Natural products and secondary metabolites manik

Natural Products and
Secondary Metabolites
PHARM 3127
Md. Imran Nur Manik
Lecturer
Department of Pharmacy
Northern University Bangladesh

Natural Products and Secondary Metabolites
Prepared By: Md. Imran Nur Manik; B.Pharm; M.Pharm Page 1
manikrupharmacy@gmail.com; Lecturer; Department of Pharmacy; Northern University Bangladesh.
Vitamins
Syllabus for Vitamins: clinical aspects of vitamins, and effects of free radicals,
synthesis of vitamins: vit-c, nicotinamide, and mechanism of action of vitamins.
Definition:
Vitamins are organic chemical compounds/substances which cannot be synthesized
(in sufficient quantities) in the body but are essential for normal metabolic
functions/reactions.
Vitamins do not furnish energy and they aren’t used as building units for cellular
structures. Lack of specific vitamins leads to distinctive deficiency states such as
Beriberi, Rickets, and Scurvy etc.
Classification:
It is convenient for a number of purposes to classify the vitamins as-
(1) Fat soluble and
(2) Water soluble.
Fat soluble vitamins:
The vitamins which are soluble in fat solvents (dietary and body fat) but relatively
insoluble in water, their absorption from the intestinal tract is associated with that of
lipids and are stored in the body in same fashion as fat are known as fat soluble
vitamins. Fat soluble vitamins are vitamin A, D, E & K.
It can be noted that fat soluble vitamins might be toxic in large doses and are
stored in the body for a long period. Their deficiency state may be caused by conditions
that impair fat absorption.
Water soluble vitamins:
These vitamins are soluble in water but generally not soluble in lipid (however
some are slightly soluble in certain organic solvents) and therefore easily eliminated
from the body.
The water soluble vitamins are vitamin B complex (including vitamin H also
known as vitamin B7) and vitamin C. Our discussion will be confined within the
water-soluble vitamins.
It should be noted that since water-soluble vitamins are easily excreted, they
have greater chance of being deficit than being overabundant.
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Vitamin C:
Introduction:
Vitamin C or Ascorbic acid (toxic to viruses, bacteria and some malignant tumor
cells) is a naturally occurring vitamin which prevents scurvy and has antioxidant
properties. It is a water soluble vitamin.
O
HO
HO
O
OH
OH
O
C
CH2OH
HO H
O
OHHO
Ascorbic acid
Deficiency symptoms:
Scurvy: It consists of the degeneration of collagen and intracellular ground
substances resulting in disturbances of bone growth, hemorrhage of the gums and other
part of the body, loosening of the teeth, capillary fragility with consequent cutaneous
hemorrhages and other abnormalities.
Synthesis:
The synthesis of vitamin C is done from D-glucose. It is a semi-synthesis.
In this process D-glucose is hydrogenated to D-sorbitol which by oxidation with
Acetobactor suboxydans (fermentation) yields L-sorbose. When L-sorbose is treated
with acetone in the presence of conc. H2SO4 and the catalyst (used in dehydrogenation)
diacetone sorbose is formed. When it is oxidized with KMnO4 in strong alkaline medium
diacetone sorburonic acid is formed which upon heating with conc.
HCl gives 2-keto-L-gulonic acid. This when treated with a solution of aqueous HCl in
ethanol-chloroform solvent leads to ascorbic acid.
Uses:
1. Prevention and treatment of scurvy
2. Facilitation of healing and recovery from extensive burns and severe trauma
3. Treatment of some types of anemia (associated with scurvy)
4. Maintenance of an acidic urine
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C
C
C
C
CH2OH
H OH
HO H
H OH
H OH
H O
H2, CuCl
CH2OH
C
C
C
C
CH2OH
H OH
HO H
H OH
H OH
D-SorbitolD-Glucose
Bacteria
Acetobactor
suboxydans
Oxidation
CH2OH
C
C
C
C
CH2OH
H OH
HO H
H OH
O
CH2OH
C
C
C
C
CH2OH
HO H
H OH
HO H
O
CH2OH
C
C
C
C
CH2OH
HO H
H OH
H
HO
O
L-Sorbose
Inverted formula Furanose form
Acetone, CuSO4
CH2OH
C
C
C
C
H2C
H
H
H
O
O
O
C
H3C
H3C
O
O
C
CH3
CH3
Diacetone sorbose
KMnO4
Strong alkaline
medium
COOH
C
C
C
C
H2C
H
H
H
O
O
O
C
H3C
H3C
O
O
C
CH3
CH3
COOH
C
C
C
C
CH2OH
HO H
H OH
HO H
O
Diacetone sorburonic acid
2-keto-L-gulonic acid
Conc. HClHeat
Aqueous HCl
CHCl3-ethanol
solution
O
HO
HO
O
OH
OH
Ascorbic acid
Dosage:
1. Prophylactic dose → 45-60 mg/per day via oral or IM routes, during pregnancy and
lactation an additional 20-40 mg is required.
2. Therapeutic dose:
a. Treatment of scurvy → 100 mg three times daily for several weeks
b. For severe burns → 200-500 mg daily
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Mechanism of action
Vitamin C plays a role in many oxidative and other metabolic reactions, e.g.
Hydroxylation of proline and lysine residues of protocollagen—essential for formation
and stabilization of collagen triple helix;
Hydroxylation of carnitine,
Conversion of folic acid to folinic acid,
Biosynthesis of adrenal steroids, catecholamines, oxytocin and vasopressin and
metabolism of cyclic nucleotides & prostaglandins.
It directly stimulates collagen synthesis and is very important for maintenance of
intercellular connective tissue. A number of ill-defined actions have been ascribed to
ascorbic acid in mega doses, but none is proven.
Vitamin C also acts
As an antioxidant (reacting directly with aqueous free radicals), which is important in
the protection of cellular function; and
To enhance the intestinal absorption of nonhaem iron.
Fig. Collagen structureMd.
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Vitamin B-complex
B-complex group of vitamins comprise a large number of water soluble vitamins which
are nutritional essentials for all forms of life, from the lowest form of yeast and bacteria
to the highest form, the man.
Apart from being important nutritionally, they form essential co enzymes to certain
important intracellular enzyme systems. There are about individual components, most of
them are synthesized by the microbial flora.
Components of vitamin B complex are:-
1. Thiamine – Vit B1
2. Riboflavin – Vit B2
3. Niacin – Vit B3
4. Pantothenic acid – Vit B5
5. Pyridoxine – Vit B6
6. Biotin – Vit B7
7. Folic acid group
8. Cyanocobalamin – Vit B12
Vitamin B1 (thiamine):
Introduction:
Vitamin B1 known as thiamine is a water-soluble vitamin that occurs in moderate
to rich quantity in dried yeast, nuts, rice, egg yolks, brans and some other vegetable. It is
biotransformed inside the body and function as co-enzyme in several metabolic
processes.
N
N
H
H3C
N
S
CH3
OH
NH2
Thiamine
Beriberi. It is manifested in mainly two forms-
1. Dry beriberi → main symptom is polyneuropathy (affect the nervous system)
2. Acute wet beriberi → Affect the CVS. Predominant symptoms are edema and
serous effusions
3. Infantile beriberi affects the children of malnourished mothers
4. Gastrointestinal beriberi affects the digestive system and other bodily systems
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Synthesis:
N
N
H
H3C
N
S
CH3
OH
NH2
N
N
H3C
Cl
NH2
N
S
CH3
OH+
Condensation
2-methyl-4-amino-5-
chloromethylpyrimidine
hydrochloride
4-methyl-5-
( -hydroxyethyl)
thiazole

Thiamine
Thiamine is rather synthesized than being isolated/ extracted from the food sources. It is
synthesized by the direct condensation of 2-methyl-4amino-5-chloromethylpyrimidine
hydrochloride and 4-methyl-5-(β-hydroxymethyl) thiazole.
Uses:
1. In thiamine deficiency situations e.g. beriberi, neuritis associated with pregnancy
and neuritis of pellagra
2. Chronic alcoholism
3. Wernicke’s encephalopathy
Dosage:
5-10 mg three times daily via oral, IM or IV route.
Biochemical functions (general):
Thiamine functions as a coenzyme in the oxidative decarboxylation of alpha-ketoacids
(involved in energy production) and in the transketolase reaction of the pentose
phosphate pathway (involved in carbohydrate metabolism).
The enzyme thiamine pyrophosphate (TPP) or co-carboxylase is intimately connected
with the energy releasing reactions in the carbohydrate metabolism.
TPP also plays an important role in the transmission of nerve impulse. This is because
TPP is required for acetylcholine synthesis and the ion translocation of neural tissue.
Functions of B1 (Specific examples):
1. Enzyme cofactor: (Thiamine pyrophosphate TPP or TDP)
A. Decarboxylation reactions
a) Pyruvate dehydrogenase
b) α-ketoglutarate dehydrogenase
c) α-keto acid dehydrogenase – branched chain amino acid metabolim.
B. Transketolation reactions
a) Transketolase – Pentose Phosphate pathway
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A. Decarboxylation
reactions
a) Pyruvate
dehydrogenase complexes
to TPP:
It catalyzes the breakdown
of pyruvate, to acetyl CoA,
and carbon dioxide.
b) Alpha ketoglutarate
dehydrogenase:
Requires TPP in the
decarboxylation of alpha
ketoglutarate to succinyl
CoA and CO2.
c) α-keto acid
dehydrogenase
– branched
chain amino
acid metabolim.
B. Transketolation reactions
Transketolase: The second group of enzymes that use TPP as co-enzyme are the
transketolases, in the Pentose phosphate pathway ( PPP ) of glucose.
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Vitamin B2 (Riboflavin):
Introduction:
Riboflavin, also known as vitamin B2 is a
water-soluble vitamin occurring widely in animal and
plant foodstuff. It is converted into FAD (flavin adenosine
dinucleotide) and necessary for metabolic processes.
1. Well defined deficiency syndrome consists of
Cheilosis, glossitis, Seborrheic follicular keratosis of
nose and forehead, burning feet etc.
2. Loss of hair (alopecia)
3. Lesions of the skin, eyes, lips, mouth and genitalia.
Synthesis:
H3C
H3C
NH
(CHOCOCH3)3
OCOCH3
O2N N NCl
H3C
H3C
NH
(CHOCOCH3)3
OCOCH3
N N NO2
NH
H
N OO
O
H3C
H3C
N
1
2
3
4
N
N
NH
O
O
OH
HO
OH
5
OH
+
Barbituric acid
4, 5-dimethyl-N-(1'-ribityl) aniline
tetraacetate
4-nitro-phenyldiazonium chloride
Azoderivative Riboflavin
Reaction between 4, 5-dimethyl-N-(1’-ribityl) aniline tetraacetate and 4-nitro-
phenyldiazonium chloride yields an azoderivative which upon reaction with barbituric
acid yield riboflavin.
N
N
NH
NH3C
H3C
O
O
OH
HO
OH
OH
Riboflavin
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Uses:
1. In well-defined vitamin B2 deficiency syndrome
2. It may also help in deficiency syndromes of other vitamin-B-complex.
Usually after the age of 40-45 vitamin deficiency becomes more pronounced. For example
deficiency of vitamin B-complex will lead to lesions of the mouth (and other types of
wounds of the mouth). Then vitamin B administration becomes necessary. Usually
riboflavin is given with other B-complex vitamins as multivitamin preparations.
Dose:
5-25 mg daily via oral route preferably in a preparation containing other B-complex
vitamins.
Functions of B2:
Riboflavin functions as a component of two flavin coenzymes – flavin mononucleotide
(FMN) and flavin adenine dinucleotide (FAD). Riboflavin through its coenzymes Flavin
mononucleotide (FMN) and Flavin adenine dinucleotide (FAD) takes part in a variety of
cellular oxidation-reduction reactions and in energy production. Examples include the
oxidation of glucose, certain amino acids and fatty acids; reactions with several
intermediaries of the Krebs cycle; conversion of pyridoxine to its active coenzyme; and
conversion of tryptophan to niacin.
Riboflavin has a role as an antioxidant. It may be involved in maintaining the integrity of
erythrocytes.
Some of the specified roles are as follows:
Integral component of electron transport chain ATP Synthesis ----NADFMNCoQ
Component of several enzymes in the metabolic pathway
• TCA cycle  succinate dehydrogenase
• Fatty Acid Oxidation  acyl CoA dehydrogenase
• Amino acid oxidation As a part of alpha ketoglutarate
• Isocitrate dehydrogenase complex ( dihydrolipoate dehydrogenase)
 FMN-dependent Enzymes
During the amino acid oxidation, FMN
is reduced. It is re-oxidized by
molecular oxygen to produce
hydrogen peroxide.
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 FAD-dependent enzymes
a) Conversion of Succinate to fumarate by succinate dehydrogenase in TCA requires
FAD.
b) Conversion of Pyruvate to acetyl CoA requires FAD,NAD as part of the Pyruvate
dehydrogenase.
c) NAD is also required in the a-Ketoglutarate dehydrogenase (Alpha ketoglutarate
to succinyl) CoA by alpha in TCA cycle.
Vitamin B3:
Introduction:
Niacin (nicotinic acid) and
niacinamide (nicotinamide) are
known as vitamin B3.
But niacin show hypocholesterolemic properties not shown by niacinamide and
excessive dosage of niacin causes flushing.
Both of these are water soluble vitamins.
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Deficiency syndrome:
The well defined deficiency syndrome is pellagra (which is associated with skin
lesions, diarrhea and other symptoms). It is characterized by 3D () or 4D symptoms
(Diarrhea, Dermatitis, Dementia and Death).
Synthesis:
O
O
O
N N
CH3
H3C CH3
CH2CH3
H3C
COOH
5-Ethyl-2-methyl-pyridineParaldehyde
(trimer of acetaldehyde)
Nicotinic acid
NH3,
P
HNO3
Oxidation

N
OH
O
N
O
O
C2H5
EtOH
NH3
N
NH2
O
Esterification
EtOH
Nicotinic acid Niacinamide
Esterification of nicotinic acid affords ethyl nicotinate. Amidation of that with
ammonia in ethanol results in niacinamide (nicotinamide).
Use:
1. Prevention and treatment of pellagra.
Dosage:
For pellagra initially 300-500 mg daily in divided doses preferably in oral route. For
maintenance multivitamin preparation is used. In the intravenous route 25-100 mg.
Physiological role and actions
Nicotinic acid is readily converted to its amide which is acomponent of the coenzyme
Nicotinamideadenine- dinucleotide (NAD) and its phosphate (NADP) involved in
oxidation-reduction reactions.
These pyridine nucleotides act as hydrogen acceptors in the electron transport chain in
tissue respiration, glycolysis and fat synthesis. Flavoproteins regenerate them by
oxidizing NADH and NADPH.
Nicotinic acid (but not nicotinamide) in large doses is a vasodilator, particularly of
cutaneous vessels. It also lowers plasma lipids.
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Some of the specified roles are as follows:
Coenzymes are active participants in oxidation-reduction reactions – Dehydrogenases
B3 function in at least 200 reactions in cellular metabolic pathways
NAD+
• Participates in catabolic reactions
• Electron and hydrogen ion acceptor
NADP+
• Anabolic reactions
• Important in biochemical pathway for fatty-acid synthesis, steroid and bile
acid synthesis.
NAD+
dependent enzymes
• Lactate dehydrogenase
(lactate → pyruvate)
NADPH utilizing reactions
• HMG CoA reductase (HMG CoA → mevalonate) in
Fatty acid metabolism
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Vitamin B6 (pyridoxine):
Introduction:
Vitamin B6 is actually a mixture of pyridoxine, pyridoxal and pyridoxamine which
are interconverted. The most stable and common analogue used in pharmaceutical
preparations is pyridoxine.
Deficiency syndrome:
1. Seborrheic and desquamative dermatitis of the eyes and mouth
2. Glossitis and stomatitis
3. Intertrigo of breasts and inguinal region of women
Synthesis:
O
O
H3C
HN
CH3
O
N
O
CH3 O
N
O
O
H3C O
H3C
NH3C
HO
N
O
HO
H3C
OH
OH
P2O5
CH3
2, 5-dihydrofurane
Mineral acid
hydroquinone
HCl.
N-formylalaninate
4-methyl-5-ethoxyoxazole
Pyridoxine hydrochloride
H2O
Salification
H3C
Decomposition
Uses:
1. When using isoniazid or other pyridoxine antagonists causes pyridoxine
deficiency. This causes peripheral neuritis. Thus when using pyridoxine
antagonists pyridoxine is given as prophylactic.
2. Used in other pyridoxine deficiency e.g. convulsions in infants, hypochromic
anemia, some types of megaloblastic anemia, homocystinuria etc.
3. It improves symptoms related to thiamine, riboflavin and niacin deficiency.
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Dose:
1. Prophylactic dose → 25-50 mg daily.
2. In pyridoxine deficiency syndromes → 10-250 mg daily in oral, IM or IV route
3. For drug induced peripheral neuritis → 50-200 mg daily.
Vitamin B5 (pantothenic acid):
Introduction:
Pantothenic acid is a water soluble vitamin widely distributed in nature. It is found
in eggs, liver, dairy products and leafy vegetables. It is included in multiple-vitamin
preparations and not generally used alone.
HO
O
N
H
O
OH
H3C CH3
OH
Pantothenic acid
Deficiency syndromes:
Deficiency of pantothenic acid leads to several discomforts e.g.
- Malaise (a general sense of discomfort)
- Fatigue
- Headache
- Sleep disturbances
- Nausea
- Abdominal cramps (a sudden and irregular pain)
Dose:
Daily 5-10 mg daily.
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Vitamin B7/Vitamin H/Biotin:
Introduction:
Biotin is a water soluble vitamin widely distributed in nature. it is normally
synthesized by the intestinal bacteria and therefore supplementation is usually
unnecessary.
H
N
S
NH
O
COOH
Biotin
Deficiency syndromes:
- Mild dermatitis
- Glossitis (inflammation of the tongue)
- Lethargy
- Abdominal pain
- Anorexia
- Mental depressions etc.
Dose:
It is included in multi-vitamin preparations at 0.15 mg/day for children and 0.30
mg/day for adults.
General References
 KD Tripathi MD: Essentials of Medical Pharmacology, 7th
Edition, Chapter 67:
Vitamins, Jaypee Brothers Medical Publishers (P) Ltd, India (2013) pp 909-918
 Dietary Supplements, 3rd
Edition (Pamela Mason) Pharmaceutical Press, UK, 2007.
 Handbook of vitamins, 4th
Edition, (Janos Zempleni, Robert B. Rucker, Donald B.
McCormick, John W. Suttie) CRC Press,U.S.A. 2007.
Laurence KM, James N, Miller MH, et al. Doubleblind randomised controlled trial of folate
treatment before conception to prevent recurrence of neural tube defects. BMJ 1981; 282:
1509–1511.
National Health Service. National Library for Health.
http://www.clinicalanswers.nhs.uk/index.cfm?question=248 (Page last accessed on
October 31, 2006).
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Alkaloids
Syllabus for Alkaloids: alkaloids as pharmaceutical raw materials, opium and its analogue, synthesis of
ephedrine, clinical comparison of ephedrine and epinephrine.
Alkaloids:
Alkaloids may be defined as basic nitrogenous compounds which occur
abundantly in the plant kingdom. They contain one or more nitrogen usually in a
heterocyclic ring and have a marked physiological action on man & animals. The
nitrogen may exist as primary (1° amines), secondary (2° amines) or tertiary (3° amines)
amine. These compounds are basic but the degree of their basicity depends on the
structure of the molecule and presence and location of other functional groups.
Alkaloids as pharmaceutical raw materials:
Alkaloids are natural products. They are the secondary metabolites of plant.
Their structure is diverse varying from simple to very complex structure and their
activity is also highly selective based on the structure. For example-
Tyrosine
Tyrosine
+
Norlaudanosoline
Reticuline
Salutaridine
Thebaine
Codeine
Morphine
Papaverine
H2C
NH2
H
COOH
HO
H2C
NH2
H
COOH
HO
NH
OH
OH
HO
HO
OMe
OMe
MeO
MeO
O
HO OH
N
CH3
O
MeO OH
N
CH3
O
MeO OMe
N
CH3
N
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The difference between morphine and codeine is that codeine contains a methoxy
group in place of phenolic hydroxyl group. Morphine is an analgesic and it is 10 times
more potent compare to codeine. But codeine is mainly used as anti-tussive drug. It has
mild analgesic.
Again thebaine has structure similar to morphine and codeine (both the hydroxyl
groups are replaced by methoxy groups). But thebaine is neither analgesic nor anti-
tussive and it is mainly used as CNS stimulant.
Thus we can see that the simple molecular modification of principle compound
can give variation of pharmacological action and thus suit the need of different diseases.
So it is easily understandable that nature can give us idea of designing drug molecules
for different indications.
Opium alkaloids:
Opium:
It is the air dried milky exudates
obtained by incising the unriped
capsules of poppy plant (Papaver
somniferum Linn. of Papaveraceae
family).
The plant poppy is an annual herb
with large, showy, solitary flowers
having color of pink to purple.
Geographical source:
The plant is indigenous to Asia
Minor. The plant poppy is cultivated in
many countries but legal opium
production is not permitted in all
countries.
Constituents:
More than 30 (23 according to
FA) alkaloids are found in opium. The
two principle types of alkaloids
present in opium are –
1. Alkaloids containing partially hydrogenated phenanthrene nucleus:
Examples include morphine, codeine, thebaine etc which act primarily on the CNS
and produce stimulation or depression as well as smooth muscle contraction.
2. Alkaloids having 1-benzyl-isoquinoline structure: Example Narcotine,
Papaverine. They have little CNS action.
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The most important are the alkaloids
1. Morphine: It is the most important opium alkaloid. It is a phenanthrene derivative
containing an alcoholic and phenolic OH group. Morphine and its salts occur as
white silky crystals, odorless and having a bitter taste. They are classified as
narcotic analgesics and are strong hypnotic and narcotic. Their use tends to induce
habit formation as well as common side-effects as nausea, vomiting and constipation.
2. Codeine: It is the most widely used opium alkaloid. It is obtained from opium, or by
methylation of morphine or by appropriate reduction and demethylation of thebaine.
If methyl group replaces the hydrogen of phenolic OH in morphine it becomes
codeine.
The drug and its salts are narcotics and antitussives. They are used as sedatives
especially in allaying coughs. Its action is similar to that of morphine but is less toxic.
Heroin: Diacetylmorphine or heroine is formed by acetylation of morphine, where the
hydrogen atoms of both the phenolic and alcoholic hydroxyl groups are replaced by
acetyl groups. Its action is similar but more pronounced than that of morphine. Due to
its potency and the danger of habit formation it is not used in medicine.
3. Noscapine
4. Thebaine
5. Papaverine
Also contains alkaloids like
i. Narceine, ii. Protopine, iii. Laudanine, iv. Codamine, iv. Cryptopine,
v. Lanthopine , vi. Meconidine
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Ephedrine:
Introduction:
Ephedrine is an Alkaloidal amine having sympathomimetic action.
Its action is similar to adrenaline but there are some differences.
Ephedrine can be extracted from stems of various species of
Ephedra or it can be chemically synthesized.
Chemical synthesis:
1. It is synthesized from benzaldehyde by condensing with
nitroethane. The corresponding compound in then reduced.
The L-isomer of the reduced compound is then methylated to obtain ephedrine.
CHO OH
NO2
CH3 CH3
NH2
OH
OH
CH3
H
N
CH3
MeIMethylation
2-methyl-2-nitro-1-
phenylethanol
[H]
2-methyl-2-amino-1-
phenylethanol
Benzaldehyde
EtNO2
Ephedrine
2. Benzaldehyde is fermented with glucose using yeast. The fermentation of glucose
leads to pyruvic acid formation with is condensed with benzaldehyde. The condensed
compound is hydrogenated in presence of methylamine to yield ephedrine.
CHO
Benzaldehyde
Glucose
Yeast
H3C
O
COOH
Pyruvic acid
OH
CH3
O
OH
CH3
H
N
CH3
Phenyl-1-hydroxypropanone-2
Condensation
CH3NH2
(H2)Pt
Ephedrine
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Comparison with epinephrine:
Criterion Ephedrine Epinephrine
Route of
Administration
Effective in oral route Must be given in IV route
(except when used as inhaler
for asthmatic attack)
Duration of
action
Prolonged Comparatively shorter
Onset of action
Slower (thus it is more suitable
more chronic asthma and colds)
Comparatively rapid
Potency Comparatively less Greater than ephedrine
Blood-Brain-
Barrier
penetration
Greater penetration Penetration is less
CNS activity Greater CNS activity Comparatively less active
Vasoconstriction
Stronger vasoconstriction Comparatively lower
vasoconstriction property.
Tolerance Possible Usually doesn’t occur
Structure
H
C
OH
CH
CH3
H
N
CH3
Ephedrine
H
C
OH
C
H2
H
N
CH3
HO
HO
Epinephrine
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Papaverine:
Introduction: Papaverine is a smooth muscle relaxant. It exerts antispasmodic action on
blood vessels, thus it relieves arterial spasm caused by acute vascular occlusion. It can
be given orally.
Chemical synthesis: Below the synthesis of Papaverine is shown. This is known as
Pictet-Gams synthesis.
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
O
CH3
O
NOH
H3CO
H3CO
O
NH2
CHO
OH
OCH3
CHO
OCH3
OCH3
HOHC
OCH3
OCH3
CN
CH2COOH
OCH3
OCH3
CH2COCl
OCH3
OCH3
CH3COCl
AlCl3
C5H11ONO C2H5ONA
C2H5OH 75%,RT,
,
,
SnCl2
HCl
RT
(CH3)2SO4 HCN 1. HI
2. Hydrolysis
PCl5
KOH
OC
NH
H2C
RT
H3CO
H3CO
O
OCH3
OCH3
Na-Hg, H2O
50 C°
OC
NH
H2C
H3CO
H3CO
OH
OCH3
OCH3
P 2
O 5
, Xylene
Reflux
N
H2C
H3CO
H3CO
OH
OCH3
OCH3
Papaverine
Md.
Imran
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Manik

Cardiac glycosides
Syllabus for Glycosides: chemical and clinical aspects of digoxin and other digitalis glycosides.
Cardiotonics:
Cardiotonics are drugs that acts by increasing the force of contraction of
myocardial fiber improve cardiac excitability, automaticity, conduction velocity and
refractory period.
In another words, cardiotonics increase the tonicity of the heart i.e. increases the cardiac
muscle tone.
Automaticity:
It is the unique property of cardiac muscles to contract without nervous
stimulation.
Conduction velocity:
The heart is capable of producing electrical impulse for the contraction of muscle.
There are specialized myocytes which depolarize spontaneously and rythmitically to
generate the electrical impulse which is conducted throughout the heart. If the conduction
velocity is increased then, the heart rate will be increased (?). In different parts of heart
conduction velocity is different as below –
 Atrial muscle fibers: 0.3m/sec
 Internodal fibers: 1m/sec
 AV node: 0.05m/sec
 Bundle of His: 0.12m/sec
 Purkinje fibers: 4m/sec
 Ventricular muscle fibers: 0.5m/sec
Tone:
The state of functioning normally. Muscle tone is defined as the resistance of
muscle to stretch
Refractory period:
It is the period of time during which cardiac muscle doesn't respond to the
electrical impulse.
Cardiac excitability:
It is the ability of cardiac muscle to excite i.e. to contract in response to a stimulus
(electrical impulse).
Inotropic effect:
It is the effect on the force of muscle contraction. If the force of muscle contraction
is increased then it is called positive inotropic effect.
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Indications of cardiotonics:
1. Congestive cardiac failure.
2. Atrial fibrillation (The atrial contractions are rapid and irregular. The atrial
contraction occurs at a rate of 300-400/minute).
3. Atrial flutter (The atrial contractions are rapid but regular. The atrial rate can rise
to 250-350/minute).
4. Paroxysmal atrial tachycardia (a suddenly occurring arrhythmia where the atrial
rate becomes higher – usually 160-200 beats per minute). It is also known as
Paroxysmal supraventricular tachycardia.
Effect of cardiotonics:
The cardiotonics increase the force of contraction of myocardial fibers. By doing
this a cardiotonic drug –
1. Increases cardiac output (the volume of blood pumped out by any ventricle per
minute). Increased cardiac output also leads to increased diuresis.
2. Lowers venous pressure and venous blood volume.
3. In CCF, the pumping is improper and blood volume in heart increases leading to
edema in heart. This increases the size of the heart. The cardiotonic counteracts
this and decreases the size of heart to normal.
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Cardiotonic drugs:
Generally the cardiac glycosides are considered as cardiotonics. There are also
some synthetic drugs that may be used for positive inotropic effect.
In acute conditions (acute ventricular failure, tachyarrythmia) synthetic drugs (or
ouabain, deslanoside) are used for rapid response. For less acute, chronic or stabilized
cardiac failure cardiac glycosides are used. Then, digitalis leaf or digitoxin is 1st
choice,
digoxin is 2nd
choice.
Cardiac glycosides:
Introduction:
Glycosides:
Glycosides are compounds which
upon hydrolysis yield a glycone (sugar)
part (such as glucose, rhamnose,
digitoxose, ribose, cymarose) and an
aglycone (also called genin, the non-
sugar part) part.
Cardiac glycosides
Cardiac glycosides are glycosides
containing a steroidal aglycone and have
highly specific and powerful action on
cardiac muscle.
They are also called cardio-active
glycosides and cardiotonic glycosides.
The principle sources of cardiac
glycosides are –
- Digitalis
- Strophanthus
- Squill
Digitalis glycosides:
There are about 80 species of Digitalis but only Digitalis purpurea and D. lanata
are main sources of cardiac glycosides.
The digitalis leaf refers to dried leaves of Digitalis purpurea. Digitoxin is obtained
from these leaves. Digoxin is obtained from dried leaves of D. lanata. Digitoxin and
digoxin are the glycosides which are frequently employed as medicine.
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Mechanism of action of cardiac glycosides:
General pharmacology:
The definite mechanism of action is not known. Some hypotheses have been
postulated –
1. The glycosides interfere with the movement of 
/KNa across the myocardial
membrane causing a loss of intracellular 
K .
2. They exert a direct action on contractile proteins in cardiac muscle i.e. actin and
myosin.
3. They raise the intracellular conc. of 
Ca by releasing it from its binding sites and
facilitating its entry into the cytosol. It is postulated that they inhibit the
ATPase
/KNa which normally maintains the gradient of the two ions across
membranes. Thus when it is inhibited the cell undergoes depolarization. So the ion
permeability is changed and 
Ca enters the cell. Thus the intracellular 
Ca conc.
is increased. Then 
Ca interacts with actin and myosin leading to contraction of
the myocardial fiber. Repolarization reverses this situation.
This theory is most accepted thus far.
Structure of cardiac glycosides:
The following structural features of cardiac glycosides are deemed important –
2
3
4
5
10
1
6
7
8
9 14
13
12
11
17
16
15
O O
CH3
CH3
O
OH
H
Sugars
OH
1. Steroidal aglycones known as genins
2. Sugars: Attached to the genins in sequence. Most common sugars are D-galactose,
D-glucose and L-rhamnose.
3. 14 β-OH group.
4. 17-α, β-unsaturated lactone ring (6-membered or five membered). If the lactone ring
is 5-membered then they are called cardenolides (aka butenolides); if the lactone
ring is 6-membered then they are called bufadienolides (aka pentadienolides).
Md.
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2
3
4
5
10
1
6
7
8
9 14
13
12
11 17
16
15
O
OH
H
CH3
CH3
O
HO
H
H
Digitoxigenin
(Cardenolide)
O O
HO
H
CH3 CH3
HO
2
3
4
5
10
1
6
7
8
9 14
13
12
11 17
16
15
OH
H
CH3
CH3
HO
H
H
Bufogenin
(bufadienolide)
HO
H
CH3 CH3
HO
O O
OH
O
OH
SAR of cardiac glycosides:
The following features are (or were) considered important for pharmacological
activity –
1. α, β-unsaturated lactone ring at 17-β position.
2. Hydroxyl group at 14 –β position.
3. cis configuration between the A & B rings and C & D rings.
The following model has been postulated for the binding of cardiac glycoside with the
ATPase
/KNa .
O O
HO
H
CH3
CH3
OH3C
O
Sugar
O
H
Site C
Site B
Site A
Site D


Green = Hydrophobic binding Violet = Hydrogen bonding
Blue = Electrostatic attraction Indigo = 1 sugar moeity involved in binding
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According to this model –
1. First a long range attraction between the lactone ring and site A is initiated.
2. Then the steroid part undergoes short-range interaction with site B via
hydrophobic bond.
3. The sugar unit attached directly with the steroid interacts with the site C which
further enhances overall binding.
4. This causes receptor to change as follows –
C
B
A
D
Drug
CBA
D
Drug
Drug-receptor
complex
An allosteric effect is thus produced and ATP can’t bind to the protein receptor.
Problems with administration of cardiac glycosides:
1. Narrow therapeutic index: The therapeutic index of cardiotonics is very low.
Infact it is lowest of all drugs. Their effective dose is 50-60% of the toxic dose.
Thus life-threatening poisoning is very common. Such a condition is called
―digitalis poisoning.
2. Hypakalemia
3. Anorexia
4. Vomiting
5. Salivation
6. Diarrhea
7. Nausea
Countering problems:
The antidote for digitalis poisoning is Digoxin immune Fab (commercial name
Digibind –GSK). It consists of antigen-binding fragments of a specific antidigoxin
antibody isolated from immunized sheep.
Other side-effects can be relieved by adjusting the dose.
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Commercial preparations of glycosides:
Two drugs digoxin and digitoxin are commercially available for administration.
Digoxin:
2
3
4
5
10
1
6
7
8
9 14
13
12
11
17
16
15
O O
CH3
CH3
O
OH
O
OO
OO
OH
OH
OH
OH
CH3
CH3
CH3
Digoxin
OH
Source:
Obtained from the dried leaves of D. lanata (family Scrophulariaceace). It has not
been successfully synthesized in laboratory yet.
Use:
It is the most widely used cardiac glycoside for the treatment of congestive heart
failure and most supraventricular tachyarrythmias.
It is given in oral or IV route.
Dose:
Dose is individualized. The average loading dose (the initial dose) is 0.75-1.5mg in 1
day when orally given and 0.5-1mg when given in IV route. The maintenance dose (the
dose given to maintain the plasma concentration of the drug to therapeutic level) is
smaller.
Md.
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Manik

Digitoxin:
2
3
4
5
10
1
6
7
8
9 14
13
12
11
17
16
15
O O
CH3
CH3
O
OH
O
OO
OO
OH
OH
OH
OH
CH3
CH3
CH3
Digitoxin
Source:
Obtained from the dried leaves of D. purpurea and D. lanata (family
Scrophulariaceace).
Use:
It is used in the treatment of congestive heart failure and most supraventricular
tachyarrythmias.
Dosage:
Dose is individualized. The general loading dose is 1-1.5mg in 1 day; or 200µg twice
daily for 4 days; or 400µg/day for 2-3 days.
Maintenance dose is smaller. Generally 100µg daily or once in two days. The dose
may be raised to 200µg/day if necessary.

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