discuss the botanical, chemical and one pharmacological effect of digoxin

Attached you will find an article discussing Digoxin. Please discuss the botanical, chemical and one pharmacological effect of digoxin (e.g. heart failure).

Volume 3, Issue 2, July – August 2010; Article 016 ISSN 0976 – 044X
International Journal of Pharmaceutical Sciences Review and Research Page 90
Available online at www.globalresearchonline.net
Dr. B. Anil Reddy
Maheshwara College of Pharmacy, Department of Pharmaceutical sciences, Hyderabad, Andhra Pradesh.
Email: drbanilreddy@gmail.com
Herbal Medicine, sometimes referred to as Herbalism or Botanical Medicine, is the use of herbs for their therapeutic or medicinal value.
An herb is a plant or plant part valued for its medicinal, aromatic or savory qualities. Herb plants produce and contain a variety of
chemical substances that act upon the body. The term digitalis or digitalis compounds are all used to refer to the entire group of inotropic
(or drugs that increase myocaridal contractility). All glycosides have a shared structure of: an aglycone ring structure. The aglycone ring
is where the pharmacological activity is found. The main use of Digitalis Purpurea today is as a effective way of treating congestive
heart failure. As a group they are classified as cardiac inotropes. Cardiac, of course, refers to the heart. An inotrope is a substance that
has a direct effect on muscle contraction. Positive inotropism is an increase in the speed and strength of muscle contraction, while
negative inotropism is the opposite. Digitalis has a positive inotropic effect on the heart muscle. During the early 20th century, the drug
was introduced as treatment of atrial fibrillation. Only subsequently was the value of digitalis for the treatment of congestive heart failure
(CHF) established.
Keywords: Digitalis, Congestive heart failure, Therapy.
Herbal medicine is the oldest form of healthcare known to
mankind. Herbs had been used by all cultures throughout
history. It was an integral part of the development of
modern civilization. Primitive man observed and
appreciated the great diversity of plants available to him.
The plants provided food, clothing, shelter, and medicine.
Much of the medicinal use of plants seems to have been
developed through observations of wild animals, and by
trial and error. As time went on, each tribe added the
medicinal power of herbs in their area to its
knowledgebase1. They methodically collected information
on herbs and developed well-defined herbal
pharmacopoeias. Indeed, well into the 20th century much
of the pharmacopoeia of scientific medicine was derived
from the herbal lore of native peoples. Many drugs
commonly used today are of herbal origin. The
physician/scientist credited with bringing digitalis into
mainstream medicine is William Withering. Foxglove10
had already been in use as a traditional herbal remedy11 for
“dropsy,” the swelling that often accompanies heart
failure. In the 1780s, Withering observed the remarkable
effectiveness of digitalis/foxglove in a woman who had
dropsy, and he began a rigorous study of the drug.
Digitalis is a drug that has been used for centuries to
treat heart disease. The active ingredient in the drug is
glycoside, a chemical compound that contains a
sugar molecule linked to another molecule. The glycoside
compound can be broken down into a sugar and nonsugar
compound. Though current digitalis drugs are synthetic,
that is, man-made, early forms of the drug were derived
from a plant. Digitalis is a derivative of the plant Digitalis
purpurea, or purple foxglove. The plant’s name, Digitalis
(from the Latin digit, finger) describes the finger-shaped
purple flowers it bears. The effects of the plant extract9 on
the heart were first observed in the late eighteenth century
by William Withering, who experimented with the extract
in fowls and humans. Withering reported his results in a
treatise entitled, “The Foxglove and an Account of its
Medical Properties, with Practical Remarks on Dropsy.”
His explanations of the effects of foxglove on the heart
have not stood up to the test of time, but his prediction that
it could be “converted to salutary ends” certainly has.
Indeed, digitalis remains the oldest drug in use for the
treatment of heart disease, as well as the most widespread,
in use today.
Digitalis2 is a biennial or perennial herb that grows up to
about 1.2 meters height. The lower basal leaves of the
plant are long stalked, hairy and egg shaped and the upper
leaves are almost without stalks, becoming smaller in size
as they go upwards. It has white or purple flowers and egg
shaped fruits.
Botanical Name: Digitalis purpurea (Linn.)
Family: N.O. Scrophulariaceae
Indian Name: Tilpushpi
Volume 3, Issue 2, July – August 2010; Article 016 ISSN 0976 – 044X
International Journal of Pharmaceutical Sciences Review and Research Page 91
Available online at www.globalresearchonline.net
Digitalis contains four important glucosides of which three
arecardiac stimulants. The most powerful is Digitoxin, an
extremely poisonous and cumulative drug, insoluble in
water, Digitalin, which is crystalline and also insoluble in
water; Digitalein, amorphous, but readily soluble in water,
rendering it, therefore, capable of being administered
subcutaneously, in doses so minute as rarely to exceed of a
grain; Digitonin, which is a cardiac depressant, containing
none of the physiological action peculiar to Digitalis, and
is identical with Saponin, the chief constituent of Senega
root. Other constituents are volatile oil, fatty matter,
starch, gum, sugar, etc. The amount and character of the
active constituents vary according to season and soil: 100
parts of dried leaves yield about 1.25 of Digitalin, which is
generally found in a larger proportion in the wild than in
the cultivated plants. The active constituents of Digitalis
are not yet sufficiently explored to render a chemical assay
effective in standardizing for therapeutic activity. The
different glucosides contained varying from each other in
their physiological action, it is impossible to assay the
leaves by determining one only of these, such as
Digitoxin. No method of determining Digitalin is known.
Hence the chemical means of assay fail, and the drug is
usually standardized by a physiological test. One of our
oldest firms of manufacturing druggists standardizes
preparations of this extremely powerful and important
drug by testing their action upon frogs.
The preparations of Foxglove on the market vary
considerably in composition and strength. Powdered
Digitalis leaf is administered in pill form. The
pharmacopoeial tincture, which is the preparation in
commonest use, is given in doses of 5.15 minims, and the
infusion is the unusually small dose of 2 to 4 drachms, the
dose of other infusions being an ounce or more. The
tincture contains a fair proportion of both Digitalin and
The Foxglove is cultivated by a few growers in this
country in order to provide a drug of uniform activity from
a true type of Digitalis purpurea. It is absolutely necessary
to have the true medicinal seeds to supply the drug market:
crops must be obtained from carefully selected wild seed
and all variations from the new type struck out. The plant
will flourish best in well drained loose soil, preferably of
siliceous origin, with some slight shade. The plants
growing in sunny situations possess the active qualities of
the herb in a much greater degree than those shaded by
trees, and it has been proved that those grown on a hot,
sunny bank, protected by a wood, give the best results. It
grows best when allowed to seed itself, but if it is desired
to raise it by sown seed, 2 lb. of seed to the acre are
required. As the seeds are so small and light, they should
be mixed with fine sand in order to ensure even
distribution. They should be thinly covered with soil. The
seeds are uncertain in germination, but the seedlings may
be readily and safely transplanted in damp weather, and
should be pricked out to 6 to 9 inches apart. Sown in
spring, the plant will not blossom till the following year.
Seeds must be gathered as soon as ripe. The flowers of the
true medicinal type must be pure, dull pink or magenta,
not pale-coloured, white or spotted externally. It is
estimated that one acre of good soil will grow at least two
tons of the Foxglove foliage, producing about 1/2 ton of
the dried leaves.
Digitalis has been used from early times in heart cases. It
increases the activity of all forms of muscle tissue, but
more especially that of the heart and arterioles, the allimportant
property of the drug being its action on the
circulation. The first consequence of its absorption is a
contraction of the heart and arteries, causing a very high
rise in the blood pressure3. After the taking of a moderate
dose, the pulse is markedly slowed. Digitalis also causes
an irregular pulse to become regular. Added to the greater
force of cardiac contraction is a permanent tonic
contraction of the organ, so that its internal capacity is
reduced, which is a beneficial effect in cases of cardiac
dilatation, and it improves the nutrition of the heart by
increasing the amount of blood. In ordinary conditions it
takes about twelve hours or more before its effects on the
heart muscle is appreciated, and it must thus always be
combined with other remedies to tide the patient over this
period and never prescribed in large doses at first, as some
patients are unable to take it, the drug being apt to cause
considerable digestive disturbances, varying in different
cases. This action is probably due to the Digitonin, an
undesirable constituent. The action of the drug on the
kidneys is of importance only second to its action on the
circulation. In small or moderate doses, it is a powerful
diuretic and a valuable remedy in dropsy, especially when
this is connected with affections of the heart. It has also
been employed in the treatment of internal haemorrhage,
in inflammatory diseases, in delirium tremens, in epilepsy,
in acute mania and various other diseases, with real or
supposed benefits. The action of Digitalis in all the forms
in which it is administered should be carefully watched,
and when given over a prolonged period it should be
employed with caution, as it is liable to accumulate in the
system and to manifest its presence all at once by its
poisonous action, indicated by the pulse becoming
irregular, the blood-pressure low and gastro-intestinal
irritation setting in. The constant use of Digitalis, also, by
increasing the activity of the heart, leads to hypertrophy of
that organ. Digitalis is an excellent antidote in Aconite
poisoning, given as a hypodermic injection. When
Digitalis fails to act on the heart as desired, Lily-of-the-
Valley may be substituted and will often be found of
service. In large doses, the action of Digitalis on the
circulation will cause various cerebral symptoms, such as
seeing all objects blue, and various other disturbances of
the special senses. In cases of poisoning by Digitalis, with
a very slow and irregular pulse, the administration of
Atropine is generally all that is necessary. In the more
severe cases, with the very rapid heartbeat, the stomach
pump must be used, and drugs may be used which depress
and diminish the irritability of the heart, such as chloral
and chloroform.
Volume 3, Issue 2, July – August 2010; Article 016 ISSN 0976 – 044X
International Journal of Pharmaceutical Sciences Review and Research Page 92
Available online at www.globalresearchonline.net
Digitalis is of value in irritable heart with palpitation from
overwork, heart strain, and the arrhythmia of simple
dilatation, in moderate degrees of ventricular dilatation,
and cardiac asthenia. It is especially commended for the
irritable heart of soldiers brought on by long marches and
fighting whereby the inhibitory-control is lost or lessened
and exhaustion of the heart-muscle is imminent. When
palpitation is purely nervous, it is of little value; cactus is
then a better remedy. It also fails often in paroxysmal
tachycardia, which is also mostly a nervous phenomenon.
In Grave’s disease, it is not curative, but sometimes
rectifies the cardiac irregularity. In functional palpitation
arising from imperfect digestion it sometimes controls the
heart symptoms, but gives little or no relief if the trouble is
purely nervous, nor does it aid the stomachic disorder.
Digitalis is a classic example of a drug derived from a
plant formerly used by folklorists and herbalists: herbalists
have largely abandoned its use because of its
narrow therapeutic index and the difficulty of determining
the amount of active drug in herbal preparations. Once the
usefulness of digitalis in regulating pulse was understood,
it was employed for a variety of purposes, including the
treatment of epilepsy and other seizure disorders, now
considered inappropriate. Below are some of the medicinal
properties of digitalis: Digitalis is mainly used in treating
heart diseases. In case of congested heart failure, it
promotes and stimulates the activity of all muscle tissues.
The herb forces more blood into the coronaries thereby
improving the nourishment to the heart. When blood
circulation gets impaired and dropsy sets in, digitalis help
in restoration and regulation of the function of the heart. It
helps urination by improving the blood supply to the
kidneys and removes obstructions within the kidneys.
Digitalis is used with gratifying results in some ointment
for local application on wounds and burns. In cases of
burns, it is very effective in preserving severely damaged
Ornamental strains of D. purpurea typically have low
concentrations of active compounds. Leaves of wild
varieties that have been used for medicinal purposes
contain at least 30 different glycosides in total quantities
ranging from 0.1% to 0.6%; these consist primarily of
purpurea glycoside A (yielding digitoxin) and glycoside B,
the precursor of gitoxin. Upon hydrolysis, digitoxin and
gitoxin lose sugar molecules, producing their respective
aglycones, digitoxigenin, and gitoxigenin. Seeds also
contain digitalis glycosides. The main glycosides of D.
lanata are the lanatosides, designated A through E.
Removal of acetate groups and sugars results in formation
of digitoxin, gitoxin, digoxin, digitalin, and gitaloxin. D.
lanata is not typically used in powder form in the United
States, but serves as a major source of lanatoside C and
Digoxin’s inotropic effect results from the inhibition of the
sodium-potassium adenosine triphosphatase
(NA+/K+ATPase) pump. The subsequent rise in
intracellular calcium (Ca++) and sodium (NA+) coupled
with the loss of intracellular potassium (K+) increases the
force of myocardial muscle contraction (contractility),
resulting in a net positive inotropic effect. Digoxin also
increases the automaticity of Purkinje fibers but slows
conduction through the atrioventricular (AV) node.
Cardiac dysrhythmias associated with an increase in
automaticity and a decrease in conduction may result. The
relationship between digoxin toxicity and the serum
digoxin level is complex; clinical toxicity results from the
interactions between digitalis, various electrolyte
abnormalities, and their combined effect on the
Na+/K+ ATPase pump. Cardiac, such as oleander,
foxglove, and lily-of-the-valley, is uncommon but
potentially lethal. Case reports of toxicity from these
sources implicate the preparation of extracts and teas as
the usual culprit.
Drug interactions are one of the most common causes of
digoxin toxicity. Some medications directly increase
digoxin plasma levels; other medications alter renal
excretion or induce electrolyte abnormalities.
Drugs that have been reported to cause digoxin toxicity
include the following:
 Amiloride – May reduce the inotropic response to
 Amiodarone – Reduces renal and nonrenal
clearance of digoxin and may have additive effects
on the heart rate
 Benzodiazepines (alprazolam, diazepam) – Have
been associated with isolated reports of digoxin
 Beta-blockers (propranolol, metoprolol, atenolol) –
May have additive effects on the heart rate;
carvedilol may increase digoxin blood levels in
addition to potentiating its effects on the heart rate
 Calcium channel blockers – Diltiazem and
verapamil increase serum digoxin levels; not all
calcium channel blockers share this effect.
 Cyclosporine – May increase digoxin levels,
possibly due to reduced renal excretion
 Erythromycin, clarithromycin, and tetracyclines –
May increase digoxin levels
 Propafenone – Increases digoxin level; effects are
 Quinidine – Increases digoxin level substantially
but clinical effect is variable; related drugs such as
hydroxychloroquine or quinine may also affect
 Propylthiouracil – May increase digoxin levels by
reducing thyroid hormone levels
 Indomethacin
 Spironolactone – May interfere with digoxin
assays; may directly increase digoxin levels; may
alter renal excretion.
Volume 3, Issue 2, July – August 2010; Article 016 ISSN 0976 – 044X
International Journal of Pharmaceutical Sciences Review and Research Page 93
Available online at www.globalresearchonline.net
 Hydrochlorothiazide
 Furosemide and other loop diuretics
 Triamterene
 Amphotericin B – May precipitate hypokalemia
and subsequent digoxin toxicity
 Succinylcholine – Increased risk of dysrhythmias
has been reported.
Herb/nutraceutical – Avoid ephedra (risk of cardiac
stimulation); avoid natural licorice (causes sodium and
water retention and increases potassium loss).
Clinical digoxin toxicity represents a complex interaction
between digoxin and various electrolyte and renal
abnormalities. A patient with normal digoxin levels (0.5-2
ng/mL) but renal insufficiency or severe hypokalemia may
have more serious cardiotoxicity than a patient with high
digoxin levels and no renal or electrolyte disturbances.
In therapeutic doses, digitalis usually produces mild toxic
effects. The toxic effects include headache, fatigue,
drowsiness, nausea, vomiting and blurred vision. It is
therefore, necessary to regulate the dose in such a manner
so as to avoid such effects. The toxic effects mentioned
should be watched carefully and the dose regulated
Direct Action:
Digitalis binds to the sodium pump1 on the myocardial cell
membrane and inhibits its function. This pump when
inhibited causes a rise in the amount of sodium inside the
heart cell, which then exchanges it for calcium through the
cell membrane, as calcium rises inside the heart cell
contractile mechanism becomes more optimal and
Indirect Action:
Parasympathetic nerve activation results in sinus6 node
slowing and thus bradycardia. It also inhibits the Atrio-
Ventricular Node.
Excretion: 60% through kidneys, 30% by the Liver
Body weight is crucial in determining the loading dose, as
in a small child with low skeletal muscle mass; less of the
loading dose will bind to skeletal muscles and will rather
rise the blood digoxin level and cause toxicity.
Digitoxin is 1,000 times more potent than the powdered
leaves and is completely and rapidly absorbed from the
gastrointestinal tract. Digoxin is 300 times more potent
than the powder prepared from D. purpurea. All cardiac
glycosides7 share the characteristic of improving cardiac
conduction, thereby improving the strength of cardiac
contractility. These drugs also possess some
antiarrhythmic activity, but will induce arrhythmias at
higher dose levels. Digitalis works by inhibiting sodiumpotassium
ATPase. This results in an increased
intracellular concentration of sodium, which in turn
increases intracellular calcium by passively decreasing the
action of the sodium-calcium exchanger in
the sarcolemma. The increased intracellular calcium gives
a positive inotropic effect. It also has a vagal effect on
the parasympathetic nervous system, and as such is used in
reentrant arrhythmias and to slow the ventricular rate
during atrial fibrillation. The dependence on the vagal
effect means that digitalis is not effective when a patient
has a high system drive, which is the case with acutely ill
persons, and also during exercise.
Congestive heart failure
Digitalis glycosides have been used clinically for the
treatment of CHF for more than 200 years.
Animal data
Research reveals no animal data regarding the use of
digitalis for CHF.
Clinical data
Numerous studies have been conducted on the use of
digitalis as a treatment of CHF in sinus rhythm. The
literature identifies a role for digitalis in the treatment of
this condition.
Antitumor activity
Recent research has shown the anticancer effects of
digitalis compounds, suggesting their possible use in
medical oncology. 9 Further research is needed to see
whether cardiac glycosides can be used as antitumor
drugs. D. lanata and D. purpurea were identified as having
cytotoxic properties, including cytotoxic activity, and
warrant further study. Another study was supportive of
investigations showing that apoptosis induction is a major
effect of digitalis on several types of tumor cells. 9 The
report demonstrated the anticancer activity of D. purpurea.
L. heywoodi on 3 human cancer cell lines. The results of
one study revealed marked differences in cytotoxicity
between the cardiac glycosides, both in potency and
selectivity, and modes of action that differ from those of
commonly used anticancer drugs. More studies are
needed to clarify a possible role of cardiac glycosides in
chemotherapy of malignant diseases.
Animal data
Short-term animal experiments concluded that toxic doses
would be needed to produce an anticancer effect in
humans. However, susceptibility for cardiac glycosides
differs between species, indicating that the results from
animal models cannot be extrapolated into humans.
Clinical data
Several investigators have postulated that digitalis
glycosides could be used in cancer therapy, and that they
may operate through novel mechanisms; however, this
idea has not found wide acceptance.
Volume 3, Issue 2, July – August 2010; Article 016 ISSN 0976 – 044X
International Journal of Pharmaceutical Sciences Review and Research Page 94
Available online at www.globalresearchonline.net
Digitalis leaf provides a narrow therapeutic index,
requiring close medical supervision for safe use. Classical
dosage started at 1.5 g of leaf divided between 2 daily
doses. Purified digoxin is typically used at daily doses of
0.125 to 0.25 mg.
All parts of the plant are toxic. Animal toxicity occurs
during grazing. Children have been made ill by sucking
the flowers or ingesting seeds or parts of the
leaves. Deaths have been reported among persons who
drank tea made from digitalis mistakenly identified for
comfrey, although the bitter taste often deters ingestion or
its emetic properties can induce vomiting. Digitalis
glycosides are excreted slowly and accumulate; therefore,
intoxications during therapy are common. The incidence
of digitalis toxicity has been estimated to range from 5%
to 23%. More stringent dosing guidelines and monitoring
techniques have dramatically reduced the incidence of
therapeutic overdose. Digitalis poisoning often is
associated with intentional ingestion by adolescents and
adults, sometimes with suicidal intent. Signs of poisoning
by the plant or purified drug include contracted pupils,
blurred vision, strong but slowed pulse, nausea, vomiting,
dizziness, excessive urination, fatigue, muscle weakness,
and tremors; in severe cases, stupor, confusion,
convulsions, and death occur. Cardiac signs include atrial
arrhythmias and atrioventricular block. The cardiac effects
are the most dangerous. Chronic4 digitalis intoxication5 is
characterized by visual halos, yellow-green vision, and
gastrointestinal upset. In mild cases of toxicity (atrial
fibrillation with a slow ventricular response or occasional
ectopic beats), temporary withdrawal of the drug and
electrocardiogram monitoring is sufficient. Gastric lavage
or emesis together with supportive measures, such as
electrolyte replacements, antiarrhythmics (eg, lidocaine,
phenytoin), atropine, and other agents that can antagonize
the cardiovascular effects of the glycosides, have been
used to manage acute poisonings. Digoxin-specific Fab
antibody fragments14 (Digibind) are effective in managing
acute intoxications caused by digitalis and related
cardioactive glycosides. This therapy is revolutionary for
the severely poisoned patient. Digoxin Fab fragment
antibodies by infusion are an effective antidote for some
plant cardiac glycosides15, but not always for digitalis.
Digitalis is of great value in chronic valvular cardiac
disease, with failing or broken compensation, but it must
be used with judgment, observing the need in the weak,
fast, and irregular pulse, deficient urination, and dropsy.
When hypertrophy of the heart overbalances dilatation,
and evidences of arterial hyperaemia are present, digitalis
is likely to aggravate the condition, or otherwise do harm.
Digitalis medication is most effective probably in mitral
insufficiency, with regurgitation, provided there are no
pericardial adhesions restraining its effects, or advanced
myocardial degeneration. It overcomes the ventricular
strain dependent upon pulmonic vascular resistance, and
helps, by contracting the ventricle rings, to attain a more
perfect closure of the mitral valves. The main way it
achieves this function is through increasing myocardial
contractility16. The World Health Organization (WHO)
estimates that 4 billion people, 80 percent of the world
population, presently use herbal medicine for some aspect
of primary health care. Herbal medicine is a major
component in all indigenous peoples’ traditional medicine
and a common element in Ayurvedic, homeopathic,
naturopathic, traditional oriental17. The digitalis drugs
come in many forms, differing in their chemical
Acknowledgement: I am thankful to Dr. Singh, Professor,
Patna. Mr. Gupta, Director, Azilent Pharma, Hyderabad,
for his extended support and providing necessary facilities
during the tenure of this work.
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