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Cardiac glycosides Flavonoids. Anna Drew with grateful acknowledgement for inspirational teaching received at The School of Pharmacy, University of London. Cardiac glycosides. Plant glycosides with specific action on heart Historical use: to assasinate people, arrow poisons

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cardiac glycosides flavonoids

Cardiac glycosidesFlavonoids

Anna Drew

with grateful acknowledgement for inspirational teaching received at

The School of Pharmacy, University of London

cardiac glycosides
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
sources
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
active compounds
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

slide5
sugars:
    • 1-4 β-linked at C3 in various combinations
    • glucose, rhamnose, deoxy-sugars
      • eg digitoxose, digitalose

StrophanidiolStrophanthus

Scillarenin (squill)

extraction
Extraction
  • large molecular weight molecules with sugars -> polar
    • soluble in water and alcohol
  • expensive – long process, solvents
digitalis
Digitalis
  • Scrophulariaceae family
    • foxglove - biennial flowering plants
      • cases of poisoning rare
      • natural emetic if eaten in excess
    • Digitalis purpurea leaf – purple, British
      • -> Digitalis Tablets B.P.
      • -> 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
chemistry of d lanata
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

i digitoxose
[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
chemistry of d purpurea
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
ii digitalose
[ii] Digitalose
  • found in both species
  • only strospeside important as emergency injection for heart attacks – quickest acting cardiac glycoside
assay of digitalis b p
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
slide14
Digitalis B.P. tablets
    • crushed dried leaves -> 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:
1 biological assay
[1] Biological assay
  • British method - inaccurate but safer
  • Tincture of extract of leaves or tablets
  • diluted with saline so alcohol <6%v/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)
slide16
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
2 chemical assay
[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 -> gitoxigenin when acid hydrolysed
slide18
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:
    • doesn’t correlate with biological activity
    • only estimating approx 60% therapeutic material
  • BOTH methods used in industry
flavonoids
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 γ-pyrone moiety
  • can get several forms of flavonoids depending on nuclei

flavonol

isoflavone

flavone

slide20
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

-> plasma leakage -> oedema

        • mainly due to high oestrogen, sometimes in males
    • tumour inhibition promotion
    • protective for gastric mucosa
slide21
sugars:
    • glucose, rhamnose, arabinose, xylose
    • 2-3 attached to phenolic groups in middle of structures
examples
Examples

(a) Rutin (Vitamin P)

  • from Fagopyrum esculentum (buckwheat)

= rhamnoglucoside of quercetin

(b) Hesperidin (‘citrin’)

  • from citrus industry

= hesperetin (methyl eriodictyol), rhamnose, glucose

isolation
Isolation
  • easy
  • water and alcohol soluble
  • give brightly coloured solutions
  • crystallise easily
  • may give colour reactions eg
    • MgCl2 -> violet -> orange
    • alkali KOH -> orange
  • easy to detect
slide24
Coumarins
  • aromatics based on α-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