Tropane Alkaloids - Suli 2020-03-02¢  Tropane Alkaloids ¢â‚¬¢ Tropane Alkaloids are classified into: ¢â‚¬¢

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  • Tropane Alkaloids

    Pharmcognosy II

  • Biosynthesis of Tropine from Ornithine

  • Tropane alkaloids

  • Tropane Alkaloids

    • Tropane Alkaloids are classified into:

    • 1- Solanaceous Tropane Alkaloids.

    2- Erythroxylon (Coca) 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.

    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.

  • 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 scopolinebase.

    • 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 scopolinebase.

    • 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

  •  Pharmacological actions and

    uses:

    The three Alkaloids are anticholinergic agents:

    • Decrease saliva and GITsecretions so used preoperative.

    • Decrease motility of smooth muscles so used asantispasmodics.

    • Stimulate respiratory system.

    • Amydriatic (causes dilatation of the eyepupil).

    • An antidote to organophosphorusinsecticides.

    • Hyoscine has more central effect so it is sedative andhypnotic.

    • 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 smal

    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

    C

    OH

    O

    OH

    Ecogonine

  • Erythroxylon cocca

  • NCH3 O

    O

    • 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.

    COOMe

    Benzoic acid

    Ecgonine base

    Cocaine

  • Production of Cocaine commercially:

    NCH3 O

    O

    • 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

    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

  • 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

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