INDOLE ALKALOIDS - WordPress.com researches… Cytotoxicity of the indole alkaloid reserpine from...
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Mohammed N. Sabir
INDOLE ALKALOIDS
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www.indiashots.com
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Dried root, rhizome and areal stem of Rauwlfia
serpentina, R. vomitoria (African) (Apocynaceae)
Contains not less than 0.15% of the active alkaloid
(Reserpine)
1- RAUWOLFIA
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Rauvolfia = Dr. Leonhard Rauwolf (German
botanist)
Serpentina = tapering, snakelike roots of the
plant.
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It was used in herbal medicine for treatment of
a variety of diseases
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www.medications.li
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flipper.diff.org
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m.ebay.com
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The plant is a shrub reaches to 1m height.
It is indigenous to India and South West
Asia.
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The principal alkaloids siolated are:-
1- Reserpine.
2- Rescinnamine.
3- Deserpidine.
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www.rxhomeo.com www.pureformulas.com
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thevitamins4u.com
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www.himalayahealth.co.za
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The plant is available for commercial
production of reserpine, no synthetic
production is needed.
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These alkaloids are antihypertensive
agents used in essential hypertension.
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The mechanism of their action:-
Depletion of catecholamine and serotonine
stores in brain and adrenal medulla.
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Monoam
ino oxidase (MAO
)
Aldehyde dehydrogenase Aldehyde reductase
COMT
COMT
Catechol-O-methyl transferase (COMT)
Metabolism of catecholamines
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Reserpine effect on VMAT has long-lasting effect
and may cause drug-induced parkinsonism.
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Also reduces the re-uptake of catecholamines
by the adrenergic neurons.
The above mechanism is also responsible for
the tranquilizing and sedative actions.
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After administration for treatment of
hypertension, a reflex bradycardia followed by
euphoria is experienced.
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1-Mild to essential hypertension.
2-As adjunct therapy with other
antihypertensive agents for other types of
hypertension.
CLINICAL USES
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These alkaloids are co-administered with
thiazide diuretics as well.
CLINICAL USES
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3- Antipsychotic agents (relief symptoms of
agitated psychotic states (Schizophrenia)),
especially in patients who cannot tolerate other
antipsychotic agents.
CLINICAL USES
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-Nasal congestion.
-Depression.
-Suicide attempt.
-Nausea.
-Vomiting.
Toxicities…
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-Weight gain.
-Gastric irritation.
-Erectile dysfunction.
-Hyperprolactinemia.
-Increase the risk of breast cancer.
-Not to be given during pregnancy.
Toxicities
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Relevant researches…
Cytotoxicity of the indole alkaloid reserpine from
Rauwolfia serpentina against drug-resistant tumor cells (Sara A.A. Abdelfatah and Thomas Efferth, 2015)
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Is an indole alkaloid
obtained from the
bark of
Pausinystalia
yohimbe (Fam:
Rubiaceae)
2-YOHIMBINE
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Yohimbine
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The plant part which is used to obtain the
active ingredient is the Bark which contain
about 6% of the total alkaloids.
It is a mild MAO-I Indicated for the
treatment of impotence secondary to
diabetes.
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Also in male sexual performance and
erection linked to increased cholinergic
activity.
This will result in increased penile blood
flow, causing erectile stimulation.
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Also used in dry mouth.
A side effect of Yohimbine is increasing
salivation which may lead to interfere with
digestion.
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Is the dried ripe seed of
Strychnos nux-vomica
Fam: Loganinaceae
Strychnos = Poison plant
(nut that cause vominting)
3-NUX VOMICA
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Is a small tree (12m),
native to east Indies and
Seri Lanka. Also in
Australia (North coast).
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The total alkaloidal content is 1.5-5%
mainly (Strychnine and Brucine)
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Is a valuable Pharmacologic tool in
physiologic and neuroanatomic research.
Act as central stimulant causing excitation of
all parts of the central nervous system
and blocks the inhibitory spinal impulses at the
postsynaptic level.
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This action result in exaggeration in
reflexes, with resulting tonic convulsions.
Toxic doses (60-90mg)
Brucine is used as alcohol dentaurant.
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The alkaloid show suppression action on allergen-
specific Immunoglobulin E (IgE) antibody response in
mice, which raise possibilities for future application in
allergic conditions.
In vitro cell-line tests, inhibit the growth of AGS human
gastric carcinoma cells.
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Calabar bean
Is the dried ripe seed of Physostigma
venenosum (Fam: Fabaceae)
Total alkaloid content 0.15%
4-PHYSOSTIGMINE
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Physostigmine should be preserved in tight
containers in shadow to avoid
degradation of the product to toxic
metabolites.
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It is a reversible inhibitor of the
Cholinesterase enzyme leading to increase of
Acetylcholine concentration in myoneural
junctions.
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On the eye….
Causes miosis, contraction of the ciliary
muscles and decrease in intraocular
pressure caused by increase out-flow of
aqueous humor.
Used to treat glaucoma
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The dried leaflets of
Pilocarpus jaborandi (Fam: Rutaceae)
Is a shrub indigenous to Brazil.
Total Alkaloid Yield = 0.5-1%
5-IMIDAZOLE ALKALOIDS (PILOCARPINE)
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The alkaloids are:-
1-Pilocarpine
2-Isopilocarpine
3-Pilocarpidine
4-Pilosine
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Is a muscarinic stimulant.
In the eye:-
Causes constriction of the pupil
and contraction of the ciliary
muscles.
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Used in narrow-angle glaucoma, since
miosis open the anterior chamber angle
to improve the outflow.
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Available as:
Ophthalmic drops (0.25 to 10%) as nitrate
salt.
Warning:
Patient should be advised to wash
hands immediately after application of the
drops.
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See the references…
Sara A.A. Abdelfatah and Thomas Efferth, “Cytotoxicity of the indole alkaloid reserpine from Rauwolfia serpentina against drug-resistant tumor cells”, Phytomedicine Volume 22, Issue 2, 15 February 2015, Pages 308–318.
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Mohammed N. Sabir
Quinoline Alkaloids
Pharmacognosy II – Third Year Lecture 1
Pharmacogonosy II 1
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Quinines and chemical modulation…
Resistance to anticancers…
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Introduction Quinoline Alkaloids
These alkaloids contain Quinoline nucleus, a major alkaloids
belong to this class are cinchona alkaloids, which has
therapeutic activity.
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The plant is indigenous in the Western Andes of South
America and were first described and introduced by Jesuit
priests who did missionary work in Peru.
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Cinchona alk. obtained
from the dried barks of
the stem and the root of
Cinchona succirubra,
Cinchona officinalis,
Cinchona calysaya and
Cinchona ledgeriana
(F: Rubiaceae)
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Cinchona is a genus of 23 species, all trees,
growing on the eastern slopes of the Andes,
mainly in Bolivia, Ecuador and Peru.
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The discovery of cinchona 1630-1650…
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The Condesa de Chinchón was cured by cinchona bark
is now known to be untrue, but led Linnaeus to name
the genus after her.
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It is, however, certain that by 1650 regular
shipments of cinchona bark were reaching
Spain. By the 1670s the bark was a well-
established remedy in Britain.
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The bark was often adulterated with useless bark from other trees. In 1751 the Spanish Crown declared a monopoly on imports.
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By the beginning of the 19th century, as Spain’s
American colonies gained independence, there was
serious concern in Europe over the quality, quantity
and price of exports of bark.
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Cracking the cinchona code: botany and
pharmacy 1850-1930
Until the 1820s pharmacists had to judge the quality of
cinchona bark, as it arrived at London Docks, by colour
and taste. There was no assay to measure the active
components.
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In 1820 the first quinine alkaloids were extracted
and described by Pierre Pelletier and Joseph
Caventou.
Within five years, the extracted alkaloids had
become standard treatment for malaria.
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Transplantation 1860-1880
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The decline of quinine (20th Century)
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The chemistry and biosynthesis of cinchona alkaloids
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N
H3CO
N
H
H
HO
H
HC
H
CH2
Quinindine
Methods of extraction follows the general method for the extraction of alkaloids.
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Filodipine was developed from quinines for anticancer activities,
but later researches showed that filodipine devoid such activity.
It is used as antihypertensive drug.
HN
O
CH3H3C
O
Cl
Cl
CH3
OOH3C
HN
O
CH3H3C
O
Cl
Cl
CH3
OOH3C
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Quinidine is free alkaloid within plant and is prepared
as quinidine sulfate.
Quinidine is white odorless crystals, when exposed to
light, become dark. It is soluble in organic solvents and
sparingly soluble in water.
Quinidine sulfate is freely soluble in water and ether.
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Quinidine is an antiarrhythmic drug act as membrane
stabilizer…
Dosage (8 mcg/ml).
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Cinchonism
Blurred vision
Skin rash
Flushing
Fever
Lost of hearing
Ringing in the ears
Toxicities
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Indications
Atrial fibrillation
Atrial flutter
Ventricular and atrial tachycardia
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Products
-Quinidine gluconate (as injection)
-Quinidine galactoronate (as oral tablets)
advantages: it releases its content slowly and constantly
enabling steady distribution of the drug and half life.
Also it has less stomach irritability when compared to
the other products.
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N
H3CO
HOH
N
CH2
H
Quininne
Quinine
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27
In 2013, malaria caused an estimated 584 000 deaths
(with an uncertainty range of 367 000 to 755 000),
mostly among African children (WHO 2014).
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Quinine physicochemical properties…
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Quinine sulfate is readily soluble in water while
insoluble in organic solvents.
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These agents are rigid planner polycyclic
molecules…
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It is Antimalarial drug, acting
by intercalation of the
quinine moiety into the DNA
strands…
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When parasite develops resistance to the drug…
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Derivatives of the quinines -Chloroquine More water solubility Better absorption form the GIT Less side effects Longer half life Less frequency in dosing Less resistance.
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Plasmodium falciparum ring-forms and gametocytes in human blood.
A plasmodium sporozoite travels the
cytoplasm of a mosquito.
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Anopheles albimanus mosquito feeding on a human arm. This mosquito is a vector of malaria and mosquito control is a very effective way of reducing the incidence of malaria.
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Countries which have regions where malaria is endemic as of 2003 (coloured yellow).
Countries in green are free of indigenous cases of malaria in all areas.
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Antimalarial drugs
Quinine and related agents Chloroquine Amodiaquine Pyrimethamine Proguanil Sulfonamides Mefloquine Atovaquone Primaquine Artemisinin and derivatives Halofantrine Doxycycline Clindamycin 38 Pharmacogonosy II
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Thanks for listening… Any questions?
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