Digitoxin is a

cardiac glycoside 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. Their beneficial medical uses are as treatments for co ...

used for the treatment of

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...

and certain kinds of

heart arrhythmia Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...

. It is a

phytosteroid Phytosteroids, also known as plant steroids, are naturally occurring steroids that are found in plants. Examples include digoxin, digitoxin, diosgenin, and guggulsterone, as well as phytosterols like β-sitosterol and other phytoestrogens A phy ...

and is similar in

structure A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...

and effects to

digoxin Digoxin (better known as Digitalis), 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 on ...

, 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.

Medical uses

Digitoxin is used for the treatment of heart failure, especially in people with impaired kidney function. It is also used to treat certain kinds of

, such as atrial fibrillation.

Contraindications

Contraindications include * problems with the heart rhythm, such as severe

bradycardia Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, a ...

(slow heartbeat),

ventricular tachycardia Ventricular tachycardia (V-tach or VT) is a fast heart rate arising from the lower chambers of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple episodes over a short period ...

(fast heartbeat caused by the ventricles),

ventricular fibrillation Ventricular fibrillation (V-fib or VF) is an abnormal heart rhythm in which the ventricles of the heart quiver. It is due to disorganized electrical activity. Ventricular fibrillation results in cardiac arrest with loss of consciousness and no p ...

, or first- to second-degree

atrioventricular block Atrioventricular block (AV block) is a type of heart block that occurs when the electrical signal traveling from the atria, or the upper chambers of the heart, to ventricles, or the lower chambers of the heart, is impaired. Normally, the sinoatr ...

, * and certain

electrolyte imbalance Electrolyte imbalance, or water-electrolyte imbalance, is an abnormality in the concentration of electrolytes in the body. Electrolytes play a vital role in maintaining homeostasis in the body. They help to regulate heart and neurological function, ...

hypokalemia Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an abno ...

(low blood potassium levels),

hypomagnesemia Magnesium deficiency is an electrolyte disturbance in which there is a low level of magnesium in the body. It can result in multiple symptoms. Symptoms include tremor, poor coordination, muscle spasms, loss of appetite, personality changes, an ...

(low magnesium), and

hypercalcemia Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defined as hypercalcemi ...

(high calcium).

Adverse effects and toxicity

Digitoxin exhibits similar toxic effects to

, namely:

anorexia Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gre ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

, vomiting, diarrhea, confusion, visual disturbances, and cardiac

arrhythmias Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...

. Antidigoxin

antibody fragment An antibody fragment can be: *a fragment antigen-binding The fragment antigen-binding region (Fab region) is a region on an antibody that binds to antigens. It is composed of one constant and one variable domain of each of the heavy and the lig ...

s, the specific treatment for digoxin poisoning, are also effective in serious digitoxin toxicity.

Interactions

Drugs that can increase digitoxin toxicity include: * calcium * substances that lower potassium or magnesium levels, such as

diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...

s and

corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...

s * inhibitors of the liver enzyme

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...

, which slow down digitoxin

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

; examples are the antibiotic

clarithromycin Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, ''H. pylori'' infection, and Lyme disease, among others. Clarith ...

, the antifungal

itraconazole Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given by mouth ...

, and

grapefruit juice Grapefruit juice is the juice from grapefruits. It is rich in vitamin C and ranges from sweet-tart to very sour. Variations include white grapefruit, pink grapefruit and ruby red grapefruit juice.The World's Healthiest Foods; Grapefruit. ''The ...

* inhibitors of the transporter protein

P-gp P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...

, such as clarithromycin *

Beta blocker Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage cardiac arrhythmia, abnormal heart rhythms, and to protect the heart from a second myocardial infarction, heart attack after a first heart ...

s add to the

(slow heartbeat) caused by digitoxin. Drugs that can decrease the effectivity of digitoxin include: * substances that increase potassium levels, such as potassium sparing diuretics * inducers of CYP3A4 or P-gp, such as

phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The intr ...

rifampicin Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), mycobacterium avium complex, ''Mycobacterium avium'' complex, leprosy, and Legionnaires’ disease. ...

and

St John's Wort ''Hypericum perforatum'', known as St. John's wort, is a flowering plant in the family Hypericaceae and the type species of the genus ''Hypericum''. Possibly a hybrid between '' H. maculatum'' and '' H. attenuatum'', the species can be found a ...

* substances that bind digitoxin in the gut, such as aluminium containing

antacid An antacid is a substance which neutralizes stomach acidity and is used to relieve heartburn, indigestion or an upset stomach. Some antacids have been used in the treatment of constipation and diarrhea. Marketed antacids contain salts of alumi ...

s or

colestyramine Colestyramine (INN) or cholestyramine (USAN) (trade names Questran, Questran Light, Cholybar, Olestyr) is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, w ...

Pharmacology

Mechanism of action

Digitoxin inhibits the sodium-potassium ATPase in heart muscle cells, resulting in increased force of contractions (positive

inotropic An inotrope is an agent that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular contraction. The term ''inotro ...

), reduced speed of electric conduction (negative

dromotropic The term ''dromotropic'' derives from the Greek word δρόμος ''drómos'', meaning "running", a course, a race. A dromotropic agent is one which affects the conduction speed (in fact the magnitude of delay) in the AV node, and subsequently the r ...

), increased excitability (positive

bathmotropic Bathmotropic often refers to modifying the degree of excitability specifically of the heart; in general, it refers to modification of the degree of excitability (threshold of excitation) of musculature in general, including the heart. It especiall ...

), and reduced frequency of heartbeat (negative

chronotropic Chronotropic effects (from ''chrono-'', meaning time, and ''tropos'', "a turn") are those that change the heart rate. Chronotropic drugs may change the heart rate and rhythm by affecting the electrical conduction system of the heart and the ner ...

Pharmacokinetics

The drug is almost completely absorbed from the gut. When in the bloodstream, 90 to 97% are bound to

plasma protein Blood-proteins, also termed plasma proteins, are proteins present in blood plasma. They serve many different functions, including transport of lipids, hormones, vitamins and minerals in activity and functioning of the immune system. Other blood pr ...

s. Digitoxin undergoes

enterohepatic circulation Enterohepatic circulation refers to the circulation of biliary acids, bilirubin, drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver. Ent ...

. It is

metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

in part by CYP3A4; metabolites include

digitoxigenin Digitoxigenin, a cardenolide, is the aglycone of digitoxin. Digitoxigenin can be used to prepare actodigin. In Lednicer's book on steroids, it is made from deoxycholic acid Deoxycholic acid is a bile acid. Deoxycholic acid is one of the sec ...

(>2%), and conjugate esters. In healthy people, 60% are eliminated via the kidneys and 40% via the faeces. In people with impaired kidney function, elimination via the faeces is increased. The

biological half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

is 7 to 8 days except when kidney ''and'' liver functions are impaired, in which case it is usually longer.

History

The first description of the use of

foxglove ''Digitalis'' ( or ) is a genus of about 20 species of herbaceous plant, herbaceous perennial plants, shrubs, and Biennial plant, biennials, commonly called foxgloves. ''Digitalis'' is native to Europe, western Asia, and northwestern Afric ...

dates back to 1775. For quite some time, the active compound was not isolated.

Oswald Schmiedeberg Johann Ernst Oswald Schmiedeberg (10 October 1838 – 12 July 1921) was a Baltic German pharmacologist. In 1866 he earned his medical doctorate from the University of Dorpat with a thesis concerning the measurement of chloroform in blood, before ...

was able to obtain a pure sample in 1875. The modern therapeutic use of this molecule was made possible by the works of the pharmacist and the French chemist Claude-Adolphe Nativelle (1812–1889). The first structural analysis was done by

Adolf Otto Reinhold Windaus Adolf Otto Reinhold Windaus (; 25 December 1876 – 9 June 1959) was a German chemist who won a Nobel Prize in Chemistry in 1928 for his work on sterols and their relation to vitamins. He was the doctoral advisor of Adolf Butenandt who also won ...

in 1925, but the full structure with an exact determination of the sugar groups was not accomplished until 1962.

Use as a weapon

Marie Alexandrine Becker, a Belgian serial killer, was sentenced to death for poisoning eleven people with digitoxin.

In fiction

Digitoxin is used as a poison or murder weapon in: *

Agatha Christie Dame Agatha Mary Clarissa Christie, Lady Mallowan, (; 15 September 1890 – 12 January 1976) was an English writer known for her 66 detective novels and 14 short story collections, particularly those revolving around fictiona ...

's ''

Appointment with Death ''Appointment with Death'' is a work of detective fiction by British writer Agatha Christie, first published in the UK by the Collins Crime Club on 2 May 1938 and in the US by Dodd, Mead and Company later in the same year. The UK edition retai ...

'' *

Elizabeth Peters Barbara Louise Mertz (September 29, 1927 – August 8, 2013) was an American author who wrote under her own name as well as under the pseudonyms Elizabeth Peters and Barbara Michaels. In 1952, she received a PhD in Egyptology from the Univers ...

' '' Die For Love'' * '' CSI'', season 9, episode 19: "The Descent of Man" * ''

Rosewood Rosewood refers to any of a number of richly hued timbers, often brownish with darker veining, but found in many different hues. True rosewoods All genuine rosewoods belong to the genus ''Dalbergia''. The pre-eminent rosewood appreciated in ...

'' season 2, episode 20: '' Calliphoridae and Country Roads'' * "Casino Royale" (2006) * "Uneasy Lies the Crown" on ''Columbo'', season 9, episode 5 (1990) * "Affair of the Heart" on ''McMillan and Wife'', season 6, episode 5 (1977) * ''Murder 101'': "College can be a Murder" * Several episodes of Murder She Wrote. *

Private Practice Private practice may refer to: *Private sector practice **Practice of law In its most general sense, the practice of law involves giving legal advice to clients, drafting legal documents for clients, and representing clients in legal negotiati ...

, season 4, episode 18: “The Hardest Part” In

The Decemberists The Decemberists are an American indie rock band from Portland, Oregon. The band consists of Colin Meloy ( lead vocals, guitar, principal songwriter), Chris Funk (guitar, multi-instrumentalist), Jenny Conlee (piano, keyboards, accordion), Nate ...

's song, "The Rake's Song" on ''

The Hazards of Love ''The Hazards of Love'' is the fifth album by the American indie rock band The Decemberists, released through Capitol Records and Rough Trade in 2009. The album was inspired by an Anne Briggs EP titled '' The Hazards of Love''. According to the ...

'' album, the narrator murders his daughter by feeding her foxglove.

Research

Digitoxin and related cardenolides display anticancer activity against a range of human

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

cell lines in vitro but the clinical use of digitoxin to treat

has been restricted by its narrow

therapeutic index The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes ...

. Digitoxin

glycorandomization Glycorandomization, is a drug discovery and drug development technology platform to enable the rapid diversification of bioactive small molecules, drug leads and/or approved drugs through the attachment of sugars. Initially developed as a facile me ...

led to the discovery of novel

neoglycosides which displayed improved anticancer potency and reduced inotropic activity (the perceived mechanism of general toxicity).

References

External links

* Comparing the Toxicity of Digoxin and Digitoxin in a Geriatric Population: Should an Old Drug Be Rediscovered? o
Medscape
, a convenience link from th
original
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