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~ Colorless crystalline heterocyclic nitrogenous compounds.

~Most alkaloids are precipitated from neutral or slightly acidic solution by Mayer's reagent (potassium mercuric iodide solution). Cream colored precipitate

Dragendorff's reagent (solution of potassium bismuth iodide) gives orange colored precipitate with alkaloids

Pg 1

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1. Tropane Alkaloids (first alkaloid group)

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1. Tropane Alkaloids (first alkaloid group)

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~ The tropane alkaloids are based on the tropane nucleus, part of which is derived from ornithine (an Amino acid).

~ Two distinct tropane alkaloid groups:
1. Those found in Solanaceae ( flowering  plant 🌱 )

(the solanaceous tropane alkaloids

e.g. atropine type)
2. Those from the Erythroxylaceae (flowering 🌳 )

(e.g. cocaine type)

pg 2

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The important solanaceous tropane alkaloids are hyoscyamin ( ester of tropine and tropic acid)  and hyoscine ( ester of scopine and tropic acid)

pg 3

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Medical indications (Hyoscyamine) -levo- isomer of atropine.

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Medical indications (Hyoscyamine) -levo- isomer of atropine.

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~These alkaloids have anticholinergic effects.
~Hyoscyamine or atropine is used as remedy against spasm in the gastrointestinal tract.
~Their antisecretory effect is used to control salivary secretion during surgical operations.
~Usually given to lessen oral and air-passage secretions before general anaesthesia.
~They are also used as mydriatics to dilate the pupil of the eye.
~It works by suppressing the parasympathetic nervous system.
- controls symptoms of Parkinson's disease.

pg 4

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Medical indications (Hyoscine) - from datura stramonium

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Medical indications (Hyoscine) - from datura stramonium

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~Hyoscine has a depressant effect on the CNS and is particularly useful as a sedative to control motion sickness. Under synonym scopolamine it is used as a “truth drug” (lack of will and amnesia).

~Hyoscine hydrobromide is used in cancer treatment to prevent nausea and vomiting that results from movement of the head.

~It is a known anticholinergic, and therefore, prevents the toxic effects that can result due to accumulation of acetylcholine in the neuromuscular junctions and the parasympathetic nervous system.

pg 5

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~Cocaine is an alkaloid obtained from the leaves of Erythroxylum coca and E. truxillense
~It is the methyl ester of benzoylecgonine. When hydrolysed, it splits into ecgonine, benzoic acid and methyl alcohol.

~Methylation with methyl iodide and benzoylation with benzoyl chloride will convert ecgonine to cocaine.

pg 6

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Comparison between Ecgonine and Atropine 

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Comparison between Ecgonine and Atropine 

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~Ecgonine has a similar ring like tropine, which contains the N atom, but there is a second ester group in ecgonine.

~The stereochemistry at the tropane ester centre. In atropine, the tropic acid is joined to the tropane nucleus by an α linkage while in cocaine, linkage is β.

~Atropine contains tropic acid estermoiety while in cocaine, it is the benzoate ester that is present.

pg 7

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~It is used as a local anaesthetic for topical application especially in ophthalmic practice. It was widely used in dentistry.
~Misused as a narcotic (additive effect).

~Brompton’s cocktail (cocaine and heroin in sweetened alcohol) widely used to control severe pain in terminal cancer patients.
~Compound play an important part in the development of other local anesthetics e.g. procaine

Adverse effects are:
~Fever & headache due to increased motor activity, vasoconstriction and increased blood pressure.

~Irregular heart beat, tachycardia, may lead to heart failure.
~Psychiatric disturbances, central stimulant addiction.

pg 8

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~Obtained from the dried leaves of the tobacco plant Nicotiana tabacum.
~Nicotine is a hygroscopic oily liquid that is miscible with water.
~Colourless to pale yellow oil with unpleasant pungent odour, and sharp, burning taste.
~Strong poison, used as insecticide especially in gardening.

effects of nicotine:
~Nicotine in small doses can act as respiratory stimulant. In larger doses can cause respiratory depression and may cause nausea and vomiting.
~It also increases the heart rate and blood pressure and reduces appetite.

pg 9

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~Obtained from the dried leaves or tops of Lobelia inflata.
~Relieve asthma and bronchitis.
~Lobeline sulphate formerly incorporated in tablets or lozenges that were intended as smoking deterrents.

pg 10

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Phenethylamines (Amino Alkaloids) - 2nd alkaloid group

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Phenethylamines (Amino Alkaloids) - 2nd alkaloid group

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~Obtained from Ephedra sinica
~Medicine in the treatment of asthma and bronchitis
~ Consist of:
1. Ephedrine
2. Mescaline
3. Colchicine

pg 11

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~White needle crystals, soluble in water, alcohol, chloroform, and ether.
~Closely resembles the structure of adrenaline -has similar pharmacological properties.

Uses of Ephedrine
~Ephedrine is a potent sympathomimetic.
~It causes increased blood pressure and pulse, contraction of blood vessels, dilation of bronchi, and vasoconstriction action on mucous membrane
~In large doses, ephedrine may cause hypertension,headache, dizziness, palpitations and vomiting.
~It is an appetite depressant and may cause anorexia.
It is a central nervous system stimulant, it may cause nervousness and insomnia.
~Ephedrine sulphate and chloride are used as broncho-dilators in the treatment of asthma and in nasal congestion.
~ Pseudoephedrine -cold preparation used as decongestant. OTC (Sudafed)

pg 12

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~Mescaline is a hallucinogenic alkaloid which is obtained from the tops of cactus Lophophora williamsii.
~Causes euphoria
~Has a chemical structure very similar to the brain neurotransmitter dopamine and noradrenaline and to the stimulant amphetamine.
~Mescaline is not physically addictive.
~Used as a hallucinogen in experimental psychiatry.

pg 13

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~ Obtained from the seeds and corm of Colchicum autumnale (autumn crocus).

~ Colchicine is non-basic, and does not form salts like other alkaloids.

Uses:
~In medicine, colchicine is used as a remedy against gout, a disease caused by the deposition of uric acid in the joints.
~It is an effective treatment for acute attacks. ( anti-inflammatory agent).

~Does not affect uric acid metabolism, which needs to be treated with other agents such as allopurinol.

~ highly toxic
~ inhibit cell division

pg 14

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Isoquinoline Alkaloids- 3rd alkaloid group 

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Isoquinoline Alkaloids- 3rd alkaloid group 

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~ consist of opium alkaloids, Ipecacuanha alkaloid and Curare alkaloids .

OPIUM ALKALOIDS
~ obtained from opium poppy and is reffered to as "golden triangle"
~Crude opium used as analgesic (Laudanum or opium tincture), sleep inducer (narcotic) and for the treatment of coughs.
~Paregoric or camphorated opium tincture is a mixture of opium, alcohol, and camphor, was used in the treatment of severe diarrhea and dysentery.

Opium alkaloids have attained wide medicinal use: morphine, codeine, papaverine and narcotine and heroine (synthetic).

pg 15

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~ The molecule contains phenolic and an alcoholic hydroxyl group. (acidic and basic)
~The alkaloid and its salts occur as white silky crystals. Stable in air, odorless and bitter-tasting.
~Morphine is a powerful analgesic and narcotic. why?
Because of its shape  'LOCK AND KEY'  that enables it to fit exactly into the active site of the receptor.
~ The benzene group of the morphine molecule fits snugly against a flat section of the receptor protein, whilst the bent neighboring group of carbon atoms fits into a nearby groove. This allows the positively charged nitrogen atom to attach to a negatively-charged group on the receptor, so locking the two molecules together .

~ Morphine is an opioid receptor agonist. Main effect is binding to and activating the μ-opioid and k-opioid receptors in the CNS.
~ Activation of μ-opioid receptors is associated with analgesia, sedation, euphoria, physical dependence and respiratory depression.

~ Activation of k-opioid receptors is associated with spinal analgesia and miosis.

Effects of Morphine
1. Nausea, vomiting, constipation ( used in some anti- diarrhoea preparations e.g. kaolin and morphine).
2. Respiratory depression and high doses can cause death by respiratory failure.
3. Morphine crosses the placental barrier
4.Highly addictive. Methadone treatment has been useful in curing morphine addiction.

pg 16

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~ Codeine is the 3-O-methyl ether of morphine.
~ It is marketed as the salts codeine sulfate and codeine phosphate.
~ Codeine is a narcotic analgesic and antitussive, but a much weaker analgesic than morphine.
~ Does not causes euphoria.

Adverse effects - Itchiness, nausea, vomiting, drowsiness, dry mouth, miosis,

urinary retention and constipation.

pg 17

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~Member of phthalide isoquinoline alkaloids.
~ Has good antitussive and cough suppressant activity
~ Has no analgesic or narcotic activity
~ Teratogenic properties.
~ Investigated as potential antitumor agent.

pg 19

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~ Heroin is a white, colourless, bitter crystalline compound that is derived from morphine.
~ It is also known as diacetylmorphine or diamorphine.
~ Formed by acetylation of morphine.
~ Heroin has high lipid solubility provided by the two acetyl groups, resulting in a very rapid penetration.
~ Widely used for terminal care of cancer patients both as an analgesic and cough suppressant.
~ Withdrawal symptoms include panic, nausea, muscle cramps,chills, and insomnia.
~ It may also cause constricted pupils, nausea, and respiratory depression, which in its extremes can result in death

pg 20

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Ipecacuanha Alkaloid - 2nd class of isoquinoline alkaloids

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Ipecacuanha Alkaloid - 2nd class of isoquinoline alkaloids

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~ Used it for the treatment of dysentery.
~  Ipecac functions as a diaphoretic (promotes perspiration).
~ Ipecac contains emetine and cephaeline alkaloids .
~ Emetine and cephaeline possess a skeleton with two tetrahydroquinoline ring systems.
~ Emetine has been useful in the treatment of amoebic dysentery .
~ Emetine is a powerful poison that produces vomiting.
~ Ipecacuanha also has expectorant activity and is used in the treatment of bronchitis stimulating bronchial secretions to make coughing easier.
~ It also has antitumor and antiviral activity but it is too toxic for therapeutic use.

pg 21

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Curare Alkaloids- 3rd class of isoquinoline alkaloids

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Curare Alkaloids- 3rd class of isoquinoline alkaloids

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~ Curare kills by producing paralysis on the voluntary muscle, blocking nerve impulse at the neuromuscular junction.

Uses of Curare
~ Useful medicinally as a muscle relaxant.

~ Valuable in certain neurological conditions, e.g. multiple sclerosis, tetanus and Parkinson’s disease, to temporarily relax rigid muscle and control convulsions.
~ Consist of tubocurarine and atricurarine.

pg 22

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~ Bis-benzylisoquinoline alkaloid.
~ Curare molecule found to contain two quaternary N atoms separated by 10 other atoms.
~Injected as a muscle relaxant in surgical operations ( due presence and distance between the two N- groups)

Atracurium.
~ Synthetic analogue of tubocurarine.
~ A bis-quaternary compound comprising two papaverinium residues, separated by 13 atoms, which includes two ester groupings

pg 23

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~ This group of alkaloids is characterized by the indole skeleton, derived biosynthetically from tryptophan.
~ May include a C5 unit (ergot alkaloids) or a C9-10 monoterpene unit (Rauvolfia and Catharanthus alkaloids).

pg 24

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~causes visual hallucinations with rapidly changing shapes and colors, different perceptions of space and times.( like mescaline )
~ Active hallucinogens are psilocybin and psilocin( active form)

1. psilocybin
~ Zwitterionic alkaloid that is soluble in water, moderately soluble in methanol and ethanol and insoluble in most organic solvents.
~ It is a pro-drug that is converted into the pharmacologically active compound psilocin in the body by dephosphorylation.
~ This chemical reaction takes place under strongly acidic conditions or enzymatically by phosphatases in the body

pg 25

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Physostigmine or Calabar beans Alkaloids

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Physostigmine or Calabar beans Alkaloids

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~ The alkaloid is unstable and needs to be kept in airtight containers with exclusion of light.

Uses
~ Miotic, to contract the pupil of the eye, often to combat effect of mydriatic such as atropine.
~ Reduces intraocular pressure in the eye by increasing outflow of aqueous humour. Valuable for treatment of glaucoma, often in combination with pilocarpine.

~ Prolongs the effect of endogenous acetylcholine; can be used as an antidote to anticholinergic poisons such as atropine.

pg 26

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~ Ergometrine and ergotamine.
~ Water-soluble group which contains amino alcohol derivatives e.g. ergometrine.

~ Water-insoluble group which contains peptide derivatives e.g. ergotamine (the peptide side chain is made up of analine, proline and phenylalanine).

> Ergometrine (Ergonovine)
~Ergometrine used as an oxytocic since it causes strong muscular contraction.

~ Reduces bleeding because of vasoconstrictor effect; valuable after caesarian operation.

> Ergotamine
~ Employed often in combination with caffeine for the treatment of migraine (by vasoconstriction of cerebral blood vessels).
~ Hydrogenation of the 9,10-double bond in the lysergic acid moiety yields dihydroergotamine.
This is employed as remedy for migraine. Often better tolerated by patients.

Pg 27

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~Does not occur in ergot but is prepared by semi-synthesisfrom lysergic acid.

~ Cure for headache.

~ Have hallucinogenic effect
~ Hallucinogenic - drugs, plants, substances inducing hallucinations.
~ React with Diethylamine, C4H11N

pg 28

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~ All ergot alkaloids contain lysergic acid as their chemical nucleus.

~ Lysergic acid is made from the tartrate salt of ergotamine derived from the ergot fungus on rye.

~ Only a small amount of ergotamine tartrate is required to produce LSD in large batches.

pg 29

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Rauwolfia Alkaloids  ( still under indole skeleton)

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Rauwolfia Alkaloids  ( still under indole skeleton)

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~ From dried rhizome and roots of Rauvolfia serpentina
~  Reserpine ajmaline and ajmalicine pure compounds
~ Rauvolfia serpentina contains a wide range of indole alkaloids (0.7-2.4%).
~ Treat a wide range of conditions ranging from snake-bites to insanity, as well as well as physical illnesses such as fevers.
~ reserpine from the plant has been found to calm laboratory animals unlike those treated with barbiturates.

1. Reserpine

~ Antipsychotic and antihypertensive.

~ First effective remedy for psychoses.

It acts by interfering with catecholamine storage, depleting levels of available neurotransmitters.

Prolonged use of the pure alkaloid reserpine has been shown to lead to severe depression in some patients.

2. Ajmaline and Ajmalicine
~ Ajmaline is used as a remedy for cardiac arrhythrimia while ajmalicine (also extracted from cantharanthus roseus)  is employed as an antihypertensive

pg 30

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3. Papaverine - benzylisoquinoline alkaloid

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3. Papaverine - benzylisoquinoline alkaloid

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~ Has little or no analgesic or hypnotic properties but possess spasmolytic vasodilator activity.
~ Acts as a muscle relaxant and used to increase the blood supply to the brain or to the heart as in the treatment of angina pectoris.
~ Treatment of gastrointestinal spasms.
~ Treatment for male impotence.

pg 18

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 Catharanthus Alkaloids ( still under indole skeleton)

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 Catharanthus Alkaloids ( still under indole skeleton)

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~ Plant was originally investigated for potential hypoglycemic activity because of folklore usage as a tea for diabetes.

~ Plant extracts have no effect on blood sugar levels in rabbits, but test animals succumbed to bacterial infection due to depleted white blood cells (leukopenia).
~ The plant (Catharanthus roseus) produces higher proportion of v inblastine than vincristine.

Fortunately possible to convert vinblastine into vincristine by controlled chromic acid oxidation or via a microbial N-demethylation using Stretomyces albogriseolus.

Catharanthine and vindoline, which are produced in much larger proportion, now possible to convert catharanthine and vindoline into vincristine in 40%.

Vinblastine/ Vincristine

~ These alkaloids have dimeric indole structures, composed of an indole and a dihydro indole unit catharanthine and vindoline moiety.
~ Both bind tightly to tubulin and inhibit the polymerization of tubulin into microtubules, preventing spindle formation in mitosis cells.

This effectively stops the tumour cells from dividing, thus causing remission of the cancer.
~ Vinblastine used mainly in treatment of Hodgkin’s disease (a type of lymphoma, which is a cancer originating from white blood cells called lymphocytes) a cancer affecting the lymph glands, spleen and liver.

Vincristine has superior antitumour activity compared to vinblastine hence more important than vinblastine (especially in treatment of childhood leukemia, lymphomas, small cell lung cancer, cervical and breast cancer) but is more neurotoxic.

pg 31

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~ Dried ripe seeds of a tree Strychnos nuxvomica (Loganiaceae)
~ Seeds contain mainly strychnine and brucine.

Strychnine

~ Intense bitter taste and does not dissolve in water nor well in alcohol.

~ It is one of the most bitter substance in the world.

~ Its taste is detectable in concentration as low  as 1 ppm It was used as a poison for rodents and other pests.

~ Very small doses can give a feeling of stimulation.

~ In larger doses (30-100mg) strychnine is deadly poison, leading to violent muscular convulsions
~ Strychnine poisoning in humans can be fatal and can be introduced to the body by inhalation, swallowing or absorption through eyes or mouth.

~ Treatment involves giving depressant e.g. intravenous diazepam, to control the convulsion and giving an activated charcoal infusion to drink, to absorb any poison remaining within the digestive system.

Brucine

~ It is a bitter alkaloid closely related to strychnine but is not as poisonous.

~ It is primarily used in the regulation of high blood pressure.

Chemically, structure of brucine is very similar to that of strychnine with methoxy groups at the aromatic ring rather than hydrogens

pg 32

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Quinoline Alkaloids ( in cinchona - Rubiaceae)     

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Quinoline Alkaloids ( in cinchona - Rubiaceae)     

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quinine,

quinidine

chloroquine

~ Difference between isoquinoline and quinoline is position of Nitrogen atom.

pg 33

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~ Quinidine is a diastereoisomer of quinine, having opposite configuration at two centers.

1. Quinine
~ is a white crystalline alkaloid with a bitter taste.

Almost insoluble in water, it dissolves readily in alcohol and other organic solvents.

~Quinine also has been used medicinally to:

Allay fever and pain

Induce uterine contraction. In very large doses, quinine also acts as an abortifacient

Muscle relaxant.

Treatment of multi-drug resistant malaria, but not suitable for prophylaxis.

Side Effects of Quinine

~ Excessive dosage or continuous use of quinine may cause cinchonism .

~ Characterized by ringing in the ears, headache, dizziness, changes in blood pressure and even death.

~ Patients treated with quinine may also suffer from hypoglycaemia (especially if administered intravenously) and hypotension.

Mechanism of action of quinine
It is toxic to the malaria parasite, by interfering with the parasite’s ability to break down and digest haemoglobin, thus starving the parasite and/or causing the build-up of toxic levels of partially degraded haemoglobin in the parasite.

2. Quinidine - stereoisomer of quinine
~ Acts as an antiarrhythmic agent in the heart.

Side Effects of Quinidine

Quinidine can lead to increased blood levels and some anti-depressants effects.

Quinidine intoxication can lead to a collection of symptoms collectively known as cinchonism with tinnitus (ringing in the ears).
3. Chloroquine
~ Is a 4-aminoquinoline drug used in the treatment or prevention of malaria.

~ Used to suppress the disease process in rheumatoid arthritis.

Side-effects include:

Gastrointestinal problems

Stomach ache

Itch

Headache

Postural hypotension

Nightmares

Blurred vision

pg 34

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~ Pilocarpus or jaborandi consists of the dried leaves of Pilocarpus jaborandi (Rutaceae)

~ Pilocarpine is a cholinergic agent and stimulates muscarinic receptors in the eye, causing  constriction of the pupil (miosis) and contraction of ciliary muscle.

~ Used as hydrochloride or nitrate salts in eye drops for treatment of glaucoma.
~ Found to give relief for dryness of the mouth (xerostomia)

~ Pilocarpine is used to treat side effects arising from radiation treatment for head and neck cancer.

Side effects

~Increased sweating.

~ Stimulate sweat glands in a sweat test to measure the concentration of chloride and sodium that is excreted in sweat.

~ Nausea, vomiting, bronchospasm, Increased bronchial mucus secretion, bradycardia, hypotension, and diarrhea.

pg 35