango. As a cardiac glycoside, cerberin disrupts the function of the heart by blocking its sodium and potassium ATPase. Cerberin can be used as a treatment for heart failure and arrhythmia.

Bufagin is a toxic steroid C24H34O5 obtained from toad's milk, the poisonous secretion of a skin gland on the back of the neck of a large toad (Rhinella marina, synonym Bufo marinus, the cane toad). The toad produces this secretion when it is injured, scared or provoked. Bufagin resembles chemical substances from digitalis in physiological activity and chemical structure.

The sodium-calcium exchanger (often denoted Na+/Ca2+ exchanger, exchange protein, or NCX) is an antiporter membrane protein that removes calcium from cells. It uses the energy that is stored in the electrochemical gradient of sodium (Na+) by allowing Na+ to flow down its gradient across the plasma membrane in exchange for the countertransport of calcium ions (Ca2+). A single calcium ion is exported for the import of three sodium ions. The exchanger exists in many different cell types and animal species. The NCX is considered one of the most important cellular mechanisms for removing Ca2+.

<i>Cerbera manghas</i> Species of plant

Cerbera manghas, commonly known as the sea mango, tangena or bintaro is a small evergreen coastal tree growing up to 12 metres (39 ft) tall. It is native to coastal areas in Africa, Asia, Australasia, and the Pacific islands. It is classified as one of the three species in the genus Cerbera that constitute mangroves.

<span class="mw-page-title-main">Daigremontianin</span> Chemical compound

Daigremontianin is a bufadienolide. Bufadienolides are steroids and cardiac glycoside aglycones that are similar to cardenolides, differing only in the structure of the C-17 substituent on the D ring. This chemical has been found to be toxic in experiments on mice. It is one of five bufadienolides that have been isolated from Kalanchoe daigremontiana.

<span class="mw-page-title-main">Cardenolide</span> Chemical compound

A cardenolide is a type of steroid. Many plants contain derivatives, collectively known as cardenolides, including many in the form of cardenolide glycosides (cardenolides that contain structural groups derived from sugars). Cardenolide glycosides are often toxic; specifically, they are heart-arresting. Cardenolides are toxic to animals through inhibition of the enzyme Na+/K+-ATPase, which is responsible for maintaining the sodium and potassium ion gradients across the cell membranes.

<span class="mw-page-title-main">Bufadienolide</span> Chemical compound

Bufadienolide is a chemical compound with steroid structure. Its derivatives are collectively known as bufadienolides, including many in the form of bufadienolide glycosides. These are a type of cardiac glycoside, the other being the cardenolide glycosides. Both bufadienolides and their glycosides are toxic; specifically, they can cause an atrioventricular block, bradycardia, ventricular tachycardia, and possibly lethal cardiac arrest.

k-Strophanthidin Chemical compound

k-Strophanthidin is a cardenolide found in species of the genus Strophanthus. It is the aglycone of k-strophanthin, an analogue of ouabain. k-strophanthin is found in the ripe seeds of Strophanthus kombé and in the lily Convallaria.

<span class="mw-page-title-main">Oleandrin</span> Chemical compound

Oleandrin is a cardiac glycoside found in the poisonous plant oleander. As a main phytochemical of oleander, oleandrin is associated with the toxicity of oleander sap, and has similar properties to digoxin.

<span class="mw-page-title-main">Arenobufagin</span> Chemical compound

Arenobufagin is a cardiotoxic bufanolide steroid secreted by the Argentine toad Bufo arenarum. It has effects similar to digitalis, blocking the Na+/K+ pump in heart tissue.

<span class="mw-page-title-main">Antiarin</span> Chemical compound

Antiarins are cardiac glycoside poisons produced by the upas tree. There are two closely related forms, α-antiarin and β-antiarin. The two share the same aglycone, antiarigenin, but differ in the sugar group that is attached to it.

<span class="mw-page-title-main">Convallatoxin</span> Chemical compound

Convallatoxin is a glycoside extracted from Convallaria majalis.

<span class="mw-page-title-main">Istaroxime</span> Chemical compound

Istaroxime is an investigational drug under development for treatment of acute decompensated heart failure

<span class="mw-page-title-main">Erythrophleine</span> Chemical compound

Erythrophleine is a complex alkaloid and ester of tricyclic diterpene acids derived from many of the plants in the genus erythrophleum. A highly toxic compound, it is most commonly known for its use in West African trials by ordeal. Exposure to erythrophleine can quickly lead to ataxia, dyspnea, heart paralysis, and sudden death. Visible effects of erythrophleine poisoning include induced terror, labored and irregular breathing, convulsions, urination, and vomiting.

<span class="mw-page-title-main">Calotropin</span> Chemical compound

Calotropin is a toxic cardenolide found in plants in the family Asclepiadoideae. In extreme cases, calotropin poisoning can cause respiratory and cardiac failure. Accidental poisoning is common in livestock who have ingested milkweed. Calotropin is commonly stored as a defense mechanism by insects that eat milkweeds as their main food source.

References

  1. 1 2 3 4 Patel S (December 2016). "Plant-derived cardiac glycosides: Role in heart ailments and cancer management". Biomedicine & Pharmacotherapy. 84: 1036–1041. doi:10.1016/j.biopha.2016.10.030. PMID   27780131.
  2. ↑ Ambrosy AP, Butler J, Ahmed A, Vaduganathan M, van Veldhuisen DJ, Colucci WS, Gheorghiade M (May 2014). "The use of digoxin in patients with worsening chronic heart failure: reconsidering an old drug to reduce hospital admissions" (PDF). Journal of the American College of Cardiology. 63 (18): 1823–1832. doi: 10.1016/j.jacc.2014.01.051 . PMID   24613328.
  3. ↑ Riganti C, Campia I, Kopecka J, Gazzano E, Doublier S, Aldieri E, et al. (2011-01-01). "Pleiotropic effects of cardioactive glycosides". Current Medicinal Chemistry. 18 (6): 872–885. doi:10.2174/092986711794927685. PMID   21182478.
  4. 1 2 "Cardiac Glycosides". www.people.vcu.edu. Retrieved 2017-05-25.
  5. 1 2 Cheeke PR (1989-07-31). Toxicants of Plant Origin: Glycosides. CRC Press. ISBN   9780849369919.
  6. 1 2 3 "Cardiac Glycoside Plant Poisoning: Practice Essentials, Pathophysiology, Etiology". Medscape. WebMD. 2017-05-05.
  7. 1 2 "Pharmacognosy 2|Digital Textbook Library". www.tankonyvtar.hu. Retrieved 2017-06-08.
  8. ↑ Züst T, Strickler SR, Powell AF, Mabry ME, An H, Mirzaei M, et al. (April 2020). "Independent evolution of ancestral and novel defenses in a genus of toxic plants (Erysimum, Brassicaceae)". eLife. 9: 761569. bioRxiv   10.1101/761569 . doi: 10.7554/eLife.51712 . PMC   7180059 . PMID   32252891.
  9. ↑ Morgan ED (2004). "Chapter 7: Higher Terpenes and Steroids: Sterols in Insects". Biosynthesis in insects. Cambridge: Royal Society of Chemistry. p. 112. ISBN   978-0-85404-691-1.
  10. ↑ Watanabe K, Mimaki Y, Sakagami H, Sashida Y (February 2003). "Bufadienolide and spirostanol glycosides from the rhizomes of helleborusorientalis". Journal of Natural Products. 66 (2): 236–241. doi:10.1021/np0203638. PMID   12608856.
  11. 1 2 3 Bullock S, Manias E (2013-10-15). Fundamentals of Pharmacology. Pearson Higher Education AU. ISBN   9781442564411.
  12. ↑ Babula P, Masarik M, Adam V, Provaznik I, Kizek R (September 2013). "From Na+/K+-ATPase and cardiac glycosides to cytotoxicity and cancer treatment". Anti-Cancer Agents in Medicinal Chemistry. 13 (7): 1069–1087. doi:10.2174/18715206113139990304. PMID   23537048. S2CID   1537056.
  13. ↑ "CV Pharmacology | Cardiac Glycosides (Digitalis Compounds)". cvpharmacology.com. Retrieved 2017-06-08.
  14. ↑ L'Hôte V, Courbeyrette R, Pinna G, Cintrat JC, Le Pavec G, Delaunay-Moisan A, et al. (September 2021). "Ouabain and chloroquine trigger senolysis of BRAF-V600E-induced senescent cells by targeting autophagy". Aging Cell. 20 (9): e13447. doi:10.1111/acel.13447. PMC   8564827 . PMID   34355491.
  15. ↑ Guerrero A, Herranz N, Sun B, Wagner V, Gallage S, Guiho R, et al. (November 2019). "Cardiac glycosides are broad-spectrum senolytics". Nature Metabolism. 1 (11): 1074–1088. doi:10.1038/s42255-019-0122-z. PMC   6887543 . PMID   31799499.
  16. ↑ Triana-Martínez F, Picallos-Rabina P, Da Silva-Álvarez S, Pietrocola F, Llanos S, Rodilla V, et al. (October 2019). "Identification and characterization of Cardiac Glycosides as senolytic compounds". Nature Communications. 10 (1): 4731. Bibcode:2019NatCo..10.4731T. doi:10.1038/s41467-019-12888-x. PMC   6803708 . PMID   31636264.
  17. ↑ "How Is Heart Failure Treated? - NHLBI, NIH". www.nhlbi.nih.gov. Retrieved 2017-06-08.
  18. ↑ Bronstein AC, Spyker DA, Cantilena LR, Green JL, Rumack BH, Giffin SL (December 2009). "2008 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 26th Annual Report". Clinical Toxicology. 47 (10): 911–1084. doi: 10.3109/15563650903438566 . PMID   20028214.
  19. ↑ Kanji S, MacLean RD (October 2012). "Cardiac glycoside toxicity: more than 200 years and counting". Critical Care Clinics. 28 (4): 527–535. doi:10.1016/j.ccc.2012.07.005. PMID   22998989.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.