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Tropane Alkaloids
Pharmcognosy II
Tropane alkaloids
Many of these psychoactive alkaloids
Tropane Alkaloids
• They are ester alkaloids resulted from the coupling of organic acids with amino alcohol (Base). Derived from tropine and consist of mandelic, tropic or benzoic acid esters of tropine.
• The parent base is the “Tropane” base.
• Tropane Alkaloids are classified into: 1-
Solanaceous Tropane Alkaloids.
2- Erythroxylon (Coca) Alkaloids.
H N
1
2
3 4
5 6
7 NH
1- Solanaceous Tropane Alkaloids
• Occurrence: Atropa, Datura, Hyoscyamus, Duboisia spp.
• Main Alkaloids are:
1 Atropine.
2 Hyoscyamine.
3. Hyoscine (Scopolamine).
Atropine & Hyoscyamine
• Hyoscyamine is the major natural alkaloid with negative
optical rotation (l- form).
• During extraction hyoscyamine racemizes to the optically
inactive dl Atropine.
• Both alkaloids composed of tropine base and tropic acid.
NCH3 O
OH O
O
Me N
O
H CH2OH N
O
O
CH2OH Me
Atropine (-)-Hyoscyamine
Tropine base
Tropic Acid
*
Atropine • Atropine is a core medicine in the World Health Organization's
"Essential Drugs List", which is a list of minimum medical needs
for a basic health care system.
• Atropine is a racemic mixture of D-hyoscyamine and L-
hyoscyamine.
• The most common atropine compound used in medicine is
atropine sulfate .
• Atropine sulfate Injection, USP
0.1 mg/mI (Adult)
0.05 mg/mL (Pediatric)
Pharmacological Action of Atropine
• A mydriatic (causes dilatation of the eye pupil).
• An antispasmodic (relaxes the intestinal and
bronchial smooth muscles).
• A preanesthetic medication to stop body
secretions.
• A CNS stimulant.
• An antidote to organophosphorus insecticides.
Side Effects of Atropine
Adverse reactions to atropine include:
• ventricular fibrillation.
• tachycardia.
• dizziness.
• nausea.
• blurred vision & dilated pupils
• loss of balance, & confusion.
N H3C
O
O
HO N H3C
O
H CH2OH
O
(-)-Hyoscyamine
Atropine
(-)-Hyoscine
Solanaceous Alkaloids
Natural Source of Atropine & Hyoscine
• Atropine & Hyoscine are tropane alkaloids
extracted from deadly nightshade (Atropa
belladonna), jimsonweed (Datura stramonium),
Duboisia(Duboisia myobroides), henbane
(hyoscyamus niger & hyoscyamus muticus) and
other plants of the family Solanaceae.
Natural Sources of Atropine & Hyoscine
Atropa belladonna
( Solanaceae)
Hyoscyamus niger
( Solanaceae) Datura stramonium
Hyoscine (Scopolamine)
• Hyoscine is an ester of l-tropic acid with scopoline base.
• Hyoscine is a syrupy liquid.
NCH3 O
O OH
O
Scopoline base
Tropic Acid
Hyoscine (Scopolamine)
• Hyoscine is an ester of l-tropic acid with scopoline base.
• Hyoscine is a syrupy liquid.
Hyoscine
Plant material and solvent
Extract
Concentration
Organic solvent dissove Impurities
Acidification
Alkalinization
Acidified Extract (Alk. as salts)
Alkaline aqueous layer
Organic solvent dissove Alkaloids
Separation of the Alkaloidal mixtures:
Alkaloids in the form of HCl salts
1- Alkalinize by NaHCO3 pH 7.5
2- Extract with Ether
Ether
Hyoscine free base
(pKa = 6.2)
Aqueous layer
Atropine & Hyoscyamine HCl
(pKa = 9.3)
Convert to oxalate salts,
Fractional Crystallization
(Acetone/ Ether)
Atropine Oxalate
Crystals Hyoscyamine Oxalate
Solution
Atropine & Hyoscyamineine Oxalates
Crystallization from
Acetone/Ether
Atropine Oxalate
Crystals Hyoscyamine Oxalate
Solution
Chemical tests:
• Vitali-Morin’s test: Solid alkaloid + fuming HNO3 → Evaporate to dryness, dissolve residue in acetone, add methanolic solution of KOH → Violet colour.
• P-dimethylaminobenzaldehyde:
Alkaloid + reagent in porcelain dish and heat on boiling water path
→ Intense Red Colour → Cherry Red after cooling.
• Gerrard’s test:
Alkaloid + 2% HgCl2 in 50% Ethanol →
Red colour Atropine
Red after warming Hyoscyamine
White ppt Hyoscine
Pharmacological actions and
uses:
The three Alkaloids are anticholinergic agents:
• Decrease saliva and GIT secretions so used preoperative.
• Decrease motility of smooth muscles so used as antispasmodics.
• Stimulate respiratory system.
• A mydriatic (causes dilatation of the eye pupil).
• An antidote to organophosphorus insecticides.
• Hyoscine has more central effect so it is sedative and hypnotic.
• Hyoscine is mainly used as antiemetic.
Synthetic and Semisynthetic Derivatives:
• Homatropine:
Synthetic drug prepared by passing HCl gas in a mixture of tropine
base and mandelic acid in the presence of water.
Homatropine is less toxic than Atropine. It is hypnotic in small
doses. Homatropine is used as Mydriatic with shorter effect than
Atropine.
NCH3 O
OH O
• Hyoscine butyl bromide:
Quaternary Semisynthetic derivative of Hyscine.
It is used as antispasmodic and antiemetic.
O
OH O
O Bu NCH3 +
Br-
2- Erythroxylon (Coca) Alkaloids
• Occurrence: Coca leaves contain about 2% total alkaloids.
• Main Alkaloids
are:
1 Cocaine.
2 Cinnamylcocaine.
3. - truxilline.
• The base for Coca Alakloid is called
“Ecogonine”
N H3C OH
C
O
OH
Ecogonine
Erythroxylon cocca
Erythroxylon cocca
• It is the major Alkaloid in Coca leaves.
• Cocaine is diester Alkaloid.
• Heating at 160 0C in conc. HCl leads to
hydrolyses of cacaine to MeOH, Benzoic acid
and Ecogonine base.
NCH3 O
O
COOMe
Benzoic acid
Ecgonine base
Cocaine
Production of Cocaine commercially:
• The total Alkaloids are hydrolysed to obtain the free
base.
• The base is then Methylated with HCl in MeOH.
• The Methylated base is then esterified with Benzoly
chloride.
Cinnamylcocaine
NCH3 O
O
COOMe
Cinnamic acid
Ecgonine base
• Uses:
Cocaine was used as local anesthetic.
Cocaine has a CNS stimulant activity so
is one of the widely abused drugs.
Datura stramonium - Solanaceae
Definition: Stramonium Leaf consists of the dried leaves or dried leaves and flowering tops of Datura stramonium. The drug should contain at least 0.25% alkaloids calculated as hyoscyamine.
Common names: Stramonium
leaf, Thornapple, Jimson or Jamestown weed
Datura stramonium - Constituents
Main (Tropane) Alkaloids
* Hyoscyamine
• Hyoscine (2:1)
Younger plants: hyoscine –
predominant alkaloid
Also contains
• Atropine
• Larger stems contain little
alkaloid, and drug should contain no more than 3% of stems with a diameter >5mm
Datura stramonium – Allied Drugs &
Adulterants
ALLIED DRUGS
Datura innoxia
Datura metel (dried
leaves are also curled
and twisted – like D.
stramonium), but are
browner in colour.
Datura sanguinea
ADULTERANTS
Xanthium, Carthamus
and
Chenopodium leaves
(easily distinguished from
original herb)
Uses of Datura stramonium
Atropine: Stimulant on CNS
Depresses nerve endings on
the secretory glands and smooth muscle
Hyoscine: lacks CNS stimulant
action of atropine
Sedative – motion sickness
Atropine & Hyoscine: used in
opthalmic practice to dilate the pupil of the eye.
Hyoscyamus niger - Solanaceae
Definition: Hyoscyamus leaf consists of the dried leaves or dried leaves and flowering tops of Hyoscyamus niger. It should contain at least 0.05% alkaloids
– hyoscyamine.
Hyoscyamus niger - Constituents
Tropane Alkaloids
Mainly
• Hyoscyamine
• Hyoscine (main
constituent)
Hyoscyamus niger - Uses
Resembles belladonna
and stramonium in
action – only weaker.
Higher hyoscine content –
less likely to cause
cerebral stimulation .
Used to relieve spasm of
the urinary tract
Atropa belladonna - Solanaceae
Definition: Belladonna herb consists of the dried leaves and flowering tops of Atropa belladonna, containing at least 0.3% alkaloids (hyoscyamine).
Should not contain >3% stem
>5mm in diameter.
USP also allows A. acuminata
in the Belladonna Leaf monograph.
Atropa belladonna - Constituents
Main (Tropane) alkaloid
• Hyoscyamine
Also contains
• Scopoletin
• Calcium oxalate
Atropa belladonna - Uses
Used as a sedative
To stop bodily secretions
(e.g. saliva)
Root preparations are
used externally