Alkaloids

th i rd s ta g e

b y : d r . h a yf a a ra s h e ed
al anssari
Introduction
The term alkaloids (or alkali-like) was first and foremost proposed by the
pharmacist, W. Meissner, in 1819, for the basic nitrogen-containing
compounds of plant origin.
alkaloids are generally defined as,—‘physiologically active basic
compounds of plant origin, in which at least one nitrogen atom forms part
of a cyclic system. (five-or six- membered ring. ) have Complex molecular
structure, and Significant pharmacological activity.
Even this definition has a few anomalies as stated below, namely:
1. Cholines and Betaines: These two substances have the N-atom in
the side chain and not in the aromatic ring as shown below:

The cholines and betaines are regarded as simple alkylamines and not
classified as alkaloids. They are designated by some school of thoughts as
‘biological-amines’ or ‘protoalkaloids’.
2. Ephedrine: It has the N-atom only in the side chain and not embedded
in the aromatic ring as given below:
3. Piperidine: It is obtained Piper nigrum (Black Pepper) and does not
possess any pharmacological activity, but has a N-atom in a heterocyclic
ring as given below:
4. Colchicine: It is found to be neither basic nor it contains the N-atom in
a heterocyclic ring, whereas it is considered as an alkaloid due to the fact it
possesses distinct pharmacological activity as shown below:
5. Thiamine (Vitamin B1): It confines to the definition of alkaloids but
is not regarded as an ‘alkaloid’ because of its almost universal distribution
in living matter.
Alkaloids function in plants:
1) poisonous agents protecting the plants against insets.
2) end products of detoxification reactions.
3) regulatory growth factors
4) nitrogen reservoirs
Occurrence & distribution of alkaloids:
In plant kingdom, alkaloids appear to have a restricted distribution in
certain families & genera.-Apocynaceae, Papaveraceae, Ranunculaceae,
Rubiaceae, Solanaceae & Berberidaceae are outstanding for alkaloids-
yielding plants.
-Amaryllidaceae & Liliaceae are two of the promising families in which to
search for alkaloids-yielding plants.
-Specific alkaloids are ordinarily confined to specific plant families(e.g.
hyoscyamine in Solanaceae, colchicine in Liliaceae), while nicotine, which
is found in a number of widely scattered plant families, is an exception to
this rule.-On other hand certain families lack alkaloids such as Laibatae &
Oleaceae.
- Alkaloids also found in m.o. (pyocyanine form Pseudomonas aeruginosa) ,
marine organism, insects, fungus (ergotamine from Claviceps purpurea) &
animals (castoramine from Canadian beaver).
alkaloids may occur in various plant parts
Seeds physostigma, areca
Roots belladonna root
Rhizomes & Roots ipecac
Barks cinchona
Underground stems sanguinaria
Nomenclature
all alkaloids must end with the suffix (–ine). The latin names end with (–ina). Thus, the
names of the alkaloids are usually obtained in a number of ways, namely: Sometimes a
prefix or suffix is added to the name of principal alkaloid to designate another
alkaloid from the same source (quinine, qunidine)
(a) From the generic name of the plant producing them: Examples: Atropine from
Atropa belladona Linn., (Solanaceae); and Hydrastine from Hydrastis canadenisis L.
(Ranunculaceae).
(b) From the specific name of the plant yielding them: Examples: Belladonine from
Atropa belladona L. (Solanaceae); and Cocaine from Erythroxylum coca Lam.
(Erythroxylaceae).
(c) From the common name of the drug producing them: Example: Ergotamine
from Claviceps purpurea (Er.) Tul. (Hypocreales) commonly known as ergot.
(d) From their specific physiological activity: Examples: Emetine from Hedera helix
L. (Araliaceae) called Ivy; Narcotine from
Papaver somniferum L. (Papaveraceae) known as Opium Poppy; and Morphine from
P. somniferum L.
(e) From the name of the discoverer: Example: Pelletierine from the barks of Puniea
granatum Linn., (Punicaceae).
(f ) From their physical property: Example: Hygrine from the roots of Withania
somniferum (L.) Dunal (Solanaceae) called Ashwagandha (Hygro = moist).
Physical properties:-

1) most of alkaloids crystalline solids. Few are amorphous & an additional

few which lack oxygen in their molecules are liquids (coniine, nicotine &
sparteine), alkaloidal salts are crystalline & these crystals are often a useful
mean of rapid microscopic identification.
2) alkaloids are insoluble or sparingly soluble in water, but the salts firmed
on reaction with acids are freely soluble. The free alkaloids are usually
soluble in organic solvents while alkaloidal salts are not, this permits a
ready means for isolation & purification of alkaloids
3) with few exceptions ( e.g. berberine is yellow), all alkaloids are colorless.
They usually possess bitter taste.
4) alkaloids generally decomposed by heating, few undergo sublimation
without decomposition (e.g. caffeine).
5) most alkaloids are optically active, usually levorotary.
Chemical properties:
1) alkaloids molecules usually contain (C, N & O) atoms , few have no
oxygen atom such as nicotine.
2) alkaloids usually contain One Nitrogen atom, some of them such as
ergotamine may contain up to 5 Nitrogen atoms, the Nitrogen may exist as
a primary amine (RNH2), as a secondary amine (R2NH), or as tertiary
amine (R3N) & some as a quaternary ammonium compounds (R4N+) such
as berberine.
3) because nitrogen atom bears unshared pair of electrons such
compounds are basic resemble 's ammonia chemical properties. The
degree of basicity varies greatly depending on the nature of molecule & the
location of other functional groups.
4) alkaloids form double salts with compounds of mercury, gold, platinum
& other heavy metals. These double salts are usually obtained as
precipitates.
The common alkaloids reagents include:-
A) Wagner's reagent B) Mayer's reagent C) Dragendorff's reagent
Classification of alkaloids
1) True alkaloids: they are toxic in nature contain heterocyclic nitrogen
which is derived from amino acids & always basic in nature, they are
normally present in plants as salts of organic acids.
2) Protoalkaloids: they are simple amines in which the nitrogen is not in a
heterocyclic ring but is in the side chain. They are also basic & prepared in
the plant from amino acids.
3) Pseudoalkaloids: include mainly steroidal & terpenoid alkaloids &
purines, they are not derived from amino acids & they do not show many of
typical characters of alkaloids but give the slandered qualitative tests for
alkaloids.
Classifications of alkaloids
a) Biosynthetic Classification
1. Indole alkaloids derived from tryptophan.
2. Piperidine alkaloids derived from lysine.
3. Pyrrolidine alkaloids derived from ornithine.
4. Phenylethylamine alkaloids derived from tyrosine.
5. Imidazole alkaloids derived from histidine
6. Alkaloids derived from Anthranilic Acid
a) Quinazoline Alkaloids b) Quinoline Alkaloids
b) Pharmacological Classification
7. Morphine as Narcotic analgesic
8. Quinine as Antimalarial
9. Strychnine as Reflex excitability
10. Lobeline as Respiratory stimulant
11. Boldine as Choleretics and laxatives
12. Aconitine as Neuralgia
13. Pilocarpine as Antiglaucoma agent and miotic
14. Ergonovine as Oxytocic
15. Ephedrine as Bronchodilator
16. Narceine as Analgesic (narcotic) and antitussive.
c) Chemical Classification

1. Pyrrolidine alkaloids e.g., Hygrine

2. Piperidine alkaloids e.g., Lobeline
3. Pyrrolizidine alkaloids e.g., Senecionine
4. Tropane alkaloids e.g., Atropine
5. Quinoline alkaloids e.g., Quinine
6. Isoquinoline alkaloids e.g., Morphine
7. Aporphine alkaloids e.g., Boldine
8. Indole alkaloids e.g., Ergometrine
9. Imidazole alkaloids e.g., Pilocarpine
10. Diazocin alkaloids e.g., Lupanine
11. Purine alkaloids e.g., Caffeine
12. Steroidal alkaloids e.g., Solanidine
13. Amino alkaloids e.g., Ephedrine
14. Diterpene alkaloids e.g., Aconitine
1. Pyridine-piperidine alkaloids:
The tertiary base pyridine on reduction is converted to secondary
base piperidine. These two nuclei form the bases of this group.
This group is divided into three subgroups:
A) derivatives of piperidine: includes lobeline from lobelia.
B) derivatives of nicotinic acid: includes arecoline from areca.
C) derivatives of both pyridine & pyrrolidine: include nicotine from
tobacco.
The important alkaloidal drugs & their alkaloids that are classified in this
group are areca, arecoline hydrobromide, lobelia, lobeline & nicotine.
a) Areca:-
areca, areca nut or betel nut is the dried ripe seed of Areca catechu
(Family: Arecaceae). Areca contains several alkaloids that are reduced
pyridine derivatives, among them are arecoline, arecaidine, guvacine &
guvacoline. The total alkaloid content can reach 0.45%. Arecoline is the
most abundant & physiologically most active alkaloid. Areca also contains
tannin, lipids, volatile oils & gums. Areca is classified as an anthelmintic in
veterinary practice & is employed as vermicide & taenifuge (agents that
expels tapeworms).
b) Lobelia:
Lobelia or Indian tobacco consists of the dried leaves & tops of
Lobelia inflata ( Family: Lobeliaceae), the drug contains 14 alkaloids of
which lobeline is the major &the most important. It is also contains a
pungent volatile oil, resin, lipids & gum. It is mainly used in treatment of
asthma & respiratory stimulant.
Lobeline, (-) –lobeline or alpha lobeline occurs as colorless crystals that
are slightly soluble in water but readily soluble in hot alcohol. Lobeline
produces similar but weaker pharmacological effects to those of nicotine
on the peripheral circulation, neuromuscular junctions & CNS. For this
reason lobeline sulfate formerly was incorporated in tablets or lozenges to
aid in breaking smoking but clinical studies showed that lobeline has a
placebo effects. In parenteral form lobeline hyd
rochloride is given for resuscitation of new born infants through umbilical
vein. It is also a cardiovascular stimulant through chemoreceptors, cough
& pain receptors are also stimulated by lobeline. It has also emetic effects.
c) Nicotine:
Is a pyridine alkaloid obtained from the dried leaves of Nicotiana
tobacum (Family: Solanaceae), it was named after Jean Nicot (a French
diplomat, who probably introduced tobacco into Europe). In addition to
nicotine, tobacco contains nornicotine & anabasine.
Nicotine is colorless to pale yellow, very hygroscopic, oily, volatile liquid
with an unpleasant pungent odor & sharp, burning, persistent taste.
Nicotine a cholinergic-receptor agonist with complex pharmacological
actions.
Chronic use of nicotine may result in psychologic & physical dependence.
The drug is available as transdermal patches to aid for cessation of cigarette
smoking & it is also available in chewing gum base bound to an ion
exchange resin. These agents help to reduce the withdrawal symptoms
associated with nicotine addiction.
• Nicotine in small dose causes respiratory stimulant
• Nicotine in large dose causes respiratory depressant
• nicotine present as salt and free base ,the free base is more toxic than
the salt
• It is more toxic to man because it is effect on CNS
• The interaction with acetylcholine receptor cause respiratory depressant
• In addition to effect on respiratory center ,it will effect on memory
(improve memory ) by stimulating the transmission of nerve impulses
and this effect may lower the incidence of Alzheimer disease in smoker
2. Tropane alkaloids:
Tropane is a dicyclic compound formed by the condensation of
pyrrolidine precursor (the amino acid ornithine) with three acetate-derived
carbon atoms. Both pyrrolidine & ppiperidine ring system can be observed
in the molecule

The 3-hydroxy derivative of tropane is known as tropine, its esterification

with (-)-tropic acid yields hyoscyamine. Which may be racemized to form
atropine. The important drugs & alkaloids in this group are belladonna
leaf, hyoscymus, stramonium, atropine, hyoscyamine, scopolamine, coca
& cocaine.
Belladonna:
Consists of dried leaf & flowering or fruiting top of Atropa
belladonna (Family: Solanaceae), the leaf yields alkaloids in
concentrations ranging up to more than 1% & about 3/4 of the isolated
alkaloids mixture is (-)-hyoscyamine & the remainder is atropine. Atropine
{ (±)-hyoscyamine } exists only in traces in fresh plant material & is
formed by racemization during the extraction process. Small but varying
amounts of other bases are found in the root but not in the leaf, these
include: apoatropine, belladonnine, cuscohydgrine & scopolamine.
Belladonna acts as anti muscarinic which accounts for its used as a
spasmolytic drug. It is used as adjunctive therapy in the treatment of
peptic ulcer, functional digestive disorders such as diarrhea. It possesses
anti cholinergic properties & it is used to control excess motor activity of
GIT. Belladonna leaf is commonly administered as tincture (30 mg
alkaloids/100ml) or extract (1.25 mg alkaloids/100g).
Hyoscyamine: it is tropine ester of(-)-tropic acid & it is readily hydrolyzed by
boiling in dilute acids or alkalies to form tropic acid & tropine. The sulfate salt
of hyoscyamine is obtained from species of Hyoscymus or other genera of
Solanaceae. It is extremely poisonous. Hyoscyamine is an anti cholinergic. It is
used to decrease gastric secretion & in visceral spasm.
Atropine { (±)-hyoscyamine }: is obtained from Atropa belladonna,
Datura & Hyoscyamus species (Family: Solanaceae), or produced
synthetically. Atropine sulfate is an anticholinergic. It is used in surgery to
control bronchial, nasal & salivary secretions. It is also used as antispasmodic
agent & antidote to cholinesterase inhibitors.
Scopolamine or (hyoscine): is an alkaloid obtained from Datura
fastuosa & Datura metel, it is an ester that yield upon hydrolysis tropic acid
& scopoline. Scopolamine hydrobromide or (hyoscine hydrobromide) is
classified as anti cholinergic. At usual therapeutic doses it is CNS depressant. It
is also effective in prevention of nausea & vomiting associated with motion
sickness.
Hyoscyamus or henbane: is the dried leaf of Hyoscyamus niger
(Family:Solanaceae), the active principles are alkaloids (hyoscyamine &
scopolamine) of which 3/4 is hyoscyamine. The Egyptian henbane is the
dried leaves of Hyoscyamus muticus yields about 1.5% of alkaloids mainly
hyoscyamine. It is indigenous to & cultivated in Egypt.
Stramonium: or jimson weed consists of drying leaf or flowering or
fruiting tops of with branches of Datura stramonium (Family:
Solanaceae). It yields not less than 0.25% of alkaloids, the drug contains
hyoscyamine (more abundant) & scopolamine.
Stramonium seed is the ripe seed of Datura stramonium, the seeds
contain 0.4% of alkaloids principally hyoscyamine with small amount of
scopolamine & traces of atropine. Stramonium is an anticholinergic & has
action similar to that of belladonna, the powdered stramonium in the
preparation is intended to burned & the resultant vapor is inhaled to
relieve asthma.
Cocaine: coca dried leaves of Erythroxylum truxillense known
commercially as Truxillo coca (Family: Erythroxylaceae). The plant is
indigenous to South America (Peru & Bolivia are the only countries that
grow coca legally for pharmaceutical market).
Coca leaves contain three basic types of alkaloids: derivatives of ecgonine
(cocaine, cinnamylcocaine, α &β- truxilline), derivatives of tropine &
derivatives of hygrine. Only ecogonine derivatives are commercially
important.
Huanuco coca contains 0.5 to 1% of ester alkaloids, derivatives of tropine &
derivatives of ecogenine of which cocaine constitutes the major part up to
75 %
Cocaine is the methyl ester of bezoylecgonine, when hydrolyzed it split
into ecgonine, benzoic acid & methyl alcohol. Cocaine has multiple actions
on central & peripheral nervous system. It is psychomotor stimulant
(cause euphoria) with strong abuse potential (cause addiction).
Cocaine in high does causes cardiac arrhythmia
Cocaine in low dose increase hart rate
Chemically Not used becouse it toxicty and addiction
Cocaine hydrochloride: occurs as colorless crystals or white crystalline
powder. It is used with combination to other medications to control sever
pain in cancers. Because of its CNS stimulant properties cocaine
counteracts the narcotic-induced sedation & respiratory depression
associated with narcotic analgesics (morphine or methadone), it is also
potentiate analgesic effects.
3. quinoline alkaloids:
Alkaloids containing quinoline as their basic nucleus include those
obtained from cinchona (quinine, quinidine, cinchonine & cinchonidine).
Cinchona & its alkaloids are the members of this group that are
therapeutically important at present. Cinchonine, which is isomeric with
cinchonidine, is the parent alkaloid of quinine series. Quinine & its isomer
(quinidine) represent 6-methoxycinchonine
1. Cinchona: (cinchona bark or Peruvian bark) is the dried bark of the
stem or of the root of Cinchona succirubra or its hybrids (red cinchona) or
C. ledgeriana or C. calisaya or their hybrids (yellow cinchona) /(Family:
Rubiaceae).
Cultivation gives the opportunity to select seeds from plants producing
high-quality bark & to hybridize one choice strain with another. Thus,
hybrids of Cinchona ledgeriana- Cinchona calisaya produce a high yield of
alkaloids than do either of the parent species.
Shade is favorable to the production of quinine. Trees that are 6-9
years old possess the maximum amount of alkaloids in the bark. When
young bark is dried, it may have an alkaloidal content three times as that in
bark from an old tree.
Cinchona contains some 25 closely related alkaloids, the most
important of which are quinine, qunidine, cinchonine & cinchonidine &
the average yield is 6 to 7% of which one half to two-thirds is quinine in
yellow barks, while in red barks cinchonidine exists in greater proportion
may reach up to 18% of total alkaloids. Another constituent of cinchona is
cinchotannnic acid (2 to 4%) which decomposes into insoluble cinchona
red.
Uses
cinchona & its alkaloids have been used in the treatment of malaria
fever for many years. Quinine continues to be used for malaria in many
parts of the world but in the USA this alkaloid is utilized primarily in the
preparation of effervescent tonic water. Quinidine is now the principal
cinchona alkaloid employed therapeutically.
Toxicity & Overdose:
overdose of cinchona products results in temporary loss of hearing &
in impaired sight. Ringing in the ears is the symptom of toxicity. When
these symptoms occur as a result of continuous use of cinchona or
quinine the condition is called cinchonism.
4. Cinchona alkaloids:
1) Quinidine: is a stereoisomer of quinine & is present in cinchona barks to
extent of 0.25% to 1.25%. Quinidine sulfate is the sulfate of alkaloid obtained
from various species of Cinchona & its hybrids & from Remijia species or
prepared from quinine. It is odorless, has a bitter taste & darkens when exposed
to light. It is readily soluble in water, alcohol, methanol & chloroform.
• anti arrhythmia ,decrease cardiac automaticity and contractility

Uses: used to treat various cardiac arrhythmias (premature atrial, AV junctional

& ventricular contrsctions, atrial & ventricular tachycardia, atrial flutter & atrial
fibrillation)
Other salts are present including quinidine gluconate(I.V.) & quinidine
polygalactouronate.
H.W: advantage of quinidine polygalactouronate over quinidine sulfate.
2)Quinine: is a diaseroisomer of quinidine. It occurs as white, odorless, bitter
crystals or as crystalline powder. It darkens when exposed to light, it is freely
soluble in alcohol, ether & chloroform but slightly soluble in water. Quinine
sulfate is the sulfate salt of alkaloid obtained from Cinchona species. The drug
is an antimalarial & once it was the only agent used to treat malaria. Quinine has
a skeletal muscle relaxant effect by increasing the refractory period by direct
action on muscle fiber leading to decreasing excitability of the motor end plate.
Chloroquinin has been used for long terms as prophylactic and anti
malarial agent this will lead to protection of new strain of protozoa with
resist the synthetic anti malarial products so the use of quinine is
encouraging
5. isoquinoline alkaloids:
The isoquinoline structure occurs in a considerable number of
alkaloids in widely separated plant families. They represent the largest
single group of plant alkaloids & there is great variation in their chemical
structure. Some of the important isoquinoline subgroups are:
1) The Benzylisoquinolines: represented by papaverine & tubocurarine.
2) The Benzophenanthridines: represented by sangunarine.
3) The Pthalideisoquinolines: which contain γ-lactone ring & are
represented by hydrastine.
4) The Morphinans: represented by the opium alkaloids(codeine,
morphine, thebaine).
5) The Protoberberines: represented by berberine.
6) Those with Emetine skeleton.

Note:
In addition with the isoquinoline group of alkaloids frequently the nitrogen
is in the quaternary form as in the case of berberine, sanguinarine &
tubocurarine which greatly influence their solubility properties.
1) Ipecac: it consist of the dried rhizomes & roots of Cephaelis
ipecacuanha, known as Rio or Brazilian ipecac. Or from Cephaelis
acuminate, known as Catergena (Colombia) or Nicaragua or Panama
ipecac . (Family: Rubiaceae).
In Rio ipecac, the total alkaloid contents reaches slightly over 2%, one
third cephaeline & two thirds emetine. While in Catergena ipecac, the total
alkaloid content reaches 2.2% two thirds cephaeline & one third emetine.
Uses: ipecac in a form of syrup is used in the treatment of drug overdose &
in poisoning (antidote). It produce emesis through a local irritant effect on
GI mucosa & stimulation of CRT zone.
DOSE & The difference between ipecac syrup & ipecac fluid extract( H.W.)
• It is longer approved in the USA because it can accumulated in the
body ,producing potentially lethal toxicity
Emetine: or methylcephaeline is an alkaloid obtained from ipecac or
prepared synthetically by methylation cephaeline. Emetine HCl occur as
white odorless crystalline powder that becomes yellowish when exposed
to light, it is freely soluble in water & alcohol. It is an antiamebic that act
primarily in the intestinal wall & liver by inhibiting polypeptide chain
elongation, thereby blocking protein synthesis. The drug is not
administered orally because it produce N & V. it possesses expectorant &
emetic properties.
2) Hydrastis:
Or called goldenseal consists of the dried rhizomes & roots of
Hydrastis Canadensis (Family: Ranunculacea). The plant is
perennial herb with short horizontal rhizomes, internally the rhizomes
&roots show a golden yellow color. The alkaloids have been isolated from
Hydrastis are hydrastine, berberine & canadine, of these hydrastine
(1.5% - 4%) is the most important. Hydrastis yields not less than 2.5% of
anhydrous ether-soluble alkaloids.
Hydrastine & berberine are used as astringents in inflammation of
mucous membranes.
a) Hydrastine: is Pthalideisoquinoline & it is readily soluble in
chloroform, alcohol & ether but insoluble in water.
b) Berberine: is readily soluble in water but insoluble in ether. The salts
of berberine form yellow crystals.(note it is quaternarnary ammonium
compound)
3) Sangunaria:

Or blood root is the dried rhizomes of Sangunaria canadensis

(Family: Papaveraceae). The generic name means blood & refer to the
color of latex & Canadensis refers that the natural habitat is Canada. The
plant is perennial herb, blood root was used by Indians to stain their
faces & was also used as an acrid emetic. Sangunaria contains alkaloids
sangunarine(1%), chelerythrine, protopine & allocryptopine. These
alkaloids are colorless but tend to form colored salts sangunarine yields
reddish salt with nitric or sulfuric acids, while yellowish salts are form
with chelerythrine.
sangunarine :- is Benzophenanthridine type of isoquinoline alkaloid.

USES
sangunarine has stimulating expectorant & emetic properties. In
addition sangunari extract incorporated in toothpaste & mouthwash for
prevention of development of dental plaque.
4) Curare:
Or South American arrow poison, is the dried extract from the bark &
stems of Strychnos castelnaei , Strychnos toxifera & Strychnos
crevauxii (Family: Loganiaceae) & from Chondodendron
tomentosum (Family: Menispermaceae), the term curare derived
from Indian word which means poison.
The most important constituent is (+)- Tubocurarine, which is quaternary
compound & contains bis-benzylisoquinoline structure, the crude extract
exhibits a paralyzing effect on voluntary muscle (curariform effect) by
blocking nerve impulses to skeletal muscle at the myoneural junction. It
also produces a toxic action on blood vessels as well as histamine–like
effect.

Tubocurarine HCL: is white crystalline powder, it is soluble in water &

alcohol bur insoluble in acetone, chloroform & ether. It is non
depolarizing neuromuscular blocking agent & given I.M.ly or I.V.ly as a
skeletal muscle relaxant in surgical procedures without deep anesthesia. It
is also used to control convulsion of tetanus & it is a diagnostic aid in
myasthenia gravis.
5) Opium:
Or gum opium is the air-dried milky exudate obtained by incising the
unripe capsules of Papaver somniferum (Family:Papaveraceae),there
are more than 30 different alkaloids have been obtained from opium & its
extracts, some of which are alteration products of the alkaloids occurring
naturally in the drug. The most important of these are morphine (4%-21%),
codeine (0.8%-2.5%), noscapine (narcotine)(4%-8%), papaverine(0.5-
%-2.5%) & theabine (0.5%-2%), & other alkaloids.
Opium also contains 3%-5% of meconic acid which exists free or in
combination with morphine & other alkaloids. It forms rhombic prisms that
are soluble in water & alcohol & gives red color in solution of ferric chloride.
The color is not altered when diluted hydrochloric acid is added. Because
meconic acid is found only in opium, this test may be used for the detection
of opium.
Alkaloids of Opium:
1) Morphine: is the most important of the opium alkaloids. Morphine &
the related alkaloids are morphinan isoquinoline derivatives. The molecule
contains a phenolic & alcoholic hydroxyl group. This alkaloid & its salts
occur as white silky crystals or as fine crystalline powder. It is stable in air,
odorless & bitter-taste.
Morphine is a prototype of opiate analgesic drugs which act at several sites
in the CNS to produce analgesia.(it has agonist activity on mu (µ) & kappa
(қ) receptors). It produces analgesia at the supraspinal level & causes
euphoria, respiratory depression & physical dependence results from
agonist activity on (µ) receptor, while agonist activity at the (қ) receptor is
responsible for analgesia at spinal level, miosis & sedation. Morphine & its
salts are classified as narcotic analgesics, they are strong hypnotic &
narcotic, their use tends to induce nausea, vomiting constipation & habit
formation.
 Most of Centrally acting analgesics have certain structural
features in common (SAR):
1) a central carbon atom with no hydrogen substitution (quaternary)
2) a phenyl group or isostere attached to this carbon atom
3) a tertiary nitrogen atom
4) a two carbon bridge separating the tertiary nitrogen atom & the central
carbon atom.
Morphine & its related opium alkaloids have these structural features.

2) Codeine: is the most widely used opium alkaloid. It may be obtained

from opium or prepared from morphine by methylation or from theabine
by reduction & demethylation.
Codeine is methylmorphine in which the methyl group replaces the
hydrogen of the phenolic hydroxyl group. Codeine & its salts are narcotic
analgesics & antitussives, they are used as sedatives & in cough. It is
considered less toxic than morphine & involve in less danger habit
formation.
 Theoloene
Re
Di du
m cti
e th on
yla
tio
n

Methylation
Morphine Codeine

Ace
t yla
tio
n
Heroin

Note :- Heroin is 100 times stronger than morphine

3) Diacetylmorphine: (Heroin): is formed by acetylation of
morphine, the (H) atoms of both phenolic & alcoholic hydroxyl groups
are replaced by acetyl groups. It action is similar but more pronounced
than that of morphine. Because of its potency & dangerous habit
formation, its production was forbidden by law & it is not used as
medicine in the USA.

4) Papaverine: it’s a naturally occurring alkaloid in opium & it may be

synthesized. Papaverine HCl is a smooth muscle relaxant, it is used
principally for the relief of cerebral & peripheral ischemia associated with
atrial spasm & myocardial ischemia complicated by arrhythmias.

5) Hydromorphone HCl or dihydromorphinone HCl :- differs

from morphine HCl because one of the hydroxyl groups of morphine is
replaced by ketone group & the adjacent double bond is removed. It is
prepared by reducing morphine HCl acid solution with hydrogen in the
presence of a catalyst. It is a powerful narcotic analgesic & causes
respiratory depression but it seems less habit forming.
6. Indole alkaloids:
There are important alkaloids possess an indole ring as part of their
structure. Strychnine & Brucine (Dimethoxystrychnine) from nux vomica
& physostigmine from physostigma belong to this group. However,
Strychnine & Brucine also contain quinoline nucleus & are classified by
some authors in quinoline group. The important drugs & their alkaloids of
the indole group are : rauwolfia, reserpine, catharanthus (vinca),
vinblastine, vincristine, pysostigma, physostigmine, ergot, ergotamine,
ergonovine & yohimbine.
1) Rauwolfia Serpentina:

Is the dried root of Rauvolfia serpentina (Family: Apocynaceae),

it contains not less than 0.15 % of the reserpine- rescinnamine group of
alkaloids calculated as reserpine.
Powdered Rauwolfia Serpentina:
Is the Rauvolfia serpentina root reduced to a fine or very fine powder
that is adjusted to conform the official requirements for reserpine-
rescinnamine group alkaloid by admixture with lactose or starch or with
powdered rauwolfia serpentina containing higher or lower content of these
alkaloids. It contains not less than 0.15% & not more than 0.2 % of
reserpine-rescinnamine alkaloids, calculated as reserpine. It is a
hypotensive (reserpine is the major alkaloid that has a strong hypotensive &
sedative activity).
There are at least 50 alkaloids isolated, that is why the whole root exhibits a
medicinal action that different from reserpine. Lowering blood pressure, slowing
pulse & general sense of euphoria. It is used in mild essential hypertension & used
to relief symptoms of agitated psychotic states (e.g. schizophrenia).

2) Yohimbine:
It is an indole alkaloid obtained from the bark of Pausinystalia yohimbe
(family: Rubiaceae). Te bark contains 6% of mixture alkaloids
(Yohimbine is the major), it is used in treat male impotence in patients with
vascular or diabetic problems..
3) Catharanthus or (vinca):
Is the dried whole plant of Cathranthus roseus (Family:
Apocynaceae), in folklore the plant was used as oral hypoglycemic
agent. But it was the ability of certain fractions to produce peripheral
granulocytopenia & bone marrow depression in that led the researchers to
isolate, the alkaloid, vinblastine which cause severe leucopenia in rats &
led to the recognition of anticancer potential of the alkaloids of this plant.
Among those four bisindole compounds (vinblastine, , vinleurosine,
vinrosidine & vincristine) possess oncolytic activity.
The active alkaloids exist in the crude drug in relatively small amounts &
approximately 500 kg is used to produce 1 g of vincristine. To satisfy this
demand the plant is collected from natural & cultivated sources in various
areas of the world.

Catharanthus Alkaloids (Vinca Alkaloids):

The alkaloids with antineoplastic activity belong to a class of
bisindole derivatives. The most characteristic effect of these drugs is the
arrest of cell division at metaphase. Both vinblastine & vincristine bind
tightly to tubuline which is a component of mitotic spindle(TBA), (inhibit
polymerization of tubuline).
Vinblastine sulfate, vincaleukoblastine sulfate (VLB): it is the salt
of alkaloid extracted from cathranthus, it is unstable & available in sealed
ampoules & should be stored in refrigerator. Used for treatment of a wide
variety of neoplasms such as Hodgkin's disease.
Vincristine sulfate, leurocristine sulfate (VCR or LCR): it is the
salt alkaloid obtained from cathranthus. The structure of this alkaloid is
quite similar to that of vinblastine different only in the substitution.
Despite the similarity in structure of these compounds there are
differences in antitumor spectra & there are no cross-resistance.
4) Nux Vomica:
Is the dried ripe seed of Strychnos nux-vomica (Family:
Loganiaceae), it contains alkaloids 1.5 to 5% consisting chiefly of
strychnine (1/3 to 1/2 of total alkaloids) & brucine (Dimethoxystrychnine).
Strychnine is extremely toxic & functioning as central stimulant. It
produces excitation of all parts of central nervous system leading to tonic
convulsion. 60 mg to 90 mg cause fatal poisoning & the drug seldomly used
employed in modern medical practice. Brucine is less toxic & it is used as
alcohol denaturant because of its extreme bitterness.
5) Ergot (Rye ergot):
Is the dried sclerotium of a fungus Claviceps purpurea (family:
Clavicipitaceae), arising in the ovary of Rye , Secale cereale (Family:
Gramineae)
Sclerotium is the dark brownish body of the fungus resulted from infection
of rye plant.
Ergot contains or produces a large number of alkaloids, the most important
are ergonovine, ergotamine, & ergotoxine(mixture of 3 alkaloids). The
alkaloids are separated into 2 groups based on their water solubility:
1)Water soluble alkaloids :ergonovine is the principal component.
2)Water-insoluble alkaloids(peptide alkaloids): ergotamine & ergotoxine.
Significant semisynthetic alkaloids include methylergonovine,
dihydroergometrine, ergoloid mesylates, methysergide & LSD.
Ergot alkaloids:
1) Ergonovine maleate or ergometrine maleate, it is water soluble
microcrystalline powder. It possess oxytocic effect that is more marked than
that of ergotoxine & ergotamine but the vasoconstrictor action is less
marked. Methylergonovine maleate is a semisynthetic homologue of
ergonovine.

2) Ergotamine tartrate: it has an oxytocic effect but it is not used for this
action, instead it is used to prevent or abort vascular headaches ,including
migraine, probably through direct vasoconstriction of the dilated carotid
artery. It is used with caffeine in the treatment of migraine headache (both
of them act as cerebral vasoconstriction).

3) Lysergic acid diethylamide(LSD): it doesn't occur in nature & it is

prepared semi synthetically. It produce a predominant central sympathetic
stimulation that parallels a slight depression. It is the most active & most
specific psychotomimitic agent known with effective oral dose of 30 to 50
µg. LSD widespread misuse lead to the restriction of the availability of this
drug only to qualified scientific investigations.
7. Imidazole Alkaloids:
The imidazole (glyoxaline) ring is the principal nucleus in pilocarpine
from pilocarpus. Pilocarpine & pilocarpus are the important drugs in this
group.
Pilocarpus or jaborandi:
Consists of the leaflets of Pilocarpus jaborandi or Pilocarpus
pinnatifolius or Pilocarpus microphyllus (family: Rutaceae), the
plants are indigenous to Brazil. Even under ideal storage conditions, the
leaves lose at least half of their alkaloidal content in one year through
deterioration.
Pilocarpine: is the lactone of pilocarpic acid, pilocarpine directly
stimulate the muscarinic receptors in the eye causing contraction of the
pupil & contraction of the ciliary muscle & it is used in the treatment of
glaucoma. Pilocarpine is a monoacidic tertiary base containing a lactone
group as well as imidazole nucleus.
8. Steroidal Alkaloids:
The steroidal alkaloids are derived biosynthetically from six isoprene units &
could be classified as triterpenoids or steroids ; however they also contain nitrogen
giving them basic properties. The nitrogen may be a part of a ring or may be as an
N-methyl substituted amino group. They are found in Apocynaceae, Buxaceae,
Liliaceae & Solanaceae families. The important drugs of this group are veratrum
viride & veratrum album.

1. Veratrum Viride(American or green hellebore):

Consist of the dried rhizome & roots of Veratrum viride (Family: Liliaceae),
veratrum contains a large number of alkaloids classified in three groups:
Group I: Esters of steroidal bases (alkamines) with organic acid (cevadine,
germidine, germitrine, neogermitrine & others)
Group II: Glucosides of alkamines: psudojervine & veratrosine.
Group III: Alkamine themselves: germine, jervine & others.
The ester alkaloids germidine & germitrine are the most important therapeutically.
Veratrum viride possesses hypotensive, cardiac depressant & sedative properties.
The complexity & their relative instability of these constituents account for the
problems encountered in the biologic standardization.
2. Veratrum album (European or white hellebore):
Is the dried rhizomes of Veratrum album (family: Liliaceae), the drug
contains a complex of mixture of ester alkaloids, the most active ester alkaloids
are protoveratrine A & protoveratrine B. white hellebore possesses hypotensive
properties. Both white & green hellebore are employed as insecticides.
9. Alkaloidal Amines:
The alkaloids in this group do not contain heterocyclic nitrogen atom. Many
are simple derivatives of phenyethylamine & as such are derived from
phenylalanine or tyrosine amino acids, such as ephedrine & colchicine.
Other alkaloidal amines are tryptophan derivatives such as gramine.
The drugs & their alkaloids classified as alkaloidal amines are ephedra, ephedrine,
colchicum seed, colchicum corm, colchicines, khat & peyote.
1) Ephedra or (ma huang):
Is the entire plant or overground portion of Ephedra sinica (family:
Gnetaceae), it contains ephedrine as the chief constituents which is an alkaloid
produced commercially either by extraction of plant material or by chemical
procedure. Ephedrine is potent sympathomimetic that stimulate α, β1, & β2
adrenergic receptors causing vasoconstriction, cardiac stimulation, raise in blood
pressure & cause bronchial smooth muscle relaxation (used in asthma). It is also
used as decongestant in nasal congestion.
2) Colchicum:
Colchicum seed is the dried ripe seed of Colchicum autumnale (Family:
Liliaceae), and Colchicum corm is the dried corm of the same species. The Arabs
recommended the use of the corm for gout in medieval times but it was abundant
due to its toxicity. Colchicum contains alkaloid colchicine up to 0.8% in the seed &
0.6 % in the corm. Colchicine used in the treatment of gout. Colchicine is lacks
pronounced basicity & does not form a well-defined series of salts as do other
alkaloids. But precipitated by many alkaloid reagents & conventionally considered
as an alkaloid.
3) Khat or Abyssinian tea:
Consist of the fresh leaves of Catha edulis (Family: Celastraceae),
the leaves are chewed habitually by many people in East African &
Arabian countries to alleviate their sensation of hunger & fatigue. The
WHO does not classify khat as a drug of habituation or addiction but the
French government considered it as a narcotic. Khat contains a potent
phenylalkylamine alkaloid called (-)-cathinone & its pharmacological
properties is analogue to those of amphetamine & of similar potency with
similar mechanism of action(induction of catecholamine release).
10. Purine Bases (Purine Alkaloids):
The purine ring is gradually elaborated by piecing together small
components from primary metabolism. The purines are derivatives of a
heterocyclic nucleus consisting of 6-membered pyrimidine ring fused to the
5-membered imidazole ring. Purine itself does not occur in nature, but
numerous derivatives are biologically significant.
The largest component incorporated is glycine, which provides a C2N unit, whilst
the remaining carbon atoms come from formate. Two of the four nitrogen atoms
are supplied by glutamine, and a third by aspartic acid. Successive methylations on
the nitrogens give caffeine by way of theobromine, whilst a different methylation
sequence can account for the formation of theophylline.
Purine alkaloids are derivatives of xanthine; The pharmaceutically important bases
of this group are all methylated derivatives of 2,6-dioxypurine (xanthine).three
well-known examples are caffeine (1,3,7-trimethylxanthine). theophylline (1,3-
dimethylaxanthine) and theobromine (3,7-dimethylxanthine).
Beverages such as tea and coffee owe their stimulant properties to these
substances. Caffeine stimulates the central nervous system and has a weak diuretic
action. whereas theobromine acts in the reverse way. Theophylline has generally
similar properties to the above with a Shorter, though more powerful diuretic
action than caffeine, it relaxes involuntary muscles more effectively than either
caffeine or theobromine. The three alkaloids are official in the EP and BP.
The methylxanthines competitively inhibit phosphodiesterase which results in an
increase of cyclic Adenosine monophosphate (cAMP, cyclic AMP) with
subsequent release of endogenous epinephrine. This results in:

1) direct relaxation of the smooth muscles of the bronchi & pulmonary blood
vessels,
2) stimulation of CNS,
3) induction of diuresis,
4) increase in gastric acid secretion,
5) inhibition of uterine contractions &
6) weak (+) chronotropic & inotropic effect on the heart.
The drugs of this group are coffee, caffeine, kola, guarana, mate, tea,
theophylline, cacao & theobromine.
Caffeine-Containing Drugs:
Kola, cola or kolanuts:
Is the dried cotyledon of Cola nitida (Family: Sterculiaceae), it yields not
less than 1% of anhydrous caffeine. Kolanut is important because of its
caffeine content & its flavor, its principle use in the USA is in the
manufacture of nonalcoholic beverages. In the tropical countries where it
grows, the fresh nut is chewed as a stimulant. Cola nitida is a large tree
indigenous to West Africa. Kolanuts contain caffeine up to 3.5% &
theobromine less than 1%. In the fresh nuts these purine derivatives are
bound to the tannin kolacatechin. During the drying process the complex is
split yielding free caffeine & theobromine & converting the colorless
kolacatechin to the red-brown kola red.
Kola possesses the central stimulating action of caffeine. It is an ingredient
in several carbonated beverages.
Coffee bean or coffee seed:
Is the dried ripe seed of Coffea arabica or Coffea liberica (Family:
Rubiacae). Roasted coffee is coffee roasted until it acquires a dark brown
color & develops the characteristic aroma. The plants are small evergreen
trees or shrubs indigenous to Ethiopia & other parts of eastern Africa.
Coffee seeds contain from 1-2% of caffeine, 0.25% of trigonelline, tannin,
fatty oil & others. The usual cup of brewed coffee contains about 100-150
mg of caffeine & a cup of instant coffee contains 85-100 mg of caffeine
(for comparative purposes of caffeine content: a cup of tea contains 60-75
mg, of cacao 5-40 mg & 12 oz of cola drink 40-60 mg). the estimated
maximum daily dose of caffeine 1.5g.
Decaffeinized coffee:
Is prepared by extracting most of the caffeine from coffee bean yet
retaining the pleasant characteristic aroma of coffee. Such preparations
contain up to 0.08% of caffeine.
Matè or Paraguay tea:
Consists of the leaves of Ilex paraguariensis (Family: Aquifoliaceae),
Matè contains caffeine up to 2% & tannins. It is used in large doses as
laxatives or purgative. It has diuretic properties. It is used in South America
in preparation of tea like beverages.
Caffeine:
It is 1,3,7-trimethylxanthine occur in all the above caffeine-containing
drugs. Although caffeine can be produced synthetically, it is usually
prepared from tea, coffee & others. The solubility of caffeine in water is
markedly increased by the presence of citric acid, benzoates & salicylates.
Medicinal compounds of this class are citrated caffeine or caffeine &
sodium benzoate. Sodium benzoate is the most suitable for IM injections as
an analeptic in the treatment of poisoning, as a stimulant in acute circulatory
failure & as diuretic. Caffeine &its related compound are CNS stimulants.
Thea:
Thea or tea consists of the prepared leaves & leaf buds of Camellia sinensis
(Family: Theaceae), the shrub or tree have evergreen leaves & it is indigenous to
eastern Asia & now is extensively cultivated in China, Japan, India & Indonesia.
Generic name is Greek (goddess) ( spp. Mean Chinese origin )
Green tea: is prepared in China & Japan by readily drying the freshly picked
leaves in copper pans over a mild artificial heat. The leaves are often rolled in the
palm of the hand as they dry.
Black tea: is prepared in Sri Lanka & India by heaping the fresh leaves until
fermentation has begun. They are then rapidly dried artificially with heat.
Tea contains 1 to 4 % of caffeine (theine) & small amount of adenine,
theobromine, theophylline & xanthine.
About 15% of gallotannic acid & about 0.75 % of a yellow volatile oil that is solid
at ordinary temperatures & has a strongly aromatic odor & taste.
The stimulating action of tea is essentially that of the contained caffeine, its
astringent properties are owing to the tannin content.
Tea leaf waste & tea dust represent important sources for the extraction of caffeine.
Theophylline:
1,3-dimethylxanthine, is isomeric with theobromine & was first isolated
from tea in 1885. It is prepared synthetically from caffeine or by other
means. Theophylline & related compounds are utilized principally as
smooth muscle relaxants for the symptomatic relief or prevention of
bronchial asthma associated with chronic bronchitis & emphysema. Also it
possesses diuretic properties.
Theobromine:
3,7-dimethylxanthine is a compound prepared from the dried ripe seed
of Theobroma cacao (Family: Stercuilaceae) or made synthetically.
Theobromine is a diuretic & smooth muscle relaxant but has a little
stimulating effect on CNS.
For black tea, the leaves are allowed to ferment, allowing enzymatic
oxidation of the polyphenols, whilst green tea is produced by steaming and
drying the leaves to prevent oxidation.
The leaves contain thease an enzymic mixture containing an oxidase,
which partly converts the phlobatannin into phlobaphene. This oxidase
may be destroyed by steaming for 30 seconds.
thease
phlobatannin phlobaphene