Isoquinoline alkaloids

1
Isoquinoline alkaloids

• 1-Benzyl isoquinoline type Papaverine An opiate
  alkaloid isolated from the plant Papaver
  somniferum and produced synthetically.
• Pharmacology
• 1-papaverine decrease the tone of smooth muscles.
  It has spasmolytic and vasodilatation effect
• 2-it is neither narcotic nor addictive
• 3-it is of beneficial effect on angina pectoris
• 4-used for treatment of pulmonary embolism and
  cerebrovuscular thrombosis.

2
2-benzyltetrahydroisoquinoline

• Ipecac alkaloids
• Emetine, cephaline, psychotrine obtained from
  the roots of Cephalis ipecacuana, (family
  Rubiaceae),it cause vomiting and has local
  reputation for use for dysentery.
• Mode of action locally by irritation of mucous
  membrane of stomach and intestine. These days its
  use as emetic is less because of this effect

• Pharmacology
• 1-for dysentry ( entamoeba histolitica ) because
  of its emesis effect
• 2-for poisoning cases in hospitals
• 3-in small doses emetine and cephaline are
  expectorant
• 4-ipecac extract used also as expectorant

3

• Pharmacology
• 1-curare posses a paralyzing effect on voluntary
  muscles, a toxic one on blood vessels and
  histamine like effect. Most of the activity
  attributed to d-tubocurarine
• Uses
• 1-in surgical anaesthesia as it produce muscular
  relaxation without a deep anaesthesia.
• 2-after shock treatment (in mental diseases) as
  it reduces convulsion
• 3-to control convulsion after strychnine
  poisoning.

• 3-Bis-benzyl isoquinoline curare alkaloids
• Tubocurarine obtaine from the bark and stems of
  Chondrodendrum tomentosum ( family Menispermaceae)

• from urari The term curare is used to indicate
  crude extract prepared from different species
  and was used by certain natives of the Amazon
  regions of South America as arrow poison. Some of
  these extracts were poisonous by virtue of a
  convulsant action and others by paralyzing
  action.
• The bark and stems of the plant are extracted by
  boiling with water and straining or by
  percolation with water or alcohol. The extract is
  concentrated to a standardized concentration to
  be used

4
Tubucurarine
5

• the plant is an annual herb with large solitary
  flowers, either white or pink in color. To obtain
  the latex by incision of the ripening capsule ,
  just changing in color from blue-green to yellow.
  The latex tubes opine one into another. The
  incision made at night , the milky exudates oozes
  out, but rapidly turns brown and coagulates ,
  collected the next morning by scrapping from the
  capsule. the raw opium is moulded into balls or
  blockes and wrapped in poppy leaves and shade
  dried.
• The plant cultivated for black market in Asia
  minor, Afphganistan, also Turkey, Burma, Laose
  and latin America (Mexico and Colombia). Official
  drug cultivated in China, India.

• 4-Opium is reported to contain many alkaloids
  (about 40), the most important of them are
• Morphine, codeine, thebaine, papaverine,
  noscapine and narceine. They are devided into 4
  groups according into structures
• 1-benzylisoquinoline like papaverine
• 4-phenanthrenee.g., morphine, codeine, thebaine
• Opium is the dried milky exudates, or latex,
  obtained by incising the unripe capsules of opium
  poppy.

6

• Oppose latex of opium
• Endogenous opiates
• Receptors for morphine and codeine have been
  detected in the brain. This resulted in isolation
  of enkephalins ( met-enkephalin, leo-enkephalin),
  endorphins and dynorphins, which are small
  peptides produced marily but not exclusively in
  the pituitary gland. it is interesting that
  codeine and morphine are present in mammalian
  tissue, particularly in brain tissue

Morphine
thebaine
Codeine
7

• Pharmacology
• The pharmacological action of opium is due to
  morphine first which act as stimulant first then
  sedative hypnotic depressing the CNS.
• Effect
• 1-analgesia
• 2-miosis
• 3-euphoria
• 4-respiratory depression
• 5-sedation
• 6-physical dependence
• 7-bradycardia
• 8-constipation

• Adverse effect
• 1-constipation
• 2-sedation
• 3-nausea and vomiting
• 4-respiratory depression
• 5-dependence addiction, if used for a long time
• 6-anticholinergic effect dry mouth , urinary
  retension
• 7-CNS excitation
• 8-tolorance increase doses required to maintane
  analgesia

Withdrawal symptoms 1-anxiety
2-irritability 3-insomnia
4-chills 5-salivation
6-diaphoresis 7-nausea 8-vomiting 9-GI
cramping and diarrhea These symptoms last for
about 10-14 days , unless a further dose of
morphine is taken.
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Uses Morphine post operative analgesic for
major operations, cancer patients (terminal
pain).

• Uses
• Codeine mainly used as antitussive, it suppress
  the coughing center in brain Codeine is less
  toxic and much weaker in action than morphine
  with less development of tolerance.

9

• Semisynthetic preparations
• 1-herion
• morphine diacetate, highly addictive analgesic,
  with more lipophilicity. resulted in much abuse
  of the drug.

• 3-pethidineless potent than morphine, with
  shorter duration of action . used by addict
  people. Less constipating

10
5-methadonesimilar activity to morphine with
longer duration of action and different
withdrawal symptoms, used in rehabilitation
program for addict patients.

• 4-fentanyl 50-100 times more analgesic effect
  than morphine.

• 6-tramadol new analgesic drug ,act by 2
  mechanism,morphine mechanism and serotonine
  adrenergic pathway. Produce typical morphine side
  effects.

11

• -in the past ergot played a tragic role as cause
  of a devastating epidemic poisoning in Europe in
  the middle ages, called Saint Antony fire (
  Ergotism). The toxicity is manifested in tow
  forms
• 1-Ergotismgangrene of the exteremities which
  resulted in bloodless, often dramatic , loss of
  blackened limbs ( vasoconstriction)
• 2-Delerium and hallucination which may lead to
  convulsions.

Indole alkaloids

• Ergot alkaloid
• Ergot is the product of filamentous fungus( dried
  sclerotium) of Claviceps purpurea family
  Hypocreaceae that grow parasitically on rye and
  other graminaceous plants.

12

• Ergometrine ( ergonovine) structure

• Production of ergot alkaloids achieved through
  the followings
• 1- Isolation from the crude drug grown
  parasitically in the field ( parasitic
  cultivation) this method involves culturing in
  vivo of the conidia suspension either by spraying
  or more efficiently by injection using for
  industrial scale production inoculation machines
  to infect large fields.
• 2-extraction from saprophytic cultures (
  artificial nutrient medium) in this commercial
  method the mycelium of a selected strain is
  allowed to grow in submerged cultures producing
  lysergic acid amide
• 3-partial and total synthesis

13

•  
• Ergot alkaloids are composed of lysergic acid and
  its isomer isolysergic acid, combined through an
  amide linkage with a peptide rest ( ergotamine
  group ) or with an aminopropanol ( ergometrine
  group ).

Lysergic acid ethyl amide ( LSD ) LSD is a
potent psychotic drug it is thought to act by
interfering with normal serotonergic
transmission. The psychic effects are very
marked perceptual changes ( shapes, sounds,
colors ) subjective time alteration , a
disintegration of the self, an increase in
suggustability.
Lysergic acid structure
14

• ergometrine

• Side effectsedit
• Possible side effects include nausea, vomiting,
  abdominal pain, diarrhea, headache, dizziness,
  tinnitus, chest pain, palpitation, bradycardia,
  transient hypertension and other cardiac
  arrhythmias, dyspnea, rashes, and shock.4

• This alkaloid causes prompt and vigorous
  contraction of the uterus ( oxytocic action ), it
  is used for prevention of hemorrhage after child
  birth.
• It has a medical use in obstetrics to facilitate
  delivery of the placenta and to prevent bleeding
  after childbirth by causing smooth muscle tissue
  in the blood vessel walls to narrow, thereby
  reducing blood flow. It is usually combined with
  oxytocin (Syntocinon) as syntometrine.
• It can induce spasm of the coronary arteries.2
  It is used to diagnose Variant (Prinzmetal's)
  angina.

Mechanism of action While it acts at
alpha-adrenergic, dopaminergic, and serotonin
receptors (the 5-HT2 receptor), it exerts on the
uterus (and other smooth muscles) a powerful
stimulant effect not clearly associated with a
specific receptor type.
15

• The official salt is ergotamine tartaret , it is
  unstable, specially in aqueous solution and on
  exposure to light. On hydrogenation ,
  dihydroergotamine is produced, which is used as
  migraine analgesic ( cafergot tablets with
  caffeine)
• Applies to ergotamine oral tablets, rectal
  suppositories, sublingual tablets
• Cardiovascular side effects have included
  hypertension, tachycardia, bradycardia,
  precordial distress
• Musculoskeletal aches, pains, and cramps, as well
  as general muscular weakness, have been reported.
• Nervous system side effects have included
  drowsiness, paresthesias, headache, peripheral
  neuropathy, vertigo, tremor

Ergotamine
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•  
• 3 Vinca rosea alkaloid.
• vinicristine and vinblastine
• These are obtained from Catharanthus roseus
  (vinca rossea)which is a Madagascar plant.
• It was used in folklore medicine for diabetes in
  Europe for centuries and had a reputation as
  magic plant.
• The alkaloids in this plant referred to as Vinca
  alkaloids

A screening programme at the pharmaceutica
company Eli Lilly revealed that extracts
inhibited growth of certain types of cancer
cells. Bioassay guided isolation of extracts of
the plant led to the finding of these 2 alkaloids
. Problem with this plant that the content are
extremely low VincristineThe generic name for
it is Oncovine ( Eli Lily)
17
Used for acute leukemia, Hodgkins disease and
other lymphomas. Mode of action inhibiting
mitosis by binding to tubulin prevent spindle s
formation. Vinblastine the other drug which is
used for Hodgkin s disease, lymphomas, advanced
testicular and breast cancer. The generic name
Vilbe
vincrstine
18

•  
• 3-strychnus alkaloids
  
  
• The genous strychnus ( Loganaceae.
• The Asian species are source of strychnine and
  brucine , while the South American species are
  the source of certain types of curares.
• Strychnos nux vomica L. and Strychnus ignati
  seeds are known to contain the principle
  alkaloids strychnine and brucine
• ( 2-3 ).
• Mode of action strychnine is CNS stimulant
  with no inhibition at the post synaptic level
  which may lead to convulsion.

• Uses
• 1-it has been used as a general tonic , but this
  use is prohibited owing to its marked toxicity.(
  lethal adult dose is 60-90 mg)
• 2- it is of limited use in modern medicine as a
  respiratory stimulant.
• 3-the greatest use of strychnine is in the form
  of biscuits ( rat poison)
• Brucine the same effect as strychnine with less
  CNS stimulation. used as ethanol denaturant

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• 4-Rauwolfia alkaloids
• They occur in the roots of Rauwolfiaserpintena,
  Apocynaceae.
• The important alkaloids in this plant are
• Reserpine , deserpidine, recinnamine
• more than 40 alkaloids had been isolated from
  different species of Rauwolfia.
• Ajmaline, ajmalicine serpentine serpentinine,
  yohimbine

uses Reserpine leads to constant loss of
serotonine, norepinephrine and dopamine from the
nervous tissue. This explain its sedative ,
tranquilizing and hypotensive effects
20
5-Calabar bean alkaloids

•  Physostigmine(eserine) is the main alkaloid in
  the seeds of Physostigma venenosum, Leguminosae
• Pharmacology and uses
• Physostigmine is a choline esterase inhibitor.
• 1-Used in the form of ointment 0.25 for
  treatment of glaucoma.
• 2-it stimulate the secretion of saliva and
  perispiration and increase the tone and
  peristalsis of the GI tract.