Digoxin

Digoxin

Overview
Digoxin INN
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...

 (icon), also known as digitalis, is a purified 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:...

 and extracted from the foxglove plant, 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...

.
Its corresponding aglycone
Aglycone
An aglycone is the non-sugar compound remaining after replacement of the glycosyl group from a glycoside by a hydrogen atom. The spelling aglycon is sometimes encountered .Classes of phytochemicals found in the aglycone and glycosides forms :...

 is 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...

, and its acetyl
Acetyl
In organic chemistry, acetyl is a functional group, the acyl with chemical formula COCH3. It is sometimes represented by the symbol Ac . The acetyl group contains a methyl group single-bonded to a carbonyl...

 derivative is acetyldigoxin
Acetyldigoxin
Acetyldigoxin is a cardiac glycoside. It is an acetyl derivative of digoxin. Its positive cardioinotropic effect starts after 3-4h and maximizes after 6-8h. It is prescribed for congestive chronic cardiac failure class II, III and IV from different reasons, tachysystolic form of fibrillation and...

. Digoxin is widely used in the treatment of various heart conditions
Heart disease
Heart disease, cardiac disease or cardiopathy is an umbrella term for a variety of diseases affecting the heart. , it is the leading cause of death in the United States, England, Canada and Wales, accounting for 25.4% of the total deaths in the United States.-Types:-Coronary heart disease:Coronary...

, namely 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...

, atrial flutter
Atrial flutter
Atrial flutter is an abnormal heart rhythm that occurs in the atria of the heart. When it first occurs, it is usually associated with a fast heart rate or tachycardia , and falls into the category of supra-ventricular tachycardias. While this rhythm occurs most often in individuals with...

 and sometimes heart failure that cannot be controlled by other medication
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

. Digoxin preparations are commonly marketed under the trade name
Trade name
A trade name, also known as a trading name or a business name, is the name which a business trades under for commercial purposes, although its registered, legal name, used for contracts and other formal situations, may be another....

s Lanoxin, Digitek, and Lanoxicaps.
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Encyclopedia
Digoxin INN
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...

 (icon), also known as digitalis, is a purified 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:...

 and extracted from the foxglove plant, 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...

.
Its corresponding aglycone
Aglycone
An aglycone is the non-sugar compound remaining after replacement of the glycosyl group from a glycoside by a hydrogen atom. The spelling aglycon is sometimes encountered .Classes of phytochemicals found in the aglycone and glycosides forms :...

 is 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...

, and its acetyl
Acetyl
In organic chemistry, acetyl is a functional group, the acyl with chemical formula COCH3. It is sometimes represented by the symbol Ac . The acetyl group contains a methyl group single-bonded to a carbonyl...

 derivative is acetyldigoxin
Acetyldigoxin
Acetyldigoxin is a cardiac glycoside. It is an acetyl derivative of digoxin. Its positive cardioinotropic effect starts after 3-4h and maximizes after 6-8h. It is prescribed for congestive chronic cardiac failure class II, III and IV from different reasons, tachysystolic form of fibrillation and...

. Digoxin is widely used in the treatment of various heart conditions
Heart disease
Heart disease, cardiac disease or cardiopathy is an umbrella term for a variety of diseases affecting the heart. , it is the leading cause of death in the United States, England, Canada and Wales, accounting for 25.4% of the total deaths in the United States.-Types:-Coronary heart disease:Coronary...

, namely 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...

, atrial flutter
Atrial flutter
Atrial flutter is an abnormal heart rhythm that occurs in the atria of the heart. When it first occurs, it is usually associated with a fast heart rate or tachycardia , and falls into the category of supra-ventricular tachycardias. While this rhythm occurs most often in individuals with...

 and sometimes heart failure that cannot be controlled by other medication
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

. Digoxin preparations are commonly marketed under the trade name
Trade name
A trade name, also known as a trading name or a business name, is the name which a business trades under for commercial purposes, although its registered, legal name, used for contracts and other formal situations, may be another....

s Lanoxin, Digitek, and Lanoxicaps. It is also available as a 0.05 mg/mL oral solution and 0.25 mg/mL or 0.5 mg/mL injectable solution. It is marketed by GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...

  and many other pharmaceutic manufacturers.

Medical use


Today, the most common indications for digoxin are 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...

 and atrial flutter
Atrial flutter
Atrial flutter is an abnormal heart rhythm that occurs in the atria of the heart. When it first occurs, it is usually associated with a fast heart rate or tachycardia , and falls into the category of supra-ventricular tachycardias. While this rhythm occurs most often in individuals with...

 with rapid ventricular response, but beta-blockers or calcium channel-blockers should be the first choice. High ventricular rate leads to insufficient diastolic filling time. By slowing down the conduction in the AV node and increasing its refractory period, digoxin can reduce the ventricular rate. The arrhythmia itself is not affected, but the pumping function of the heart improves owing to improved filling.

The use of digoxin in heart problems during sinus rhythm
Sinus rhythm
In medicine, sinus rhythm is the normal beating of the heart, as measured by an electrocardiogram . It has certain generic features that serve as hallmarks for comparison with normal ECGs.- ECG structure :...

 was once standard, but is now controversial. In theory the increased force of contraction should lead to improved pumping function of the heart, but its effect on prognosis is disputable and other effective treatments are now available. Digoxin is no longer the first choice for 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...

, but can still be useful in patients who remain symptomatic despite proper diuretic
Diuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...

 and ACE inhibitor
ACE inhibitor
ACE inhibitors or angiotensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension and congestive heart failure...

 treatment.

It has fallen out of favor because did not demonstrate a mortality
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....

 benefit in patients 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...

; however, it did demonstrate a reduction in hospitalizations for 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...

. Because other therapies have shown a mortality benefit in 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...

, it is recommended to maximize other therapies (eg, beta-blockers) first before using digoxin.

Pharmacokinetic properties


Digoxin is usually given by mouth, but can also be given by IV injection in urgent situations (the IV injection should be slow, heart rhythm should be monitored). While IV therapy may be better tolerated (less nausea), digoxin has a very long distribution half-life into the cardiac tissue, which will delay its onset of action by a number of hours. The half-life is about 36 hours, digoxin is given once daily, usually in 125 μg or 250 μg dosing.

In patients with decreased kidney function the half-life is considerably longer, calling for a reduction in dosing or a switch to a different glycoside 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...

 (not available in the United States), which has a much longer elimination half-life of around 7 days but is mainly eliminated from the body via the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

, and thus not affected by changes in kidney function.

Effective plasma levels vary depending on the medical indication. For 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...

, levels between 0.5 to 1.0 ng/mL are recommended. This recommendation is based on post-hoc analysis of prospective trials, suggesting that higher levels may be associated with increased mortality rates. For heart rate control (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...

), plasma levels are less defined and are generally titrated to a goal heart rate. Typically, digoxin levels are considered therapeutic for heart rate control between 1.0 and 2.0 ng/mL. In suspected toxicity or ineffectiveness, digoxin levels should be monitored. Plasma potassium levels also need to be closely controlled (see side effects below).

Quinidine, verapamil, and amiodarone increases plasma levels of digoxin (by displacing tissue binding sites and depressing renal digoxin clearance) so plasma digoxin must be monitored carefully.

Researchers at Yale University looked at data from an earlier study to see if digoxin affected men and women differently. That study determined that digoxin, which has been used for centuries and makes the heart contract more forcefully, did not reduce deaths overall but did result in less hospitalization. Researcher Dr. Harlan Krumholz said they were surprised to find that women in the study who took digoxin died more frequently (33%) than women who took a placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...

 pill (29%). They calculated that digoxin increased the risk of death in women by 23%. There was no difference in the death rate for men in the study.

Digoxin is also used as a standard control substance to test for p-glycoprotein
P-glycoprotein
P-glycoprotein 1 also known as multidrug resistance protein 1 or ATP-binding cassette sub-family B member 1 or cluster of differentiation 243 is a glycoprotein that in humans is encoded by the ABCB1 gene...

 inhibition.

Adverse effects



The occurrence of adverse drug reaction
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

s is common, owing to 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 ....

 (the margin between effectiveness and toxicity). Adverse effects are concentration-dependent, and are rare when plasma digoxin concentration is <0.8 μg/L. They are also more common in patients with low potassium levels (hypokalemia
Hypokalemia
Hypokalemia or hypokalaemia , also hypopotassemia or hypopotassaemia , refers to the condition in which the concentration of potassium in the blood is low...

), since digoxin normally competes with K+ ions for the same binding site on the Na+/K+ ATPase pump.

Common adverse effects (≥1% of patients) include: loss of appetite
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...

, 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...

 and diarrhea
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...

 as the gastrointestinal motility increase. Other common effects are blurred vision
Blurred vision
-Causes:There are many causes of blurred vision:* Use of atropine or other anticholinergics* Presbyopia -- Difficulty focusing on objects that are close. The elderly are common victims....

, visual disturbances (yellow-green halos and problems with color perception), confusion
ConFusion
ConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...

, drowsiness, dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....

, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...

, nightmare
Nightmare
A nightmare is an unpleasant dream that can cause a strong negative emotional response from the mind, typically fear or horror, but also despair, anxiety and great sadness. The dream may contain situations of danger, discomfort, psychological or physical terror...

s, agitation
Psychomotor agitation
Psychomotor agitation is a series of unintentional and purposeless motions that stem from mental tension and anxiety of an individual. This includes pacing around a room, wringing one's hands, pulling off clothing and putting it back on and other similar actions...

, and depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...

, as well as a higher acute sense of sensual activities.Less frequent adverse effects (0.1%–1%) include: acute psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...

, 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...

, amnesia
Amnesia
Amnesia is a condition in which one's memory is lost. The causes of amnesia have traditionally been divided into categories. Memory appears to be stored in several parts of the limbic system of the brain, and any condition that interferes with the function of this system can cause amnesia...

, convulsion
Convulsion
A convulsion is a medical condition where body muscles contract and relax rapidly and repeatedly, resulting in an uncontrolled shaking of the body. Because a convulsion is often a symptom of an epileptic seizure, the term convulsion is sometimes used as a synonym for seizure...

s, shortened QRS complex, atrial or ventricular extrasystoles, paroxysmal atrial tachycardia
Atrial tachycardia
Atrial tachycardia is a type of atrial arrhythmia in which the heart's electrical impulse comes from an ectopic atrial pacemaker rather than from the SA node. Atrial tachycardias are characterized by very regular rates ranging from 140–220 bpm....

 with AV block, ventricular tachycardia or fibrillation, and heart block Rarely, digoxin has been shown to cause thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...

. Gynaecomastia (enlargement of breast tissue) is mentioned in many textbooks as a side-effect – thought to be due to the estrogen-like steroid moiety of the digoxin molecule but when systematically sought, the evidence for this is equivocal.
The pharmacological actions of digoxin usually results in electrocardiogram
Electrocardiogram
Electrocardiography is a transthoracic interpretation of the electrical activity of the heart over a period of time, as detected by electrodes attached to the outer surface of the skin and recorded by a device external to the body...

 (ECG) changes, including ST depression or T wave inversion, which do not indicate toxicity. PR interval prolongation, however, may be a sign of digoxin toxicity. Additionally, increased intracellular Ca2+ may cause a type of arrhythmia called bigeminy (coupled beats), eventually ventricular tachycardia
Ventricular tachycardia
Ventricular tachycardia is a tachycardia, or fast heart rhythm, that originates in one of the ventricles of the heart...

 or fibrillation
Fibrillation
Fibrillation is the rapid, irregular, and unsynchronized contraction of muscle fibers. An important occurrence is with regards to the heart.-Cardiology:There are two major classes of cardiac fibrillation: atrial fibrillation and ventricular fibrillation....

. The combination of increased (atrial) arrhythmogenesis and inhibited atrio-ventricular conduction (for example paroxysmal atrial tachycardia with A-V block - so-called "PAT with block") is said to be pathognomonic
Pathognomonic
Pathognomonic is a term, often used in medicine, that means characteristic for a particular disease. A pathognomonic sign is a particular sign whose presence means that a particular disease is present beyond any doubt...

 (i.e. diagnostic) of digoxin toxicity.

An often described but rarely seen adverse effect of digoxin is a disturbance of colour vision (mostly yellow and green colour) called 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....

. It has been proposed that the painter Vincent van Gogh
Vincent van Gogh
Vincent Willem van Gogh , and used Brabant dialect in his writing; it is therefore likely that he himself pronounced his name with a Brabant accent: , with a voiced V and palatalized G and gh. In France, where much of his work was produced, it is...

's "Yellow Period" may have somehow been influenced by concurrent digitalis therapy. Other oculotoxic effects of digoxin include generalized blurry vision as well as seeing a "halo" around each point of light. The latter effect can also be seen in van Gogh's Starry Night. Evidence of van Gogh's digoxin use is supported by multiple self portraits that include the foxglove plant, from which digoxin is obtained. (E.g. Portrait of Dr. Gachet)

Digoxin plasma concentrations may increase while on antimalarial medication hydroxychloroquine
Hydroxychloroquine
Hydroxychloroquine is an antimalarial drug, sold under the trade names Plaquenil,Axemal, Dolquine, and Quensyl, also used to reduce inflammation in the treatment of rheumatoid arthritis and lupus...

 (based on two case reports from 1982).

In overdose, the usual supportive measures are needed. If arrhythmias prove troublesome, or malignant hyperkalaemia occurs (inexorably rising potassium level due to paralysis of the cell membrane bound ATPase-dependent Na/K pumps), the specific antidote is antidigoxin (antibody fragments against digoxin, trade names of Digibind and Digifab). Toxicity can also be treated with higher than normal doses of potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...

. Digoxin is not removed by hemo or peritoneal dialysis with enough effectiveness to treat toxicity.

Digoxin has potentially dangerous interactions with verapamil
Verapamil
Verapamil is an L-type calcium channel blocker of the phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches. It is also an effective preventive medication for migraine...

, 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...

, erythromycin
Erythromycin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...

, and epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...

 (as would be injected with a local anesthetic).

Actions


The main pharmacological effects of digoxin are on the 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...

. Extracardiac effects are responsible for some of the therapeutic and many of the adverse effects (see below). It has mechanical effects as it increases myocardial contractility, however, the duration of the contractile response is just slightly increased. Overall, the heart rate is decreased, while blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...

 increases as the stroke volume is increased, leading to increased tissue perfusion
Perfusion
In physiology, perfusion is the process of nutritive delivery of arterial blood to a capillary bed in the biological tissue. The word is derived from the French verb "perfuser" meaning to "pour over or through."...

. Myocardial efficiency improves due to improved hemodynamics
Hemodynamics
Hemodynamics, meaning literally "blood movement" is the study of blood flow or the circulation.All animal cells require oxygen for the conversion of carbohydrates, fats and proteins into carbon dioxide , water and energy in a process known as aerobic respiration...

, and the ventricular function curve is improved.

Other, electrical effects are an initial brief increase in action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...

, followed by a decrease as the K+
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...

 conductance increases due to an increased intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...

 amounts of Ca2+
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...

 ions. The refractory period
Refractory period
In physiology, a refractory period is a period of time during which an organ or cell is incapable of repeating a particular action, or the amount of time it takes for an excitable membrane to be ready for a second stimulus once it returns to its resting state following an excitation...

 of the atria and ventricle
Ventricle (heart)
In the heart, a ventricle is one of two large chambers that collect and expel blood received from an atrium towards the peripheral beds within the body and lungs. The Atria primes the Pump...

s is decreased, while it increases in the sinoatrial
Sinoatrial node
The sinoatrial node is the impulse-generating tissue located in the right atrium of the heart, and thus the generator of normal sinus rhythm. It is a group of cells positioned on the wall of the right atrium, near the entrance of the superior vena cava...

 and AV nodes. A less negative resting membrane potential is made, leading to increased excitability. Other, more indirect effects are cholinomimetic
Cholinergic
The word choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin...

 because of vagal
Vagus nerve
The vagus nerve , also called pneumogastric nerve or cranial nerve X, is the tenth of twelve paired cranial nerves...

 stimulation, giving rise to AV nodal delay.

The conduction velocity increases in the atria, but decreases in the AV node. The effect upon Purkinje fibers and ventricles is negligible. Automaticity is also increased, in the atria, AV node, Purkinje fibers and ventricles.

ECG changes are increased PR interval, due to decreased AV conduction, and a decreased QT interval because of the altered duration of decreased action potential. Also, the T wave is inverted, accompanied by ST depression. It may cause AV junctional rhythm and ectopic beats (bigeminy) resulting in ventricular tachycardia
Ventricular tachycardia
Ventricular tachycardia is a tachycardia, or fast heart rhythm, that originates in one of the ventricles of the heart...

 and fibrillation
Ventricular fibrillation
Ventricular fibrillation is a condition in which there is uncoordinated contraction of the cardiac muscle of the ventricles in the heart, making them quiver rather than contract properly. Ventricular fibrillation is a medical emergency and most commonly identified arrythmia in cardiac arrest...

.

Slight vasodilation
Vasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...

 is seen in heart failure. This effect is contrary to effects that should be seen as a result of increased intracellular calcium levels, but this occurs since digoxin improves hemodynamics, which leads to restored angiotensin
Angiotensin
Angiotensin, a peptide hormone, causes blood vessels to constrict, and drives blood pressure up. It is part of the renin-angiotensin system, which is a major target for drugs that lower blood pressure. Angiotensin also stimulates the release of aldosterone, another hormone, from the adrenal cortex...

 levels and decreased sympathetic
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...

 discharge, causing indirect vasodilation.

Digoxin also affects the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

 by increased renal blood flow and increased GFR. A mild diuretic
Diuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...

 effect is seen only in heart failure.

Mechanism of action


The mechanism of action is not completely understood; however the current hypothesis is outlined below.

Digoxin binds to a site on the extracellular aspect of the α-subunit of the Na+/K+ ATPase pump in the membranes
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...

 of heart cells (myocytes) and decreases its function. This causes an increase in the level 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
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...

s in the myocytes, which leads to a rise in the level of intracellular calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...

 ions. This occurs because the sodium/calcium exchanger on the plasma membrane depends on a constant inward sodium gradient to pump out calcium. Digoxin decreases sodium concentration gradient and the subsequent calcium outflow, thus raising the calcium concentration in myocardiocytes and pacemaker cells.

Increased intracellular calcium lengthens Phase 4 and Phase 0 of the cardiac action potential
Cardiac action potential
In electrocardiography, the cardiac action potential is a specialized action potential in the heart, necessary for the electrical conduction system of the heart....

, which leads to a decrease in heart rate. Increased amounts of Ca2+ also leads to increased storage of calcium in the sarcoplasmic reticulum, causing a corresponding increase in the release of calcium during each action potential. This leads to increased contractility, the force of contraction, of the heart.

There is also evidence that digoxin increases vagal activity, thereby decreasing heart rate by slowing depolarization of pacemaker cells in the AV node. This negative chronotropic effect would therefore be synergistic with the direct effect on cardiac pacemaker cells. Digoxin is used widely in the treatment of various arrhythmias.

Society and culture


Charles Cullen
Charles Cullen
Charles Edmund Cullen is a former nurse who is the most prolific serial killer in New Jersey history, and suspected to be the most prolific serial killer in American history. Cullen told authorities in December 2003 that he could specifically recall the murder of perhaps 40 patients during the 16...

admitted in 2003 to killing as many as 40 hospital patients with overdoses of heart medication—usually digoxin—at hospitals in New Jersey and Pennsylvania over his 16-year career as a nurse. On March 10, 2006 he was sentenced to 18 consecutive life sentences and is not eligible for parole.

On April 25, 2008 the FDA issued a press release alerting the public to a Class I recall of Digitek, a brand of digoxin produced by Mylan.It was found that some tablets had been released at double thickness and therefore double strength, causing some patients to experience digoxin toxicity. A class-action lawsuit against the Icelandic generic drug maker Actavis was announced two weeks later.

On March 31, 2009 the FDA announced another generic digoxin pill recall by posting this company press release on the agency's web site: "Caraco Pharmaceutical Laboratories, Ltd. Announces a Nationwide Voluntary Recall of All Lots of Digoxin Tablets Due to Size Variability".

This March 31 press release from Caraco, a generic pharmaceutical company, states that:
On May 6, the Public Radio program Health in a Heartbeat, produced by the University of Florida, discussed a recent study of the National Academy of Sciences, which suggests that digoxin has beneficial effects not only for the heart but also in reducing the risk of certain kinds of cancer.. However, an article published in the Proceedings of the National Academy of Sciences soon after indicated that digoxin is not effective at reducing cancer risk at therapeutic concentrations of the drug.

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