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Tropane alkaloids and drugs containing them
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7/21/2019 2. b Tropane Alkaloids
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Presentation for
Class: Fifth Semester B. Pharm
Subject: Pharmacognosy (250006)
Topic: Tropane Alkaloids
Prepared by: Dr. U. M. Upadhyay
Designation: Principal
College: Sigma Institute of PharmacyAt. Bakrol, Ta. Waghodia, Dist. Baroda
College code: SIP (261)
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Alkaloids are cyclic organic compounds
containing nitrogen in a negative state of
oxidation with limited distribution among
living organisms.
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Distribution and occurrence:• Rare in lower plants.
• Dicots are more rich in alkaloids than
Monocots.
• Families rich in Alkaloids: Apocynaceae,
Rubiaceae, Solanaceae and Papaveracea.
• Families free from Alkaloids: Rosaceae,
Labiatae
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Distribution in Plant:
• All Parts e.g. Datura.
• Barks e.g. Cinchona
•
Seeds e.g. Nux vomica• Roots e.g. Aconite
• Fruits e.g. Black pepper
• Leaves e.g. Tobacco• Latex e.g. Opium
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Psychoactive alkaloids
Stimulants Hallucinogens Depressants
Cocaine Tropane alkaloids Morphine
Ephedrine Mescaline Codeine
Caffeine Psilocybin Heroin
Ergot alkaloids (LSD)
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Tropane alkaloids
Many of these psychoactive alkaloids
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Tropane Alkaloids• They are ester alkaloids resulted from the coupling of
organic acids with amino alcohol (Base). Derived fromtropine and consist of mandelic, tropic or benzoic acidesters of tropine.
• The parent base is the “Tropane” base.
• Tropane Alkaloids are classified into:
1- Solanaceous Tropane Alkaloids.
2- Erythroxylon (Coca) Alkaloids.
HN1
2
34
56
7NH
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1- Solanaceous Tropane Alkaloids
• Occurrence: Atropa, Datura, Hyoscyamus, Duboisia spp.
• Main Alkaloids are:1- Atropine.
2- Hyoscyamine.
3. Hyoscine (Scopolamine).
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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
OHO
N
O
Me
O
H CH2OH
N
O
O
CH2OHMe
Atrop ine (-)-Hyoscyamine
Tropine base
Tropic Acid
*
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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.
Hyoscyamine
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Atropine
• Atropine is a core medicine in the World HealthOrganization's "Essential Drugs List", which is a list ofminimum 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)
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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.
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Side Effects of Atropine
Adverse reactions to atropine include:
• ventricular fibrillation.
•
tachycardia.• dizziness.
• nausea.
• blurred vision & dilated pupils• loss of balance, & confusion.
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NH3C
O
O
HO NH3C
O
H CH2OH
O
(-)-Hyoscyamine
Atropine
(-)-Hyoscine
Solanaceous Alkaloids
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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.
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Natural Sources of Atropine & Hyoscine
Atropa belladonna
( Solanaceae)
Hyoscyamus niger ( Solanaceae)
Datura stramonium
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Hyoscine (Scopolamine)
• Hyoscine is an ester of l -tropic acid with scopoline base.
• Hyoscine is a syrupy liquid.
NCH3 O
OHO
O
Scopoline base
Tropic Acid
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Hyoscine (Scopolamine)
• Hyoscine is an ester of l -tropic acid with scopoline base.
• Hyoscine is a syrupy liquid.
Hyoscine
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Plant material and solvent
Extract
Concentration
Acidified Extract (Alk. as salts)
Organic solvent dissove Impurities
Acidification
Alkalinization
Alkaline aqueous layer
Organic solvent dissove Alkaloids
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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
CrystalsHyoscyamine Oxalate
Solution
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Atropine & Hyoscyamineine Oxalates
Crystallization from
Acetone/Ether
Atropine Oxalate
Crystals
Hyoscyamine Oxalate
Solution
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Chemical tests:
• Vitali-Morin’s test:
Solid alkaloid + fuming HNO3 → Evaporate to dryness, dissolveresidue 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
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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.
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Synthetic and Semisynthetic Derivatives:
• Homatropine:
Synthetic drug prepared by passing HCl gas in a mixture of tropinebase 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 thanAtropine.
NCH3 O
OHO
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• Hyoscine butyl bromide:
Quaternary Semisynthetic derivative of Hyscine.
It is used as antispasmodic and antiemetic.
NCH3 O
OHO
O Bu+
Br-
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2- Erythroxylon (Coca) Alkaloids
• Occurrence:Coca leaves contain about 2% total alkaloids.
•Main Alkaloids are:1- Cocaine.
2- Cinnamylcocaine.
3. a- truxilline.
• The base for Coca Alakloid is called “Ecogonine”
N
H3C OH
C
O
OH
Ecogonine
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Erythroxylon cocca
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Erythroxylon cocca
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Erythroxylon cocca
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• 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:
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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
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• Uses:
Cocaine was used as local anesthetic.
Cocaine has a CNS stimulant activity so is oneof the widely abused drugs.
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Hyoscine
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Datura stramonium - Solanaceae
Definition: Stramonium Leafconsists of the dried leavesor dried leaves andflowering tops of Daturastramonium. The drugshould contain at least0.25% alkaloids calculatedas hyoscyamine.
Common names: Stramoniumleaf, Thornapple, Jimson orJamestown weed
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Datura stramonium
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Datura stramonium - Constituents
Main (Tropane) Alkaloids
* Hyoscyamine
• Hyoscine (2:1)
Younger plants: hyoscine –
predominant alkaloid
Also contains
• Atropine
• Larger stems contain littlealkaloid, and drug shouldcontain no more than 3% ofstems with a diameter >5mm
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Datura stramonium – Allied Drugs &
Adulterants
ALLIED DRUGS
Datura innoxia
Datura metel (dried leaves
are also curled andtwisted – like D.
stramonium), but are
browner in colour.
Datura sanguinea
ADULTERANTS
Xanthium, Carthamus and
Chenopodium leaves
(easily distinguished fromoriginal herb)
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Uses of Datura stramonium
Atropine: Stimulant on CNS
Depresses nerve endings onthe secretory glands andsmooth muscle
Hyoscine: lacks CNS stimulantaction of atropine
Sedative – motion sickness
Atropine & Hyoscine: used inopthalmic practice to dilatethe pupil of the eye.
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Hyoscyamus niger - Solanaceae
Definition: Hyoscyamusleaf consists of thedried leaves or driedleaves and flowering
tops of Hyoscyamusniger . It should containat least 0.05% alkaloids
– hyoscyamine.
Common names:Henbane
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Hyoscyamus niger - Constituents
Tropane Alkaloids
Mainly
• Hyoscyamine
• Hyoscine (main
constituent)
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Hyoscyamus niger – Allied Drugs
• Hyoscyamus albus(petiolate stem-leaves andpale yellow, non-veined
petals – bottom left).• Hyosycamus muticus (top
right)
• Hyoscyamus pusillus
• Hyoscyamus aureus
• Hyoscyamus reticulatus
(Indian henbane – bottomright)
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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
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Hyoscyamus niger
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Hyoscyamus niger - flower
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Atropa belladonna - Solanaceae
Definition: Belladonna herbconsists of the dried leavesand flowering tops of
Atropa belladonna,containing at least 0.3%alkaloids (hyoscyamine).
Should not contain >3% stem>5mm in diameter.
USP also allows A. acuminatain the Belladonna Leafmonograph.
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Atropa belladonna - Constituents
Main (Tropane) alkaloid
• Hyoscyamine
Also contains
• Scopoletin
• Calcium oxalate
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Atropa belladonna
ALLIED DRUGS
Indian belladonna ( Atropaacuminata) – yellow-brown flowers &
brown-green leaves.
Atropa baetica (yellowflowers and blackberries) – endangeredspecies
ADULTERANTS
Phytolacca decandra
Ailanthus glandulosa
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Atropa belladonna - Uses
Used as a sedative
To stop bodily secretions
(e.g. saliva)
Root preparations areused externally
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Atropa belladonna
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Withania somnifera• B.S. - Dried Roots and Stems of Withania
somnifera
• Family – Solanaceae
• C.C. –
– Steroidal Lactone
Withanolide A, Withanolide B
– Alkaloids –
Anaferine, Withanine, Tropine• Chemical Test – It gives Vitali-Morin Test.
• Use - Immunomodulator
It is known as Indian Ginseng.
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Withania somnifera
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Duboisia myoporoides
• B.S. - Dried Leaves of Duboisia myoporoides
• Family – Solanaceae
• C.C. – Atropine
Scopolamine
• Chemical Test – It gives Vitali-Morin Test.
•
Use - Parasympatholytic
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Duboisia myoporoides
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Duboisia myoporoides
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Duboisia
myoporoides