DIGOXIN Chemical Properties

Melting point:

248 °C

alpha 

25Hg +13.4 to 13.8° (c = 10 in pyridine)

Boiling point:

661.93°C (rough estimate)

Density 

1.1110 (rough estimate)

refractive index 

12 ° (C=10, Pyridine)

Flash point:

9℃

storage temp. 

Refrigerator

solubility 

Soluble in dimethyl sulfoxide and methanol.

form 

powder

pka

13.50±0.70(Predicted)

color 

White to Almost white

Water Solubility 

46.08mg/L(room temperature)

Merck 

14,3167

BRN 

77011

BCS Class

1 (LogP), 3 (CLogP)

LogP

1.260

CAS DataBase Reference

20830-75-5

IARC

2B (Vol. 108) 2016

EPA Substance Registry System

Digoxin (20830-75-5)

Safety Information

Hazard Codes 

T,T+,F

Risk Statements 

25-26/27/28-23/25-39/23/24/25-23/24/25-11-28-26

Safety Statements 

22-36/37/39-45-36/37-16-28A

RIDADR 

UN 3462 6.1/PG 2

WGK Germany 

3

RTECS 

IH6125000

F 

3-10

TSCA 

Yes

HazardClass 

6.1

PackingGroup 

II

HS Code 

29389090

Hazardous Substances Data

20830-75-5(Hazardous Substances Data)

Toxicity

cat,LD50,oral,200ug/kg (0.2mg/kg),Archives Internationales de Pharmacodynamie et de Therapie. Vol. 159, Pg. 1, 1966.

MSDS

• Language:English Provider:SigmaAldrich
• Language:English Provider:ALFA

DIGOXIN Usage And Synthesis

Description

Digoxin, 3β,14β-dihydroxy-5β-card-20(22)-enolide-3-rigitoxide, is also a glycoside isolated from various types of foxgloves. It differs from digitoxin in that it has an additional hydroxyl group at C16 of the steroid skeleton. It is extracted form the leaves of Digitalis lanta, Digitalis orientalis, or Scrophulariaceae.

Description

Digoxin is a cardiac glycoside and metabolite of digitoxin that binds to and inhibits the Na⁺/K⁺-ATPase in cardiac tissues in an ATP- and Mg²⁺-dependent manner. This inhibition results in loss of the transmembrane Na⁺ gradient, which decreases activity of the Na⁺/Ca²⁺ exchanger, increasing intracellular Ca²⁺ levels, inotropy, and cardiac force. It increases activity of mitochondrial ATPase and actomyosin ATPase in rat hearts, which is directly correlated with increased myofibrillar contractile strength. In vivo, digoxin also decreases right atrial pressure and increases cardiac output in a canine model of congestive heart failure produced by pulmonary artery constriction. Formulations containing digoxin have been used to treat atrial fibrillation.

Chemical Properties

White Crystalline Powder

Physical properties

Appearance: white crystals or crystalline powder, odorless. Solubility: easily dissolved in pyridine, slightly soluble in dilute alcohol, slightly soluble in chloroform, insoluble in water and ethyl ether. Specific optical rotation: +9.5 to +12.0°. Melting point: 248–250?°C.

Originator

Digoxin,Alexandria Co.

History

Digitalis, a kind of scrophulariaceae biennial or perennial herb, originating in Europe in central and southern mountains, which was isolated from plants of the genus Digitalis, has a long history of treating heart disease. Digitalis was also recorded in Chinese Materia Medica and now is largely cultivated in China.
In clinical practice, the commonly used digitalis so far is known as the cardiac glycoside. (In the twentieth century, this kind of structure was called a glucoside. In the late twentieth century, domestic individual chemical researchers proposed renaming it glycoside, identical to lanatoside k Huang Zhong). In 1930, a researcher from Burroughs Wellcome pharmaceutical company named Sydney Smith successfully isolated several steroid glycosides, including digoxin. The later production of digoxin by Burroughs Wellcome’s successor company GlaxoSmithKline is called LANOXIN, which is also called DIGITEK.? Since that time, digoxin has been widely used in clinical practice to treat patients with CHF and atrial arrhythmia. Now digoxin is still the basis of heart failure treatment, and in most cases it is one of the preferred first-line drugs.
In 1954, researchers from the Institute of Materia Medica of the Chinese Academy of Medical Sciences improved the method of extracting digitoxin, resulting in a simpler and 3.5 times higher yield than that of extracting digitoxin in German pharmaceutical. In addition, the purity of domestic digitalis was improved. The injection preparation was then produced and applied in clinical practice.
Recently greatly advances have been made in research on the effects of cardiac glycoside on cancer. Using high-throughput screening methods that have been widely applied to the identification of new cardiac glycosides, researchers found that cardiac glycoside can inhibit transplantation tumor growth in mice. This research also helped in the development of the domestic pharmaceutical industry.

Uses

Digoxin exhibits strong systolic action and slows heart rate. It is removed from the organism faster than digitoxin. It is used from chronic cardiac insufficiency in decompensated valvular disease of the heart, myocardium overload in arterial hypertension, tachycardia, ventricular fibrillation, and other analogous situations.

Uses

Cardiotonic

Uses

cardiac stimulant

Definition

ChEBI: A cardenolide glycoside that is digitoxin beta-hydroxylated at C-12. A cardiac glycoside extracted from the foxglove plant, Digitalis lanata, it is used to control ventricular rate in atrial fibrillation and in the management of congestive heart failure with atrial fibrillation, but the margin between toxic and therapeutic doses is small.

Indications

Digoxin is used for congestive heart failure (CHF), paroxysmal supraventricular tachycarelia, atrial fibrillation, and atrial flutter.

Manufacturing Process

It has long been known that digitalis leaves owe their physiological activity to the presence in them of certain glucosidal constituents. A method of preparation of a well-defined crystalline glucoside is described. The new glucoside is separated in the following manner. The total glucosides of the leaf of Digitalis lanata prepared by the usual methods (e.g. that of Keller and Fromme, Lehrbuch der Pharm. Chem., Schmidt) are stirred with acetone or methyl ethyl ketone in the cold using approximately two parts of acetone or methyl ethyl ketone to one part of the glucosidal mixture. After standing the sparingly soluble glucosides (A) are separated. The filtrate is fractionally precipitated with water until no more solid separates on further addition of water. The solid (B) is separated and the filtrate is saturated with salt when a further precipitate (C) is formed. This salt precipitate is dried and extracted in the cold with methyl or ethyl alcohol and the solution diluted with water. On standing crystals of the new glucoside separate. The glucoside is freed from more soluble glucosides by boiling with small quantities of chloroform, acetone or methylethyl ketone in which it is sparingly soluble and then crystallized by concentrating a solution in hot 80% methyl or ethyl alcohol. The glucoside can also be crystallized by the addition of water or ether to a solution of the substance in pyridine. Further quantities of the glucoside may be obtained by extracting the aqueous filtrate from salt precipitate (C) with cold chloroform. The chloroform extract after evaporation is stirred with acetone or methyl ethyl ketone and the sparingly soluble portion is further purified by boiling with small quantities of chloroform and the sparingly soluble portion crystallized as above described. The glucoside is also present in precipitate, which separates from the acetone or methyl ethyl ketone and in the fraction (B) precipitated by water from the acetone or methyl ethyl ketone solution. It may be separated from these solutions by fractional crystallization from hot dilute alcohol, followed by boiling the less soluble fractions with acetone, methyl ethyl ketone, or chloroform and crystallization of the sparingly soluble portions above described. The new glucoside digoxin crystallizes in stout plates; MP: at about 265°C. (decomp.); αD25 =+17.9°.

brand name

Lanoxin (GlaxoSmithKline).

Therapeutic Function

Cardiotonic

General Description

Clear to white crystals or white crystalline powder. Odorless. Used as a cardiotonic drug.

General Description

Digitalis (Crystodigin) is isolated fromD. lanata and D. purpurea among other Digitalis spp., and isthe chief active glycoside in digitalis leaf, with 1 mg digitoxinequal to 1 g of digitalis leaf therapy. In patients who missdoses, digitalis is very useful for maintenance therapy becauseof the longer half-life it provides. The longer durationand increased half-life are a result of the lack of the C-12hydroxy that is present in digoxin. In digoxin, this hydroxyplays two roles: (a) it serves as a site for metabolism, whichreduces the compound’s half-life; and (b) it gives more hydrophiliccharacter, which results in greater water solubilityand ease in renal elimination.

General Description

Digoxin (Lanoxin) is a purified digitalis preparationfrom D. lanata and represents the most widely useddigitalis glycoside. This wide use is primarily a result of itsfast onset and short half-life. Position 3 of the steroid is substitutedwith three digitoxose residues that, when removed,provide a genin or aglycone steroid that is still capable of receptorbinding but with altered pharmacokinetics.

Health Hazard

Material is a digitalis glycoside. Ingestion can cause death. Material is considered super toxic; probable human oral lethal dose is less than 5 mg/kg, a taste (less than 7 drops) for a 70 kg (150 lb.) person. Persons at risk include those taking drugs for thyroid and renal diseases. Quinidine and diuretics taken concurrently with DIGOXIN can be hazardous. It should be used with extreme care during pregnancy and in nursing mothers.

Fire Hazard

Avoid light.

Clinical Use

Supraventricular arrhythmias
Supraventricular arrhythmias

Safety Profile

A deadly poison by most routes. Human systemic effects by ingestion: anorexia, cardlac arrhythmias, nausea and vomiting, visual field changes, pulse rate decrease, fall in blood pressure. An experimental teratogen. When heated to decomposition it emits acrid and irritating fumes. See also DIGITALIS.

Potential Exposure

NaturalProduct; Reproductive Effector. Digoxin is used as a cardiotonic drug.

target

HIF | Sodium Channel | ATPase | Potassium Channel

Drug interactions

Potentially hazardous interactions with other drugs
Angiotensin-II antagonists: concentration increased by telmisartan
Anti-arrhythmics: concentration increased by amiodarone, dronedarone and propafenone (half maintenance dose of digoxin).
Antidepressants: concentration reduced by St John’s wort - avoid.
Antifungals: increased toxicity if hypokalaemia occurs with amphotericin; concentration increased by itraconazole
Antimalarials: concentration possibly increased by quinine, hydroxychloroquine and chloroquine; increased risk of bradycardia with mefloquine
Antivirals: concentration increased by daclatasvir
Calcium-channel blockers: concentration increased by diltiazem, lercanidipine, nicardipine, verapamil and possibly nifedipine; increased risk of AV block and bradycardia with verapamil.
Ciclosporin: concentration increased by ciclosporin.
Colchicine: possibly increased risk of myopathy
Diuretics: increased toxicity if hypokalaemia occurs; concentration increased by spironolactone and possibly potassium canrenoate.
Ticagrelor: concentration of digoxin increased

First aid

If this chemical gets into the eyes, remove anycontact lenses at once and irrigate immediately for at least15 min, occasionally lifting upper and lower lids. Seek medical attention immediately. If this chemical contacts theskin, remove contaminated clothing and wash immediatelywith soap and water. Seek medical attention immediately. Ifthis chemical has been inhaled, remove from exposure,begin rescue breathing (using universal precautions, including resuscitation mask) if breathing has stopped and CPR ifheart action has stopped. Transfer promptly to a medicalfacility. When this chemical has been swallowed, get medical attention. Give large quantities of water and inducevomiting. Do not make an unconscious person vomit.

Environmental Fate

Molecular weight: Digitoxin, 764.96; Digoxin, 780.96. Cardiac glycosides have a characteristic chemical structure called an aglycone ring. This is coupled with one or more sugars. The aglycone portion of the glycoside includes a steroid nucleus and a lactone ring at the C17 position. Hydroxyl groups, oriented to the beta position, are present at the C3 and C14 positions. Increases in numbers of hydroxyl groups cause an increase in polarity and decrease in lipid solubility. Increases in numbers of sugars also increase polarity and reduce lipid solubility. Sugars are attached to the steroid nucleus through a hydroxyl group at the C3 position and influences solubility, absorption, toxicity, and other pharmacological parameters.

Metabolism

Digoxin is mainly excreted unchanged in the urine by glomerular filtration and tubular secretion; reabsorption also occurs. Extensive metabolism has been reported in a minority of patients Metabolites that have been detected in the urine include digoxigenin, dihydrodigoxigenin, the mono- and bisdigitoxosides of digoxigenin, and dihydrodigoxin. Digoxigenin mono- and bisdigitoxosides are known to be cardioactive whereas dihydrodigoxin is probably much less active than digoxin.
In about 10% of patients there is considerable reduction to cardio-inactive metabolites, chiefly dihydrodigoxin, and 40% or more of a dose may be excreted in the urine as dihydrodigoxin. Bacterial flora in the gastrointestinal tract appear to be responsible for this metabolism and antibacterials can reduce the process.a Excretion of digoxin is proportional to the glomerular filtration rate. After intravenous injection 50-70% of the dose is excreted unchanged.

storage

Store at RT

Shipping

This compound falls in the DOT ID and ERGNumber: UN3249. Medicine, solid, toxic, n.o.s. categoryand requires a shipping label of “POISONOUS/TOXICMATERIALS.” It falls in Hazard Class 6.1 and PackingGroup III.

Purification Methods

Crystallise digoxin from aqueous EtOH, aqueous pyridine, EtOH/CHCl3, and dry it in a vacuum at 100o. The melting point depends on heating rate, but when placed in a bath at 260o and heated slowly it decomposes at 265o. In EtOH it has max at 220nm ( 12,800). [Smith J Chem Soc 508 1930, X-ray: Go et al. Cryst Struct Commun 8 149, 1031 1979, Beilstein 18/4 V 381.] HIGHLY TOXIC.

Toxicity evaluation

Digitalis glycosides inhibit the Na–K–ATPase pump, causing increased intracellular sodium, and loss of intracellular potassium and subsequent increase in intracellular calcium. This results in a positive inotropic effect and decreased rate of cardiac conduction through the sinoatrial and atrioventricular nodes.

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