Cardiac glycosides

Cardioactive glycosides A considerable number of plants scattered throughout the plant kingdom contain C23 or C24 steroidal glycosides which exert on the failing heart a slowing and strengthening effect. In Western medicine it is the glycosides of various Digitalis species that are extensively employed.

Structure of glycosides Two types of genin may be distinguished according to whether there is a five-or six-membered lactone ring. These types are known respectively as cardenolides (e.g. digitoxigenin) and bufanolides or bufadienolides (e.g. scillarenin). The following formulae indicate their structure and ring numbering:

The sugar moieties, attached to the aglycone by a C-3, β -linkage, are composed of up to four sugar units which may include glucose or rhamnose together with other deoxy-sugars whose natural occurrence is, to date, known only in association with cardiac glycosides. A number of the deoxy-sugars are 2,6-dideoxyhexoses (e.g. digitoxose) or their 3-0-methyl ethers (e.g. cymarose). In addition to rhamnose and fucose, a number of other 6-deoxyhexose derivatives have more recently been discovered together with 2-0-methyl and 2-0-acetyl sugars. In the case of fucose, the D-form is known only in cardiac glycosides, whereas the L-form is widely distributed in nature.

Cardenolides The cardenolides have an unsaturated butyrolactone ring while the bufadienolides have a pyrone ring. The lactone of cardenolides has a single double bond and is attached at the C-17 position of steroidal nucleus. They are five-membered lactone ring and form a C23 steroids , while the lactone of bufadienolids have two double bond which is attached at the 17 α-position of the steroidal nucleus. They are six-memberd lactone ring and form C24 steroids .

Digitalis leaf Digitalis (Purple Foxglove Leaves) consists of the dried leaves of Digitalis purpurea (Scrophulariaceae). It is required to contain not less than 0.3% of total cardenolides calculated as digitoxin. The foxglove is a biennial or perennial herb which Is very common in the UK and most of Europe. including some Mediterranean regions of Italy. and is naturalized in North America.

Collection Either first- or second-year leaves are permitted by the pharmacopoeias. After collection the leaves should be dried as rapidly as possible at a temperature of about 60 °C and subsequently stored in airtight containers protected from light. Their moisture content should not be more than about 6%.

Constituents of Digitalis purpurea The primary (tetra) glycosides ( purpurea glycoside A, purpurea glycoside B and glucogitaloxin) all possess at C-3 of the genin; a linear chain of three digitoxose sugar moieties terminated by glucose. on drying, enzyme degradation takes place with the loss of the terminal glucose to give digitoxin, gitoxin and gitaloxin, respectively. Digitoxin and gitoxin are therefore the main active components of the dried drug. Purpurea glycosides A and B, constitute the principal active constituent of the fresh leaves.

Poor storage conditions will lead to further hydrolysis and complete loss of activity. The aglycones digitoxigenin and gitoxigenin are produced by acid hydrolysis of the respective glycosides but they are not found in quantity in the fresh or dried leaves. Digitalis purpurea leaves also contain anthraquinone derivatives, Saponins have also been isolated from the leaves, A number of leaf flavonoids have been described.

Digitalis lanata leaves The plant. Digitalis lanata (Scrophulariaceae). the leaves of which are used as a source of the glycosides digoxin and lanatoside C,

Constituents of D. Lanata the primary glycosides resemble those of D. purpurea but are acetylated at the digitoxose moiety next to the terminal glucose. This confers crystalline properties on the compounds. making them more amenable to isolation, Partial hydrolysis of the glycosides occurs during the drying and storage of leaves, and deacetylation will produce products the same as in D. purpurea. In addition to the above series of glycosides. two others, involving digoxigenin and diginatigenin are found in the leaves. Anthraquinone derivatives, similar to those found in D. purpurea, have been recorded in the leaves and a number of flavonoid glycosides characterized.

Uses The leaves are used almost exclusively for the preparation of the lanatosides and digoxin. Over the past decades digoxin has become the most widely used drug in the treatment of congestive heart failure. In long-term treatments patients require about 1 mg /day and the world-wide use of the drug now amounts to several thousand kilograms per year. Acting similar to digitalis leaf, digoxin is more rapidly absorbed from the gastrointestinal tract than are the purpurea glycosides, which renders it of value for rapid digitalization in the treatment of atrial fibrillation and congestive heart failure.

Bufadienolides The bufadienolides are less widely distributed in nature than are the cardenolides; they are found in some Liliaceae and Ranunculaceae, and in the toad venoms the genins are partly free and partly combined with suberylarginine. Therapeutically they find little use as cardioactive drugs because of their low therapeutic index and their production of side-effects. However squill (q.v.) has a time-honoured place as an expectorant and has been widely used in the treatment of cough.

Squill Squill consists of the dried sliced bulbs of Urginea maritima (Liliaceae) from which the membranous outer scales have been removed.

Collection and preparation of Squill The bulbs are collected in August, a month in which the plant has finished flowering and is without aerial leaves. After the dry outer scales have been removed, the bulbs are cut transversely into thin slices. These are dried in the sun or by stove heat.

Constituents of Squill a crystalline glycoside. scillaren A, and an amorphous mixture of glycosides, scillaren B. Small quantities of glucoscillaren A (a triglycoside) also occur in the bulb. Many flavonoids have been detected in extracts of the bulb of U. maritima; they include quercetin derivatives and kaempferol polyglycosides together with C-glycosides such as vitexin and isovitexin. The drug also contains sinistrin, a fructan resembling inulin.

Squill’s action and uses The glycosides are poorly absorbed from the gastrointestinal tract, they are of short-action duration and they are not cumulative. In small doses the drug promotes mild gastric irritation causing a reflex secretion from the bronchioles. It is for this expectorant action that it is widely used; in larger doses it causes vomiting