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Phytochemistry and Plant Metabolism
Intermediary Metabolism:
enzyme-mediated and carefully regulated chemical reactions (Metabolic
Pathways)
Primary Metabolism:
Biochemistry Processes resulting in primary metabolites (carbohydrate, amino
acid,..)
Secondary Metabolism:
Natural Products chemistry resulting in secondary metabolites ( Flavonoids,
alkalaoids,…). Building clocks for 2ry metabolites are derived from 1ry
metabolites, namely, acetate, mevalonate and shikimate.
Alkaloids are:
Secondary Metabolites
Alkali-Like compounds…Difficult to be defined…But,
Generally known as
“All Organic Nitrogenous Compounds With a Limited
Distribution in Nature”… “have Physiological Activity”
Not homogenous group of compounds!
Found in plants, microorganisms.
Extracted from seeds, fruits, leave, roots and barks
• Non-peptidic, non-nucleosidic nitrogen containing
cpds usually derived from an amino acid.
• Found in plants, insects, amphibians, fungi,
sponges etc.
Bitter tasting, generally white solids (exception nicotine is a brown liquid).
Alkaloids are “secondary metabolites”, they are
not involved in primary metabolism.
• Most studied group of natural products
• Many have heterocyclic rings as a part of their
structure
• Many are basic (“alkaline”, due to an unshared pair
on N)
Discovery:
Narcotine first alkaloid discovery
Coniine first alkaloid to have its structure established
and synthesized
Paclitaxel revolution in alkaloid
Naming: (ends with ine)
From plant generic name (Atropine)
From specific plant yielding it (Cocaine)
From physiological activity (emetine)
From discoverer
Chemistry:
Alkaloids may contain one or more nitrogen atoms, as 1o, 2o,
3o & 4o.
Most of them contain oxygen
Found as free or nitrogen oxides
Degree of basicity depends on the structure
Converted to their salts when treated with H+, while when
treated with OH, they give up their free amine.
Properties:
Sparingly soluble in water… salts are freely soluble in water.
Free alkaloids are soluble in ether, chloroform and non-polar
solvent…important for isolation and purification
Crystalline to amorphous or liquid when lack Oxygen
Have bitter taste
Form double salts with heavy metals reagents (I, Hg),
Wagners, Mayer, and Dragendroff reactions
Functions:
Provide Nonspecific Basic compounds (N)
•Source for their associated acids
•End products
•Part of some metabolic sequences
•Defense
N.B.
Plants which accumulate alkaloids develop even
when deprived the alkaloid
Plants which do not produce alkaloid survive when
administered alkaloid
Tests:
• Alkaloids are precipitated when treated with neutral - slightly
acidic solution of Dragendroff, Mayer, Wagner reagents.
• Precipitates are amorphous to crystalline
• Proteins can give false positive rxn
• Caffeine gives false negative rxn, and can be detected by
potssium chlorate and HCl solution and exposing the dried
residue to NH3.
•
They give a precipitate with heavy metal
iodides.
–
–
–
Most alkaloids are precipitated from neutral or
slightly acidic solution by Mayer's reagent
(potassiomercuric iodide solution). Cream coloured
precipitate.
Dragendorff's reagent (solution of potassium
bismuth iodide) gives orange coloured precipitate
with alkaloids.
Caffeine, a purine derivative, does not precipitate
like most alkaloids.
Extraction:
• Powder is moistened and treated with lime, extracted with
organic solvent and back extracted with aqueous acid
OR
• Powder is extracted with water or acidified aq. alcohol,
organic acids remove the organic material and free alkaloids
are precipitated by adding Na-bicarbonate or NH3
Isolation of Alkaloids
• Process remained unchanged >1,000 years
Wash with petroleum ether
Plant Material
Petroleum ether extracts Residue: polar material
non-polar fats and waxes
1) Methanol
EtOAc: neutral/weakly
basic alkaloids
EtOAc: basic alkaloids
2) Concentrate
3) Partition EtOAc/2% acid
Acid solution
1) Ammonia
2) Partition with EtOAc
Basic aqueous solution
of quaternary alkaloids
Purification of Alkaloids
• Gradient pH as alkaloids are basic
• Volatile alkaloids: distillation
• Crystallisation
• Fractional or acid/base pair
• Chromatography
• HPLC, GC, TLC and CC
MORPHINE - A TYPICAL ALKALOID
basic due to the
unshared pair
contains nitrogen
..
N CH3
Plant source.
Most alkaloids
are found in
plants.
heterocyclic ring
MeO
O
OH
Found only in the Opium Poppy - papaver somniferum
….. not ubiquitous.
There are three main types of
alkaloids:
colchicine
Terpenoids or
purines
HOW ARE ALKALOIDS CLASSIFIED ?
Common classification schemes use either:
• The heterocyclic ring systems found as a
part of the compound’s structure.
- in terms of their BIOLOGICAL activity,
- BIOSYNTHETIC pathway (the way they are produced in the plant).
• The plant or plant family where they originate*
* The majority of alkaloids (>90%) are found in plants therefore, we will speak mostly about plants and their
biochemistry.
HETEROCYCLIC RING SYSTEMS
N
N
N
H
H
H
pyrrole
piperidine
pyrrolidine
N
N
pyridine
N
N
H
quinoline
isoquinoline
indole
N
H
dihydroindole
HETEROCYCLIC RING SYSTEMS
H
N
N
N
tropane
pyrrolizidine
quinolizidine
N
N
N
C C N
N
N
H
benzylisoquinoline
purine
-phenylethylamine
(cont)
Some Examples of Classification
BY RING TYPE
MeO
OMe
NH
MeO
-O
OMe
O
P OH H3C
O
+ CH3
N
N
H
emetine
O
H3C
N
H
N
nicotine
CH3
O
N
N
N
N
CH3
CH3
caffeine
N
CH3
psilocybin
Amino Acid Precursors
from
ornithine
H3CO
H3 C
NH2
N
N
CH3
N
OCH3
HO
N
O
mescaline
nicotine
N
CO2 CH3
Ph
O
from
tyrosine
H3CO
from
tryptophan
from
ornithine
cocaine
O
O
H
from
tyrosine
HO2 C
N
CH3
strychnine
from
tryptophan
O
N
H
HO
N
H3 CO
CH3
HO
NH
from
tryptophan
morphine
N
lysergic acid
HO
N
H3 C
N
from
lysine
N
O
H
Lycopodine
N
H
Histrionicotoxin
O
NH
MeO 2 C
OH
from
tryptophan
MeO
OH
N
R
R= -CH 3 vinblastine
R= -CHO vincristine
O
CO 2CH 3
Some Examples of Classification
BY PLANT FAMILY : “Amaryllis” Alkaloids
MeO
OH
HO
belladine
O
MeO
N
O
N
MeO
lycorine
H
The other three
are biochemically
derived from
MeO
belladine.
OH
H
galanthamine
H
N CH3
O
OH
O
O
O
MeO
tazettine
These alkaloids are found in Amaryllidaceae
daffodils
narcissus
lillies
etc
N CH3
THE PURPOSE OF ALKALOIDS IN PLANTS (?)
The spectacular pharmacological properties of many of the
alkaloids keeps asking about their purpose in plants.
Many ideas have been advanced:
Defense Mechanisms Insect Repellants Herbivore Attractants
Nitrogen Storage Growth Regulation Insect Attractants
Vestiges of Old Metabolic Experiments
Anti-fungals
Metal ion transport (chelates)
Competitive Herbicides
What seems most likely is that there are many reasons why plants
elaborate alkaloids, and in many cases the purpose of the alkaloid
may be unique to a given plant.
Alkaloids derived from lysine
and ornithine (arginine)
NH2
HO2C
H
N
NH2
pyridoxal
phosphate
NH2
H2O
NH2
HO2C
- CO2
NH2
pyridoxal
phosphate
NH2
HO2C
NH2
lysine
putrescine
ornithine
arginine
H2N
NH2
- CO2
cadaverine
H2N
NH2
Alkaloids derived from ornithine:
Biosynthesis of Cocaine
SAM
NH2
H2N
H3C
putrescine
pyridoxal
phosphate
NH2
N
H
O
H3C
N
H
O2C
-H2O
O
O
SCoA
N
H
N
- CO2
CH3
SCoA
CH3
O
O
O2C
O
O
P450
SCoA
N
- CO2
CH3
O
-H2O
N
CH3
HO
SCoA
H
N
CH3
O
H3C
O
N
SCoA
SCoA
O
O
SCoA
Biosynthesis of Cocaine
O
H3C
O
H3C
N
-H2O
SCoA
N
OH
O
O
O
H3C
N
OCH3
SAM
NADPH
O
H3C
N
OCH3
OH
O
O
H3C
N
OCH3
O
Cocaine
Ph
O
Alkaloids derived from tyrosine.
Morphine Biosynthesis
CO2 H
-CO 2
NH2
HO
NH2
PAL
HO
NH2
hydroxylation
HO
HO
Dopamine
Tyramine
PAL
CO2 H
HO
-CO2
O
HO
H3 CO
HO
HO
H
thiamin
O
HO
HO
N
CH3
2 SAM
NH
HO
HO
HO
HO
Norcoclaurine
NH
+
H3 CO
H3 CO
N
HO
CH3
1) hydroxylation
2) SAM
N
HO
CH3
epimerization
HO
H3CO
HO
Reticuline
H3CO
H3 CO
N
HO
"- 2 H•"
HO
CH3
N
HO
CH3
H3CO
H3 CO
OH
H3 CO
H3 CO
•O
O
H3 CO
N
N
CH3
H3 CO
N
CH3
H3 CO
O•
HO
•
•
CH3
H3 CO
O
O
H3CO
H3CO
NADPH
HO
H3CO
HO
O
N
N
N
CH3
CH3
CH3
H3CO
H3CO
H3CO
OH
O
HO
H3CO
1) P450
2) isomerization
3) NADPH
P450
O
O
N
N
CH3
HO
Codeine
CH3
HO
Morphine
Alkaloids derived from
tryptophan. Physostigmine
biosynthesis
asenosyl
H3C S
R
CO2H
N
H
PAL
NH2
NH2
N
H
tryptophan
tryptamine
CH3
N
H
CH3
NH2
N
H
O
H3C
CH3
O
NH
N
N
CH3
CH3
physostigmine
N
H
Alkaloid Biosynthesis
COOH
R-CHNH2
COOH
R’-CHNH2
CO2
R-CH2NH2
Transamination
-CO2
Amino Acids
R’-CHO
-H2O
RN=CHR’
Schiff Base
+
H-C-H
R”
carbonion
Schiff Base
Mannich Condensation
RNH-CH-R’ CH2R’’
Alkaloid
Alkaloid
Classification: (BioSynthetic Origin)
1. Ornithine Derived Alkaloids
2. Lysine Derived Alkaloids
3. Nicotinic Acid Derived Alkaloids
4. Tyrosine Derived Alkaloids
5. Tryptophan Derived Alkaloids
6. Anthranilic Acid Derived Alkaloids
Based on
Amino Acid
from which
they
were derived
7. Histidine Derived Alkaloids
8. Amination Reacrion Derived Alkaloids
9. Purine Alkaloids
1-Ornithine Derived Alkaloids
1. Pyrrolidine and Tropane Alkaloids (Hyoscymine, Hyoscine, Atropine)
2. Pyrrolizidine Alkaloids
2-Lysine Derived Alkaloids
1. Piperidine Alkaloids (Lobelia)
2. Quinolizidine Alkaloids
3. Indolizidine Alkaloids
3-Nicotinic Acid Derived Alkaloids
1. Pyridine Alkaloids (Nicotinic Acid)
4-Tyrosine Derived Alkaloids
1. Phenylethylamin and simple tetrahydroisoquinoline Alkaloids (curarine)
2. Modified Benzyltetrahydroisoquinoline Alkaloids (Opium Alkaloids)
3. Phenethylisoquinoline Alkaloids (Colchicine)
4. Terpenoid Tetrahydroisoquinoline Alkaloids ( Emetine)
5-Tryptophan Derived Alkaloids
1. Simple Indole Alkaloids (Psilocybin)
2. Simple Carboline Alkaloids
3. Terpenoid Indole Alkaloids (Reserpine, Deserpine, Vincristine, Vinblastine, Strychnine)
4. Quinoline Alkaloids (Quinidine, Quinine)
5. Pyrroloindoline Akaloids (Physostigmine)
6. Ergot Alkaloids (Ergotamine)
6-Anthranilic Acid Derived Alkaloids
1. Quinazoline Alkaloids
2. Quinoline and Acridine Alkaloids
7-Histidine Derived Alkaloids
1. Imidazole Alkaloids (Pilocarpine)
8-Amination Reaction Derived Alkaloids
1. Acetate Derived Alkaloids
2. Phenylalanine derived alkaloids (Ephedrine)
3. Terpenoid Alkaloids
4. Steroid Alkaloids
9-Purine Derived Alkaloids
Caffeine, theobromine, theophylline
1-Ornithine Derived Alkaloids
Tropane alkaloid
• There are two important types of tropane
alkaloids:
1-Ornithine Derived Alkaloids
Tropane Alkaloids
What do these groups have in common?
They all possess the tropane nucleus.
Bicyclic system made up of a 5-membered ring
(1, N, 5, 6, and 7) and a 6-membered ring (1, 2,
3, 4, 5, N). N is common to both. The nucleus
always carries an oxygen in position 3.
Tropane Alkaloids
•Are esters of hydroxytropanes and various acids (tropic, tiglic)
-Tropane moiety is formed from ornithine
-Acid moiety from Phenylalanine.
•Plant family contains tropane alkaloids are Solanaceae
•Alkaloids found in roots and leaves mainly.
•Vary with age, length and light intensity.
•Belladonna and Scopolia contains hyoscyamine and Datura Stronium
as dominant alkaloid
•Hyoscine is found in other spp of Datura as dominant alkaloid
•Atropine mainly is found in Atropa Belladona
•Cocaine is found Erythroxylum Coca
1.A. Solanaceous alkaloids
• Solanaceous alkaloids come from the solanaceae
(tomato and potato). Some of the alkaloids they produce
are:
• Atropine
• Hyoscyamine
• Hyoscine
• Hyoscyamine is the pure optical isomer;
(+)Hyoscyamine, (-)Hyoscyamine. Atropine is the
racemic of hyoscyamine.
• Atropine = (±)Hyoscyamine.
• The 3-hydroxy derivative of tropane is known as
TROPINE.
Esterification of tropine with tropic
acid yields hyoscyamine (tropine
tropate).
Anticholinergics
Inhibit the
neurological
signals transmitted
by the endogenous
neurotransmitter,
acetylcholine.
Symptoms of poisoning
include mouth dryness,
dilated pupils, ataxia,
urinary retention,
hallucinations, convulsions,
coma, and death
Atropine has a stimulant
effect on the CNS and heart,
whereas scopolamine has a
sedative effect .
Hyoscyamine and Hyoscine
Atropine
or
 Hyoscyamine
Scopolamine
or
Hyoscine
• These alkaloids compete with acetylcholine for
the muscarinic site of the parasympathetic
nervous system, thus preventing the passage of
nerve impulses, and are classified as
anticholinergics.
• Acetylcholine binds to two types of receptor site,
described as muscarinic or nicotinic, from the
specific triggering of a response by the Amanita
muscaria alkaloid muscarine or the tobacco
alkaloid nicotine respectively.
• The structural similarity
between acetylcholine and
muscarine can readily be
appreciated, and hyoscyamine
is able to occupy the same
receptor site by virtue of the
spatial relationship between
the nitrogen atom and the
ester linkage .
• The side-chain also plays a
role in the binding, explaining
the difference in activities
between the two enantiomeric
forms.
• The agonist properties of hyoscyamine and
hyoscine give rise to a number of useful effects,
• Including:
• antispasmodic action on the gastrointestinal
tract,
• antisecretory effect controlling salivary
secretions during surgical operations,
• and as mydriatics to dilate the pupil of the eye.
• Hyoscine has a depressant action on the central
nervous system and finds particular use as a
sedative to control motion sickness.
• One of the side-effects from oral
administration of tropane alkaloids is
dry mouth (the antisecretory effect)
but this can be much reduced by
transdermal administration.
• In motion sickness treatment,
hyoscine can be supplied via an
impregnated patch worn behind the
ear.
• Hyoscine under its synonym
scopolamine is also well known,
especially in fiction, as a ‘truth drug’.
• This combination of sedation, lack of
will, and amnesia was first employed
in child-birth, giving what was termed
‘twilight sleep’, and may be compared
with the mediaeval use of
stramonium.
• The mydriatic use also has a very long history.
Indeed, the specific name belladonna for deadly
nightshade means ‘beautiful lady’ and refers to
the practice of ladies at court who applied the
juice of the fruit to the eyes, giving widely dilated
pupils and a striking appearance, though at the
expense of blurred vision through an inability to
focus.
• Atropine also has useful antidote action in cases
of poisoning caused by cholinesterase inhibitors,
e.g. physostigmine and neostigmine and
organophosphate insecticides.
• It is valuable to reiterate here that the
tropane alkaloid-producing plants are all
regarded as very toxic, and that since the
alkaloids are rapidly absorbed into the
blood stream, even via the skin, first aid
must be very prompt. Initial toxicity
symptoms include skin flushing with raised
body temperature, mouth dryness, dilated
pupils, and blurred vision.
Semisynthetic Derivatives
• Homatropine is a semi-synthetic ester of tropine with racemic
mandelic (2-hydroxyphenylacetic) acid and is used as a
mydriatic, as are tropicamide and cyclopentolate
• Tropicamide is an amide of tropic acid, though a pyridine nitrogen is
used to mimic that of the tropane.
• Cyclopentolate is an ester of a tropic acid-like system, but uses a
non-quaternized amino alcohol resembling choline.
• Glycopyrronium has a quaternized nitrogen in a pyrrolidine ring, with
an acid moiety similar to that of cyclopentolate.
• This drug is an antimuscarinic used as a premedicant to dry
bronchial and salivary secretions.
• Hyoscine butylbromide is a gastro-intestinal
antispasmodic synthesized from (−)-hyoscine
by quaternization of the amine function with
butyl bromide.
• The quaternization of tropane alkaloids by Nalkylation proceeds such that the incoming
alkyl group always approaches from the
equatorial position.
• The potent bronchodilator ipratropium bromide
is thus synthesized from noratropine by
successive isopropyl and methyl alkylations
whilst oxitropium bromide is produced from
norhyoscine by N-ethylation and then Nmethylation. Both
drugs are used in
inhalers for the treatment of
chronic bronchitis.
• Benzatropine (benztropine) is an ether
of tropine used as an antimuscarinic drug
in the treatment of Parkinson’s disease.
It is able to inhibit dopamine reuptake,
helping to correct the deficiency which is
characteristic of Parkinsonism.
Structure Activity Relationship
A, B = Bulky Groups
C = H,OH
A
B -C C
Chain
N
Cationic Head: Positively charged Quaternary ammonium compounds
Cyclic substitution: at least one cyclic substituent, aromatic the most used
Esteratic Group: Necessary for effective binding
Hydroxyl Group: enhances the activity
Position of OH to Nitrogen in receptive area 2-3oA
Stereochemistry is of small contribution for antagonistic activity
Atropa Belladona
• Belladonna
• The deadly nightshade Atropa belladonna (Solanaceae) has a long
history as a highlypoisonous plant. The generic name is derived
from Atropos, in Greek mythology the Fatewho cut the thread of life.
• The berries are particularly dangerous, but all parts of the plant
• contain toxic alkaloids, and even handling of the plant can lead to
toxic effects since the alkaloids are readily absorbed through the
skin.
• Although humans are sensitive to the toxins,some animals, including
sheep, pigs, goats, and rabbits, are less susceptible.
• Cases are known where the consumption of rabbits or birds that
have ingested belladonna has led to human poisoning.
• Belladonna herb typically contains 0.3–0.6% of alkaloids,
mainly (−)-hyoscyamine
• Belladonna root has only slightly higher alkaloid content
at 0.4–0.8%, again mainly (−)-hyoscyamine.
• Minor alkaloids including (−)-hyoscine and cuscohygrine
• are also found in the root, though these are not usually
significant in the leaf.
• The mixed alkaloid extract from belladonna herb is still
used as a gastrointestinal sedative, usually in
combination with antacids. Root preparations can be
used for external pain relief, e.g. in belladonna plasters.
Datura Stramonium
Datura stramonium
• is commonly referred to as thornapple on account of its spikey fruit.
It is a tall bushy annual plant widely distributed in Europe and North
America, and because of its alkaloid content is potentially very toxic.
• Indeed, a further common name, Jimson or Jamestown weed,
originates from the poisoning of early settlers near
Jamestown,Virginia. At subtoxic levels, the alkaloids can provide
mild sedative action and a feeling of well-being.
• In the Middle Ages, stramonium was employed to drug victims prior
to robbing
• them. During this event, the victim appeared normal and was
cooperative, though afterwards could usually not remember what
had happened.
• For drug use, the plant is cultivated in Europe and South America.
The leaves and tops are harvested when the plant is in flower.
• Stramonium leaf usually contains 0.2–0.45% of alkaloids,
principally (−)-hyosycamine and
• (−)-hyoscine in a ratio of about 2:1. In young plants, (−)-hyoscine
can predominate
Hyoscyamus Niger
Hyoscyamus
•
•
•
•
•
•
•
•
Hyoscyamus niger (Solanaceae), or henbane, is a European native with a
long history as a medicinal plant. Its inclusion in mediaeval concoctions and
its power to induce hallucinations with visions of flight may well have
contributed to our imaginary view of witches on broomsticks.
The plant has both annual and biennial forms, and is cultivated in Europe
and
North America for drug use, the tops being collected when the plant is in
flower, and then dried rapidly.
The alkaloid content of hyoscyamus is relatively low at 0.045–0.14%, but
this can
be composed of similar proportions of (−)-hyoscine and (−)-hyosycamine.
Egyptian henbane, Hyosycamus muticus, has a much higher alkaloid
content than H. niger, and although it has mainly been collected from the
wild, especially from Egypt, it functions as a major commercial
source for alkaloid production. Some commercial cultivation occurs in
California.
The alkaloid content of the leaf is from 0.35% to 1.4%, of which about 90%
is (−)-hyoscyamine.
Duboisia Hopwoodii
Mandragora Officinarum
Scopolia Carniolica
anisodus tanguticus var.
viridulus (C. Y. Wu & C. Chen).
• Solanaceae
• Herbs perennial, 40-80(100) cm tall. Roots
stout. Stems glabrous or
pubescent. Petiole 1-3.5
cm; leaf blade
lanceolate, oblong, or
ovate.
Anisodamine
• Anisodamine is an anticholindergic alkaloid that had been
recently been isolated from Anisodus tanguticus, an herb
found primarily in the Tibetan region.
• This compound was introduced into clinical use in China as a
synthetic drug in 1965, initially for the treatment of epidemic
meningitis. Later, anisodamine was shown to produce
favorable results in treatment of numerous serious ailments,
including shock, glomerular nephritis, rheumatoid arthritis,
hemorrhagic necrotic enteritis, eclampsia, and lung edema. The
mechanism of its actions were sought and traced to a
vasodilating action that affected the microcirculation. In China
it is believed that anisodamine possesses good and reliable
effects in the treatment of septic shock and morphine addiction.
However, this drug is not without its side effects.
Anisodamine
1.B. Cocaine
Aneasthetic Effect
Better local aneasthetic
were discovered
CNS Stimulant:
Brompton’s cocktail
Drug of Abuse
The free base is used for
inhalation
Cocaine
Structure Activity Relationship
O
║
Aryl -C- O -
Chain
Aryl group connected to carboxylic acid ester
Lipophilic hydrocarbon chain
Basic amino group
N
Erythroxylum Coca
Cocaine Addiction
Cocaine
• Coca leaves
• Coca leaves
The coca paste is dissolved in hydrochloric or
sulphuric acid. Potassium permanganate mixed
.
with water is added to the paste and acid solution
How is cocaine used?
•
•
•
•
•
•
The principal routes of cocaine administration are
oral,
intranasal,
intravenous,
and inhalation.
The slang terms for these routes are, respectively,
"chewing," "snorting," "mainlining," "injecting," and
"smoking" (including freebase and crack cocaine).
Snorting is the process of inhaling cocaine powder
through the nostrils, where it is absorbed into the
bloodstream through the nasal tissues.
• Injecting releases the drug directly into the
bloodstream, and heightens the intensity
of its effects. Smoking involves the
inhalation of cocaine vapor or smoke into
the lungs, where absorption into the
bloodstream is as rapid as by injection.
The drug can also be rubbed onto mucous
tissues. Some users combine cocaine
powder or crack with heroin in a
"speedball."
• Cocaine use ranges from occasional use to
repeated or compulsive use, with a variety of
patterns between these extremes.
• There is no safe way to use cocaine.
• Any route of administration can lead to
absorption of toxic amounts of cocaine, leading
to acute cardiovascular or cerebrovascular
emergencies that could result in sudden death.
Repeated cocaine use by any route of
administration can produce addiction and
other adverse health consequences.
How does cocaine produce its
effects?
• A great amount of research has been devoted to
understanding the way cocaine produces its
pleasurable effects, and the reasons it is so
addictive.
• One mechanism is through its effects on
structures deep in the brain. Scientists have
discovered regions within the brain that, when
stimulated, produce feelings of pleasure. One
neural system that appears to be most affected
by cocaine originates in a region, located deep
within the brain, called the ventral tegmental
area (VTA).
• Nerve cells originating in the VTA extend
to the region of the brain known as the
nucleus accumbens, one of the brain's
key pleasure centers.
• In studies using animals, for example,
all types of pleasurable stimuli, such as
food, water, sex, and many drugs of
abuse, cause increased activity in the
nucleus accumbens.
• Researchers have discovered that, when a pleasurable
event is occurring, it is accompanied by a large increase
in the amounts of dopamine released in the nucleus
accumbens by neurons originating in the VTA.
• In the normal communication process, dopamine is
released by a neuron into the synapse (the small gap
between two neurons), where it binds with specialized
proteins (called dopamine receptors) on the neighboring
neuron, thereby sending a signal to that neuron. Drugs
of abuse are able to interfere with this normal
communication process.
• For example, scientists have discovered
that cocaine blocks the removal of
dopamine from the synapse, resulting in
an accumulation of dopamine. This
buildup of dopamine causes continuous
stimulation of receiving neurons, probably
resulting in the euphoria commonly
reported by cocaine abusers.
• As cocaine abuse continues,
tolerance often develops. This
means that higher doses and
more frequent use of cocaine are
required for the brain to register
the same level of pleasure
experienced during initial use.
• Recent studies have shown that,
during periods of abstinence from
cocaine use, the memory of the
euphoria associated with cocaine
use, or mere exposure to cues
associated with drug use, can trigger
tremendous craving and relapse to
drug use, even after long periods of
abstinence.
What are the short-term
effects of cocaine use?
• Cocaine's effects appear almost immediately
after a single dose, and disappear within a few
minutes or hours.
• Taken in small amounts (up to 100 mg), cocaine
usually makes the user feel
• euphoric,
• energetic,
• talkative,
• and mentally alert, especially to the sensations
of sight, sound, and touch.
• It can also temporarily decrease the
need for food and sleep.
• Some users find that the drug helps
them to perform simple physical and
intellectual tasks more quickly, while
others can experience the opposite
effect.
• The duration of cocaine's immediate euphoric
effects depends upon the route of
administration. The faster the absorption, the
more intense the high. Also, the faster the
absorption, the shorter the duration of action.
The high from snorting is relatively slow in onset,
and may last 15 to 30 minutes, while that from
smoking may last 5 to 10 minutes.
• The short-term physiological effects of cocaine
include constricted blood vessels; dilated pupils;
and increased temperature, heart rate, and
blood pressure
• Large amounts (several hundred
milligrams or more) intensify the user's
high, but may also lead to bizarre, erratic,
and violent behavior. These users may
experience tremors, vertigo, muscle
twitches, paranoia, or, with repeated
doses, a toxic reaction closely resembling
amphetamine poisoning.
• Some users of cocaine report feelings of
restlessness, irritability, and anxiety. In
rare instances, sudden death can occur on
the first use of cocaine or unexpectedly
thereafter. Cocaine-related deaths are
often a result of cardiac arrest or seizures
followed by respiratory arrest.
What are the long-term
effects
of
cocaine
use?
Auditory hallucinations
•
• Cocaine is a powerfully addictive drug. Once having tried
cocaine, an individual may have difficulty predicting or
controlling the extent to which he or she will continue to
use the drug. Cocaine's stimulant and addictive effects
are thought to be primarily a result of its ability to inhibit
the reabsorption of dopamine by nerve cells. Dopamine
is released as part of the brain's reward system, and is
either directly or indirectly involved in the addictive
properties of every major drug of abuse.
• An appreciable tolerance to cocaine's high may
develop, with many addicts reporting that they
seek but fail to achieve as much pleasure as
they did from their first experience.
• Some users will frequently increase their
doses to intensify and prolong the euphoric
effects. While tolerance to the high can
occur, users can also become more sensitive
(sensitization) to cocaine's anesthetic and
convulsant effects, without increasing the
dose taken.
• This increased sensitivity may explain some
deaths occurring after apparently low doses of
cocaine.
• Use of cocaine in a binge, during which the drug
is taken repeatedly and at increasingly high
doses, leads to a state of increasing irritability,
restlessness, and paranoia.
• This may result in a full-blown paranoid
psychosis, in which the individual loses touch
with reality and experiences auditory
hallucinations.
What are the medical complications
of cocaine
• Gastrointestinal complications
• There are enormous medical complications
associated with cocaine use. Some of the most
frequent complications are cardiovascular
effects, including disturbances in heart rhythm
and heart attacks; such respiratory effects as
chest pain and respiratory failure; neurological
effects, including strokes, seizure, and
headaches; and gastrointestinal complications,
including abdominal pain and nausea.
• Cocaine use has been linked to many
types of heart disease. Cocaine has been
found to trigger chaotic heart rhythms,
called ventricular fibrillation; accelerate
heartbeat and breathing; and increase
blood pressure and body temperature.
Physical symptoms may include chest
pain, nausea, blurred vision, fever, muscle
spasms, convulsions and coma.
• Different routes of cocaine administration can
produce different adverse effects.
• Regularly snorting cocaine, for example, can
lead to loss of sense of smell, nosebleeds,
problems with swallowing, hoarseness, and an
overall irritation of the nasal septum, which can
lead to a chronically inflamed, runny nose.
• Ingested cocaine can cause severe bowel
gangrene, due to reduced blood flow.
• And, persons who inject cocaine have puncture
marks and "tracks," most commonly in their
forearms.
• Intravenous cocaine users may also experience
an allergic reaction, either to the drug, or to
some additive in street cocaine, which can
result, in severe cases, in death.
• Because cocaine has a tendency to decrease
food intake, many chronic cocaine users lose
their appetites and can experience significant
weight loss and malnourishment.
• Research has revealed a potentially dangerous
interaction between cocaine and alcohol. Taken
in combination, the two drugs are converted by
the body to cocaethylene.
• Cocaethylene has a longer duration of action in
the brain and is more toxic than either drug
alone. While more research needs to be done, it
is noteworthy that the mixture of cocaine and
alcohol is the most common two-drug
combination that results in drug-related death.
Medicinal use
• Medicinally, cocaine is of value as a local anaesthetic
for topical application. It is rapidly absorbed by mucous
membranes and paralyses peripheral ends of sensory
nerves. This is achieved by blocking ion channels in
neural membranes.
• It was widely used in dentistry, but has been replaced by
safer drugs, though it still has applications in ophthalmic
and ear,
• nose, and throat surgery.
• As a constituent of Brompton’s cocktail (cocaine and
heroin in
• sweetened alcohol) it is available to control pain in
terminal cancer patients. It increases the overall
analgesic effect, and its additional CNS stimulant
properties counteract the sedation normally associated
with heroin
• The essential functionalities of cocaine
required for activity were eventually
assessed to be the
• aromatic carboxylic acid ester
• and the basic amino group,
• separated by a lipophilic hydrocarbon
chain. Synthetic drugs developed from the
cocaine structure have been introduced to
provide safer, less toxic local anaesthetics
Synthetic and semi synthetic derivatives
• Benzocaine is used
topically, but has
• a short duration of
action
• Procaine, though
little used now, was
the first major
analogue employed
• Tetracaine (amethocaine),
oxybuprocaine, and proxymetacaine
• are valuable local anaesthetics employed
principally in ophthalmic work. The ester
function can be replaced by an amide, and
this gives better stability toward hydrolysis
in aqueous solution or by esterases.
Lidocaine
Lidocaine (lignocaine) is an example of an
amino amide analogue and is perhaps the
most widely used local anaesthetic, having
rapid action, effective absorption, good
stability, and may be used by injection or
topically.
• Lidocaine, although introduced as a local anaesthetic,
was subsequently found to be a potent antiarrhythmic
agent, and it now finds further use as an antiarrhythmic
drug, for treatment of ventricular arrhythmias especially
after myocardial infarction.
• Other cocaine related structures also find application in
the same way, including tocainide, procainamide,
• and flecainide. Tocainide is a primary amine analogue
of lidocaine, whilst procainamide is an amide analogue
of procaine. In mexiletene, a congener of lidocaine, the
• amide group has been replaced by a simple ether
linkage.
Pyrrolizidine Alkaloids
• Two molecules of ornithine are utilized in
formation of the bicyclic pyrrolizidine skeleton,
the pathway proceeding via the intermediate
putrescine.
• Because plants synthesizing pyrrolizidine
alkaloids appear to lack the decarboxylase
enzyme transforming ornithine into putrescine,
ornithine is actually incorporated by
• way of arginine
• Many pyrrolizidine alkaloids are known to produce
• pronounced hepatic toxicity and there are many
recorded cases of livestock poisoning.
• Potentially toxic structures have 1,2-unsaturation in the
• pyrrolizidine ring and an ester function on the
• side-chain.
• Although themselves non-toxic, these alkaloids are
transformed by mammalian liver oxidases into reactive
pyrrole structures, which are potent alkylating agents
and react with suitable cell nucleophiles, e.g. nucleic
acids and proteins
• The tobacco alkaloids, especially nicotine, are derived
from nicotinic acid but also contain a pyrrolidine ring
system derived from ornithine as a portion of their
structure.
2-Lysine Derived Alkaloids
Piperidine Alkaloids
Lysine Derived Alkaloids
As the next homologue to ornithine, lysine
and its associated compounds give rise to a
number of alkaloids, some of which are
analogous to the ornithine group.
• LOBELIA
• Lobelia BHP; BP 1988 (Lobelia Herb,
Indian Tobacco) consists of the dried
aerial parts of Lobelia inflata
(Campanulaceae), an annual herb
indigenous to the eastern USA and
Canada. It is cultivated in the USA and
Holland.
Lobelia inflata
Campanulaceae
Constituents: Lobelia contains about
0.24-0.4% of alkaloids (BP 1988, not less
than 0.25% as determined by a standard
stas-Otto procedure) the most important
of which is lobeline.
Uses:
Minor alkaloids identified include closely related
structures, e.g. lobelanine . The North American
Indians employed lobelia as an alternative or
substitute for tobacco (Nicotiana tabacum;
Solanaceae), and it is found that lobeline stimulates
nicotinic receptor sites in a similar way to nicotine, but
with a weaker effect.
Lobeline has been employed in preparations
intended as smoking deterrents. The crude plant drug
has also long been used to relieve asthma and
bronchitis, though in large doses it can be quite toxic.
Biosynthesis of lobeline
Pomegranata
The barks, fruit-rind and seeds of
the pomegranate, Punica granatum
(Punicaceae) all find medicinal use.
Both stem and root barks are used
and occur in curved or channeled
pieces about 5-10cm long and 1-3cm
wide.
Constituents: They contain about
0.5-0.9% of volatile liquid alkaloids,
the chief of which are pelletierine
and pseudopelletierine, together
with about 22% of tannin.
Uses: anthelminthic, Tapeworms,
Astringent.
Seed extract for use in the treatment
of diarrhea, (Antidiarrhoea).
Punica granatum
Punicaceae
Chemical composition
PELLETIERINE
Piper nigrum
• The pungency of the fruits of black pepper
• (Piper nigrum; Piperaceae), a widely used
• condiment, is mainly due to the piperidine
alkaloid
• Piperine. In this structure, the piperidine
ring forms part of a tertiary amide
structure, and is incorporated via
piperidine itself, the reduction product of
Δ1-piperideine