ARC Digoxin Administration and Monitoring Guideline April 2013
Digoxin
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Transcript of Digoxin
A
SEMINAR ON
DIGOXIN, GINSENOSIDES
By
T. Sri Krishna
CONTENTS
History of Digoxin
Structure, Identification tests, Mechanism of action, SAR and Uses of Digoxin
History of Ginsenosides
Structure, Identification tests, Mechanism of action, SAR and Uses of Ginsenosides
HISTORY OF DIGOXIN
Digoxin is used from many year ago.
William Withering(1785) -- the properties
and medicinal uses of Digital.
1799 -- direct action of digitalis on the heart.
GLYCOSIDES
Glycosides – Two part the sugar(glycone)
and the aglycone.
Glycone -- non therapeutic activity and it
contains sugar moieties (ex: galacose,
mannose,arabinose).
Aglycone -- therapeutic activity.
SOURCE FOR DIGOXIN
Digoxin -- Chemical
Component of Digitalis
Lanata.
Source -- Leaves
Scientific name --
Digitalis Lanata.
Common name --
Woolly foxglove , Austrial
digitalis.
Family --
Scrophulariaceae.
CHEMICAL STRUCTURE
These are
composed of
two structural
features:
1) The sugar
(glycone) moiety.
2) The non-sugar
(aglycone -
steroid) moieties.
R - GROUP
The R group at the 17 position difines the class of cardiac
glycoside.
Two class
1.cardenolides
2.bufadienolides
The cardenolides contains unstrutrated butyrolactone ring.
The bufadienolides contains a pyrone ring.
CARDENOLIDES VS BUFADIENOLIDES
Cardenolide
It contains five
membered ring.
It is butyrolactone ring.
Bufadienolides
It contains six
membered ring.
It is a pyrone ring.
STRUCTURAL FEATURES
Steroidal nucleus most be present.
3β-OH group involved in glycosidic linkage.
14β-OH group at C-14.
A/B ring junction cis
B/C ring junction trans
C/D ring junction cis
Additional OH group at C-5,C-11 and C-16 may be present.
The presence of lactone ring.
IDENTIFICATION TESTS :-
General test for Steroids:
Liebermann’s test :
Glycoside in acetic anhydride+ few drop
of conc. H2SO4 Reddish violet
Green.
Test For Deoxysugars:
Keller – kiliani’s Test:
Glycoside in acetic andhydride
containing of FeCl3+ conc. H2SO4 on the
wall of the tube.
Acetice acid layer acquire Bluish
–green colour (Digitalis).
Acetice acid layer acquire red
colour (Squill).
Legal’s test :
Cardenolide in pryidine +Na nitroprusside
+ NaOH deep red colour .
Kedde’s test :
Cardenolide +3,5 dinitrobezoic acid
(kedde’s reagent A)+NaOH (Kedde’s reagent
B)
Violet colour .
MECHANISM OF ACTION
ACTION POTENTIAL
Digoxin inhibits the Na-K-ATPase membrane pump, resulting in an increase in intracellular sodium.
sodium calcium exchanger (NCX)in turn tries to extrude the sodium and in so doing, pumps in more calcium.
Increased intracellular concentrations of calcium may promote activation of contractile proteins.
Digoxin also acts on the electrical activity of
the heart, increasing the slope of phase 4
depolarization.
And shortening the action potential duration,
and decreasing the maximal diastolic
potential.
STRUCTURE-ACTIVITY RELATIONSHIPS
Steroidal framework :-
The cis junctions between A/B and C/D rings, is
an essential request for the highest interaction
energy.
Modifying A and/or B rings related to B-C plane,
decreases the interaction energy.
The OH group at position C14 is not an
essential feature for inotropic activity, although
when it is replaced by a Hydrogen atom potency
decreases.
Lactone ring :-
The presence of alpha and beta
unsaturated lactone ring increases the
activity.
If we try to saturated it losses the activity.
The lactone ring has been replaced by other
heterocycles like pyridine or piridazine rings,
energetic contribution is only partially.
Sugar :-
The sugar part increases absorption and
distribution of drug in the body.
Ex:- Glucose, Rhamnose ,Cymarose,
Digitose
GINSENOSIDES
HISTORY
Panax ginseng –5000years ago--hills of
Manchuria in China.
The word Panax, from the Greek word
meaning “all-healing”.
Widely distributed in higher plants
Toxic by i.v. injection & harmless by oral
route
SOURCE OF GINSENOSIDES
Ginsenosides is
chemical component of
Panax ginseng.
Source : Main source
is root.
All parts of ginseng.
Family : Araliaceae
ROOT OF GINSENG
CHEMICAL STRUCTRUE
Ginsenosides are mainly divided in two types
based on chemical structure.
One is panaxadiols
And another is panaxatriols
PANAXADIOLS
PANAXATRIOLS
STRUCTURAL FEATURES
Four trans-ring rigid steroid skeleton.
Sugar attachment at positions C-3, C-6, or C-
20.
Ring A and B ,C and D is in Cis.
It contains steroidal nucleus.
And its triterpene .
CHEMICAL TEST
Test for Sugars :
Small quantity of extract was dissolved in 4 ml of distilled water and filtered and the filtrate was subjected to Molisch’s testand Iodine Test.
Test for Glycosides :
A few mg of residue was dissolved 4 ml of distilled water and filtrated and the filtrate was subjected to Legal Test and Borntrager’stest.
CHEMICAL TEST
Froth test:
1 ml of aqueous solution of saponin or plant extract + shake persistent & voluminous froth.
Haemolysis test:
Suspension of RBCs in normal saline + equal volume of plant extract in normal saline + shake gently clear red solution indicating heamolysis of RBCs (compared with blank ).
Test for Terpenoids :-
Knollar’s test:-
5 mg of extract is treated with 2ml of 0.1% anhydrous stannic chloride in pure thionyl chloride. A deep purple color that changes to red indicates the presence of terpenoids.
Salkowski test:-
Treat the extract with few drops of concentrated sulphuric acid ,red color at lower layer indicates presence of steroids and formation of yellow colored lower layer indicates presence of triterpenoids.
STRUCTURE–ACTIVITY RELATIONSHIPS OF
GINSENOSIDES AGAINST CANCER
Number of sugar molecules :-
Anticancer activities increase with the decrease in the
number of sugar moieties.
Ginsenosides with four or more sugar molecules, such
as Rb1 and Rc, show no significant anti-proliferative
effects.
Ginsenosides Rg3 (two sugar residues), Rh2 (one
sugar residue), IH-901 (one sugar residue), PPT (no
sugar residues), and PPD (no sugar residues) inhibit
different types of cancer cells and also enhance the
efficacy of conventional chemotheraphy.
With a sugar substitute at C-6, the anticancer activity of ginsenosides is decreased compared to activity with linkages at C-3 or C-20.
Dehydration at C-20 increases the bioactivity of ginsenosides .
Rg5 differs from Rg3 only by the presence of a hydroxyl group at C-20 in Rg3 and is approximately four times more effective than Rg3 at inhibiting cell proliferation .
MECHANISM OF GINSENOSIDES
Ginsenosides Modulation of Immune
Function:
Different immunomodulatory effects of
ginseng have been reported, including both
immunostimulatory and immunosuppressive
effects.
Ginseng polysaccharides is used for the
Prevention and treatment of the common
cold.
IMMUNOSTIMULATORY EFFECTS
enhances IL-2 interferon gamma (INF-
γ) increased proliferation of (B
lymphocytes
increased plasma level of
immunoglobulin G enhanced macrophage
production , TNF-α, IL-6 elevated the
number of spleen, bone marrow and natural
killer cells.
ANTI CANCER
Cell signaling pathways involved in
apoptotic response targeted by selected
ginsenosides