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Cardiac glycosides Flavonoids

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Cardiac glycosides Flavonoids Anna Drew with grateful acknowledgement for inspirational teaching received at The School of Pharmacy, University of London – PowerPoint PPT presentation

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Title: Cardiac glycosides Flavonoids


1
Cardiac glycosidesFlavonoids
  • Anna Drew
  • with grateful acknowledgement for inspirational
    teaching received at
  • The School of Pharmacy, University of London

2
Cardiac glycosides
  • Plant glycosides with specific action on heart
  • Historical use
  • to assasinate people, arrow poisons
  • Historical sources
  • South American toad skins, African plant extracts
  • Modern use
  • to treat congestive heart failure (dropsy)
  • aglycone structure important for activity

3
Sources
  • Scrophulariaceae
  • Digitalis purpurea leaves (foxglove)
  • Digitalis lanata leaves white flowers
  • Apocyanaceae
  • Strophanthus vine seeds Africa
  • Liliceae
  • Urginea bulbs (squill) Europe, India
  • Convallaria leaves (lily of the valley) also
    produces a volatile oil perfume

4
Active compounds
  • steroid nucleus
  • AB cis-junction
  • CD cis-junction
  • not planar
  • C14 3y -OH
  • C3 2y OH
  • sugars attached
  • C17 lactone ring
  • classified into 2 groups

Cardenolides more common opens in alkali
Bufanolides
5
StrophanidiolStrophanthus
Scillarenin (squill)
  • sugars
  • 1-4 ß-linked at C3 in various combinations
  • glucose, rhamnose, deoxy-sugars
  • eg digitoxose, digitalose

6
Extraction
  • large molecular weight molecules with sugars -gt
    polar
  • soluble in water and alcohol
  • expensive long process, solvents

7
Digitalis
  • Scrophulariaceae family
  • foxglove - biennial flowering plants
  • cases of poisoning rare
  • natural emetic if eaten in excess
  • Digitalis purpurea leaf purple, British
  • -gt Digitalis Tablets B.P.
  • -gt Tincture of Digitalis B.P.
  • commercially grown Holland, E. Europe
  • NB no extraction for these products
  • Digitalis lanata leaf white, Mediterranean
  • used for manufacture of pure glycosides
  • ie digoxin, lanatoside C
  • commericially produced Holland, Equador, USA

8
Chemistry of D.lanata
  • compounds belong to cardenolide series
  • 5 membered lactone ring
  • approx 96 compounds
  • 1930-1950 Stroll worked on structures


Acetyl group confers crystalline properties -
makes compounds more easily isolated
9
i Digitoxose
  • sugar found on primary glycosides of D.lanata
  • glucose on the end of a chain of O-linked
    digitoxose sugars at C3
  • during harvesting and drying enzymes can remove
    acetyl groups and the end glucose
  • hence drying method needs to be followed or
    glycosides degrade further
  • after collection dried as rapidly as possible at
    60oC, stored in airtight containers protected
    from light (contain no more than 6 moisture)
  • expect about 10 compounds from D.lanata
  • important ones
  • Digoxin Lanoxin Wellcome 0.25 µg white
    tablet
  • Digitoxin Digitalin 0.25 µg small pink tablet
  • Lanatoside Cedilanid 0.10 µg less well
    absorbed but used for rapid digitalisation
  • Others not marketed, used experimentally

10
Some cardioactive glycosides from D.lanata
Ref Trease Evans
11
Chemistry of D.purpurea
  • Steroid cardenolides
  • contains 30 glycosides, 6 main ones
  • only has 3 aglycones
  • Purpurea 1y glycosides
  • do NOT have acetylated digitoxose third sugar
  • but these are found in smaller quantities
  • called ABE series

12
ii Digitalose
  • found in both species
  • only strospeside important as emergency injection
    for heart attacks quickest acting cardiac
    glycoside

13
Assay of Digitalis B.P.
  • required to contain not less than 0.3 total
    cardenolides calculated as digitoxin
  • important to guarantee reproducibility of
    products (drug dosage)
  • narrow therapeutic index
  • can cause cardiac arrest
  • slowly excreted, bound to serum proteins
  • long term therapy for patients
  • patients tend to be older, weak

14
  • Digitalis B.P. tablets
  • crushed dried leaves -gt green tablet
  • contain 30 glycosides each with different onset,
    action and excretion profiles
  • in different amounts
  • influenced by growing conditions
  • (temp, water, sun, drying process)
  • assay for each glycoside as accurately as
    possible dilute effects by adding grass
  • Two ways

15
1 Biological assay
  • British method - inaccurate but safer
  • Tincture of extract of leaves or tablets
  • diluted with saline so alcohol lt6v/v
  • guinea pigs (6 test, 6 control) x 3 36
  • expensive but can average results
  • measure volume injected into vein of leg/foot
    before heart stops beating
  • monitor heart rate via ECG
  • or open chest wall and watch inserted needle with
    flag on move
  • Better to watch ECG have to differentiate from
    death from too large an injected volume
  • trained staff required, can calculate potency
  • assay acceptable within 80-120 error margin (not
    that accurate)

16
  • Disadvantages
  • inaccurate, expensive
  • injecting material IV (avoiding absorption,
    excretion)
  • end point is death
  • toxicity test not therapeutic assessment
  • Advantages
  • assessing some biological activity
  • safety mechanism

17
2 Chemical assay
  • Problem 30 different glycosides can measure
    them accurately but may not correlate with
    therapeutic activity of drug
  • Make a tincture (with alcohol)
  • decolourise with lead subacetate
  • extract glycosides by partition with CHCl3
  • evaporate to give residue (containing cardiac
    glycosides)
  • hydrolyse with HCl to remove sugars leaving
    aglycone
  • residue contains gitoxigenin and digitoxigenin
    (AB series)
  • gitaloxigenin -gt gitoxigenin when acid hydrolysed

18
  • Colourimetric assay to separately determine
    material amounts
  • (i) total aglycone
  • purple colour with dinitrobenzoic acid and alkali
  • (ii) digitoxigenin only
  • green colour with FeCl3 acetic acid
  • can substract answers to work out
  • Digitoxigenin (A series) content
  • Gitoxigenin (B series) content
  • Advantages
  • precise method (reproducible 2, standard error
    5)
  • unqualified staff, quicker
  • Disadvantages
  • doesnt correlate with biological activity
  • only estimating approx 60 therapeutic material
  • BOTH methods used in industry

19
Flavonoids
  • mainly O-linked glycosides
  • occur in plants, lichens, moss
  • those in free state and glycosides largest
    naturally occurring group of phenols
  • aromatic, based on ?-pyrone moiety
  • can get several forms of flavonoids depending on
    nuclei

flavonol
isoflavone
flavone
20
  • often yellow (flavus Latin yellow)
  • known for a long time
  • interest in them for
  • anti-inflammatory (and analgesic) properties
  • anti-allergic effects
  • antithrombotic, vasoprotective properties
  • decrease capillary fragility
  • phlebitis changes in vessel walls in
    extremities
  • -gt plasma leakage -gt oedema
  • mainly due to high oestrogen, sometimes in males
  • tumour inhibition promotion
  • protective for gastric mucosa

21
  • sugars
  • glucose, rhamnose, arabinose, xylose
  • 2-3 attached to phenolic groups in middle of
    structures

22
Examples
  • (a) Rutin (Vitamin P)
  • from Fagopyrum esculentum (buckwheat)
  • rhamnoglucoside of quercetin
  • (b) Hesperidin (citrin)
  • from citrus industry
  • hesperetin (methyl eriodictyol), rhamnose,
    glucose

23
Isolation
  • easy
  • water and alcohol soluble
  • give brightly coloured solutions
  • crystallise easily
  • may give colour reactions eg
  • MgCl2 -gt violet -gt orange
  • alkali KOH -gt orange
  • easy to detect

24
  • Coumarins
  • aromatics based on a-pyrone
  • widely distributed in plants
  • Leguminosae
  • Rubiaceae
  • Umbelliferae
  • Solanaceae
  • first medicinal compounds from clover
  • certain types toxic to animals in summer
  • anticoagulant activity found
  • dicoumarols produced clinically
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