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