Cardioactive Glycosides PDF

Cardioactive glycosides By Dr. ENASS NAJEM  Cardioactive glycosides The glycosides of this group are characterized by their highly specific action on cardiac muscle, increasing tone, excitability and contractility. The aglycones of these glycosides are referred to as "cardiac...

Cardioactive glycosides By Dr. ENASS NAJEM  Cardioactive glycosides The glycosides of this group are characterized by their highly specific action on cardiac muscle, increasing tone, excitability and contractility. The aglycones of these glycosides are referred to as "cardiac genin". They are steroidal in nature, specifically, they are derivatives of cyclopentaphenanthrene containing an unsaturated lactone ring attached to C17.  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: 1- the cardenolide. In the cardenolide (aglycones with 23 carbons), the lactone ring attached at C17 is a butenolide (4 carbons), which is also referred as α,β- unsaturated lactone ring. E.g. the glycosides of digitalis and strophanthus species  Cardenolide (c23) Digitalis glycosides R=CH3 Strophanthus glycosides R=CHO OR CH2OH 2- the scilladienolide (which are referred to as bufadienolide). In the scilladienolide (aglycone with 24 carbons), the lactone ring attached at C17 is a pentadienolide (5 carbons with two double bonds) which is also called a pentenolide. These two types of lactone rings give different reactions to certain color tests. the squill glycosides and, Bufotoxin.  Bufadienolides Squill glycosides R1=OH, R2=H Bufotoxin R1 & R2 = ester group The glycone portion at position C-3 of cardiac glycosides may contain four monosaccharide molecules linked in series. Thus, from a single genin one may have a monoside, a bioside, a trioside or a tetroside. All cardioactive glycosides are characterized by the following structural features 1. The presence of β-OH at position C-3, which is always involved in a glycosidic linkage to a mono, di, tri, OR tetra saccharide. 2. The presence of another β-OH group at C-14. 3. The presence of unsaturated 5 or 6- membered lactone ring at position C-17, also in the β configuration. 4. Additional OH groups may be present at C-5, C-11 and C-16. Nomenclature of cardioactive glycosides The sequence of nomenclatureis as follows: 1- arrange the functional groups and denote their configuration. 2- denote 5 whether α or β. 3- denote the type of glycoside. 4- denote the position of the double bonds. Example: O 3 β hydroxyl- 11-oxo- 5α-card-6,15,20 -trienolide If the compound has one double bond then it is called cardenolide, if has two double bonds then it's called dienolide, but if it has no double bond then it is called cardanolide and bufanolide. Biosynthesis of cardioactive glycosides: Most of the knowledge of the biosynthesis of steroids has been derived from studies of cholesterol production. Aglycones of the cardiac glycosides are derived from mevalonic acid but the final molecules arise from a condensation of a C21 steroid with a C2 unit (the source of C-22 and C-23). Bufadienolides are condensation products of a C21 steroid and a C3 unit Drugs containing cardioactive glycosides 1- Digitalis or foxglove It’s the dried leaf of Digitalis purpurea; F: Scrophulariaceae. Digitalis is from the latin digitus, meaning finger and refers to the finger shaped corolla, purpurea is latin and refer to the purple color of the flower. Constituents The drug contain a large number of glycosides of which the most important from the medicinal view point are: Digitoxin, gitoxin and gitaloxin. The average concentration is about 0.16%. Nearly 30 other glycosides have been identified in the drug e.g. purpurea glycosides A, purpurea glycoside B, gluco-gitaloxin, gluco-digitoxigenin. Primay glycosides with acetylated sugar moieties Digitalis lanata Nearly 70 different glycosides have been detected in the leaves of Digitalis lanata. All are derivatives of five different aglycones, three of which (digitoxigenin, gitoxigenin and gitaloxigenin) also occur in Digitalis purpurea. The other two types of glycosides are derived from digoxigenin and diginatigenin occur in Digitalis lanata but not in digitalis purpurea. the leaves of which are used as a source of the glycosides digoxin and lanatoside C  Lantoside A ,B and E are acetyl derivatives of purpurea A,B and E respectively. Glycosides derived from Digitoxigenin: a- Lanatoside A = Digitoxigenin---DX---DX----DX(AC)---G. b- Acetyl-digitoxin = Digitoxigenin---DX---DX----DX---(AC). c- Digitoxin = Digitoxigenin------DX---DX----DX. d- Purpurea gly A = Digitoxigenin---DX---DX----DX---G DX = Digitoxose, DX (AC)=Acetyldigitoxose,G = Glucose. Mechanism of action It act through inhibition of Na+/K+ ATPase enzyme (membrane bound enzyme). This enzyme keep K+ inside the cell and Na+ outside the cell; so when this enzyme is inhibited K+ transport back into the cell is blocked and its concentration in the extracellular fluid increases, at the same time Na ions will enter the cell and this will promote or facilitate the entry of Ca +2 which are essential for the contraction of actin and myosine. Therefore these agents used in the treatment of congestive heart failure. 2- Strophanthus Is the dried ripe seeds of strophanthus kombe or strophanthus hispidus F: Apocyanaceae. The principal glycosides are K- strophanthoside, K-strophanthin-B and cymarin, all based on the genin strophanthidin Constituents: k-strophanthoside, also known as strophoside. Is the main glycoside in both S.kombe and S.hispidus. it is composed of the genin strophanthidin coupled to a trisaccharide consisting of cymarose, β-glucose and α- glucose. Strophanthin is used I.V. as a cardiotonic. Ouabin (G-strophanthin) It is obtained from S.grantus (F: apocynaceae) Uses: it is a most polar cardioactive glycosides Act as a cardiotonic. i.v. for prompt therapeutic effect. It is absorbed so slowly and irregularly from the alimentary canal that the oral administration is not recommended and is even considered unsafe.  Ouabin (G-strophanthin) (ouabagenin, the sugar is rhamnose) Ouabagenin differs from K-strophanthidin in having 2 additional (OH) groups at C-1 and C-11 and having a alcoholic group at C- 10 instead of the aldehydic group. 3- Oleander Is another plant that contains cardiac glycosides. The leaves of Nerium oleander ( F: Apocyanaceae) have been used to treat cardiac insufficiency. The main constituent is oleanderin (is a promising agent for anticancer treatment). Oleander has historically been considered a poisonous plant because some of its compounds may exhibit toxicity, especially to animals, when consumed in large amounts. sugar Oleanderin 4-(bufadienolide) squill bulb of the white variety of Urginea maritima known as white or Mediterranean squill, or of Urginea indica known in commerce as indian squill, F: liliaceae. The genins of squill glycosides differ from those of the cardenolides in two important aspects: 1- They have six membered doubly unsaturated lactone ring in position C-17. 2- They have at least one double bond in the steroid nucleus. Uses: as an expectorant but it also possesses emetic, cardiotonic and diuretic properties. Red squill consists of the bulb of the red variety of Urginea maritima, which is mostly used as rat poison