Cardioactive Glycosides
Drugs

Author: Federica Taddei
Date: 23/03/2008

Description

DESCRIPTION

Cardioactive glycosides, like digoxin, ouabain and related compounds, are drugs that inhibit Na+/K+-ATPase and have a strong inotropic effect on heart: they cause the Na+/Ca2+ exchanger to extrude Na+ in exchange with Ca2+ and therefore increase the [Ca2+]i concentration.
For this reason, some of these drugs are currently used in the treatment of congestive heart failure and cardiac arrhythmias.

CLASSIFICATION

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INDICATIONS

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PHARMACOKINETICS

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MOLECULAR MECHANISM

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PHARMACOGENOMICS

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SIDE EFFECTS

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TOXICITY

During February 1993-May 1995, the New York City Poison Control Center (NYCPCC) was informed about onset of illness in five previously healthy men after they ingested a substance marketed as a topical aphrodisiac; four of the men died. These cases were investigated by the New York City Department of Health, the New York City Department of Environmental Protection, and the Food and Drug Administration (FDA). Four cases were referred to the NYCPCC and one case to the New York City medical examiner's office. The decedents died from cardiac dysrhythmias, and all five patients had measurable levels of digoxin* detected in their serum. Digoxin had not been prescribed for therapeutic purposes for any of these patients, and none had medical conditions associated with endogenous digoxin-like immunoreactive substances. The purported aphrodisiac contains bufadienolides, naturally occurring cardioactive steroids that have digoxin-like effects. This report describes three of the five case reports, summarizes the investigations of the five cases, and underscores the health risks associated with inappropriate use of preparations containing digoxin-like substances.
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molecular intervenction ouabain digoxin

Figure 1.

Comparison of the chemical structures of one well-known cardenolide, i.e., ouabain (A), with 2″-oxovoruscharin (UNBS1244; B) and its hemisynthetic derivative, UNBS1450 (B).
The cardenolide UNBS1450 is able to deactivate nuclear factor κB–mediated cytoprotective effects in human non–small cell lung cancer cells 2006

Cardiovascular drugs in human mechanical nociception: digoxin, amlodipine, propranolol, pindolol and atenolol. 2010

Role of endosomal Na+-K+-ATPase and cardiac steroids in the regulation of endocytosis.2007

Novel therapeutic applications of cardiac glycosides 2008

Each molecule of this family consists of three distinct structural motifs:

  • a steroid nucleus
  • a sugar moiety
    • the sugar moiety defines the affinity for specific Na+/K+ATPase isoforms
  • a lactone moiety
    • the lactone moiety defines the functional class of each compound.
      • Cardenolides contain a five-membered unsaturated butyrolactone ring
      • Bufadienolides contain a six-membered unsaturated pyrone ring

List of natural cardiac glycosides

Digoxin

Ouabain

DESCRIPTION

Digoxin is one of the cardiac glycosides, a group of drugs having in common specific effects on the myocardium. These drugs are found in a number of plants. Digoxin is extracted from the leaves of Digitalis lanata.
The glycosides are composed of two portions: a sugar and a cardenolide (hence "glycosides"). Its molecular formula is C41H64O14 and its structural formula is:

Digoxin HMD

Ouabain

A fresh facet for ouabain action 2001

INDICATIONS

Digoxin is indicated for the treatment of mild to moderate heart failure. Digoxin increases left ventricular ejection fraction and improves heart failure symptoms.
Digoxin is indicated for the control of ventricular response rate in patients with chronic atrial fibrillation. High ventricular rate leads to insufficient diastolic filling time. By slowing down the conduction in the AV node and increasing its refractory period, digoxin can reduce the ventricular rate. The arrhythmia itself is not affected, but the pumping function of the heart improves owing to improved filling.

MOLECULAR MECHANISM

Digoxin is an inhibitor of the Na+/K+ATPase pump and it connects with its alpha subunit.
The drugs prefers to connect with the enzyme after the fosforilation of a beta aspartate,located on the surface of the alpha subunit.
During the ripolarization process Ca++ is repumped into the SR by means of a Ca++/ATPase pump and it is removed from the cell through a Na+/Ca++ exchange pump.The ability of the exchanger to expell Ca++ depends on the intracellular concentration of the Na+.The inhibition of pump Na+/K+ ATPase increases the quantity of Na+ in the cytoplasm;there is not the gradient which allows and Ca++ to be pumped outside the cell.The Ca++ in excess is taken by the SR in order to make it avaible for a new contraction.
The extracellular K+ helps the defosforilation of the enzyme during the traslocation of this cation into the cytoplasm,allowing to reduce the affinity of the enzyme for the drug.
The beneficial effects of digoxin result from direct actions on cardiac muscle, as well as indirect actions on the cardiovascular system mediated by effects on the autonomic nervous system.
The autonomic effects include
- a vagomimetic action, which is responsible for the effects of digoxin on the sinoatrial and atrioventricular nodes;
- baroreceptor sensitization, which results in increased afferent inhibitory activity and reduced activity of the sympathetic nervous system and renin-angiotensin system for any given increment in mean arterial pressure.
The pharmacologic consequences of these direct and indirect effects are:
- a positive inotropic action;
- a decrease in the degree of activation of the sympathetic nervous system and renin-angiotensin system (neurohormonal deactivating effect);
- slowing of the heart rate;
- decreased conduction velocity through the AV node (vagomimetic effect).
The effects of digoxin in heart failure are mediated by its positive inotropic and neurohormonal deactivating effects, whereas the effects of the drug in atrial arrhythmias are related to its vagomimetic actions.
In high doses, digoxin increases sympathetic outflow from the central nervous system (CNS). This increase in sympathetic activity may be an important factor in digitalis toxicity.

Ouabain induces endocytosis of plasmalemmal Na/K-ATPase in LLC-PK1 cells by a clathrin-dependent mechanism 2004

Schematic representation of the ouabain-induced endocytosis of Na/K-ATPase. Na/K-ATPase depicted show binding to ouabain (Oua, blue oval), Src (purple oval), EGFR (dark green oval), and later PIK (light green oval) and AP2 (light blue oval). Possible fates, including degradation in lysosomes, recycling to the plasmalemma, and translocation to the nucleus for signaling are illustrated.

Na+-K+–ATPase-Mediated Signal Transduction: From Protein Interaction to Cellular Function 2002

ciclo ed effetto

DOSAGE

Digoxin has a narrow therapeutic index (the margin between effectiveness and toxicity). Therapeutic serum digoxin concentrations is between 0.8 and 2.0 ng/mL.

SIDE EFFECTS

The occurrence of adverse drug reactions is common, owing to its narrow therapeutic index. Adverse effects are concentration-dependent, and are rare when plasma digoxin concentration is <0.8 μg/L.
They are also more common in patients with low potassium levels (hypokalemia), since digoxin normally competes with K+ ions for the same binding site on the Na+/K+ ATPase pump. Because some patients may be particularly susceptible to side effects with digoxin, the dosage of the drug should always be selected carefully and adjusted as the clinical condition of the patient warrants. Cardiac adverse reactions accounted for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse reactions.
High doses of digoxin may produce a variety of rhythm disturbances, such as first-degree, second-degree (Wenckebach), or third-degree heart block (including asystole); atrial tachycardia with block; unifocal or multiform ventricular premature contractions (especially bigeminy or trigeminy); ventricular tachycardia; and ventricular fibrillation. Digoxin produces PR prolongation and ST segment depression which should not by themselves be considered digoxin toxicity. Cardiac toxicity can also occur at therapeutic doses in patients who have conditions which may alter their sensitivity to digoxin. Digoxin may cause anorexia, nausea, vomiting, and diarrhea. Digoxin can produce visual disturbances (blurred or yellow vision), headache, weakness, dizziness, apathy, confusion, and mental disturbances (such as anxiety, depression, delirium, and hallucination).

Platelets

Digoxin use is associated with increased platelet and endothelial cell activation in patients with nonvalvular atrial fibrillation. 2005
Heart Rhythm. 2005 May;2(5):525-9.
Chirinos JA, Castrellon A, Zambrano JP, Jimenez JJ, Jy W, Horstman LL, Willens HJ, Castellanos A, Myerburg RJ, Ahn YS.

Comment * Heart Rhythm. 2005 May;2(5):530-1.

Abstract

OBJECTIVES: The purpose of this study was to determine whether digoxin use is associated with increased flow cytometric markers of endothelial cell and platelet activation in patients with nonvalvular atrial fibrillation (AF). BACKGROUND: Increased intracellular calcium is a key event in platelet activation, and several studies have demonstrated that digitalis activates platelets in vitro. Intracellular calcium also is a key regulator of endothelial cell function, and endogenous digitalis-like substances have been shown to affect biologic processes in endothelial cells. METHODS: We studied 30 patients with nonvalvular AF. We measured the levels of (1) platelet expression of P-selectin (CD62P), (2) platelet microparticles (PMP); and (3) endothelial microparticles (EMP) identified by anti-CD31 (EMP31) and by anti-E-selectin antibodies (EMP62E). RESULTS: Patients who were taking digoxin (n = 16; mean digoxin level = 0.93 ng/dL) did not demonstrate any significant differences in clinical or echocardiographic characteristics compared with patients not taking digoxin (n = 14). Patients taking digoxin had significantly increased levels of CD62P expression in platelets and platelet-leukocyte conjugates and markedly increased markers of endothelial activation: EMP62E and EMP31. After adjusting for potential confounders (including age, congestive heart failure, coronary artery disease, ejection fraction, antiplatelet, beta-blocker, and calcium channel blocker use), the differences persisted. CONCLUSIONS: Digoxin use in patients with AF is associated with increased levels of endothelial and platelet activation. If digitalis activates endothelial cells and platelets at pharmacologic doses, use of digitalis in conditions such as AF could predispose to thrombosis and vascular events.

TREATMENT OF ADVERSE REACTIONS

Digoxin should be temporarily discontinued until the adverse reaction resolves. Once the adverse reaction has resolved, therapy with digoxin may be reinstituted, following a careful reassessment of dose. Once the adverse reaction has resolved, therapy with digoxin may be reinstituted, following a careful reassessment of dose.
If there is a the rhythm disturbance should be given DIGIBIND [Digoxin Immune Fab (Ovine)]which is a sterile lyophilized powder of antigen binding fragments (Fab) derived from specific antidigoxin antibodies raised in sheep. DIGIBIND is a specific antidote when there is a digoxin overdosage.
It also can be given potassium canrenoate.
Every effort should be made to maintain the serum potassium concentration between 4.0 and 5.5 mmol/L.

Antiarrhythmic activity of potassium canrenoate in man.

In vitro antiproliferative and/or apoptotic effects of cardiac glycosides in cancer cells 2008

TOXICITY

During February 1993-May 1995, the New York City Poison Control Center (NYCPCC) was informed about onset of illness in five previously healthy men after they ingested a substance marketed as a topical aphrodisiac; four of the men died. These cases were investigated by the New York City Department of Health, the New York City Department of Environmental Protection, and the Food and Drug Administration (FDA). Four cases were referred to the NYCPCC and one case to the New York City medical examiner's office. The decedents died from cardiac dysrhythmias, and all five patients had measurable levels of digoxin* detected in their serum. Digoxin had not been prescribed for therapeutic purposes for any of these patients, and none had medical conditions associated with endogenous digoxin-like immunoreactive substances. The purported aphrodisiac contains bufadienolides, naturally occurring cardioactive steroids that have digoxin-like effects. This report describes three of the five case reports, summarizes the investigations of the five cases, and underscores the health risks associated with inappropriate use of preparations containing digoxin-like substances.
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RESISTANCE

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DEPENDENCE AND WITHDRAW

molecular intervenction ouabain digoxin

Figure 1.

Comparison of the chemical structures of one well-known cardenolide, i.e., ouabain (A), with 2″-oxovoruscharin (UNBS1244; B) and its hemisynthetic derivative, UNBS1450 (B).
The cardenolide UNBS1450 is able to deactivate nuclear factor κB–mediated cytoprotective effects in human non–small cell lung cancer cells 2006

Cardiovascular drugs in human mechanical nociception: digoxin, amlodipine, propranolol, pindolol and atenolol. 2010

Role of endosomal Na+-K+-ATPase and cardiac steroids in the regulation of endocytosis.2007

Comments
2012-01-25T17:29:57 - Gianpiero Pescarmona

Atdhe Grezda

Na+, K+-ATPase inhibitors as ER antagonists

It has been found out that these “toxins” have benefits in breast cancer as they act as an anti-breast cancer drug. It has been demonstrated that prolonged exposure to 17beta-estradiol (E2) is a key factor for human breast cancer. The biological effects and carcinogenic effects of E2 are mediated via estrogen receptors (ERs), ER alpha and ER beta. Anti-estrogens, such as Tamoxifen, and aromatase inhibitors have been used to treat ER-positive breast cancer. While anti-estrogen therapy is initially successful, a major problem is that most tumors develop resistance and the disease ultimately progresses, pointing to the need of developing alternative drugs targeting to other critical targets in breast cancer cells. Has been identified that Na+, K+-ATPase , a plasma membrane ion pump, has unique/valuable properties that could be used as a potentially important target for breast cancer treatment:

non si possono fare osservazioni cosi importanti senza voci bibliografiche

  1. it is a key player of cell adhesion and is involved in cancer progression;
  2. it serves as a versatile signal transducer and is a target for a number of hormones including estrogens
  3. its aberrant expression and activity are implicated in the development and progression of breast cancer

There are several lines of evidence indicating that compounds extracted from Digitalis (the potent inhibitors of Na+, K+-ATPase) possess potent anti-breast cancer activity. While it is not clear how the anti-cancer activity of these drugs work, several observations point to digitalis as being potential ER antagonists. Modulators, such as digoxin and digitoxin, could be useful to develop valuable anti-breast cancer drugs as both Na+, K+-ATPase inhibitors and ER antagonists.

Sodium/potassium ATPase (Na+, K+-ATPase) and ouabain/related cardiac glycosides: A new paradigm for development of anti- breast cancer drugs?, 2005

Diabetes Mellitus

It has been discovered that dysregulation of Na/K-ATPase in associated to the pathogenesis of Diabetes Mellitus and its complications. Recently has been demonstrated that, in addition to endogenous ouabain or related digitalis (which are both inhibitors of Na/K ATPase pump), mammalian tissues contain another Na/K-ATPase inhibitor, a bufadienolide marinobufagenin (MBG). In vitro MBG, a natriuretic and a vasoconstrictor, acts as a selective inhibitor of alpha-1 Na/K-ATPase, the main isoform of the sodium pump in renal tubules and vascular smooth muscle. To determine whether digitalis-like Na/K-ATPase inhibitors are linked to Na/K-ATPase dysregulation in Diabetes Mellitus have been studied changes in renal excretion and plasma levels of MBG and digitalis-related toxins and the activity of erythrocyte Na/K-ATPase in male rats with type 1 diabetes mellitus and type 2 diabetes mellitus. Rats with type 1 diabetes mellitus were studied four weeks following a single intraperitoneal injection of streptozotocin, and rats with type 2 diabetes mellitus were studied 10 weeks after intraperitoneal injection of streptozotocin during the neonatal period . Renal excretion and plasma levels of digitalis-related toxins did not change in rats with both types of diabetes mellitus as compared to that in the control groups. Renal excretion and plasma levels of MBG increased, and Na/K-ATPase activity in erythrocytes was inhibited by 50% in rats with type 1 diabetes mellitus as compared to controls. In rats with type 2 diabetes mellitus, plasma levels and renal excretion of MBG also became elevated, but less than in the animals with type 1 diabetes mellitus. Accordingly, activity of Na/K-ATPase in erythrocytes from rats with type 2 diabetes mellitus was inhibited by 35%. In vitro treatment of erythrocytes from rats with type 1 and type 2 diabetes mellitus with anti-MBG antibody reversed the diabetes mellitus induced inhibition of the Na/K-ATPase . These results suggest that digitalis-like factors are involved in the pathogenesis of diabetes mellitus and that MBG, rather than digitalis-related toxins, is responsible for diabetes mellitus-induced Na/K-ATPase inhibition.

Endogenous digitalis-like ligands and Na/K-ATPase inhibition in experimental diabetes mellitus, 2005

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