Digoxin

Abstract

Cardiac glycosides are directly responsible for the survival of people with heart

defects or who have experienced heart failure; as societies see an increase in

heart related diseases and aging populations with increased risk of heart failure

it is vital that there be an understanding of these incredibly crucial drugs.

Discoveries made in the 18th century have and will continue to have a great

impact on how we are able to face future challenges and treat those in need in

ever more effective ways.

Methodology

The primary sources for research referenced are textbooks relating directly to

the function and mechanics of drugs and medicines. Specific information

concerning even relatively well known drugs and medicines is often sporadic

and unreferenced when published directly on websites; the exception being

online published journals, however these may also appear far too complex to

someone outside of the specific field of research and only few relevant pieces of

information were found from them.

University and college libraries were used, though there were far more

opportunities for tangible research using online libraries such as Google books
which is where the majority of the information was procured (rare or costly

journals and textbooks which are readily available through google books).

Findings

Digoxin (common brand name Lanoxin) is a purified form of cardiac glycoside;

it belongs to a group of organic compounds that contain a glycoside, or sugar,

which acts on the cardiac muscle and especially effecting its contractility

(Cheeke, 1989, p.63)

Digoxin and many other cardiac glycosides owe their synthesis to the

discoveries made by William Withering whilst studying digitalis (Foxglove) in the

late 18th century. In his book Withering made careful note of patients, their

symptoms, dosage and reaction to concentrations of digitalis; in many cases the

outcomes were positive, however cautious records of people reacting differently

to the same dosage etc were also made (Withering, 1822, 186)
 Fig 1. Structure of Digoxin

(Vardanyan and Hruby, 2006, p.240)

Commonly known as digoxin its systematic (IUPAC) name is as follows;

4-[(3S,5R,8R,9S,10S,12R,13S,14S)-3-[(2S,4S,5R,6R)-5-[(2S,4S,5R,6R)-5-

[(2S,4S,5R,6R)-4,5-dihydroxy-6-methyl-oxan-2-yl]oxy-4-hydroxy-6-methyl-oxan-

2-yl]oxy-4-hydroxy-6-methyl-oxan-2-yl]oxy-12,14-dihydroxy-10,13-dimethyl-

1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-

yl]-5H-furan-2-one

(Sfetcu, 2014)

Digoxin is isolated from multiple varieties of the foxglove plant and diverges with

digitoxin via the addition of an additional hydroxyl group at C 16 of the above

skeleton [Fig 1] and does not stay in the body as long as digitoxin (Vardanyan

and Hruby, 2006, p.240)

Cardiac glycosides in general, with Digoxin being no exception, must fulfil

certain structural requirements in order to behave chemically the way they do,

these include the presence of a configured unsaturated lactone ring at C-17,

configured hydroxyl (OH) group at C-14 with A and B rings joined cis, as shown

below (Gupta, 2015, p.323);

Fig 2. Basic cardiac glycoside structure

(Monoclonal antibody against cardiac glycoside, 2015)

The mechanism by which digoxin is effective is in the inhibition of the

sodium/potassium (Na+/K+) pump leading to an increase in Na+ levels; this is

done via binding to a site on?the?extracellular?-subunit of the pump within the

membranes of myocites (heart cells) [Fig 3] (Sfetcu, 2014)

An increase in Na+ levels decreases the release of Ca2+ (Calcium2+ ions) via the

exchange pump which may then be stored and released by each action

potential, thus increasing the strength and efficiency of contractions and

correcting abnormal rhythm; interestingly digoxin simultaneously escalates

vagal action due to its effect on the central nervous system, allowing for its

clinical use in treating arrhythmias (Aschenbrenner and Venable, 2009, p.543)

Digoxin is a selective or competitive inhibitor owing to its binding to the plasma

membrane-bound enzyme Na+/K+ ATPase (sodium-potassium adenosine

triphosphatase) competing with the K+ ions which would normally bind to those

receptor sites; this in turn inhibits the pumps ability to transport Na + (Kapoor and

Raju, 2013, p.455) [Fig 4/5]

Fig 3. Mechanism of action within the cell

(Glycosides, 2015)
 Fig 4. Competitive inhibition of Na+/K+ ATPase

(Kapoor and Raju, 2013, p.456)

Ouabain is an alternative cardiac glycoside in use similar in structure and

function to Digoxin with the systematic name;

1,3,5,11,14,19-hexahydroxy-5-card-20(22)-enolide 3-O-(-L-

rhamnopyranoside)

(Lipidmaps.org, 2015)

Oubains structural similarity to Digoxin can be seen below, as well as the

specific overview of binding to the -Subunit of Na +/K+-ATPase;

 Fig 5. Structural overview of binding/glycoside molecules

(Pnas.org, 2015)

Ouabain and digoxin are currently the only cardiac glycosides in use, however

owing to its superior oral bioavailability Digoxin may be preferred as Ouabain

can only be administered intravenously; it is almost completely insoluble in fat

thus will not cross mucosal membranes required when taken orally (Antman,

2007, p.35)

Owing to its narrow therapeutic index the boundary between being used as

an effective treatment, and toxicity adverse reactions are rare as

concentrations are kept extremely low (less than 0.8g/L), however some

commonly noted effects may include: nausea, dizziness and loss of appetite

though these are reported in less than 1% of total cases (Movahed, 2009,

p.432). Due to the nature and priority of the conditions it can treat, and

potentially preventing early death, digoxin is on the World Health organisation

(WHO) list of essential medication required in a basic health care system

(who.int, 2013)

The global population of the elderly is estimated to grow to approximately 2

billion by the year 2015, in the United States alone heart failure is the most

commonly diagnosed in those over 65, with atrial fibrillation most commonly

effecting those over 70 (Khan, 2006, p.1).

Although digoxin and other inotropic drugs increase the efficiency and beat

strength of the heart, in older patients with severely weakened hearts this may

place an increasing strain on its ability to support additional metabolic stress;

there are medications those who have chronic disease can take without any

change in efficacy of digoxin however such as D-Ribose to supplement ATP

levels (Sinatra M.D and Roberts M.D, 2010, p.158).

Conclusions

With aging populations, heart conditions will become, if not are already

becoming, one of the most abundant health problems; if we are to ensure that in

the future we can provide the best possible chance for overcoming those

problems then innovation and research must be continued. 18 th century

discoveries have led to modern drug designs which have saved countless lives,

and investment in the development of future discoveries must be done.

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