Plants containing toxic alkaloids

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Plants containing toxic alkaloids
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• Ergot Alkaloids
• Opium Alkaloids

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Ergot Alkaloids

• Ergot refers to a group of fungi of the genus
  Claviceps.
• The most prominent member of this group is
  Claviceps purpurea .
• Parasitic on different grasses and cereals Fam.
  Graminae (Poaceae).

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Ergot

• Ergot is the fungus, at the sclerotium stage.
• Claviceps purpurea most commonly affects species
  such as rye, wheat and barley ??????.
• It affects oats ??????? only rarely.
• Ergot of rye (Secale cornutum) is the variety
  used medicinally.
• Controlled field cultivation on rye is the main
  source of the crude drug.

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Life cycle

• An ergot sclerotium develops when the ovary of
  floret of grass or cereal is infected by spores
  of a fungal species of the genus Claviceps.
• The proliferating fungus destroys the plant ovary
  and connects with the vascular tissue of the
  plant.

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• The first stage of ergot infection is a white
  soft tissue (known as sphacelia stage) producing
  sugary honeydew (sugar-rich sticky substance),
  which often drops out of the infected ovaries.
• This honeydew contains millions of spores which
  are dispersed to other florets by insects.
• Later, the sphacelia convert into a hard dry
  sclerotium inside the ovaries.
• At this stage, alkaloids (mycotoxins) accumulate
  in the sclerotium.

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• When a mature sclerotium drops to the ground, the
  fungus remains dormant until proper conditions
  (onset of spring, rain period, climate etc).
• It germinates, forming one or several fruiting
  bodies with head and stalk.
• In the head, spores are formed, which are
  ejected simultaneously (at the same time).

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Ergot fungus on wheat
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Ergot mycotoxins

• The ergot sclerotium contains high concentrations
  of alkaloids.
• They contains (up to 2 of dry mass) of the ergot
  alkaloids (ergolines).

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Ergot mycotoxins

• They are medicinally important indole alkaloids.
• Biogenetically they are derived from the amino
  acid tryptophan.

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• Indole
• Tryptamine
• Tryptophan

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Classification

• There are two main groups of ergot alkaloids
• A-The clavine type .
• B-The lysergic acid derivatives type.

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Classification (cont.)

• B- The lysergic acid derivatives group is further
  subdivided into
• i- The simple lysergic acid amides (lysergic
  acid and simple amine)
• ii- The polypeptide alkaloids
• (complex amides of lysergic acid with
• several different amino acids).

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• Ergot alkaloids
• Clavine type Lysergic acid
  type
• Simple LS Amide Polypeptide Amide

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Ergot alkaloids

• The clavine type alkaloids as well as the
  lysergic acid derivative alkaloids are product of
  condensation of tryptophan (or tryptamine) with
  isoprenyl moiety ( 5 Carbons )
• Ergot alkaloids

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A-The clavine type alkaloids

• Alkaloids of this class all end with the suffix
• (-clavine) e.g. agroclavine, elemoclavine..
• They are all simple water soluble bases.
• Not physiologically active as the lysergic acid
  derivatives.
• Recently few examples show significant oxytocic
  activity.
• Agroclavine is a powerful uterine stimulant.

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Example of clavine type alkaloids

• Agroclavine

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The Peptide Bond

• A peptide bond is a covalent bond that is formed
  between two molecules of amino acids.
• When the COOH gp. of one molecule reacts with
  the NH2 gp. of the another molecule, releasing a
  molecule of water.
• This is a condensation reaction and usually
  occurs between amino acids.
• The resulting OC - NH bond is called a peptide
  bond, and the resulting molecule is an amide.

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Formation of the peptide bond

• The carboxylic acid group of one amino acid
  reacts with the amine group of the other. For
  example, two amino acids (glycine) combining
  through the formation of a peptide bond to form a
  dipeptide.

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Amide

• O O
• NH3
• R C OH R C NH2

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Peptides

• Peptide includes wide range of compounds.
• Varying from low to very high molecular wt.
• The lowest members are derived from two molecules
  of amino acids.

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Peptides (cont.)

• Any number of amino acids can be joined together
  in chains called polypeptides.
• Over 100 amino acids called proteins.
• A number of hormones, antibiotics, antitumor
  agents and neurotransmitters are peptides
  (proteins).

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• Ergot alkaloids
• Clavine type Lysergic acid
  type
• Simple LS Amide Polypeptide Amide

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B-The lysergic acid derivatives i-The simple
lysergic acid amides

• All are water soluble alkaloids.
• Low molecular weight.
• All are amides of lysergic acid with simple
  amines.

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• NH3
• ()lysergic acid Ergine

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• The simplest naturally existing is ergine
  (lysergic acid amide, LSA) and erginine
  (isolysergic acid amide).
• Ergine is a psychoactive component, it is known
  as natural LSD.
• The semithynthetic LSD is more potent than ergine
  as a psychedelics drug.
• Psychedelics are part of a wider class of
  psychoactive drugs known as hallucinogens.

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i-The simple lysergic acid amides (cont.)

• The most important members of this group is the
  potent oxytocic alkaloid ergometrine (ergonovine
  in USA).
• Ergometrine (Ergonovine) is the amide of lysergic
  acid with 2-amino propanol.
• And the famous hallucinogen (LSD) lysergic acid
  diethylamide.
• LSD is a semisynthetic drug with a very potent
  action on the CNS in extremely small doses.

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LSD

• LSD was first semi-synthesized by Albert Hofmann
  in 1938 from ergot.
• The short form LSD comes from its early code name
  LSD-25, which is an abbreviation for the German
  "Lyserg Säure-diethylamid" followed by a
  sequential number.
• It is commonly semi-synthesised by
• reacting diethylamine with lysergic acid.
• or from ergine (lysergic acid amide, LSA).

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General structure of lysergic acid amides
R3 R2 R1 Name
H H H Ergine
H CH(CH3)CH2OH H Ergometrine
H CH(CH2CH3)CH2OH H Methergine
H CH(CH2CH3)CH2OH CH3 Methysergide
CH2-CH3 CH2-CH3 H LSD
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Ergometrine

• Is a potent oxytocic alkaloid.
• Contraction of uterus.
• Facilitate labour.
• Prevent postpartum hemorrhage.
• Metre ???

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ii-The polypeptide lysergic acid amides

• Complex in structure.
• High molecular weight.
• Water insoluble.
• They are build up from a lysergic acid moiety
  forming an amide with a complex polycyclic
  polypeptide moiety.
• The polypeptide moiety is formed of three
  different amino acids.

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The polypeptide alkaloids(cont.)

• From this group are the ergotamine and the
  ergotoxine alkaloids.
• Ergotamine has been used extensively to relieve
  migraine headaches through the constriction of
  blood vessels.

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Lysergic and isolysergic acid alkaloids

• Members related to lysergic acid (e.g.ergotamine
  and ergometrine).
• They are levorotatory.
• Pharmacologically more active.
• Designated by the suffix ine
• Members related to isolysergic acid (e.g.
  ergotaminine and ergometrinine).
• They are dexorotatory.
• Pharmacologically less active.
• Designated by the suffix inine

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Medical applications

• Ergot alkaloids have a wide range of biological
  activities.
• 1- Ergotamine is used in the treatment of
  migraine.
• It has the ability to constrict dilated blood
  vessels in the cerebral membranes.
• Hypertension is a side effect.
• 2- Ergometrine is used after childbirth after
  expulsion of the placenta to stimulate uterine
  contractions and to prevent postpartum
  hemorrhage.

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Medical applications (cont.)

• ? Some ergot alkaloids are used in the treatment
• of dementia (brain disorders and psychosis).

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Ergotism (ergot poisoning)

• Ergotism is due to consuming cereals contaminated
  with the fungus.
• Ergotism is the effect of long-term ergot
  poisoning.
• More recently by the action of a number of
  ergoline-based drugs.

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Ergotism, other sources

• Similar toxins are present in certain plants.
• The seeds of the Ipomoea tricolor and Rivea
  corymbosa (Convulvulaceae)
• It is structurally related to ergot alkaloids.

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Ergotism, synonyms

• It is also known as ergotoxicosis, ergot
  poisoning, ergot intoxication.

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Dose-dependent ergotism

• Human disease can occur when cereals contains 1
  ergot.
• An ergot content of 2 can result in epidemics .
• At 7 there is a high mortality rate (dose
  dependent) .
• Alkaloids can also pass through lactation from
  mother to child, causing ergotism in infants.

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Ergotism, clinical aspects

• People who ingest ergot mycotoxins with their
  food may develop various symptoms.
• The symptoms can be divided into
• 1- Convulsive symptoms (neurological) .
• 2- Gangrenous symptoms (vasospastic or spasm of
  blood vessels). The effect is upon circulation.

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1- Neurological Convulsive symptoms

• Usually the gastrointestinal effects precede
  central nervous system effects.
• There is diarrhea, itching, headaches, nausea and
  vomiting.
• There will be mental confusion with
  hallucinations (resembling those produced by LSD
  ), for instance seeing brightly coloured objects,
  wild animals, or visions of blood running down
  the walls.
• The victim has involuntary muscular contractions,
  convulsions (seizure).

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Neurological symptoms (cont.)

• Seizures are symptoms of abnormal electrical
  activity in the brain. .
• These convulsions end to an extreme arching of
  the back, with the head thrown backwards, even
  touching the heels.
• The convulsive symptoms are caused by clavine
  alkaloids and simple lysergic acid derivatives.
• The victims describe a pronounced burning or
  itching sensation of the skin or a tingling like
  insects crawling under the skin.

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Neurological symptoms

• Gastrointestinal disturbances.
• Central nervous system effects.
• Hallucinations.
• Convulsions (seizure).
• Pronounced burning or itching sensation of
• the skin.

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2- Vasospastic Gangrenous symptoms

• Gangrene is the result of vasoconstriction
  induced by the ergotamine alkaloids of the
  fungus.
• It affects the more poorly vascularized distal
  structures, such as the fingers, hands, feet,
  ears and nose.
• Symptoms include weak of pulse, loss of
  peripheral sensation, death and loss of the
  affected tissues.

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General ergotism symptoms

• Intense pain in the lower abdomen, low body
  temperatures and cold fingertips, extreme
  convulsions, hallucinations and burning skin
  sensation .

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Ergotism, historical overview

• In middle ages, ergotism is known to have
  occurred on a large scale in some regions of
  Europe.
• In 857, for example, there was an epidemic in
  Germany characterized by necrosis of limbs and
  culminating in death.
• In 944, some 40,000 people in the south of France
  died from ergot poisoning.
• Between 837 and 1347, some fifty epidemics were
  recorded in Central Europe.

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Ergotism, historical overview (cont.)

• It was a common belief that the symptoms were
  caused by witchcraft.
• In the Salem witchcraft (USA), entire communities
  in and around Salem Village had symptoms of
  ergotism (including some animals).
• Rumors soon spread that witchcraft was involved,
  but subsequent investigation showed that the
  symptoms had been caused by ergotism.

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Ergotism, historical overview (cont.)

• ? In 1670, a French physician, Dr Thuillier,
  suggested that food could play a role in this
  disorder.
• Later, others showed that when ergot was fed to
  animals, they died.
• All the victims had eaten rye bread.
• In August 1951, in France more than a hundred
  people were poisoned and several died as a
  result.
• During the 1st half of the twenty century an
  intoxication have been reported in Egypt and was
  owed to ergot-contaminated wheat flour.

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Ergotism, treatment

• In acute poisoning with a risk of gangrene,
  treatment consists of vasodilators,
  anticoagulants and low molecular weight dextrans
  (plasma expander).
• If necessary, a sympathetic nerve blockade may
  be carried out.
• (Sympathetic nervous system causes
  vasoconstriction)
• Temporary sedation will be necessary in
  hallucination (e.g. haloperidol, major
  tranquillizer). Diazepam (minor tranquillizer is
  used for convulsions).
• There is no specific antidote.

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• A floatation method can be used to separate the
  infected grains from the non-infected grains .
• The grain is immersed in a 30 KCl solution.
• The infected grains are lighter and float to the
  surface.
• They can then be skimmed off and destroyed.
• There are no ergot-resistant cereal varieties
  currently available.
• Fungicides may be used.

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Detection and estimation of ergot alkaloids

• 1- Calorimetrically, based on that the blue color
  produced with p-dimethyl aminobenzaldehyde is
  concentration dependent. The absorbance is
  measured at 590 nm.
• 2- Fluoremetrically, based on that ergot
  alkaloids are fluorescent.

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Pharmaceutical preparations
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Raw opium

• Raw opium is the air dried latex obtained by the
  incisions from the unripe capsules of Papaver
  somniferum (Papaveraceae).
• Opium is the source of many alkaloids, including
  morphine, thebaine, codeine, papaverine, and
  noscapine.
• Morphine is the predominant one.

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Overview

• Opiates are constituents or derivatives of
  constituents found in opium.
• Opiates are narcotic analgesic.
• Narcotic refers to the pain-relieving and
  sleep-inducing properties of these
  highly-addictive alkaloids, including morphine,
  codeine and thebaine.
• Morphine is named after Morpheus the god of
  sleep, while (somniferum) means "to sleep" in
  Latin.

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• The major biologically active alkaloids found in
  opium are morphine, codeine, thebaine, papaverine
  and noscapine.
• Papaverine and noscapine, have little to no
  effect on the human central nervous system, and
  are not usually considered to be narcotic or
  opiates, they have have a different mechanism of
  action.
• papaverine is smooth-muscle relaxant and
  noscapine is antitussive.

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Classification

• Natural opiatesare alkaloids contained in the
  latex of opium as morphine, codeine, and
  thebaine.
• Semi-synthetic opioids created from the natural
  opiates, such as heroin, oxycodone, and
  hydrocodone are derived from morphine, codeine,
  and thebaine.
• heroin is diacetylmorphine.

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• Fully synthetic opioids such as pethidine,
  methadone, tramadol.
• Endogenous opioid peptides, produced naturally in
  the body, such as endorphins, enkephalins,
  dynorphins, and endomorphins.

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Opium alkaloidsClassification

• Phenanthrene group
• Benzylisoquinoline group,
• Phenylethylamine group.
• Bis-isoquinoline group.
• Opium alkaloids occur naturally combined with
  specific acid (meconic acid).
• Meconic acid test.

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Opium alkaloids (cont.)

• Phenanthrene gp.
• Benzylisoquinoline gp.

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• Phenylethylamine gp.

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Pharmacology and uses

• Opiates and Opioids bind to specific opioid
  receptors in the central nervous system and other
  tissues.
• .
• They have long been used to treat acute pain such
  as post-operative pain.
• They have also been found to be valuable in
  palliative care (cancer, and degenerative
  conditions such as rheumatoid arthritis )

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• In palliative or painkilling care the goal is to
  prevent and relieve suffering and to improve
  quality of life for people with serious and
  complex illness.

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Adverse side effects

• Common adverse reactions in patients taking
  opiates and opioids for pain relief include
  nausea and vomiting, drowsiness, itching, dry
  mouth, miosis, and constipation.
• These effects are overcome by medication during
  the course of treatment.

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Opiate poisoning

• Opiate poisoning can range from discomfort like
  constipation to death from respiratory
  depression.
• Alcohol and other sedatives enhance the effect of
  opiates, especially respiratory depression.