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 include treatments for ...

used for the treatment of

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...

and certain kinds of

heart arrhythmia Arrhythmias, also known as cardiac arrhythmias, are irregularities in the cardiac cycle, heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – ab ...

. It is a

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

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 disease, heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. ...

, 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 Atrial fibrillation (AF, AFib or A-fib) is an Heart arrhythmia, abnormal heart rhythm (arrhythmia) characterized by fibrillation, rapid and irregular beating of the Atrium (heart), atrial chambers of the heart. It often begins as short periods ...

Contraindications

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

bradycardia Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathological processes, it is commonly a physiological response to cardiovascular conditioning or due ...

(slow heartbeat),

ventricular tachycardia Ventricular tachycardia (V-tach or VT) is a cardiovascular disorder in which fast heart rate occurs in the ventricles of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple ...

(fast heartbeat caused by the ventricles),

ventricular fibrillation Ventricular fibrillation (V-fib or VF) is an abnormal heart rhythm in which the Ventricle (heart), ventricles of the heart Fibrillation, quiver. It is due to disorganized electrical conduction system of the heart, electrical activity. Ventricula ...

, 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 a ...

(low blood potassium levels),

hypomagnesemia Magnesium deficiency is an electrolyte disturbance in which there is a low level of magnesium in the body. Symptoms include tremor, poor coordination, muscle spasms, loss of appetite, personality changes, and nystagmus. Complications may in ...

(low magnesium), and

hypercalcemia Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range for total calcium 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 def ...

(high calcium).

Adverse effects and toxicity

Digitoxin exhibits similar toxic effects to

, namely:

anorexia Anorexia nervosa (AN), often referred to simply as anorexia, is an eating disorder characterized by Calorie restriction, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. Individuals wit ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

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

arrhythmias Arrhythmias, also known as cardiac arrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – above 100 beats ...

. 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 li ...

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 ...

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 invo ...

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, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

, which slow down digitoxin

metabolism Metabolism (, from ''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 cellular processes; the co ...

; 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. Clari ...

, 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 ...

, 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 G ...

* 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 abnormal heart rhythms ( arrhythmia), and to protect the heart from a second heart attack after a first heart attack ( secondary prevention ...

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 diuretic Potassium-sparing diuretics or antikaliuretics refer to drugs that cause diuresis without causing potassium loss in the urine. They are typically used as an adjunct in management of hypertension, cirrhosis, and congestive heart failure. The ster ...

s * inducers of CYP3A4 or P-gp, such as

phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an anticonvulsant, 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 se ...

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

and St John's Wort * substances that bind digitoxin in the gut, such as aluminium containing

antacid An antacid is a substance which neutralization (chemistry), neutralizes gastric acid, stomach acidity and is used to relieve heartburn, indigestion, or an upset stomach. Some antacids have been used in the treatment of constipation and diarrhe ...

s or colestyramine

Pharmacology

Mechanism of action

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

inotropic An inotrope or inotropic is a drug or any substance 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 co ...

), 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 th ...

), increased excitability (positive

bathmotropic Bathmotropic often refers to modifying the degree of membrane_potential#Cell_excitability, excitability specifically of the heart; in general, it refers to modification of the degree of excitability (threshold of excitation) of musculature in gene ...

), 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 cardiac cycle, rhythm by affecting the electrical conduction system of the hea ...

Pharmacokinetics

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

plasma protein Plasma proteins, sometimes referred to as blood proteins, are proteins present in blood plasma. They perform many different functions, including transport of hormones, vitamins and minerals in activity and functioning of the immune system. Other b ...

s. Digitoxin undergoes

enterohepatic circulation Enterohepatic circulation is 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. Enterohepa ...

. It is

metabolized Metabolism (, from ''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 cellular processes; the co ...

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 (elimination half-life, pharmacological half-life) is the time taken for concentration of a drug, biological substance (such as a medication) to decrease from its maximum concentration (chemistry), concentration (Cmax (pharm ...

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 perennial plants, shrubs, and biennials, commonly called foxgloves. ''Digitalis'' is native to Europe, Western Asia, and northwestern Africa. The flowers are tubular in sha ...

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

Use as a weapon

Digitoxin has been used for at least 7,000 years as an

arrow poison Arrow poisons are used to poison arrow heads or darts for the purposes of hunting and warfare. They have been used by indigenous peoples worldwide and are still in use in areas of South America, Africa and Asia. Notable examples are the poisons se ...

. 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 people, English author known for her 66 detective novels and 14 short story collections, particularly those revolving ...

'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 Universi ...

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

Rosewood Rosewood is any of a number of richly hued hardwoods, often brownish with darker veining, but found in other colours. It is hard, tough, strong, and dense. True rosewoods come from trees of the genus '' Dalbergia'', but other woods are often ca ...

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

The Decemberists The Decemberists are an American indie rock band from Portland, Oregon, formed in 2000. The band consists of Colin Meloy (lead vocals, guitar), Chris Funk (guitar, multi-instrumentalist), Jenny Conlee (piano, keyboards, accordion, backing vocals ...

's song, "The Rake's Song" on '' The Hazards of Love'' album, the narrator murders his daughter by feeding her foxglove. In Metal gear Solid V the phantom pain, venom snake uses digitalis to obtain digoxin for tranquilizer rounds to incapacitate enemies.

Research

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

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

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 with regard to risk of overdose. It is a comparison of the amount of a therapeutic agent that causes toxicity to the ...

. 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
{{Estrogen receptor modulators Cardenolides Estrogens Drugs developed by Merck