Glycoside DefinitionA substance which on hydrolysis yields a reducing sugar + one or more non-sugar substances (genin/aglycone) • Normally aromatic in nature • Known as the aromatic aglycone or genin portion
Glycosides Glycoside = Broad & general term • Embraces all the many various combinations of sugars & aglycones • e.g. Cardiac glycosides, flavonoid glycosides, phenolic glycosides etc.
Glycoside FormationIn nature: Formed by the interaction of the nucleotide of a sugar group with the alcoholic or Phenolic group of a 2nd compound. This glycoside is called an O-glycoside Most numerous kind found in nature
Other Glycoside Formation Other glycosides occur through sulphur links • Called S-glycosides Nitrogen links • Called N-glycosides Through Carbon links • Called C-glycosidesNOTE: Reactions for both the formation and Hydrolysis ofglycosides are reversible
Glycosidal Reduction Glycosides themselves do not reduce Fehling’s solution, But the simple sugars they produce on hydrolysis (aglycones) do (precipitate red cuprous oxide)
Glycosidal Sugars Sugars found in glycosides may be Monosaccharides Glucose Rhamnose Fructose Deoxysugars (more rare) Cymarose • E.g. those found in the cardiac glycosides
Terms used to Describe GlycosidesA Glycoside is a Glucoside Has glucose as the sugar component Pentoside Has a sugar such as arabinose Rhamnosides Contains rhamnose Rhanmoglucosides Contains both rhamnose and glucose
Terms used for Aglycones Normally self-explanitory E.g. Phenol Anthroquinone Sterol glycoside
Other Glycosidal Terms saponin (soap-like) Cyanogenic (producing hydrocyanic acid) Cardiac (having an action on the heart) Terms: Are used to group glycosides together which have similar functions & chemical structure.
GLYCOSIDE STRUCTURE 2 types of genin are distinguished Based on the structure of the lactone ring 5-membered ring bufanolides or bufadienilolides E.g. scillarenin 6-membered ring cardinolides or cardiac active glycosides (medicinally more significant)
Cardio-Active Glycosides A small group of plant glycosides act directly on the heart muscle. These include (but are not limited to cardiac glycosides or cardenolides) Cardenolides are steroidal glycosides exert a slowing and strengthening effect on the failing cardiac muscle.
Cardiac Glycosides E.g. Digitalis purpurea (Purple Foxglove). Other uses of the plant (and glycoside) include being used as arrow poisonings.
Pharmacological Action of Cardiac Glycosides Effectiveness depends on both the aglycones and the sugar attachments. Medicinal action depends on the aglycone But the sugars make the compound more soluble in increases the fixation of the glycoside to the heart muscle
Pharmacological Action of Cardiac Glycosides The overall action of Digitalis glycosides is complicated by the number of different effects produced. The exact mode of action on the myocardial muscle still needs investigation. It is thought to act in competition with K ions for specific receptor enzymes (ATPase) sites in the cell membranes of the heart muscle when there is an influx of Na ions. Effect is to increase the force of heart contraction Diuretic action relates to the improved circulatory effects.
Digitalis puruperea – (Scrophulariaceae) Description: A perennial herb growing up to 1.5m with a single erect stem, broad lance- shaped leaves and bell- shaped, purple-pink or white flowers in long spikes History: The poisonous nature of the leaves are well known, and the drug was recommended for use since 1542. Discovered by William Withering, an 18th century country doctor (cardiac effect) His work led to the production of a life-saving medicine
Digitalis purpurea – Purple Foxglove Definition: Digitalis consists of the dried leaves of Digitalis purpurea. It is required to contain at least 0.3% of total cardinolides calculated as digitoxin.
Digitalis purpurea Parts Used: Leaves Habitat: Native to Western Europe. Although the plant is cultivated, wild plants are thought to be superior. Collection: First or second-year leaves are permitted. After collection the leaves should be dried as soon as possible at a temperature of about 60ºC. Stored in airtight containers & protected from light. Moisture content should be no more than 6%.
Digitalis purpurea - Collection There is a general belief that the pharmacological activity of the leaves increase during the course of the day to reach a maximum in the early afternoon (when they should be harvested). This was supported by assays done in 1956 which showed a greater activity of the leaves at noon than 8am, irrespective of if the leaves where in the sun or shade. However, other work indicates that there is no glycosidal content variation of the leaves when measured at 3-hour intervals.
Microscopical Characteristics Stomata and hairs present on both surfaces (more on lower surface) No calcium oxalate Clothing hairs are uniseriate Glandular hairs
Active Constituents glycosides purpurea glycoside A purpurea glycoside B (2 main actives in the fresh leaf) Glucogitaloxin At C-3 of the genin:a linear chain of 3 digitoxose sugar moieties terminated by glucose
Active Constituents On drying: enzyme degradation takes place loss of the terminal glucose. Produces Digitoxin Gitoxin Gitaloxin (main actives in dried leaves) Poor storage leads to further hydrolysis and complete loss of action
Digitalis – Active Constituents also contains anthraquinone glycosides Saponins Sopogenins Flavonoids
Active Constituents Other glycosides (present in smaller quantities) include Digitalose Glucose Verdoxin (x3 more toxic than gitaloxin)
Digitalis – Active Constituents It is generally agreed that the first-year leaves collected in Jan-Feb (Southern Hemisphere) have the highest content of total glycosides. After that they decrease during the winter months. After that another peak is reached during the time of flowering, but not as high as the first one.
Digitalis – Medicinal Actions tonic effect on the diseased heart glycosides enable the heart to beat more strongly, slowly and regularly, without using or needing more O2. Stimulates urine production lessening the load on the heart.
NB! Kellar-Keliani Test for digitoxise Pg 509/Pg146
Digitalis purpurea Cautions Potential for overdose Only under professional supervision Plant is subject to legal restrictions.
Digitalis lanata – Woolly FoxgloveToday’s main source of cardiac glycosides Self-study: Pg 147-9
Convalaria majalis – (Liliaceae) Cardioactive properties Similar to Digitalis, but less cumulative Therefore sometimes preferred rather than Digitalis (tolerated better, fewer side effects) Therapeutic Action: Heart stimulant
Convallaria majalis – lily of the valley Parts used: Collected parts include aerial parts (when flowers begin to open) rhizomes & roots
Convallaria - Cautions very toxic only administered by professionals. may cause nausea, vomiting & GIT symptoms if taken in large amounts Because Convallaria cardenolides are poorly absorbed in the stomach and intestines they are rarely deadly.
Strophanthus kombe Part Used: Dried seeds (ripe) Habitat: East Africa. Greek strophos (a twisted cord or rope) anthos (a flower)
Strophanthus kombe Constituents Strophanthoside strophanthin cymarin all based on genin - strophanthidin) Alkaloid: Inoeine Fixed oil, resin mucilage Strophanthin Glycoside Molecular formula: C29H44O12
Strophanthus kombe Uses - similar to Digitalis Chronic cardiac weakness Diuretic action (thought to be more powerful than Digitalis) Can be administered IV Actions Similar to Digitalis POISONOUS
Bufadienolides Less commonly distributed in nature than cardenolides Occur in some Liliaceae and Ranunculaceae Species. Also occur in toad venoms. Therapeutically there is not much value as the therapeutic index is low and production of side effects high. Squill, however has a time-honoured place as an expectorant Widely used in the treatment of cough.
Urginea maritima – (Liliaceae) Definition: Consists of the dried sliced bulbs of Urginea maritime, from which the membranous outer scales have been removed. It is commercially known as white squill. Description: A perennial herb growing up to 1.5 m from a large white (or red) bulb. It has a single flowering stem, a rosette of large basal leaves, and a dense spike of white flowers.
Urginea maritima - Squill Parts used: Bulbs Collection & Preparation: The bulbs are collected when the plant is finished flowering and has no aerial leaves. The dry outer scales are removed Bulbs cut transversely into thin slices Then dried in the sun or by stove heat. When 80% of the wt is lost, they are packed into bags/barrels.
Urginea maritima - Squill History Squill appears in Egyptian Ebers papyrus (1500BC) In Greece it was used by Pythagoras & Hippocrates in the 6th & 5th centuries BC.
Urginea maritima - Squill Microscopical Characteristics mucilage calcium oxalate small starch grains stomata are absent or rare (wide guard cells) Constituents Glycosides Scillaren A (most NB) Scillaren B
Urginea maritima - Squill Actions & Uses glycosides are poorly absorbed in GIT short action duration (not cumulative) In small doses: mild gastric irritation causing a reflex secretion of bronchioles Reflex expectorant action Larger doses: emetic Diuretic Cardiotonic
Urginea maritima - Squill Cautions: Only under professional supervision. Toxic in excessive doses Unofficial varieties Red Squill – contains squilloriside – very toxic Indian Squill – Urginea indica