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 Mg
2+-dependent manner. This inhibition results in loss of the transmembrane Na
+ gradient, which decreases activity of the Na
+/Ca
2+ exchanger, increasing intracellular Ca
2+ 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.
Indications
Digoxin is used for congestive heart failure (CHF), paroxysmal supraventricular
tachycarelia, atrial fibrillation, and atrial flutter.
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.
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
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.
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.
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.
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.
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.
References
[1] HIDEO MATSUI Arnold S. Mechanism of cardiac glycoside inhibition of the (Na+-K+)-dependent ATPase from cardiac tissue[J]. Biochimica et Biophysica Acta (BBA) - Enzymology, 1968, 151 3: Pages 655-663. DOI:
10.1016/0005-2744(68)90013-2[2] CLAODETE HASSELSTROM NEVES. Digoxin Induces Cardiac Hypertrophy Without Negative Effects on Cardiac Function and Physical Performance in Trained Normotensive Rats[J]. International journal of sports medicine, 2017, 38 1: 263-269. DOI:
10.1055/s-0042-119727[3] De Souza, F.I., Zumiotti, A.V., and Da Silva, C.F. Neuregulins 1-α and 1-β on the regeneration the peripheral nerves[J]. Acta Ortop Bras.
[4] J O DAVIS R E H D S HOWELL. Effects of acute and chronic digoxin administration in dogs with right-sided congestive heart failure produced by pulmonary artery constriction.[J]. Circulation research, 1955, 3 3: 259-263. DOI:
10.1161/01.res.3.3.259[5] DIPAK KOTECHA. A review of rate control in atrial fibrillation, and the rationale and protocol for the RATE-AF trial.[J]. BMJ Open, 2017, 7 7: e015099. DOI:
10.1136/bmjopen-2016-015099
