Digitalis

Digitalis

Overview
Digitalis is a genus of about 20 species of herb
Herb
Except in botanical usage, an herb is "any plant with leaves, seeds, or flowers used for flavoring, food, medicine, or perfume" or "a part of such a plant as used in cooking"...

aceous perennials
Perennial plant
A perennial plant or simply perennial is a plant that lives for more than two years. The term is often used to differentiate a plant from shorter lived annuals and biennials. The term is sometimes misused by commercial gardeners or horticulturalists to describe only herbaceous perennials...

, shrubs, and biennials
Biennial plant
A biennial plant is a flowering plant that takes two years to complete its biological lifecycle. In the first year the plant grows leaves, stems, and roots , then it enters a period of dormancy over the colder months. Usually the stem remains very short and the leaves are low to the ground, forming...

 that are commonly called foxgloves. This genus was traditionally placed in the figwort family Scrophulariaceae
Scrophulariaceae
Scrophulariaceae, the figwort family, are a family of flowering plants. The plants are annual or perennial herbs with flowers with bilateral or rarely radial symmetry. Members of the Scrophulariaceae have a cosmopolitan distribution, with the majority found in temperate areas, including...

, but recent reviews of phylogenetic research have placed it in the much enlarged family Plantaginaceae
Plantaginaceae
Plantaginaceae Juss. or plantain family, are a family of flowering plants in the order Lamiales. The type genus is Plantago L..In older classifications it used to be the only family of the order Plantaginales, but numerous phylogenetic studies, summarized by the Angiosperm Phylogeny Group, have...

. This genus is native to western and south western Europe, western and central Asia, and northwestern Africa. The scientific name means "finger-like" and refers to the ease with which a flower
Flower
A flower, sometimes known as a bloom or blossom, is the reproductive structure found in flowering plants . The biological function of a flower is to effect reproduction, usually by providing a mechanism for the union of sperm with eggs...

 of Digitalis purpurea can be fitted over a human fingertip.
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Encyclopedia
Digitalis is a genus of about 20 species of herb
Herb
Except in botanical usage, an herb is "any plant with leaves, seeds, or flowers used for flavoring, food, medicine, or perfume" or "a part of such a plant as used in cooking"...

aceous perennials
Perennial plant
A perennial plant or simply perennial is a plant that lives for more than two years. The term is often used to differentiate a plant from shorter lived annuals and biennials. The term is sometimes misused by commercial gardeners or horticulturalists to describe only herbaceous perennials...

, shrubs, and biennials
Biennial plant
A biennial plant is a flowering plant that takes two years to complete its biological lifecycle. In the first year the plant grows leaves, stems, and roots , then it enters a period of dormancy over the colder months. Usually the stem remains very short and the leaves are low to the ground, forming...

 that are commonly called foxgloves. This genus was traditionally placed in the figwort family Scrophulariaceae
Scrophulariaceae
Scrophulariaceae, the figwort family, are a family of flowering plants. The plants are annual or perennial herbs with flowers with bilateral or rarely radial symmetry. Members of the Scrophulariaceae have a cosmopolitan distribution, with the majority found in temperate areas, including...

, but recent reviews of phylogenetic research have placed it in the much enlarged family Plantaginaceae
Plantaginaceae
Plantaginaceae Juss. or plantain family, are a family of flowering plants in the order Lamiales. The type genus is Plantago L..In older classifications it used to be the only family of the order Plantaginales, but numerous phylogenetic studies, summarized by the Angiosperm Phylogeny Group, have...

. This genus is native to western and south western Europe, western and central Asia, and northwestern Africa. The scientific name means "finger-like" and refers to the ease with which a flower
Flower
A flower, sometimes known as a bloom or blossom, is the reproductive structure found in flowering plants . The biological function of a flower is to effect reproduction, usually by providing a mechanism for the union of sperm with eggs...

 of Digitalis purpurea can be fitted over a human fingertip. The flowers are produced on a tall spike, are tubular, and vary in colour with species, from purple to pink, white, and yellow. The best-known species is the "Common Foxglove", Digitalis purpurea
Digitalis purpurea
Digitalis purpurea , is a flowering plant in the family Plantaginaceae , native to most of Europe.-Description:...

. This is a biennial plant
Biennial plant
A biennial plant is a flowering plant that takes two years to complete its biological lifecycle. In the first year the plant grows leaves, stems, and roots , then it enters a period of dormancy over the colder months. Usually the stem remains very short and the leaves are low to the ground, forming...

 which is often grown as an ornamental plant
Ornamental plant
Ornamental plants are plants that are grown for decorative purposes in gardens and landscape design projects, as house plants, for cut flowers and specimen display...

 due to its vivid flower
Flower
A flower, sometimes known as a bloom or blossom, is the reproductive structure found in flowering plants . The biological function of a flower is to effect reproduction, usually by providing a mechanism for the union of sperm with eggs...

s. These range in colour from various purple tint
Tint
In color theory, a tint is the mixture of a color with white.Tint may also refer to:* Tint control, an adjustment to correct for phase error in the picture color on a NTSC television set* Tint , an album by Merzbow...

s through various shades of light gray, and to purely white. The flowers can also possess various marks and spottings.

The first year of growth of the Common Foxglove produces only the stem with its long, basal leaves. During the second year of the plant's life, a long leafy stem from 50 to 255 centimeters tall grows atop the roots of healthy plants.

The larva
Larva
A larva is a distinct juvenile form many animals undergo before metamorphosis into adults. Animals with indirect development such as insects, amphibians, or cnidarians typically have a larval phase of their life cycle...

e of the insect the "Foxglove pug
Foxglove Pug
The Foxglove Pug is a moth of the family Geometridae. It has a scattered distribution across Europe, closely following the range of its food plant. Where present it can be very common....

" consume the flowers of the Common Foxglove for food. Other species of Lepidoptera
Lepidoptera
Lepidoptera is a large order of insects that includes moths and butterflies . It is one of the most widespread and widely recognizable insect orders in the world, encompassing moths and the three superfamilies of butterflies, skipper butterflies, and moth-butterflies...

 eat the leaves of the Common Foxglove, including Lesser Yellow Underwing
Lesser Yellow Underwing
The Lesser Yellow Underwing is a moth of the family Noctuidae. It is found throughout Europe. It was introduced into British Columbia in about 1982 and has spread southward in the Pacific Northwest. It has recently been reported from Ontario . Full synonymy given in Lafontaine...

.

The term digitalis is also used for drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...

 preparations that contain cardiac glycoside
Cardiac glycoside
Cardiac glycosides are drugs used in the treatment of congestive heart failure and cardiac arrhythmia. These glycosides are found as secondary metabolites in several plants, but also in some animals, such as the milkweed butterflies. -Function:...

s, particularly one called digoxin
Digoxin
Digoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...

, that are extracted from various plants of this genus.

Etymology


There have been many suggestions for the derivation of the name "foxglove". According to the 19th century book, English Botany, Or, Coloured Figures of British Plants:

Dr. Prior, whose authority is great in the origin of popular names, says "It seems probably that the name was in the first place, foxes' glew, or music, in reference to the favourite instrument of an earlier time, a ring of bells hung on an arched support, the tintinnabulum"... we cannot quite agree with Dr. Prior for it seems quite probable that the shape of the flowers suggested the idea of a glove, and that associated with the name of the botanist Fuchs, who first gave it a botanical name, may have been easily corrupted into foxglove. It happens, moreover, the name foxglove is a very ancient one and exists in a list of plants as old as the time of Edward III. The "folks" of our ancestors were the fairies and nothing is more likely than that the pretty coloured bells of the plant would be designated "folksgloves," afterwards, "foxglove." In Wales it is declared to be a favourite lurking-place of the fairies, who are said to occasion a snapping sound when children, holding one end of the digitalis bell, suddenly strike the other on the hand to hear the clap of fairy thunder, with which the indignant fairy makes her escape from her injured retreat. In south of Scotland it is called "bloody fingers" more northward, "deadman's bells" whilst in Wales it is known as "fairy-folks-fingers" or "lambs-tongue-leaves".

Habitat


Digitalis thrives in acidic soils, in partial sunlight to deep shade, in a range of habitats including open woods, woodland clearings, moorland, and heath margins, sea-cliffs, rocky mountain slopes and hedge banks. It is commonly found on sites where the ground has been disturbed, such as recently cleared woodland, or where the vegetation has been burnt.

Medicinal use and mechanism of action


A group of medicines extracted from foxglove plants are called Digitalin. The use of Digitalis purpurea
Digitalis purpurea
Digitalis purpurea , is a flowering plant in the family Plantaginaceae , native to most of Europe.-Description:...

extract containing cardiac glycoside
Cardiac glycoside
Cardiac glycosides are drugs used in the treatment of congestive heart failure and cardiac arrhythmia. These glycosides are found as secondary metabolites in several plants, but also in some animals, such as the milkweed butterflies. -Function:...

s for the treatment of heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...

 conditions was first described in the English speaking medical literature by William Withering
William Withering
William Withering was an English botanist, geologist, chemist, physician and the discoverer of digitalis.-Introduction:...

, in 1785, which is considered the beginning of modern therapeutics. It is used to increase cardiac contractility (it is a positive inotrope
Inotrope
An inotrope is an agent that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions...

) and as an antiarrhythmic agent
Antiarrhythmic agent
Antiarrhythmic agents are a group of pharmaceuticals that are used to suppress abnormal rhythms of the heart , such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation....

 to control the heart rate, particularly in the irregular (and often fast) atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...

. Digitalis is hence often prescribed for patients in atrial fibrillation, especially if they have been diagnosed with congestive heart failure
Congestive heart failure
Heart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...

. Digoxin was approved for heart failure in 1998 under current regulations by the Food and Drug Administration on the basis of prospective randomized study and clinical trials. It was also approved for the control of ventricular response rate for patients with atrial fibrillation. Recent American College of Cardiology/American Heart Association guidelines recommend digoxin for symptomatic chronic heart failure for patients with reduced systolic function, preservation of systolic function, and/or rate control for atrial fibrillation with a rapid ventricular response. Recent Heart Failure Society of America guidelines for heart failure provide similar recommendations. Despite its relatively recent approval by the Food and Drug Administration and the guideline recommendations, digoxin use is decreasing in patients with heart failure. This is likely the result of several factors. Digoxin has not been promoted by the pharmaceutical industry and has received little attention at national and international meetings, possibly the result of the development and promotion of other, newly patented therapies for heart failure. Also, safety concerns about digoxin therapy–increased mortality in women also may have contributed to this decrease in its use.

A group of pharmacologically active compounds are extracted mostly from the leaves of the second year's growth, and in pure form are referred to by common chemical names such as digitoxin
Digitoxin
Digitoxin is a cardiac glycoside. It has similar structure and effects to digoxin . Unlike digoxin , it is eliminated via the liver, so could be used in patients with poor or erratic kidney function. However, it is now rarely used in current Western medical practice...

or digoxin
Digoxin
Digoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...

, or by brand names such as Crystodigin and Lanoxin, respectively. The two drugs differ in that Digoxin has an additional hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...

 group at the C-3 position on the B-ring (adjacent to the pentane). Both molecules include a lactone
Lactone
In chemistry, a lactone is a cyclic ester which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule...

 and a triple-repeating sugar
Sugar
Sugar is a class of edible crystalline carbohydrates, mainly sucrose, lactose, and fructose, characterized by a sweet flavor.Sucrose in its refined form primarily comes from sugar cane and sugar beet...

 called a glycoside
Glycoside
In chemistry, a glycoside is a molecule in which a sugar is bound to a non-carbohydrate moiety, usually a small organic molecule. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. These can be activated by enzyme...

.

Digitalis works by inhibiting sodium-potassium ATPase. This results in an increased intracellular concentration of sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...

 ion and thus a decreased concentration gradient across the cell membrane. This increase in intracellular sodium activates a sodium/calcium exchange pump that brings calcium ions into the cell while extruding sodium in order to restore its gradient across the membrane. The increased cytosolic calcium ion concentration results in increased calcium ion storage in the sarcoplasmic reticulum. Upon action potential (cardiac contraction) more calcium is released from the sarcoplasmic reticulum and this gives a positive inotropic effect (higher contractility).
Digitalis also has a vagal effect on the parasympathetic nervous system
Parasympathetic nervous system
The parasympathetic nervous system is one of the two main divisions of the autonomic nervous system . The ANS is responsible for regulation of internal organs and glands, which occurs unconsciously...

, and as such is used in reentrant cardiac arrhythmias and to slow the ventricular rate during atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...

. The dependence on the vagal effect means that digitalis is not effective when a patient has a high sympathetic nervous system
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...

 drive, which is the case with acutely ill persons, and also during exercise.

Digitalis toxicity (Digitalis intoxication) results from an overdose of digitalis and causes anorexia, nausea, vomiting and diarrhoea, as well as sometimes resulting in xanthopsia
Xanthopsia
Xanthopsia refers to the predominance of yellow in vision due to a yellowing of the optic media of the eye. The most common cause is digoxin toxicity and the development of cataracts which can cause a yellow filtering effect....

 (jaundiced or yellow vision) and the appearance of blurred outlines (halos). Bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...

 also occurs. Because a frequent side effect of digitalis is reduction of appetite, some individuals have used the drug as a weight loss aid.

Digitalis is an example of a drug that is derived from a plant that was formerly used by folklorists and herbalist
Herbalist
An herbalist is:#A person whose life is dedicated to the economic or medicinal uses of plants.#One skilled in the harvesting and collection of medicinal plants ....

s: herbalists have largely abandoned its use because of its narrow therapeutic index
Therapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....

 and the difficulty of determining the amount of active drug in herbal preparations. Once the usefulness of digitalis in regulating the human pulse
Pulse
In medicine, one's pulse represents the tactile arterial palpation of the heartbeat by trained fingertips. The pulse may be palpated in any place that allows an artery to be compressed against a bone, such as at the neck , at the wrist , behind the knee , on the inside of the elbow , and near the...

 was understood, it was employed for a variety of purposes, including the treatment of epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...

 and other seizure disorders, which are now considered to be inappropriate treatments.

Toxicity




Depending on the species, the digitalis plant may contain several deadly physiological and chemically related cardiac and steroidal glycosides. Thus, the digitalis has earned several more sinister names: Dead Man’s Bells, and Witches’ Gloves.

The entire plant is toxic (including the roots and seeds), although the leaves of the upper stem are particularly potent, with just a nibble, being enough to potentially cause death. Early symptoms of ingestion include nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

, vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...

, diarrhoea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

, abdominal pain, wild hallucinations, delirium
Delirium
Delirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...

, and severe headache. Depending on the severity of the toxicosis the victim may later suffer irregular and slow pulse, tremors, various cerebral disturbances, especially of a visual nature (unusual colour visions with objects appearing yellowish to green, and blue halos around lights), convulsions, and deadly disturbances of the heart. For a case description, see the paper by Lacassie.

There have been instances of people confusing digitalis with the relatively harmless Symphytum
Symphytum
Symphytum is a genus in the Boraginaceae family. Its species are known by the common name comfrey. Some species and hybrids, particularly S. officinale and S. × uplandicum, are used in gardening and herbal medicine.Species include:...

(comfrey) plant (which is often brewed into a tea) with fatal consequences. Other fatal accidents involve children drinking the water in a vase containing digitalis plants. Drying does not reduce the toxicity of the plant. The plant is toxic to animals including all classes of livestock and poultry, as well as felines and canines.

Digitalis poisoning can cause heart block
Heart block
A heart block can be a blockage at any level of the electrical conduction system of the heart .* Blocks that occur within the sinoatrial node are described as SA nodal blocks....

 and either bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...

 (decreased heart rate) or tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...

 (increased heart rate), depending on the dose and the condition of one's heart. It should however be noted, that electric cardioversion (to "shock" the heart) is generally not indicated in ventricular fibrillation in digitalis toxicity, as it can increase the dysrhythmia in digitalis toxicity. Also, the classic drug of choice for VF (ventricular fibrillation) in emergency setting, amiodarone
Amiodarone
Amiodarone is an antiarrhythmic agent used for various types of tachyarrhythmias , both ventricular and supraventricular arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985...

, can worsen the dysrhythmia caused by digitalis, therefore, the second-choice drug Lidocaine
Lidocaine
Lidocaine , Xylocaine, or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.- History :Lidocaine, the first amino...

 is more commonly used.

Digoxigenin


Digoxigenin
Digoxigenin
Digoxigenin is a steroid found exclusively in the flowers and leaves of the plants Digitalis purpurea, Digitalis orientalis and Digitalis lanata , where it is attached to sugars, to form the glycosides Digoxigenin (DIG) is a steroid found exclusively in the flowers and leaves of the plants...

 (DIG) is a steroid found exclusively in the flowers and leaves of the plants Digitalis purpurea
Digitalis purpurea
Digitalis purpurea , is a flowering plant in the family Plantaginaceae , native to most of Europe.-Description:...

and Digitalis lanata
Digitalis lanata
Digitalis lanata is a species of foxglove that is part of the Plantaginaceae family. It gets its name due to the texture of the leaves. Digitalis lanata, like some other foxglove species, is highly toxic in all parts of the plant...

. It is used as a molecular probe to detect DNA or RNA. It can easily be attached to nucleotides by chemical modifications. DIG molecules are often linked to uridine
Uridine
Uridine is a molecule that is formed when uracil is attached to a ribose ring via a β-N1-glycosidic bond.If uracil is attached to a deoxyribose ring, it is known as a deoxyuridine....

 nucleotides; DIG labelled uridine
Uridine
Uridine is a molecule that is formed when uracil is attached to a ribose ring via a β-N1-glycosidic bond.If uracil is attached to a deoxyribose ring, it is known as a deoxyuridine....

 (DIG-U) can then be incorporated into RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....

 probes via in vitro transcription. Once hybridisation occurs in situ, RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....

 probes with the incorporated DIG-U can be detected with anti-DIG antibodies that are conjugated to alkaline phosphatase
Alkaline phosphatase
Alkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation...

. To reveal the hybridised transcripts, alkaline phosphatase
Alkaline phosphatase
Alkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation...

 can be reacted with a chromogen to produce a colour precipitate.

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