Isoquinoline alkaloids1-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 addictive3-it is of beneficial effect on angina pectoris

4-used for treatment of pulmonary embolism and cerebrovuscular thrombosis.

2-benzyltetrahydroisoquinoline

Pharmacology:1-for dysentry ( entamoeba histolitica ):

because of its emesis effect2-for poisoning cases in hospitals

3-in small doses emetine and cephaline are expectorant

4-ipecac extract used also as expectorant

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

3-Bis-benzyl isoquinoline : curare alkaloidsTubocurarine: 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

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

Uses1-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.

Tubucurarine

•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-phenanthrene:e.g., morphine, codeine, thebaine

•Opium is the dried milky exudates, or latex, obtained by incising the unripe capsules of opium poppy.

•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.

•Oppose: latex of op[ium•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

Codeine

thebaine

PharmacologyThe pharmacological action of opium is due to morphine first which act as stimulant first then sedative hypnotic depressing the CNS.Effect:

1-analgesia2-miosis

3-euphoria4-respiratory depression

5-sedation6-physical dependence

7-bradycardia8-constipation

Adverse effect:1-constipation

2-sedation3-nausea and vomiting

4-respiratory depression5-dependence : addiction, if

used for a long time6-anticholinergic effect: dry

mouth , urinary retension7-CNS excitation

8-tolorance: increase doses required to maintane analgesia

Withdrawal symptoms:1-anxiety 2-irritability

3-insomnia 4-chills5-salivation 6-diaphoresis

7-nausea 8-vomiting 9-GI cramping and diarrheaThese symptoms last for about 10-14 days , unless a further dose of morphine is taken.

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.

Uses : Morphine : post operative analgesic for major operations, cancer patients (terminal pain).

Semisynthetic preparations:1-herion:

morphine diacetate, highly addictive analgesic, with more lipophilicity. resulted in much abuse of the drug.

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

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

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

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

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

-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-Ergotism:gangrene 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

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

•Ergometrine ( ergonovine) structure:

 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 structure :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.

ergometrine

•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.

Side effects[edit]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]

Mechanism of actionWhile 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.

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 tabletsCardiovascular side effects have included hypertension, tachycardia, bradycardia, precordial distressMusculoskeletal 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

 

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 lowVincristine:The generic name for it is Oncovine ( Eli Lily)

Used for acute leukemia, Hodgkin”s 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

  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.

Uses1-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

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

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.