ERGOT ALKALOIDS ERGOT ALKALOIDS
ÇAVDAR MAHMUZU ALKALOİTLERİ ÇAVDAR MAHMUZU ALKALOİTLERİ
Prof. Dr. İhsan Çalış
Prof. Dr. İhsan Çalış
References
• Pharmacognosy: Pharmacognosy: Jean BRUNETON – Phytochemistry, Medicinal Plants Phytochemistry, Medicinal Plants
– Lavosier, 1999 (English Ed.), 2009 (French Ed.) Lavosier, 1999 (English Ed.), 2009 (French Ed.) – Paris, Lavosier Paris, Lavosier
• Drogen analyse: Drogen analyse: H. Wagner, S. Bladt, E.M.
Zgainski
– Springer-Verlag, Berlin, 1983 Springer-Verlag, Berlin, 1983
Ergot Alkaloids Ergot Alkaloids
• General
• Distribution of Alkaloids Derived from Ergoline
• Biosynthetic Origin
• Ergot of Rye
– A. The Fungus, the Drag – B. Alkaloid Production
• Field Cultivated Ergot
• Industrial Fermentation
– C. Chemical Composition – D. Tests
– E. Pharmacological Activity
– F. Uses of Ergot Alkaloids Rye Rye
Secale cereale Secale cereale Çavdar
Çavdar
Ergot Alkaloids Ergot Alkaloids
• Alkaloids in this group are from a
– tetracyclic, octahydroindolo- octahydroindolo- quinoline quinoline – nucleus, namely ergoline ergoline.
• T T hese are commonly classified as hese are commonly classified as
– clavines, clavines
– simple lysergic acid derivatives, and simple lysergic acid derivatives – ergopeptines, ergopeptines
N H
2 4 9 10 5
11 12
13
14
Ergoline nucleus
Ergot Alkaloids Ergot Alkaloids
• Ergoline alkaloids can be substituted at C-8; Ergoline alkaloids
– by a methyl group (e.g., festuclavine festuclavine), – or a hydroxymethyl group (e.g.,
dihydrolysergol dihydrolysergol),
• 8-Ergolene alkaloids 8-Ergolene alkaloids
• can be substituted at C-8 can be substituted at C-8
– by a methyl group (e.g., agroclavine agroclavine),
– a hydroxymethyl group (e.g., elymoclavine), elymoclavine – or a carboxyl group (e.g., paspalic acid). paspalic acid
• Secoergoline alkaloids have an open D ring Secoergoline alkaloids
– (e.g., chanoclavine I). chanoclavine I
N
N H
2 4 5 7 6 8
9 10
11 12
13
14
Ergoline nucleus
9-9-ErgolErgolene alkaloidsene alkaloids
Ergot Alkaloids
N
N H
N
N CH3
H OR
O H NH2
N H OH
H H
N H H
N H COOH
N
N CH3
H H H
N
N CH3
H H H
OH
N
N CH3
H H H
N
N CH3
H H H
OH O
2 4 5 7 6 8
9 10
11 12 13
14
Ergoline nucleus
Festuclavine
Lysergic acid
and ergopeptines Norchanoclavine I
Dihydrolysergol
Clavicipitic acids I and II
Agroclavine Paspalic acid
Ergoline alkaloids
Ergoline alkaloids 8-8-ErgolErgoleene alkaloidsne alkaloids Related
Related alk alks.s.
Secoergoline alk Secoergoline alks.s.
Ergot Alkaloids Ergot Alkaloids
• 9-Ergolene alkaloids include 9-Ergolene alkaloids the the chief alkaloids of the ergot of rye chief alkaloids of the ergot of rye,
– whether they have an amino acid structure
• (ergometrine ergometrine),
– a peptide structure with a cyclol moiety
• (ergopeptines),
– or a peptide structure without a cyclol moiety
• (ergopeptams).
N
N H N
N CH3
H
O H
2 4 5 7 6 8
9 10
11 12
13
14
Ergoline nucleus Lysergic acid and ergopeptines
DISTRIBUTION OF ALKALOIDS DERIVED FROM DISTRIBUTION OF ALKALOIDS DERIVED FROM
ERGOLINE ERGOLINE
• These alkaloids were initially characterized in the ergot ergot of rye
of rye, Claviceps purpurea Claviceps purpurea.
• The genus Claviceps Claviceps comprises about fifty species fifty species, and several of them are capable of infesting Poaceae, Poaceae
including cereals and non-cereals, and particularly the Paniceae
Paniceae.
• Examples: C. purpurea on Secale cereale Examples Secale cereale,
• C. paspali on Paspalum Paspalum spp., and spp
• C. fusiformis on Pennisetum Pennisetum.
• C. purpurea and C. paspali elaborate mostly ergopeptines
ergopeptines and simple lysergic acid derivatives lysergic acid derivatives, respectively.
• Most of the other Claviceps Claviceps synthesize clavines clavines.
DISTRIBUTION OF ALKALOIDS DERIVED FROM DISTRIBUTION OF ALKALOIDS DERIVED FROM
ERGOLINE ERGOLINE
• The clavines clavines are also synthesized by other fungi (Aspergillus, Balansia, Penicillium, Rhizopus Aspergillus, Balansia, Penicillium, Rhizopus) which, in rare cases, elaborate more complex structures (dihydroergosine of Sphacelia sorghi, ergobalansine of Balansia spp.).
• Curiously, certain higher plants are capable of certain higher plants are capable of producing clavines
producing clavines, simple amides (ergine, hydroxyethylamide), and even ergosine, for example several species in the family
Convolvulaceae
Convolvulaceae, more specifically in the genera Argyreia, Ipomoea, Turbina,
Argyreia, Ipomoea, Turbina, and Strictocardia. Strictocardia.
BIOSYNTHETIC ORIGIN
BIOSYNTHETIC ORIGIN: : Tryptophan Tryptophan
• Labelling experiments show that the precursors of the precursors of the
ergoline nucleus
ergoline nucleus are tryptophan
tryptophan, mevalonic acid mevalonic acid, and methionine methionine:
– tryptophan provides the tryptophan indole nucleus, C-4, C-5C-4, C-5, and N-6; N-6
– mevalonic acid, via mevalonic acid
dimethylallyl pyrophosphate, is the origin of C-7, -8, -9, C-7, -8, -9,
-10; -10
– methionine methionine (as 5-adenosyl- methionine) methylates N-6.
N
N CH3
H O
NH H
N
N
O
R1 H O
O
H OH
ERGOTAMINE
5 4 6 7 8 9
10
BIOSYNTHETIC ORIGIN BIOSYNTHETIC ORIGIN
• Several mechanisms have been proposed to rationalize the first step in the elaboration of ergoline, in other words the formation of
dimethylallyltryptophan
dimethylallyltryptophan (DMAT).
NH
DMAT
NH2
COOH
Di D i M M ethylA ethyl Alyl lyl Tryptophan T ryptophan
DMAT DMAT
BIOSYNTHETIC ORIGIN BIOSYNTHETIC ORIGIN
• The next step leads to chanoclavinechanoclavine:
• DMATDMAT (D (DiiMMethylethylAAlyllylTTryptophanryptophan)is M-methylated and ) decarboxylated
decarboxylated, the methyl group (Z) oxidized to a hydroxy-hydroxy- methyl group
methyl group (probably via an epoxide), and the double bond isomerized.
NH
DMAT
NH2
COOH
NH NH
COOH OH
CH3
HN
N H
Chanoclavine
OH
H
H
CH3
BIOSYNTHETIC ORIGIN BIOSYNTHETIC ORIGIN
• The next step is the formation of agroclavine agroclavine upon closure of the D ring closure of the D ring.
• The hydroxymethyl group is oxidized to an aldehyde, which reacts with the secondary amine.
HN
N H
Chanoclavine
OH
H
H
CH3
N
N CH3
H H
H
Agroclavine DD
BIOSYNTHETIC ORIGIN BIOSYNTHETIC ORIGIN
• Subsequently, a mono-oxygenase induces the hydroxylation of the C-8 methyl group
(elymoclavine elymoclavine).
N
N CH3
H H
H
Elymoclavine
OH
HN
N H
Chanoclavine
OH
H H
CH3
N
N CH3
H H H
Agroclavine
BIOSYNTHETIC ORIGIN BIOSYNTHETIC ORIGIN
• A hypothesis is that peptide alkaloids are formed from the ald ald e e hyde which arises from the hyde the oxidation of the oxidation of the
hydroxymethyl group of elymoclavine
hydroxymethyl group of elymoclavine, without going through an acid as an intermediate (lysergic lysergic or
paspalic
paspalic acid). acid
N
N CH3
H H
H
Elymoclavine
OH
N
N CH3
H H
H H
O N
N CH3
H OR
O H
N
N CH3
H H
H OH
O
Paspalic acid Lysergic acid and ergopeptines
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne ERGOTISM
ERGOTISM
• It was around 1000 A.D. that the first precise
descriptions of "St. Anthony's fire St. Anthony's fire" appeared; they
referred to ergotism ergotism outbreaks, which ravaged western Europe for several centuries .
• Ergotism, the consequence of the ingestion by humans Ergotism of the cereals cereals contaminated contaminated by by the the fungus, commonly fungus occurred as one of two forms:
– Gangrenous G angrenous form form ("St. Anthony's fire St. Anthony's fire"); the disease began with a painful inflammation of the extremities, and
resulted in numb, blackened, and dry extremities,
sometimes ending with their spontaneous loss at a joint;
– Convulsive C onvulsive form; the dominant Symptoms were mental form
agitation, delirium, and sensory perturbations.
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne
• The prevalence of ergotism decreased decreased rapidly as agriculture
agriculture improved and as improved nutrition nutrition became became more
more diversified. diversified
• Ergotism epidemies did take place in the the north north and and the the east of east of Europe until the nineteenth Europe
Century , and in the the former former Soviet Soviet Union until Union 1926.
• More recently (1977-78), 47 deaths linked to the ingestion of contaminated cereals were
documented in Ethiopia Ethiopia.
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne
• The responsibility of bread made from infested rye was not The responsibility of bread suspected until the end of the seventeenth century, and it was not demonstrated in animals until one century later.
• The fungal nature of ergot was recognized in 1711 The fungal nature of ergot 1711, but the mystery of its development cycle was not elucidated until 1853. 1853
• The twentieth century was to be that of the isolation of the isolation of the alkaloids
alkaloids (ergotamine, Stoll, 1918 1918), of the demonstration of their pharmacological properties, and later, of their mass production by fermentation.
• The oxytocic properties of ergot had long been known The oxytocic properties of ergot (Lonicer, 1582 1582) and used (pulvis parturiens) before they
became reserved for the control of post-partum hemorrhage
(this led to a decrease in the number of still births!).
ERGOT OF RYE, ERGOT OF RYE, Claviceps
Claviceps purpurea purpurea
• The Fungus, the Drug
• At first glance, the fungus exists in two forms:
• the vegetative form vegetative form which is a conidiospore-bearing stroma conidiospore-bearing stroma known as sphaceliasphacelia,
• and the resting form or sclerotium
sclerotium.
• The sphacelia is formed by the mycelium, whose hyphae have invaded the ovary of the rye flower.
• It is at the end of some of the hyphae that the conidiospores develop as the organs of
asexual reproduction.
ERGOT OF RYE, ERGOT OF RYE, Claviceps
Claviceps purpurea purpurea
• The Fungus, the Drug
• The sclerotium is an elongated,
• arched, and purplish black mass,
• destined to spend the winter on the ground.
• These two forms alternate according to a complex cycle:
• the sexual cycle begins in the spring with the formation, on the the sexual cycle
sclerotium, of masses of stromata on stalks, each containing numerous perithecia, in other words follicles opening by an ostiole and containing the asci.
• The filamentous ascospores released and carried by the wind infect the flowers of other plants. At this point, the mycelium develops into a stroma, which produces the conidiospores;
• the conidiospores, transported by insects, ensure the asexual reproduction of the haploid mycelial gametophyte.
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne
• B. Alkaloid Production
• For a long time, the needs of the pharmaceutical industry were fulfilled exclusively by extraction from sclerotia extraction from sclerotia
obtained by artificially infesting rye. artificially infesting rye
•
• Later, it became possible to meet part of the international demand for active alkaloids by saprophytic culture of saprophytic culture of
selected strains
selected strains of various species of Claviceps.
• The alkaloids extracted from the culture media were used directly or after chemical transformation ( semisynthesis). semisynthesis
• Rehacek and Sajdl (1990) note that: "...the the parasitic culture parasitic culture of ergot
of ergot in the western h in the western h emisph e misphe e re (predominantly re
Switzerland) has almost stopped".
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne Field Cultivated Ergot (Çavdar Mahmuzu)
• Ergots are obtained by artificial infestation artificial infestation of cereals with strains of the fungus selected for their virulence and their high concentration of alkaloids. This infestation was initially practiced on rye.
• The traditional methodThe traditional method::
– First, the selected strain is cultured in a liquid medium with a
composition appropriate for inducing the formation of conidiospores.
– At the time of infestation, an inoculum is prepared by suspending the spores in water (3,000-5,000 spores per mm3).
– Next, the inoculum is used to inoculate the young ears (at the latest at the very beginning of the floration).
– The injection is accomplished using Systems resembling hypodermic syringes connected to a reservoir containing the conidiospore
suspension; a specially designed mechanical device brings the ears in contact with the needles.
– The harvest may begin six to seven weeks after inoculation.
– The yield of sclerotia is very variable and can reach 300 kg/hectare (=
300 kg/2.47 acres).
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne
Industria
Industrial l Fermentation Fermentation
• The knowledge of how to develop Claviceps on synthetic media is about one hundred years old.
• The different Claviceps can be cultured at pHs near 5.5, which are best adjusted with ammonium salts of the acids of Krebs' cycle (succinate, citrate).
• Frequently, the alkaloid production is dependent on the phosphate concentration of the medium, and for many strains, on the precise concentrations of minerals (iron, zinc, copper, boron) which directly influence the productivity.
• The oxygenation of the culture medium must be intense. Cell
differentiation and alkaloid production are controlled by the addition of nutrients: a rich medium causes the formation of abundant hyphal
mycelium and no alkaloid production.
• For many strains, it is the phosphate concentration that conditions the passage from the mycelium proliferation phase to the biochemical
differentiation phase. Tryptophan, added at the beginning of the
fermentation, acts as an enzymatic inducer, and therefore it increases the quantity of alkaloids formed.
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne
• Alkaloids produced
• Two approaches are possible:
• A. The first one consists of producing simple ergolenesA. producing simple ergolenes, namely paspalic acid or the hydroxyethylamide of lysergic acid.
• Once isolated from the culture medium, the two ergolene derivatives are transformed—the first by isomerization, the second by hydrolysis—into lysergic acid, the starting material for the synthesis of non-peptidic
alkaloids used in therapeutics (ergometrine and others).
– Some clavines can also be the starting materials for the synthesis of more complex products.
• B. The second approach, which is more recent, leads to the B. direct direct production of ergopeptines
production of ergopeptines, particularly ergocryptine, from strains of C. ergocryptine purpurea and possibly from other species.
• The fermentation is lengthy, and the ergopeptines are obtained in a yield on the order of g/L. The culture can be directed by adding to the medium the amino acids that are the precursors of the desired tricyclic peptide.
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne
• C. Chemical Composition C. Chemical Composition : :
• The ergot of rye is a drug of complex
composition. Besides the sugars and a large
number of amino acids, the drug contains a high proportion of lipids: 20 to 40% of its mass
consists of an oil which readily turns rancid,
hence its degradation in storage. Note also the presence of sterols (ergosterol and related ergosterol and related
compounds
compounds ), amines amines arising from the
decarboxylation of amino acids, and pigments.
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne
• C. Chemical Composition C. Chemical Composition
• Some are minor and anthraquinone-like anthraquinone-like (clavorubin clavorubin, endocrocin), the others are dominant and are mostly
xanthone dimers
xanthone dimers or ergochromes.
• The concentration of ergoline alkaloids, varies greatly: it might reach 1% in strains intended for the artificial
infestation of cereals.
COOH OH
HO
OH
O OH
O
O
OH O
OH
H3CO O OH
CClavorubinlavorubin
Monomeric xanthone Monomeric xanthone
Alkaloids of
Alkaloids of Claviceps purpurea Claviceps purpurea
• T T wo main groups of alkaloids are wo main groups of alkaloids distinguished:
– 1. 1. The simple amides of lysergic acid. The simple amides of lysergic acid.
– 2. The ergopeptines 2. The ergopeptines
Alkaloids of
Alkaloids of Claviceps purpurea Claviceps purpurea
1. 1. The simple amides of lysergic acid The simple amides of lysergic acid
1. 1. The simple amides of lysergic acid represent The simple amides of lysergic acid about 20% of the total alkaloids.
• The chief alkaloid in the group is ergonovine ergonovine (ergobasine, ergometrine ergobasine, ergometrine), the amide of the amide of
lysergic acid and of 2-amino-propanol lysergic acid and of 2-amino-propanol.
• Ergot also contains a small amount of ergine ergine
(lysergic acid amide lysergic acid amide).
• 2. 2. The ergopeptines are insoluble in water, are by The ergopeptines far the principal alkaloid constituents (80% of the total alkaloids).
• The hydrolysis of ergopeptines affords
– lysergic acid, lysergic acid – proline, proline
– ammonia, ammonia
– an amino acid amino acid which may be
• phenylalanine, leucine, isoleucine, or valine, and
– an α α-ketoacid -ketoacid
• pyruvic acid, dimethylpyruvic acid, α-ketobutyric acid
Alkaloids of
Alkaloids of Claviceps purpurea Claviceps purpurea
2. 2. The ergopeptines The ergopeptines
• The characteristic structural element of the ergopeptines
ergopeptines is the cyclol cyclol formed by the reaction of the hydroxyl group on the α-carbon of an amino acid (that which, by hydrolysis of the peptide, leads to the α-ketoacid), and the carboxyl group of proline.
• The principal alkaloids in this group are ergotamine and "ergotoxine", a mixture of ergocornine,
ergocryptine (α + β), and ergocristine.
• The other alkaloids are not abundant and are of no therapeutic interest.
Alkaloids of
Alkaloids of Claviceps purpurea Claviceps purpurea
2. 2. The ergopeptines The ergopeptines
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne
N
N CH3
H O
N H
N
N O H R O O
H OH
ERGOTAMINES
H
N
N CH3
H O
N H
N
N O H R O O
H OH
H
N
N CH3
H O
N H
N
N O H R O O
H OH
H
ERGOXINES ERGOTOXINES
H H H
AA BB CC
R R A: Ergotamines B: Ergoxines C: Ergotoxines
-CH2C6H5 Ergotamine Ergostine Ergocristine
-CH2CH(CH3)2 α-Ergosine α-Ergoptine α-Ergocryptine
-CH2CH(CH3)2 β-Ergosine - β-Ergocryptine
-CH(CH3)2 Ergovaline Ergonine Ercocornine
-CH2CH3 Ergobine Ergobutine Ergobutyrine
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne
N
N CH3
H O
N H
H
H HO
ERGONOVINE (= Ergometrine)
N
N CH3
H O
N H
N
N O H O
O
H OH
H
ERGOCRISTAM
H N
N CH3
H H
ERGINE
O H2N
H
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne
• Comment: instability of lysergic acid derivatives.
• The derivatives of lysergic acid readily epimerize at C-8 to form derivatives of isolysergic acid.
• This epimerization is enhanced in polar solvents and goes through an enol intermediate. The nomenclature of the two series differs by the ending of the name of the alkaloid,
which is -ine -ine for lysergic acid derivatives, and -inine for lysergic acid derivatives -inine for the for the corresponding C-8 epimers
corresponding C-8 epimers or isolysergic acid derivatives (e.g., ergonovine and ergonovinine, ergosine and
ergosinine).
• The chief consequence of epimerization is of a
pharmacological nature: the derivatives of isolysergic acid
are devoid of activity.
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne
• The aqueous solutions of alkaloids derived from lysergic acid
lysergic acid are sensitive to UV radiation: the sensitive to UV radiation photoaddition of a molecule of water across the 8,9-double bond yields stereoisomers.
N
N CH3
H H O
HO N
N CH3
H H OH
HO N
N CH3
H H O
HO
Lysergic acid
Lysergic acid Isolysergic acidIsolysergic acid
D. Tests D. Tests
• The alkaloids can be detected by color reactions.
• The ergot alkaloids react with 4- 4- dimethylaminobenzaldehyde
dimethylaminobenzaldehyde under acidic
conditions to give a blue color blue color (van Urk reaction van Urk reaction).
• This color reaction can be used for quantitation (Pharmacopoeia).
• The analysis of complex alkaloid mixtures (total alkaloids, fermentation media, pharmaceutical formulations) can be performed efficiently by HPLC (UV detection).
N
CH3 H
• SS:
– A. Toluol – EtOAc - Diethylamine (70:20:10)A – B. Toluol – Chlororform – EtOH (28,5:57:14,5)B
• Detection: Van URK Reagent Van URK Reagent
– Van URK Reagent (0.2 g 4-Dimethylaminobenzaldehyde is solved in 25% HCl adding one drop 10% FeCl3)
Ergot Alkaloids:
Ergot Alkaloids:
TLC Analysis TLC Analysis
S : S : Secale cornutumSecale cornutum T3 = Ergometrine T3 = Ergometrine T4 = Ergotamine T4 = Ergotamine T5 = Ergocristine T5 = Ergocristine
SS SS
D. Tests D. Tests
M. Ruhland, J. Tischler,
M. Ruhland, J. Tischler, Mycotoxin Research Vol. 24, No. 2 (2008), 73-79Mycotoxin Research Vol. 24, No. 2 (2008), 73-79
ERGOT
ERGOT : E. Pharmacological Activity :
• The pharmacological activity of the ergot alkaloids is particularly complex due to their structural analogy with endogenous amines: noradrenaline, noradrenaline,
dopamine,
dopamine, and serotonin. serotonin.
• This structural similarity explains the affinity of the alkaloids and their derivatives for the endogenous amine receptors and their ability to exert
agonistic or antagonistic effects on those receptors agonistic or antagonistic effects on those receptors.
• It also explains how, even though these alkaloids may develop a preferred activity on one specific type of receptor (α-adrenergic, dopaminergic, or α-adrenergic, dopaminergic, or
serotonergic serotonergic).
Nor-adrenaline
Nor-adrenaline DopamineDopamine SerotoninSerotonin
OH
N H HO
O R
H
H
HO
OH
N
O R
H
H HO
NH
N
O R
H
H OH
2
HO
OH
NH2
HO
OH
NH
NH2 HO
Nor-adrenaline
Dopamine
Serotonine
E. Pharmacological Activity E. Pharmacological Activity
• Ergonovine Ergonovine
• This alkaloid is a potent oxytocic: it increases basal tone, and the frequency and strength of uterine
contractions; the more advanced the pregnancy, the stronger the effect is.
• This activity is thought to be linked to the stimulation of the α α -adrenergic receptors in the myometrium (uterus -adrenergic receptors kası).
• Uterine hypertonicity is at the origin of the Uterine hypertonicity
antihemorrhagic effects of ergonovine. In practice,
methylergonovine is the preferred medication.
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne
• E. Pharmacological Activity E. Pharmacological Activity Ergotamine
Ergotamine
• At low doses, ergotamine ergotamine is a potent vasoconstrictor vasoconstrictor acting by stimulation of the α-adrenergic receptors (or of the serotonergic receptors in the case of the cranial blood vessels). Cranial = Kafatası
• The change in vascular tone is particularly marked peripherally and in the branches of the external
carotid; this reaction is accompanied by the closure of the arterio-venous shunts. At higher doses, an
adrenergic antagonist activity appears, which is weak, and illustrates the duality in the activities of this
compound. In addition, ergotamine ergotamine is an oxytocic oxytocic.
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne
• Hydrogenated Derivatives of Naturally-occurring Alkaloids
• 9,10-Dihydroergotamine. 9,10-Dihydroergotamine results from the hydrogenation of the 9,10-double bond, which greatly decreases the agonist activity at the a-adrenergic receptors (the intensity of the activity is thought to be dependent on the preexisting vascular tone) and reinforces the potency of the adrenergic and serotonergic antagonist activity.
• 9,10-Dihydroergotamine is more active on veins than
arteries; it is a vasoregulator which "stabilizes vascular
tone".
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne
• Hydrogenated Derivatives of Naturally-occurring Alkaloids
• 9,10-Dihydroergotoxine. 9,10-Dihydroergotoxine has a complex pharmacology (stimulation of
central receptors, peripheral vasodilation,
regulating activity on the neuronal metabolism)
which might explain its beneficial effects on what
are commonly thought of as behavioral problems
due to senile cerebral insufficiency.
Semisynthetic or Synthetic Derivatives Semisynthetic or Synthetic Derivatives
• Methysergide is a potent serotonergic potent serotonergic antagonist
antagonist, devoid of intrinsic vasoconstricting effect. All of its activities (inhibition of the
increase in permeability caused by serotonin, decrease of the release of histamine by
mastocytes, and more) contribute to making it a basic treatment of migraine headaches
basic treatment of migraine headaches.
N
N CH3
H H O
NH HO H H
Methysergide
Methysergide
Semisynthetic or Synthetic Derivatives Semisynthetic or Synthetic Derivatives
• Nicergoline Nicergoline is a synthetic derivative, more specifically an ester of 10α-methoxylysergol in which the ergoline nucleus is hydroxymethylated at C-8.
• Nicergoline Nicergoline is pure α-1-adrenergic antagonist, nicergoline is a "cerebral vasodilator cerebral vasodilator": it increases the arterial blood it increases the arterial blood
flow to the brain and enhances glucose and oxygen flow to the brain and enhances glucose and oxygen
utilization by brain cells
utilization by brain cells; it also decreases platelet aggregation.
Nicergoline Nicergoline
N
N CH3
H
O H
O H N
Br
Semisynthetic or Synthetic Derivatives Semisynthetic or Synthetic Derivatives
• 2-Bromo- 2-Bromo- α α -ergocryptine (= bromocriptine -ergocryptine bromocriptine) results from the introduction of a bromine atom bromine atom (Br) on the carbon atom of (Br) indole moiety, and its postsynaptic dopaminergic agonist postsynaptic dopaminergic agonist
properties
properties are exacerbated (intensified).
• Bromocriptine inhibits the secretion of prolactin inhibits the secretion of prolactin . .
• It compensates the dopamine depletion due to the dopamine depletion
degeneracy of the pathway between the substantia nigra and the corpus striatum in parkinsonism. in parkinsonism
2-Bromo-
2-Bromo- α α -ergocriptine -ergocriptine
N
N CH3
H O
N H
N
N O H O
O
H OH
H
H
Br
• Lisuride Lisuride is a synthetic derivative of the 8 8 α α - - aminoergoline type
aminoergoline type.
• Like bromocriptine, it is a dopaminergic agonist dopaminergic agonist with predominant central activity.
• It is also active at serotonergic receptors.
N
N CH3
H H C N
H N
O
Semisynthetic or Synthetic Derivatives Semisynthetic or Synthetic Derivatives
Lisuride
Semisynthetic or Synthetic Derivatives Semisynthetic or Synthetic Derivatives
• LSD is a semisynthetic derivative, of no use in therapeutics, and it is a potent
psychedelic
psychedelic: it is thought to act by interfering with normal serotonergic serotonergic
transmission transmission.
Lysergic acid diethylamide =
Lysergic acid diethylamide = LSD LSD
• Its psychic effects are very marked, and manifest themselves by perceptual changes (shapes, colors, sounds), subjective time alterations, a disintegration of the self, an increase in suggestibility, the resurgence of forgotten memories, and more.
• Physiologically, mydriasis, tachycardia, and tremors are observed, as well as a
desynchronization of the electroencephalogram. The environment and the state of mind of the subject (previous experiences, expectations) are determining factors in the onset of undesirable effects: propensity to panic, anxiety, fear of death and insanity, changes in personality, persistence of a psychotic syndrome, and
spontaneous recurrence, sometimes for long periods of time, of the psychedelic experience in the absence of further ingestion of the product.
• LSD induces tolerance, but no physical dependence (no withdrawal symptoms)
• withdrawal symptoms = yoksunluk sendromu.
N
N CH3
H
N H
O H
• Methylergometrine Methylergometrine . Methylergometrine maleate is indicated (injectable solution) for obstetric emergencies: afterbirth delivery and post-partum hemorrhages, after cesarean sections, after curettage, after abortion by suction or curettage, and for uterine atony after giving birth.
• The compound must not be used in breast-feeding women.
• The blood pressure of patients taking it must be monitored, and side effects are rare (hypertension attacks).
• When it is used by the oral route (solution, tablets), ergometrine is indicated:
– 1. for afterbirth delivery and post-partum hemorrhages (following post-partum hemorrhages oxytocics administered parenterally);
– 2. for metrorrhagia of various origins (after giving birth, therapeutic abortion, spontaneous abortion);
– 3. for the adjunctive treatment of menorrhagia in the absence of pregnancy after attempts have been made todetermine the cause of the disorder (but for this indication, some feel that the benefit-to-risk ratio is unfavorable).
F. Uses of Ergot Alkaloids F. Uses of Ergot Alkaloids
(natural, modified, semisynthetic, synthetic analogs)
(natural, modified, semisynthetic, synthetic analogs)
• F. Uses of Ergot AlkaloidsF. Uses of Ergot Alkaloids
• Ergotamine. Ergotamine tartrate is used orally or rectally, in combination with caffeine, which accelerates and reinforces its digestive resorption by about 45%.
• This compound provides a specific treatment of the acute attack of migraine headache and related vascular headaches; it must not be considered a basic treatment of the patient with migraines.
• In the majority of cases, the administration of 2 mg is sufficient (in adults) (max 6 mg per day, and in case of multiple doses per week, 10 mg per week).
• If ischemic symptoms appear (vasoconstriction of the extremities, tingling) the treatment must be discontinued immediately.
• Although the risk of ergotism is low, a certain number of pathological
conditions increase it, and therefore there are contraindications: occlusive vascular disease, arterial hypertension, coronary insufficiency, and severe hepatic or renal insufficiency.
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne
• F. Uses of Ergot AlkaloidsF. Uses of Ergot Alkaloids
• Dihydroergotamine is used for the treatment of migraines and vascular headaches; to improve the symptoms of venous and lymphatic vessel insufficiency.
• It is also proposed for the treatment of orthostatic hypotension.
• The administration on an empty stomach is to be avoided (risk of nausea). It is best to avoid giving it to pregnant or breast-feeding women.
• First vasoconstrictive phase due to the release of serotonin
(scintillating scotoma, tingling, psychic symptoms) and a second phase—the headache—due to vasodilation (decrease in serotonin levels, passive relaxation of the blood vessels).
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne
• F. Uses of Ergot AlkaloidsF. Uses of Ergot Alkaloids
• Dihydroergotoxine - dihydroergocristine. Dihydroergotoxine mesylate is available under various forms designed for oral
administration (solution, tablets or single dose lyophilisate, capsules containing microgranules for slow release) and as an injectable
solution.
• Also used as a mesylate, dihydroergocristine is commonly combined with an adrenergic antagonist like raubasine (= ajmalicine) or to a substance that will enhance its intestinal absorption (lomifilline).
• These two alkaloids have similar indications: they are proposed for oral administration (2-5 mg/day) as a corrective treatment of senile cerebral insufficiency (lack of attention, memory loss), to treat the sequelae of cerebrovascular accidents, dizziness in the elderly,and retinal disorders of vascular origin.
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne
• F. Uses of Ergot AlkaloidsF. Uses of Ergot Alkaloids
• Methysergide . Methysergide maleate is used orally, only in adults (1
mg/day with gradual increase to 4-6 mg/day in France; 2-mg tablets for a usual adult dose of 4-8 mg/day) for the following principal indications:
– basic treatment of migrainesmigraines and – facial pain of vascular origin. facial pain
• It is not a treatment for permanent migraine. It is contraindicated in cases of severe hypertension, coronary insufficiency, peripheral vascular
symptoms, serious hepatic or renal insufficiency, pregnancy, and breast- feeding.
– Continuous administration must not exceed 6 months, and successive courses of treatment must be separated by 1 month.
• Possible side effects, especially at the beginning of treatment, include Possible side effects digestive and nervous symptoms (nausea, dizziness, insomnia, or
drowsiness).
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne
• F. Uses of Ergot Alkaloids
• Nicergoline (INN). Nicergoline (a controlled substance on French liste II, i.e., a prescription drug), given its a- blocking properties, is indicated for the adjunctive treatment of the intermittent claudication due to
chronic occlusive arterial disease of the lower limbs. It is proposed orally or parenterally to improve some of the symptoms of senile cerebral insufficiency (lack of attention, memory loss), or dizziness in the elderly. It is proposed by the parenteral route for acute
cerebrovascular accidents of ischemic origin and for the acute manifestations of arteritis of the lower limbs (see above).
ERGOT OF RYE,
ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne (Fries) Tulasne
• F. Uses of Ergot AlkaloidsF. Uses of Ergot Alkaloids
• 2-Bromo-α-ergocryptine (= bromocriptine, INN). There are three main groups of indications for this substance.
• 1. Prolactin-secreting adenomas: basic treatment; in preparation for surgical procedures in case of macroadenoma; in case of early or late failure following surgery: for the clinical consequences of recurring hyperprolactinemia.
• Clinical consequences of hyperprolactinemia: severe disturbances of the menstrual cycle, sterility, galactorrhea, and in men, gynecomastia (Meme dokusunun büyümesi) and impotence.
• 2. Inhibition of lactation: prevention and inhibition of physiological lactation for
• 3. Treatment of parkinsonism alone (patients over 65 years of age) or in combination with levodopa (to decrease the doses of each drug and delay the onset of fluctuations in efficacy and abnormal movements).
