For Al-Azhar Pharmacy Students, Cairo, Egypt

1. Ph. D. Ahmed Metwaly

2. Alkaloids with Exocyclic Nitrogen
(Proto-alkaloids)
(Non-Heterocyclic Alkaloids)
* This group of alkaloids have the nitrogen atom originated from an amino group but is
not present in a heterocyclic ring.
* Many are simple derivatives of Phenylethylamine and as such, are derived from the
common amino acids Phenylalanine or Tyrosine.
•They includes the alkaloids of
Ephedra alkaloids
Khat alkaloids
Capsicum alkaloids
And Colchicum alkaloids

3. TyrosinePhenylalanine

4. 1) Ephedra alkaloids
* Present in the arial parts of several Ephedra species (Family
Ephedraceae).
* Ephedrine is the main alkaloid in Epherda sp.
*Ephedrine is structurally related to the animal hormone Adrenaline
(or Epinephrine) and has similar pharmacological actions.
*Ephedrine was first isolated in 1885. It is on theWorld Health
Organization's List of Essential Medicines, (the most effective and safe
medicines needed in a health system).
* The drug is collected in the autumn, this being important, as the
amount of alkaloid present shows considerable variation at different
seasons

5. Ephedrine
Pseudo ephedrine
Amphetamine
Epinephrine

6. Properties of Ephedrine:
◘ The free base is volatile with steam****
(it can be determined in the drug and when present associated
with other non-volatile alkaloids.
◘ It decomposes on exposure to light.
◘ It is a strong base, soluble in water.***
◘ Its alcoholic solution is levo-rotatory.
◘ Chloroform is not recommended for the extraction of
ephedrine.
Ephedrine in CHCl3  Ephedrine hydrochloride
with release of the toxic aldehyde phosgene.

7. Ephedrine biosynthesis

8. Preparation of Ephedrine:
1) Steam distillation (since the free base is volatile).
2) Extraction by using benzene as solvent instead of
chloroform.

9. Separation of ephedrine from the less active
pseudo-ephedrine
◘ Ephedrine is more soluble in water than -ephedrine.
◘ Ephedrine oxalate is less soluble in water than
-ephedrine oxalate.
◘ Ephedrine HCl is less soluble in CHCl3 and alcohol
than -ephedrine HCl.

10. Special chemical tests for ephedrine:
Dissolve ephedrine
in water
1) dil. HC1
2) drops of 5% copper sulphate
3) sod. Hydroxide (20%),
Violet color
Add ether and shake.
1) Chen's test:
Ether layer Aqueous layer
Purple Blue

11. 2) Ephedrine + crystal of potassium ferricyanide + drops of
water in porcelain dish. Heat on water bath  bezaldehyde odor.
3) Dragendorrf’s reagent  long plates-shaped
crystals.
Benzaldehyde

12. Uses of Ephedrine:
• Often used to prevent low blood pressure during spinal
anesthesia
• The CNS effects resemble amphetamines, but are less
potent, (it leads to release of noradrenaline and
dopamine in the substantia nigra).
• Amphetamine is a potent central nervous system (CNS)
stimulant that is used in the treatment of attention
deficit hyperactivity disorder (ADHD), narcolepsy, and
obesity.

13. Uses of Ephedrine:
* Ephedrine's basic pharmacological action resembles epinephrine (adrenaline),
but is considerably less active, can also be absorbed orally.
•Ephedrine is an indirectly acting as Sympathomimetic amine.
* It used in cough mixtures to relieve asthma and hay fever due to its
bronchodilator activity (relaxes bronchial and uterine muscle).
* It is a potent nasal decongestant due to its vasoconstrictor action on blood
capillaries of mucous membranes.
* Ephedrine increases blood pressure, and heart rate.

15. weight loss by increasing the metabolic rate of adipose tissue by ephedrine
increasing blood
pressure

16. Interactions;
The alkaloid may interact with beta-blockers, COMT (Catechol-O-methyl
transferase) inhibitors, MAO (Monoamine oxidase) inhibitors, antidepressants,
ergot alkaloids or cardiac glycosides
Side effects;
It may cause dizziness, insomnia, blood sugar disturbances, several allergic
reactions, stomach irritation, loss of appetite

17. * Khat or “ Abyssinian tea” consists of the fresh leaves of Catha Edulis (Family
Celastraceae). A small tree cultivated in Ethiopia, East and South Africa, and the
Yemen.
* The leaves are widely employed where they are chewed for a stimulant effect.
* The major alkaloids are Cathine (d-nor-y-ephedrine) and (-)-Cathinone.
* They are primary amines derived from Phenylalanine amino acid.
* For maximum effects, the leaves must be fresh.
CH3
OH
NH2
CH3
NH2
O
(+)-Norpseudoephedrine (Cathine) (-)-Cathinone (+)-amfetamine (amphetamine)
CH3
NH2
1) Ephedra alkaloids2) Khat

18. Khat chewed for a CNS stimulant effect inYmen

19. Uses:
* Dried leaves contain up to 1% cathine (+)- norpseudoephedrine, but young
fresh leaves contain (−)-cathinone as the principal CNS stimulant.
* Cathinone has similar pharmacological properties as the synthetic CNS
stimulant (+)-amphetamine.
* Both compounds act by inducing release of catecholamines.

20. Mescaline
(3, 4, 5-trimethoxy–phenylethylamine)
MeO
MeO
NH2
OMe
Mescaline
■Dried tops of the Cactus lophophora (Fam. Cactaceae)
■ Mescaline is a hallucinogenic alkaloid, derived from phenylalanine
amino acid
Uses:
◘ Mescaline is regarded as the first of a series of hallucinogens or
psychomimetics, in a dose of 400-700 mg by injection.
◘ Habituation and addiction do not result from repeated use of mescaline, so it
is not regarded as a narcotic drug.

21. Cactus (Peyotes)

22. Capsaicin
* The amide capsaicin constitutes the powerfully pungent principle isolated
from chilli peppers (Capsicum annum; Family Solanaceae).
* Capsaicin is an example of a phenolic amide alkaloid.
* Capsaicin imparts a pungent taste to water, even when diluted.
The pungency is destroyed by oxidation with KMnO4.
N
H
O
CH3
CH3
H3CO
HO Capsaicin
1) Ephedra alkaloids3) Capsicum

23. * Capsaicin does not possess basic characters, due to the presence of nitrogen in an
amide group.Therefore can be extracted with ether from acid medium.
Chemical Tests:
Uses:
* Capsaicin is used as a counter-irritant in medicated plasters to relief Rheumatism and
Lumbago.
* it is also used medicinally in creams to counter neuralgia caused by herpes infections
• A topical analgesic.
• Aids hair growth by increasing blood supply to hair follicles
Capsaicin in alcohol
FeCl3
Green color (due to phenolic character).1)
Capsaicin Solution in Conc H2SO4 + Sucrose Violet color2)

24. The burning and painful sensations associated with capsaicin result from its
chemical interaction with sensory neurons.
Capsaicin, as a member of the vanilloid family, binds to a receptor called the
vanilloid receptor subtype 1 (TRPV1), which can also be stimulated with heat, and
physical abrasion, permits cations to pass through the cell membrane when
activated.
The resulting depolarization of the neuron stimulates it to signal the brain.
By binding to the TRPV1 receptor, the capsaicin molecule produces similar
sensations to those of excessive heat or abrasive damage, explaining why the
spiciness of capsaicin is described as a burning sensation.

25. Lower back pain
For hair growthCapsicum

26. Alkaloids of the Tropolone skeleton
Colchicum autumnale (Liliaceae)
Colchicine no longer has its nitrogen atom in a ring system.
Colchicine
O
OCH3
H3CO
H3CO
OCH3
H
N
H CH3
O
1) Ephedra alkaloids4) Colchicum
Amide
group

27. ● Colchicine, being an N-acetyl derivative (amide), is a very weak
base and does not form well-defined salts.
● It occurs as yellow needles.
Isolation:
● Defatted seeds are extracted with CHCl3.
● Concentrate CHCl3 extract; add alcohol until whitish precipitate
is formed.
● Cool, crystallize colchicine and recrystallize from ethyl acetate.
Tests for identification:
1) Colchicine + mineral acids (HCL or H2SO4)  yellow color.
2) Colchicine + conc. HNO3  dirty green color  brown yellow.

28. Uses:
* Colchicine Used in the treatment of gout, a painful
condition in which impaired purine metabolism leads to a
build-up of uric acid crystals in the joints.
* It appears to act primarily as an anti-inflammatory agent,
decreases the uric acid precipitation, decreases
phagocytosis of uric acid crystals but does not itself affect
uric acid metabolism nor act as uricosuric.
*

29. Potential anticancer agent.
Colchicine binds to tubulin in the
mitotic spindle, preventing
polymerization and assembly into
microtubules as do vincristine (In
vivo tested on breast, bowel, lung
and prostate cancers)

30. Familial Mediterranean fever
(FMF)

31. Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder.
FMF is an autoinflammatory disease caused by mutations in Mediterranean fever
gene, which encodes a 781–amino acid protein called pyrin
here are seven types of attacks.
Ninety percent of all patients have their first attack before they are 18 years old.
All develop over 2–4 hours and last anywhere from 6 hours to 4 days.
Most attacks involve fever
Between attacks, you'll likely feel normal. Symptom-free periods may be as short as a
few days or as long as several years.
Signs and symptoms of familial Mediterranean fever include:
Fever
Abdominal pain
Chest pain
Achy, swollen joints
Constipation followed by diarrhea
A red rash on your legs, especially below your knees
Muscle aches
A swollen, tender scrotum

32. Complications
• Abnormal protein in the blood. During attacks of
familial Mediterranean fever, your body may
produce an abnormal protein (amyloid A).The
protein can accumulate in your body and cause
organ damage (amyloidosis).
• Kidney damage. Amyloidosis can damage the
kidneys, causing nephrotic syndrome.
• Infertility in women. Inflammation caused by
familial Mediterranean fever may also affect the
female reproductive organs, causing infertility.
• Joint pain. Arthritis is common in people with
familial Mediterranean fever.
The most commonly affected joints are the knees,
ankles, hips and elbows.

33. Colchicine, decreases attack frequency in FMF patients.
The exact way in which colchicine suppresses attacks is unclear.
It may markedly improve quality of life in patients.
The dosage is typically 1–2 mg a day.
Development of amyloidosis (a disease in which abnormal
protein, known as amyloid fibrils, builds up in tissue) is delayed
with colchicine treatment

34. Dose;
a single dose equivalent to 1 mg of colchicine, not more than 8 mg daily.
Toxic dose: 10 mg of colchicine
Side effects;
Diarrhea, aplastic anemia,
agranulocytosis,
myopathy,
Vomiting.

35. CH3
OH
NH CH3
CH3
OH
NH CH3
(-)- Ephedrine (+)-Pseudoephedrine
CH3
OH
NH2
(-)- Norephedrine
OH
NH CH3
Adrenaline
(Epinepherine)
HO
HO




CH3
OH
NH2
CH3
NH2
O
(+)-Norpseudoephedrine (Cathine) (-)-Cathinone (+)-amfetamine (amphetamine)
CH3
NH2
MeO
MeO
NH2
OMe
Mescaline
N
H
O
CH3
CH3
H3CO
HO Capsaicin
Colchicine
O
OCH3
H3CO
H3CO
OCH3
H
N
H CH3
O
1) Ephedra
2) Khat
Cactus 3) Capsicum 4) Colchicum

36. Ph. D. Ahmed M. Metwaly
Assistant professor, Pharmacognosy
department,
Faculty of Pharmacy, Al-Azhar University.
ametwaly@azhar.edu.eg