Pharmaceutical Sciences

PHARMACEUTICAL SCIENCES

Subject : Pharmaceutical Sciences

(For Under Graduate Students)

Paper No. : B. Pharm VIIIth Sem

Paper – 38
Herbal Drug Technology

Topic No. & Title : 452:

Alkaloids – II:
Chemistry, Biogenesis and Pharmacological
Activity of Morphine, Papaverine,
Ephedrine, Ergot and Vinca Alkaloids

Academic Script

Plant source of morphine and papaverine: Opium

Biological source: It is the dried latex obtained by incision from unripe capsules of
Papaver somiferum Linn., family Papaveraceae, dried or partly dried by heat or
spontaneous evaporation, and worked into somewhat irregularly shaped masses
(natural opium) or moulded into masses of more uniform size and shape
(manipulated opium). It contains not less than 9.5 percent of morphine.
Geographical source: India, Pakistan, Afghanistan, Turkey, Russia, China and Iran
History: Opium was well known to ancients due to its narcotic properties. It was first
cultivated in Mediterranean regions and probably brought by Alexander in 327 B.C.
to India. The use of opium spread from Asia Minor to Persia, where opium eating
became popular, and from there to India and China. The earliest written record about
opium is revealed from Historia plantarum and De Materia Medica. Opium was
cultivated in India during Middle Ages, and the monopoly of the Mogul Government
was taken over first by the East India Company and then by the British Government.
Formerly, Indian opium, being prepared mainly for smoking, were little esteemed for
pharmaceutical purposes.
Cultivation: The plant cultivated in India under licence is P. somniferum var. album.
Indian opium is considered as the only legal source of opium to many countries
including USA and Britain. Poppy is an erect plant attaining 60-120 cm height. It is
rarely branched. The leaves are linear, oblong or ovate oblong and have a dentate or
serrate margin. It bears bluish white, purple or violet colored large flowers. Opium
poppy is grown from November to March and collection April to June. Propagation is
1
Pharmaceutical Sciences

done by sowing the seeds, for which 3-4 kg of seeds per hectare are necessary. The
distance between two plants maintained is usually 25 cm and the plant reaches
maximum height of one meter. Periodically, the thinning of plants is done to get
uniform growth and better development.
After sowing, within 3-4 months, the plants bear flowers, which are converted to
capsules within few days and attain maturity after 15-20 days.
Collection and Preparation: The incisions are made in the afternoon with an
instrument known as ‘nushtur’. This bears narrow iron spikes which are drawn down
the capsule to produce several longitudinal cuts. The incision must not penetrate into
the interior of the capsule otherwise latex will be lost. The latex, which is first white,
rapidly coagulates and turns brown. Early in the morning of the day following the
making of the incisions the partly dried latex is scraped off with a trowel-like
‘seetooar’. Each capsule is cut several times at intervals of 2 or 3 days. After
collection the latex is placed in a tilted vessel so that the dark fluid which is not
required may drain off. By exposure to air the opium acquires a suitable consistency
for packing. Indian opium is exported in 5 kg blocks, packed 12 to a lightweight
wooden case to facilitate air transport. Each block is wrapped in grease-proof paper,
tied with tape and placed in a polythene bag. The drug has a soft consistency and so
arrives as rounded, somewhat flattened, cakes. It contains about 9-12% of morphine.

Macroscopic Characters:

Taste - Bitter
1. Indian Opium:
Color - Dark brown
It is found in the form of cubical pieces weighing about 900 g for marketing
purpose. It is enclosed in tissue paper and is brittle and plastic in nature.
Internally, it is homogeneous. Depending upon the requirement the powder
form is available in the pack of 5 to 10 kg.
2. Persian opium:
Color - Dark brown
It is found in the form of brick shaped masses, weighing 450 g. It is hygroscopic
in nature, granular or nearly smooth with brittle fracture.
3. Manipulated Turkish opium:
Color - Chocolate or dark brown
It is covered with broken leaves externally. The masses of this type are oval
and flattened on upper and lower surface weighing about 2000 g. It is
somewhat plastic or even brittle.
4. Manipulated European opium:

2
Pharmaceutical Sciences

Color - Dark brown internally and covered with broken

leaves
It is found in the form of elongated masses with rounded ends weighing 150-500g. It
is firm plastic and with brittle fracture.

Chemical Constituents:
Opium contains about 30 alkaloids, which are largely combined with meconic acid.
The drug also contains sugar and salts, albuminous substances, coloring matters and
water. Morphine, Codeine, thebaine noscapine, narceine and papaverine are the six
major alkaloids of opium. The first group (eg. morphine) consists of alkaloids which
have a phenanthrene nucleus whereas those of the papaverine group have a
benzylisoquinoline structure. Some of the less important opium alkaloids are e.g.
prtopine and hydrocotarnine are of different structural types. The morphine
molecule has both a phenolic and an alcoholic hydroxyl group and when acetylated
forms diacetyl morphine or heroin. Codeine is ether of morphine (methylmorphine),
and other morphine ethers which are used medicinally are ethylmorphine and
pholcodine. The opium alkaloids are present as salts of meconic acid.

Chemical Test:
a) The general test to detect opium is by testing presence of meconic acid. The
alkaloids are present as the salt of meconic acid. Opium is dissolved in water and
filter. Add ferric chloride solution to the filtrate, a deep reddish purple color is
produced, which persists even on addition of hydrochloric acid.
b) Morphine when sprinkled on nitric acid gives orange red color. Codeine does not
respond to this test.
c) The treatment of morphine solution with potassium ferricyanide and feeric
chloride solutions gives bluish green color. Codeine does not respond to this test.
d) Papaverine solution in hydrochloric acid gives a lemon yellow color with
potassium ferricyanide.

Biogenesis of Morphine and Papaverine:

The biogenetic precursor is reticuline, whose substitution is the only one that allows
the ortho-para oxidative coupling leading to the phenanthrene nucleus.
The biosynthesis of morphinan alkaloids only appears as if it should be complex.
Various labeling experiments prove unambiguously that morphine is formed from
norlaudanosoline, which arises from the metabolism of tyrosine. O-and N-
methylation of norlaudanosoline to reticuline, the (R)-(-) isomer of the latter is
cyclized to salutaridine, and this dienone is reduced to a dienol; the dehydration of
salutaridinol I and the formation of the 4, 5-ether bridge afford thebaine. From this

3
Pharmaceutical Sciences

first representative of the morphinan alkaloid series, all of the biosynthetic steps are
irreversible: demethylation of the enol ether to neopinone, isomerization of the
latter to codeinone reduction to codeine, and demethylation of codeine to morphine.
Morphine is also formed in part via oripavine (3-demethylthebaine) by the sequence:
Thebaine → Oripavine → Morphinone → Morphine

Pharmacological Activity of Morphine:

Morphine exerts its effects by binding stereospecifically, reversibly and with a very
high affinity to the specific receptors found mainly at various levels of the CNS. These
effects are classically considered to include central and peripheral activities.
01. CNS Activity
Analgesic Effect: Morphine induces a selective analgesia. It markedly depresses
nociceptive perception, and raises the threshold of pain perception. The mind-
altering activity of the alkaloid also contributes to the analgesic activity.
The psychomotor activities of morphine vary depending on the animal species, and in
humans, they depend on pre-existing pain. Thus, in a subject in pain, sedation,
indifference to physical or psychic sentations and sometimes, a state of euphoria
linked to a decrease in the affective reaction to pain are observed, whereas in a
normal subject, the administration of morphine frequently causes more or less
intense agitation, delirium, anxiety and nausea among others.
Morphine is a pure agonist which acts by mimicking the activity of endorphins on the
presynaptic receptors of the myelinated fibers of small diameter that transmit
nociceptive information: the result is an inhibition of the release of substance P,
which is a pain neurotransmitter.
a) Respiratory effect: Morphine depresses the respiratory centers in the brain
stem: the decrease in sensitivity of these centers to carbon dioxide and to
hypoxia is proportional to the administered dose; with higher doses,
substantial bradypnea and irregular rhythm appear.
b) Other Central Effects: Morphine depresses the cough center. It causes myosis
at least in humans and in animal species that respond to narcotization.
Morphine acts on the pituitary to decrease the secretion of FSH, LH and ACTH.
c) Dependence: The psychoactive effects of morphine are substantial. The
euphoria and the transient sensation of well-being or sleepiness explain the
development of the psychic dependence soon followed by tolerance.

02. Peripheral Activity

Morphine causes decrease in tone of the longitudinal fibers and an increase in tone
of the tissue and sphincter fibers. The result is lasting constipation, an effect for

4
Pharmaceutical Sciences

which little tolerance develops. Morphine induces urinary retention. It is antidiuretic

and also, at high doses, bradycardic, vasodilating and hypotensive.
Pharmacological Activity of Papaverine:
a) Papaverine is practically devoid of effects on the CNS.
b) It is musculotropic spasmolytic which relaxes smooth muscle fibres, especially
those of cerebral, pulmonary and systemic peripheral blood vessels, but also
those of the bronchia, intestines, ureters and biliary ducts.
c) The spasmolytic activity is more pronounced in the case of a pre-existing
spastic condition.
d) Papaverine has an effect on the heart muscle: it decreases conductibility and
excitability prolongs the refractory period and increases coronary blood flow.
Its activity is linked to its ability to inhibit the phophodiesterase which
hydrolyzes cAMP, and to decrease the intracellular calcium concentration (by
inhibiting its entry into the cell or increasing its uptake by the reticulum).

5
Pharmaceutical Sciences

EPHEDRINE
Plant source of Ephedrine: Ephedra, Ma-huang
Biological source: It consists of the dried young stems of Ephedra gerardiana (wall.)
and E. nebrodensis (Tineo.) belonging to family Ephedraceae. Ephedra should contain
not less than 1 percent of total alkaloids, calculated as ephedrine.
Geographical source: China, Pakistan, North-West parts of India, Australia, Kenya
spain and Yugoslavia
History: Ma-huang was known to the Chinese over 5000 years ago and ephedrine
was isolated in 1887, it only came into extensive use during the last century. It is
called Ma-Huang where ‘Ma’ denotes astringent taste and ‘Huang’ is for yellow color
of drug. The references about this drug are found in the herbal of the emperor Shen
Nung (2700 B.C.) and in ‘Chinese medicinal plant’ (1596 A.D.) by Pen T’sao Kang Mu.
In those times it was used for treatment of respiratory problems, fever and also for
circulation.
Cultivation: Ephedra can be cultivated at an altitude of 2500 to 3000 m. Annual
rainfall should not exceed 50 cm. it can be propagated by seeds layers or divisions of
the root stock. Seeds are sown early in the spring at a distance of 5 cm, keeping the
distance of one meter between 2 rows.
Collection and Preparation: The plants are collected after attaining the age of 4 years
for the extraction of alkaloid. During this period, proper irrigation and weeding are
necessary. The alkaloidal content of the drug varies from season to season. It is found
to be maximum in autumn, when plants and twigs are dark in color. Twigs are
generally dried in sun.
Macroscopic Characters: Ephedra stem is woody and much branched. It bears ribs
and longitudinal channels. The leaves are very small with connate base. Types of
leaves and length of nodes and internodes are important diagnostic features of the
various species. Ephedra stem has a slight odor and a bitter taste.
Chemical Constituents: The ephedras contain about 0.5-2.0 % of alkaloids. Of the
total ephedrine (and its isomers) forms 30 to 90%, according to the species.
Pseudoephedrine is also present. The roots also contain a number of macrocyclic
alkaloids (ephedradines) and feruloyl histamine which have hypotensive properties.
Chemical Test: Ephedrine is dissolved in water and dilute hydrochloric acid and then
treated separately with copper sulphate and sodium hydroxide. The solution gives
violet color. If shaken with solvent ether, the organic layer shows purple and aqueous
layer shows blue color.

6
Pharmaceutical Sciences

Biogenesis of ephedrine and related compounds:

Ephedrine is obtained from plant Ephedra, which is a protoalkaloid. These alkaloids
are formed by a union of a C6-C1 unit and a C2 unit. For many years it has been known
that phenylalanine is the originator of the C6-C1 moiety, being converted first to
benzaldehyde or benzoic acid. Benzoic acid combines with the intact CH3CO group of
pyruvic acid to form ephedrine and related alkaloids with 1-phenylpropan-1, 2-dione
and (S)-(-)-2-amino-1-phenylpropan-1-one (cathinone) serving as intermediates.

Pharmacological Activity of Ephedrine:

a) Ephedrine is an indirect sympathomimetic. Structurally very close to
adrenaline it triggers the release of endogenous catecholamines from the post-
ganglionic sympathetic fibers.
b) It stimulates cardiac automaticity and has a positive inotropic activity; it
accelerates respiration and increases its intensity.
c) It is a bronchodilator and a stimulant of the brain stem respiration center
d) It decreases the contractility of the bladder.
e) It is not metabolized much, can be used orally, and its duration of action is
longer than that of adrenaline.
f) High doses can cause headaches, anxiety, tremors, insomnia and psychotic
manifestations; redness of the face; nausea; tachycardia and precordial pain;
sweating; urinary retention and more.

7
Pharmaceutical Sciences

ERGOT
Plant source of Ephedrine: Ergot of Rye, Ergota
Biological source: Ergot is the dried sclerotium of a fungus, Claviceps purpurea
developed in ovary of rye plant, Secale cereal (Graminae). It contains not less than
0.19 percent of the total alkaloids of ergot, calculated as ergotoxine, of which not less
than 15 percent consists of water soluble alkaloids of ergot, calculated as
ergometrine.
Geographical source: Switzerland, Yugoslavia, Hungary and Czechoslovakia
History: The name of this drug is originated from a from a French word ‘Argot’ which
means fur and indicates the shape and attachment of the sclerotia to the infected rye
spikes, like the fur which is attached to the body of birds. Even in old days, ergot
fungus was known to be a pathogen, infecting the rye fields in European countries
and Russia. It is known that the toxic effects were observed owing contamination of
ergot with rye grains. The toxic symptoms were gangrene in the extremities and
convulsions. In middle ages, such symptoms were reported and called as St. Antony’s
fire. After knowing the cause, it was called as ergotism which had severely occurred
in sixteenth century in Germany. Further, it was discovered that ergot has specific
uses in obstetrics and came into wide use from nineteenth century onwards. In 1836,
it was introduced in London Pharmacopoeia. The life history of fungus was studied
and the name Claviceps purpurea was first coined by Tuasne 1853.
Cultivation and Collection: Ergots are sown in boxes of sandy earth and are exposed
in the open to the winter frosts. In the spring they germinate and the ascospores are
sown upon a nutrient gelatin in Petri dishes, where they germinate readily and form
colonies. The colonies are cut out and transferred to a fluid medium in large flasks,
where great numbers of spores are developed. The diluted culture is sprayed on to
the rye crop when plants are in flower. Ergots are sometimes picked by hand, but are
usually separated from the rye after threshing the crop. The separation is effected
either by the use of special machinery or by throwing the grain into a 20-30 percent
solution of common salt upon which the ergots float while rye sinks.

Macroscopic Characters:
Color - Externally, it is dark violet to black.
Internally, it is whitish or pinkish white
Odor - Disagreeable and faint
Taste - Unpleasant
Size - The sclerotia are 1 to 3 cm in length and 1to 5 mm
in width
Shape - Sclerotia are fusiform, triangular and usually
tapering on both the ends

8
Pharmaceutical Sciences

Fracture - It is brittle with short fracture

Extra features - Longitudinal furrows and transverse cracks are
present on each surface

Chemical Constituents: The ergot of rye is a drug of complex composition. Besides

the sugars and a large number of amino acids, the drug contains a high proportion of
lipids: 20 to 40% of its mass contains of an oil which readily turns rancid, hence its
degradation in storage. Ergot contains large number of potent indole alkaloids (0.1 to
0.25%), which are derivatives of lysergic acid. Lysergic acid is present in its peptide
derivative form and hence the alkaloids are also called as peptide alkaloids. The six
pairs of alkaloids are broadly grouped into water soluble and water insoluble
categories. Each pair contains levo-form which is medicinally active, while dextro
form is inert in action.
The water soluble alkaloids are ergometrine, ergotamine, ergosine, ergocristine,
ergocryptine and ergocornine. The water insoluble group is further divided into
ergotamine and ergotoxine

Chemical Test:
a) Keller's Test: To a solution of the alkaloid in glacial acetic acid add a few mg of
solid FeCl3 and then add 1-2 ml of concentrated sulphuric acid along the side of
the tube. The appearance of an intense blue colouration is accomplished at the
junction of the two layers.
b) Van Urk Test: When a solution containing an ergot alkaloid is mixed with Van
Urk Reagent, it gives rise to a characteristic deep blue coloration.
c) Preperation of Van Urk Reagent Mix togetehr 0.125g of para-dimethylamino.
benzaldehyde; 0.1 ml of FeCl3 soln. (5% w/v), and 15% (v/v) H2SO4 to make
100 ml.
d) Glyoxylic Acid Reagent Test: Ergot alkaloids give a blue coloration with the
addition of Glyoxylic acid reagent and a few drops of concentrated H2SO4.
e) Fluorescence Test: The aqueous solutions of the salts of ergot alkaloids
produce a distinct blue fluorescence.
f) Ergotamine responds to a specific test. Little quantity of ergotamine is
dissolved in glacial acetic acid and ethyl acetate. A small portion of this is
treated with sulphuric acid and shaken well by which blue color with red tinge
appears. By addition of ferric chloride, blue color deepens, while red tinge
becomes faint.

9
Pharmaceutical Sciences

Biogenesis of ergot alkaloids: L-Tryptophan is a neutral heterocyclic amino acid

containing essentially an indole ring system. It has been observed that it serves as a
precursor for a wide spectrum of indole alkaloids. The various alkaloids derived from
tryptophan are conveniently classified into the following categories, namely:
a) Simple Indole Alkaloids
b) Simple b-Carboline Alkaloids
c) Terpenoid Indole Alkaloids
d) Quinoline Alkaloids
e) Pyrroloindole Alkaloids
f) Ergot Alkaloids

The ergoline nucleus is derived from trptophan, mevalonic acid and methionine.
Trptophan provides the indole nucleus, C-4, C-5 and N-6; mevalonic acid, via
dimethylallyl pyrophosphate is the origin of C-7, -8, -9, -10 and of the C-8 substituent;
methionine methylates N-6. The formation of dimethylallyltryptophan (DMAT): it
involves the alkylation of tryptophan by dimethylaallyl pyrophosphate directly at C-4,
catalyzed by a specific enzyme, DMAT synthetase. The next step leads to
chanoclavine: DMAT is N-methylated and decarboxylated, the methyl group oxidized
to a hydroxymethyl group, and the double bond isomerized. During the next step,
which is the formation of agroclavine, and it converts to elymoclavine, lysergic acid
and ergotamine.

Pharmacological Activity of Ergot: The pharmacological activity of the ergot of rye

alkaloids is particularly complex and is due to their structural analogy with
endogenous with endogenous amines: noradrenaline, dopamine and serotonin. This
structural similarty explains the affinity of the alkaloids and their derivatives for the
endogenous amine receptors and their ability to exert agonistic or antagonistic
effects on those receptors.

Ergonovine: This alkaloid is a potent oxytocic. It increases basal tone, the frequency
and strength of uterine contractions. It exerts stronger effect in advance pregnancy.
This activity is thought to be linked to the stimulation of the α-adrenergic receptors
in the myometrium. Uterine hypertonicity is at the origin of the antihemorrhagic
effects of ergonovine. In practice, methylergonovine is the preferred medication. This
is the amide of lysergic acid and of 2- aminobutanol a semisynthetic derivative which
is more active on the uterus; it also has a vasoconstrictive activity on arteries (at high
doses).

10
Pharmaceutical Sciences

Ergotamine: At low doses, ergotamine is potent vasoconstrictor acting by stimulation

of the α-adrenergic receptors (or of the serotonergic receptors in the case of the
cranial blood vessels). The change in vascular tone is particularly marked peripherally
and in the branches of the external carotid; this reaction is accompanied by the
closure of the arterio-venous shunts. At higher doses, an adrenergic antagonist
activity appears, which is weak, and illustrates the duality in the activities of this
compound. In addition, ergotamine is an oxytocic.

VINCA ALKALOIDS
Plant source of Vinca: Catharanthus, periwinkle
Biological source: It is the dried whole plant of Cathranthus roseus, belonging to
family Apocynaceae. It is also known as Vinca rosea.
Geographical source: South Africa, India, USA, Europe, Australia and Caribbean island
History: Vinca has been known since B.C. 50 in European countries as antidysentric,
antihaemorrhagic, diuretic and wound healing. This plant was used in the form of
‘tea’ for treatment of diabetes in Jamaica and in Brazil for toothache. This plant was
first scientifically investigated by Canadian workers Noble, Beer and Cutts. During
these studies, it was found that it does not have any oral hypoglycemic principle, but
contains alkaloid possessing antileukemic principle and the alkaloid was named as
vincaleucoblastine.
Cultivation and Collection: Vinca grows all over India upto 500 meters. Vinca does
not require any special conditions of soil. It favorably grows in light sandy soils, rich in
humus. For the propagation, the fresh seeds are used and sown in nurseries or
sometimes direct sowing is also done. For direct sowing, about 2.5 kg of seeds per
hectare are required. They are mixed with 10 times quantity of sand and sown in
monsoon in rows of 45 cm apart. When the plants are sufficiently grown up, they are
thinned out and a distance of about 30 cm is left between two plants. Nursery sowing
is found to be economical. In February or March, they are sown in nursery and
transplanted in open fields after 2 months when they achieve 6-7 cm height. They are
transplanted in open fields at 45 cm X 30 cm distance and about 74,000 plants per
hectare are necessary. The plants do not need much water supply and are drought
resistant. The stems are cut about 7-8 cm above the ground level after one year of
growth and the leaves, stems and seeds are separated and air dried. For collection of
roots, the field is profusely irrigated and roots are dug out by ploughing, which are
further washed, dried in shades and packed in bales. The seeds are collected from
matured fruits for next propagation.
Macroscopic Characters:
Vinca is an erect, pubescent herb, with branched tap-root. Leaves are simple, petiole,
ovate or oblong, unicosate, reticulate, entire, brittle with acute apex and glossy

11
Pharmaceutical Sciences

appearance. Flowers are bractate, pedicellate, complete, hermaphrodite, noemally 2

to 3 cm in cymose asillary clusters. Fruits are follicles with several black seeds.

Color
Leaves - Green
Roots - Pale grey
Flowers - Violet pink-white or carmine-red
Odor - Characteristic
Taste - Bitter
Chemical Constituents:
A large number of indole alkaloids are present in vinca. Out of them about 20
bisindole alkaloids which having antineoplastic activity including leurocristine
(vincristine) and vincaleukoblastine (vinblastine). Vinblastine is produced by coupling
of the indole alkaloids catharanthine and vindoline, both of which occur free in
plants. Vincristine is structurally similar to vinblastine, but has a formyl group rather
than a methyl on the indole nitrogen in the vindoline derived portion. Because these
alkaloids are only minor constituents of the plant (Vincristine is obtained in about
0.0002%yield from the crude drug).

Biogenesis of vinca alkaloids: Vinca is an indole type alkaloid. Indole alkaloids are
derived from tryptophan. Tryptophan converts into tryptamine. Condensatioden of
secologanin with tryptamine is a Mannich-type reaction gives rise to tetrahydro-b-
carboline system and generates strictosidine. The nucleophilie vindoline C-5 of the
indole nucleus is being activated adequately by the OMe at C6 besides the N-atom of
the indole moiety. The resulting adduct is subsequently reduced in the
dihydropyridinium ring by the NADH-dependent 1, 4 addition giving the substrate of
hydroxylation. Its ultimate reduction gives rise to vinblastine. Vincristine is the
oxidized product of vinblastine.
Pharmacological Activity of Vinca: Vinblastine and vincristine are antimitotics. They
bind to tubulin and prevent the formation of the microtubules whose role is well
known in the formation of the mitotic spindle. Thus these compounds block mitosis
and cause an accumulation of cells in the metaphase. The microtubule assembly also
plays a role at other levels, particularly in neurotransmission (axon microtubules),
hence the neurotoxicity of these alkaloids. They are generally in vitro inhibitors of the
biosynthesis of proteins and nucleic acid. The treatment of cell populations with
vincristine or vinblastine leads to an accumulation of cells in M and G2 phase, and the
effect is lethal in the S phase.

12