Alkaloids

Prepared By: Dr. Harminder singh

harminder.singh@lpu.co.in
• Alkaloids are the naturally occurring
nitogeneous compounds which are isolated
from plants.
• These are basic in nature and contain atleast
one nitrogen atom in the form of heterocyclic
ring which may be pyridine, pyrrole, quinoline
etc. in nature.
• e.g. connine, quinine, nicotine, caffeine,
atropine etc.
 Alkaloid Natural Products
•Largest class of secondary metabolites, >6500 compds known
•Contains N, most compds basic (alkaline), often heterocyclic
•Often highly toxic
•Found in certain higher plants (seldom in bacteria)
•Little is known regarding why alkaloids are produced
•Biosynthesis from amino acids

Alkaloid: Difficult to define

No definitive difference between an alkaloid and naturally occurring complex
amines.

Alkaloids: plant derived, are alkali and contain at least one N2-atom. They
also normally have a significant physiological action on humans and
animals.
 Alkaloid Description
Contains nitrogen - usually derived from an amino acid.

• Bitter tasting, generally white solids (exception -

nicotine is a brown liquid).

• They give a precipitate with heavy metal iodides.

– Caffeine, a purine derivative, does not precipitate like most
alkaloids.

• Alkaloids are basic - they form water soluble salts.

Most alkaloids are well-defined crystalline substances
which unite with acids to form salts. In plants, they
may exist
– in the free state,
– as salts or
– as N-oxides.
Occur in a limited number of plants. Nucleic acid exists in all
plants, whereas, morphine exists in only one plant species.
 Occurrence, Distribution & Location of
Alkaloids
•Occur in bacteria (Pseudomonas aeruginosa)
and rarely in fungi (pscilocin from
hallucinogenic mushrooms).

•Some alkaloids occur in several genera from

different species (caffeine), but most occur in
closely related species.

•Some occur in certain families (hyoscyamine),

while others occur only in a specific species
(morphine).

•Rarely do plants contain more than 1 type of

alkaloid.

•All alkaloids of one plant will have a common

biogenenetic origin
•Alkaloids occur in all plant parts, but are usually localized in
one organ (e.g. the bark or seeds).

•Within the plant, [alkaloid] can vary widely from part to part –
some parts may contain no alkaloids.

•Occasionally, different alkaloids also form in different parts of

the plant.

•Alkaloid concentrations occur in wide ranges – e.g.

Madagascan periwinkle contains 3g per (anti-cancer) alkaloids
per tonne of leaves.
 The Nitrogen of Alkaloids

The N2 atom can either be

1º, 2º, 3º or 4º
(quaternary).

This N2 feature affects the

alkaloid derivatives which
can be prepared and the
isolation procedures.
 Physical-Chemical Properties of Alkaloids

MW: 100 – 900

• Most bases which do not contain O2 are liquid at room
temperature (nicotine), while those that do are solids.
In rare cases they are coloured.
• Most solid bases rotate the plane of polarized light, have
high melting points.
• Normally are not soluble in water (occasionally slightly
soluble).
• Soluble in non-polar or slightly polar organic solvents.
Soluble in concentrated hydro-alcoholic solutions
 Classification of Alkaloids
Alkaloids have a large variety in their botanical & biochemical
origin, in chemical structure and pharmaceutical action. A
range of different classification systems exist for grouping
alkaloids.

They can therefore be classified according to their

•Biological origin
•Chemical structure - 2 divisions
• i. Atypical/non-hetrocyclic alkaloids (protoalkaloids or biological
amines)
• ii. Typical/hetrocyclic alkaloids (divided into 14 groups according
to their ring structure)
•Biosynthetic pathway
 Extraction of Alkaloids
Extraction is based on the basicity of alkaloids
and on the fact that they normally occur in
plants as salts (i.e.: on the solubility of bases
and salts in water and organic solvents).
Herbs often contain other materials which can
interfere with extraction such as large
amounts of fat, waxes, terpenes, pigments
and other lipophilic substances (e.g by
forming emulsions) – avoided by defatting the
crushed herb (using petroleum ether and
hexane)
 Alkaloid Extraction
Extraction method normally
depends on the raw material,
the purpose of extraction &
the scale on which is to be
performed.
For research purposes:
chromatography allows for
quick and reliable results.
If larger amounts of alkaloids
need to be extracted, one of
the following methods can be
used.
1. Alkaloid Extraction in basic
medium.
2. Alkaloid Extraction in acidified
medium
In both methods purification is
needed
TLC plate
 Extraction in an Alkaline Medium
Step 1: Powdered, defatted herb is mixed with an alkaline
aqueous solution.

This displace alkaloids from their salt combinations.

Free bases are then extracted with organic solvents.

Normally aqueous ammonia is used, but a carbonate solution is

used when alkaloids contain fragile elements such as a ester or
lactone.

In some cases, e.g. Cinchona bark, a mixture of calcium hydroxide

& sodium hydroxide should be used as the alkaloids are bound
to tannins.

Organic solvent: chloroform, dichloromethane or ethyl acetate –

depends on the toxicity, safety, cost & ease of recovery and
recycling of the solvent).
 Extraction of Alkaloids: Step II
Organic solvent containing alkaloids
(bases) is separated from residue
& concentrated by distillation
under pressure if needed.

Solvent is stirred with an acidic

aqueous solution: alkaloids go
into the solution as salts.
Impurities remain in the organic
phase.

Repeated until the organic phase no

longer contains alkaloids.

Many acids can be used (HCL,

Sulfuric, citric, tartaric), but
always in very dilute
concentrations (1-5%)
 Alkaloid Extraction: Step III
Aqueous solution of alkaloid salts is washed
with an non-polar solvent (hexane)

Alkalinized with a base using an organic

solvent not miscible with water.

Alkaloids precipitate and dissolve in the

organic phase.

Extraction of aqueous phase continues till all

alkaloids have moved into the organic
phase (tested when Mayer’s reaction on
the aqueous phase becomes negative).

This purification step may be carried out in a

separation funnel or in centrifugal
extractors.

Separation Funnel
 Final Step
• Organic solvent containing
alkaloid bases is decanted,
freed from water traces
(drying over anhydrous salt
e.g. sodium sulphate) and
evaporated under reduced
pressure.
A dry residue remains: total
basic alkaloids.

Kava Powder
 Isolation of Alkaloids
Large-scale extractions may be sent to a
factory for purification & separation (for
cinchona and cocoa alkaloids).

Separation and final purification may be

done using fractional precipitation or
fractional crystallization of salts.

Chromatograpy is used for complex alkaloids

and if only small amounts of alkaloids are
needed.

Volatile liquid alkaloids (nicotine) are

isolated by distillation – alkaloid is
distilled off in steam. Nicotine is an
important insecticide, and large amounts
are prepared from the parts of the
tobacco plant which is not used for
tobacco manufacture
 Pharmacological Action & Uses
CNS Action: stimulants (caffeine) or
depressants (morphine)
ANS: sympathomimetics (ephedrine)
or sympatholytics (yohimbine,
ergot alkaloids), anticholinergics
(choline), ganglioplegics
(nicotine).
Also: local anesthetics (cocaine),
defibrillation (quinidine), anti-
tumour agents (ellipticine), anti-
malarial (quinine), anti-bacterials
(berberine), and amoebicides
(emetine).
These actions lead to the
extensive use of
alkaloid containing
herbs and drugs.
Although some are used
as galenicals
(belladonna, datura,
and henbane), most are
used as starting
materials for industrial
extraction (morphine
from poppy straw or
opium, and quinine
from Cinchona bark.
 Pyridine Alkaloids
Nicotine is a naturally occurring
liquid alkaloid.

An alkaloid is an organic
compound made out of
carbon, hydrogen, nitrogen
and sometimes oxygen.

These chemicals have potent

effects on the human body.
For example, many people It is extracted in an acidified medium
enjoy the stimulating effects of
another alkaloid, caffeine.

Nicotine (Nicotiana tabacum and

other Nicotina spp) – toxic 
used as an insecticide
•When you smoke, nicotine is absorbed through the skin and
mucosal lining of the mouth and nose or by inhalation in the
lungs.
•Once in the body, it activates the same reward system as do
other drugs such as cocaine or amphetamine, although to a
lesser degree.
•In the brain, nicotine increases the level of the neurotransmitter
dopamine, which is a chemical in the brain responsible for
feelings of pleasure.
•The acute effects of nicotine subside within minutes, so people
continue dosing themselves frequently throughout the day to
maintain the pleasurable effects of nicotine and to prevent
withdrawal symptoms.
Some facts related with smoking:
- Smoking is the second major cause of death in the
world. It's responsible for the death of one in ten adults
worldwide.

- Smoking accounts for about 80-90% of all chronic

obstructive pulmonary disease.

- Smoking is involved in 85% of all lung cancer deaths.

- Smoking is the major cause of cancer of the lips,
tongue, mouth, pharynx, larynx and esophagus.

- Smoking has many other harmful effects in the body,

a too long list to include it here.
Why smoking causes cancer?
It's because tobacco and tobacco smoke contain more than
60 carcinogenic compounds. In general, more than 4,000
individual substances have been identified in tobacco smoke,
including carbon monoxide, hydrogen cyanide, ammonia and
other highly toxic irritants. Yes, it's not a mistake, more than
4,000 toxic substances that can go inside your body when
you smoke!

Besides all the harmful effects of tobacco, it is addictive, and

this explains why although 70% of smokers want to quit and
35% attempt to quit each year, fewer than 7% succeed. And
the main reason why tobacco becomes addictive is due to its
content of nicotine, which alters brain functioning.
 Purine Alkaloids
Also known as non-alkaloids (xanthines)
* Amphoteric Character
* Peculiar solubility in warm water and in chlorinated
solvents.

Example is caffeine (seeds of coffee plants, kola plants, tea

leaves and guarana seeds).
Beverages such as tea and coffee owe their stimulant
action to the purine alkaloids.
Caffeine: stimulates CNS and
has a weak diuretic action.
Theobromine: opposite
action.
Theophylline: relaxes
involuntary muscles more
effectively than caffeine or
theobromine
Caffeine does not precipitate
like most alkaloids.
 Pharmacological Activity of Caffeine
CNS activity, enhances alertness,
facilitates thought formation,
decreases the sensation of
fatigue.
Very high doses: induces
nervousness, insomnia &
tremors.
Stimulates respiratory centre of
the brain (increasing sensitivity
to CO2).
Cardiovascular activity: Positive
inotropic action, causes
tacchycardia, increases CO,
slight peripheral dilation, mild
diuretic action
 Caffeine: Uses
In combinations with
antipyretics and
analgesics, cold and flu
medication.
(increases the intestinal
absorption of some of
these drugs; or to
counteract drowsiness).
Ingredient in non-
alcoholic beverages and
“energizing” beverages
 Caffeine Side Effects
Sinus tacchycardia
Epigastric pain
Nausea
Vomiting
Headaches
Nervousness
Insomnia
tremors
Caffeine operates using the same mechanisms of amphetamines,
cocaine, and heroin to stimulate the brain, though with milder
effects. It manipulates the same channels as the other drugs, and
that is one of the things that gives caffeine its addictive qualities.

There is a chemical in our brain called adenosine, that binds to

certain receptors and slows down nerve cell activity when we
are sleeping. To a nerve cell, caffeine looks like adenosine and
it binds to the adenosine receptors. However, as it's not really
adenosine, it doesn't slow down the cell's activity like
adenosine would. So the cell cannot "see" adenosine anymore
because caffeine has taken up all the receptors adenosine
binds to. Then instead of slowing down because of the
adenosine level, the cells speed up.
The pituitary gland sees all of this activity and thinks some sort
of emergency must be occurring, so it releases hormones that
tell the adrenal glands to produce adrenaline. Adrenaline is the
"fight" hormone, and it makes your heart to beat faster, the
breathing tubes to open up, the liver to release sugar into the
bloodstream for extra energy and your muscles to tighten up,
ready for action.
Because of this, after consuming a big cup of coffee your
muscles tense up, you feel excited and you can feel your heart
beat increasing.
Moreover, as amphetamines, caffeine also increases the levels
of dopamine, which is associated with the pleasure system of
the brain, providing feelings of enjoyment and reinforcement.
 Tropane Alkaloids
Derived from tropine and consist of mandelic, tropic or
benzoic acid esters of tropine.
Are very closely related to each other
All have pronounced physiological actions.

Natural alkaloids include

Hyoscyamine
Hyoscine
Atropine
Cocaine
The above mentioned alkaloids occur within the
Solanaceae family (except cocaine – from
Erythroxylaceae family)
 Atropine
Atropine – deadly nightshade, Atropa belladonna: ,
jimsonweed(Datura stramonium), mandrake
(Mandragora officinarum) and other plants of the
family Solanaceae.
It is classified as an anticholinergic drug.
dilates eye pupils,
decreases sweating,
produces stomach acid and saliva &
relaxes smooth muscle (asthma and colic).
Treatment of bradycardia or Resuscitation
Atropine
 Side Effects
• tachycardia,
• dizziness,
• nausea,
• blurred vision,
• loss of balance,
• dilated pupils,
• photophobia,
• dry mouth and potentially extreme confusion,
dissociative hallucinations and excitation
especially amongst the elderly.