ALKALOIDS

Md. Iqbal Ahmed Assistant Professor Pharmacy Discipline, KU 1

DEFINITION
Alkaloid: Difficult to define. No definitive difference between an alkaloid and naturally occurring complex amines.

Alkaloids: plant derived, are alkali/basic and contain at least one N2-atom (usually in a heterocyclic ring). They also normally have a significant physiological action on humans and animals.

ALKALOID DEFINITION

Proto-alkaloid/ amino-alkaloid applied to compounds which lack one or more of the properties of typical alkaloids. Other alkaloids which do not conform with the general definition are synthetic compounds not found in plants but are very closely related to natural alkaloids.

DEVIATION FROM DEFINITION

Basicity: Some alkaloids are not basic e.g. Colchicine, Piperine, Quaternary alkaloids. Nitrogen: The nitrogen in some alkaloids is not in a heterocyclic ring e.g. Ephedrine, Colchicine, Mescaline. Plant Origin: Some alkaloids are derived from Bacteria, Fungi, Insects, Frogs, Animals.
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CLASSIFICATION

True (Typical) alkaloids that are derived from amino acids and have nitrogen in a heterocyclic ring. e.g Atropine Protoalkaloids that are derived from amino acids and do not have nitrogen in a heterocyclic ring. e.g Ephedrine Pseudo alkaloids that are not derived from amino acids but have nitrogen in a heterocyclic ring. e.g Caffeine False alkaloids are non alkaloids give false positive reaction with alkaloidal reagents.

ALKALOID DESCRIPTION
Contains nitrogen - usually derived from an amino acid. Bitter tasting, generally white solids (exception - nicotine is a brown liquid). They give a precipitate with heavy metal iodides.
Caffeine,

a purine derivative,

PROPERTIES CONT

Alkaloids are basic - they form water soluble salts. Most alkaloids are well-defined crystalline substances which unite with acids to form salts. In plants, they may exist

in the free state, as salts or as N-oxides.

In addition to the elements C, H and N, most alkaloids contain oxygen.

Coniine from hemlock and nicotine from tobacco are oxygen free and are liquids

Although coloured alkaloids are relatively rare, they are not unknown;

Berberine is yellow and the salts of sanguinarine are 7 copper - red

TESTS FOR ALKALOIDS

Most

alkaloids are precipitated from neutral or slightly acidic solution by Mayer's reagent (potassiomercuric iodide solution) Cream coloured precipitate. Dragendorff's reagent (solution of potassium bismuth iodide) orange coloured precipitate. Wagners reagent (iodine in potassium iodide) red-brown precipitate

TESTS FOR ALKALOIDS

Hagers

reagent (picric acid) yellow precipitate Solution of tannic acid Caffeine does not precipitate like most alkaloids. Murexide test (potassium chlorate and few drops of HCl evaporation to dryness and exposing the residue to ammonia vapour-purple colour is produced)
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OCCURRENCE, DISTRIBUTION & LOCATION OF ALKALOIDS

Occur in bacteria (Pseudomonas aeruginosa) and rarely in fungi (pscilocin from hallucinogenic mushrooms). Some alkaloids occur in several genera from different species (caffeine), but most occur in closely related species. Some occur in certain families (hyoscyamine), while others occur only in a specific species (morphine). Rarely do plants contain more than 1 type of alkaloid. All alkaloids of one plant will have a common biogenetic origin
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Alkaloids occur in all plant parts, but are usually localized in one organ (e.g. the bark or seeds). Within the plant, [alkaloid] can vary widely from part to part some parts may contain no alkaloids. Occasionally, different alkaloids also form in different parts of the plant. Alkaloid concentrations occur in wide ranges

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FUNCTION IN PLANTS

They may act as protective against insects and herbivores due to their bitterness and toxicity. They are, in certain cases, the final products of detoxification (waste products). Source of nitrogen in case of nitrogen deficiency. They, sometimes, act as growth regulators in certain metabolic systems. They may be utilized as a source of energy in case of deficiency in carbon

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BIOLOGICAL ACTIONS
High biological activity Produce varying degrees of physiological and psychological responses - largely by interfering with neurotransmitters

others

interfere with membrane transport, protein synthesis or other processes

In large doses - highly toxic - fatal In small doses, many have therapeutic value

muscle

relaxants, tranquilizers, pain killers, mind altering drugs, chemotherapy

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PSYCHOACTIVE ALKALOIDS
Although only a small percent are psychoactive, these get much focus Affect the central nervous system often by influencing neurotransmitters Categories of psychoactive cmpds

Stimulants Hallucinogens Depressants

May also be narcotic (addictive)

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PSYCHOACTIVE ALKALOIDS
Stimulants Hallucinogens
Cocaine Ephedrine Caffeine Tropane alkaloids Mescaline Psilocybin Ergot alkaloids (LSD)

Depressants
Morphine Codeine Heroin

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THE NITROGEN OF ALKALOIDS

The N2 atom can either be 1, 2, 3 or 4 (quaternary).

This N2 feature affects the alkaloid derivatives which can be prepared and the isolation procedures.

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PHYSICAL-CHEMICAL PROPERTIES OF ALKALOIDS

MW: 100 900 Most bases which do not contain O2 are liquid at room temperature (nicotine), while those that do are solids. In rare cases they are coloured. Most solid bases rotate the plane of polarized light, have high melting points. Normally are not soluble in water (occasionally slightly soluble). Soluble in apolar or slightly polar organic solvents. Soluble in concentrated hydroalcoholic solutions
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The basicity of alkaloids depends on the availability of the lone pair of e- on the N2 atoms: e- donating groups enhance basicity, while ewithdrawing groups decrease it. Because some alkaloids have a carbonyl group on the amide, they can also be neutral (colchicine & piperine). Basicity is also influenced by steric constraints. Basic characteristic renders complex alkaloids unstable, so that in solution they are sensitive to heat, light & oxygen.

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Basic character of alkaloids also allows them to form salts with mineral acids (such as hydrochlorides, nitrates and sulphates) or inorganic acids (tartrates, sulfamates).

Alkaloid salts are soluble in water and dilute alcohols. Solid salts can be conserved well and are a common commercial form of alkaloids.

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Solubility:
Both alkaloidal bases and their salts are soluble in alcohol. Generally, the bases are soluble in organic solvents and insoluble in water Exceptions: Bases soluble in water: caffeine, ephedrine, codeine, colchicine, pilocarpine and quaternary ammonium bases. Bases insoluble or sparingly soluble in certain organic solvents: morphine in ether, theobromine and theophylline in benzene.

Salts are usually soluble in water and, insoluble or sparingly soluble in organic solvents. Exceptions:
Salts insoluble in water: quinine monosulphate. Salts soluble in organic solvents: lobeline hydrochlorides are soluble in chloroform. and apoatropine
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NOMENCLATURE:
Names should end by "ine". These names may refer to: The genus of the plant, such as Atropine from Atropa belladona. The plant species, such as Cocaine from Erythroxylon coca. The common name of the drug, such as Ergotamine from ergot. The name of the discoverer, such as Pelletierine that was discovered by Pelletier. The physiological action, such as Emetine that acts as emetic, Morphine acts as narcotic. A prominent physical character, such as Hygrine that is hygroscopic.
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PREFIXES AND SUFFIXES:

Prefixes: "Nor-" designates N-demethylation or N-demethoxylation, e.g. norpseudoephedrine and nornicotine. "Apo-" designates dehydration e.g. apomorphine. "Iso-, pseudo-, neo-, and epi-" indicate different types of isomers. Suffixes: "-dine" designates isomerism as quinidine and cinchonidine. "-ine" indicates, in case of ergot alkaloids, a lower pharmacological activity e.g. ergotaminine is less potent than ergotamine.
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CLASSIFICATION OF ALKALOIDS
Alkaloids have a large variety in their botanical & biochemical origin, in chemical structure and pharmaceutical action. Therefore, like flavonoids, a range of different classification systems exist for grouping alkaloids.

They can therefore be classified according to their Biological origin Chemical structure - 2 divisions

i. Atypical/non-hetrocyclic alkaloids (protoalkaloids or biological amines) ii. Typical/hetrocyclic alkaloids (divided into 14 groups according to their ring structure)
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Biosynthetic pathway

NON HETEROCYCLIC ALKALOIDS

Hordenine or N-methyltyramine
In germinating barley, Hordeum distochon

Mescaline Lophophora williamsii

Ephedrine Ephedra spp.

Colchicine Colchicum spp. 24

Jurubin (steroid with 3 amino acid) Solanum paniculatum

Pachysandrine A Pachysandra terminalis

Erythromycin
Streptomyces erythreus

Taxol Taxus brevifolia

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HETEROCYCLIC ALKALOIDS

Pyrrole and Pyrrolidine

Hygrine- Coca spp Stachydrine- Stachys tuberifera

Pyrrolizidine
Symphitine, echimidine- Symphytum spp Senecionine, seneciphylline- Senecio spp.

Pyridine and piperidine

Trigonelline- Fenugreek, Strophanthus, Coffee Coniine- Conium maculatum Arecoline- Areca catechu Lobeline- Lobelia spp. Pelletrerine- Punica granatum Nicotine- Nicotiana tabacum and other spp Anabasine Nicotiana glauca, Anabasis aphylla Piperine- Piper spp Ricinine- Ricinus communis

N H

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Tropane (piperidine/nmethyl pyrrolidine)

Hyoscyamine, atropine, hyoscine Atropa spp. Datura, Duboisia, Scopolia Cocaine- Coca spp. Pseudo pelleterine- Punica granatum

Quinoline
Quinine, quinidine, chinchonine, chinchonidine- Cinchona spp Cusparine Angostura or cusparia bark

Isoquinoline
Papaverine, narcotine, morphine, codeine - Papaver somniferum Hydrastine,berberine Emetine Cephaelis spp. Tubocurarine-

N
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Aporphine
Boldine- Peumus boldus

Norlupinane Indole or benzopyrrole

Ergometrine, ergotamine- Claviceps spp. Lysergic acid amide- Rivea corymbosa Physostigmine- Physostigma venenosum Ajmaline, serpentine, reserpine-Rauwolfia spp. Vinblastine, vincristine- Catharanthus roseus Strychine, brucine- Strychos spp.

Sparteine, Cytisine, Lupanine, laburnine

N H

Indolizidine
Castanospermine- Castanospermum australe
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Imidazole or glyoxaline
H

Pilocarpine- Pilocarpus spp.

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Purine
Caffeine- Tea, coffee Theobromine- Cocoa

1 N 2

7 N

8 4 N 3 Purine N 9

Steroidal

Solanidine and veratrum alkalamine Funtumine- Funtumina elastica

Terpenoid

Aconitine, atisine, lyctonineAconitum and Delphinium spp.

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EXTRACTION OF ALKALOIDS
Extraction is based on the basicity of alkaloids and on the fact that they normally occur in plants as salts (i.e.: on the solubility of bases and salts in water and organic solvents). Herbs often contain other materials which can interfere with extraction such as large amounts of fat, waxes, terpenes, pigments and other lipophilic substances (e.g by forming emulsions) avoided by defatting the crushed herb (using petroleum ether and hexane)

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ALKALOID EXTRACTION
Extraction method normally depends on the raw material, the purpose of extraction & the scale on which is to be performed. For research purposes: chromatography allows for quick and reliable results. If larger amounts of alkaloids need to be extracted, one of the following methods can be used.

TLC plate
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EXTRACTION IN AN ALKALINE MEDIUM

Process A: Powdered, defatted herb is mixed with an alkaline aqueous solution. This displaced alkaloids from their salt combinations, such as tannis and other phenolic substances. Free bases are then extracted with organic solvents such as ether or petroleum spirit. Concentrated organic liquid is then stirred with an acidic aqueous solution: alkaloids go into the solution as salts. Impurities remain in the organic phase.

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ISOLATION OF ALKALOIDS Repeated until the organic phase no longer contains alkaloids. Many acids can be used (HCL, Sulfuric, citric, tartaric), but always in very dilute

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PROCESS B

The powdered material is extracted with water or aqueous alcohol containing dilute acid. Pigments and other unwanted materials are removed by shaking with chloroform or other organic solvents. The free alkaloids are then precipitated by the addition of excess34

ISOLATION OF ALKALOIDS
Normally aqueous ammonia is used, but a carbonate solution is used when alkaloids contain fragile elements such as a ester or lactone.

In some cases, e.g. Cinchona bark, a mixture of calcium hydroxide & sodium hydroxide should be used as the alkaloids are bound to tannins. Organic solvent: chloroform, dichloromethane or ethyl acetate depends on the toxicity, safety, cost & ease of recovery and recycling of the solvent).
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THE SOXHLET APPARATUS

Industry: uses solid-liquid extractors based on the principle of countercurrent extraction, such Soxhlet apparatus.

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ISOLATION OF ALKALOIDS
All methods of extraction yield compounds, so therefore have separated. TLC and HPLC commonly used. alkaloid impure alkaloids to be

are

most Crystals of Hydrastine

Under the best conditions, alkaloids can be obtained by direct crystallization: simply by neutralizing the acidic extraction medium.

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ISOLATION OF ALKALOIDS
Large-scale extractions may be sent to a factory for purification & separation (for cinchona and cocoa alkaloids). Separation and final purification may be done using fractional precipitation or fractional crystallization of salts such as oxalates, tartrates or picrates. Chromatograpy is used for complex alkaloids and if only small amounts of alkaloids are needed.
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ISOLATION OF ALKALOIDS
Volatile liquid alkaloids (nicotine and coniine) are isolated by distillation An aqueous extract is made alkaline with caustic soda or sodium carbonate and alkaloid is distilled off in steam. Nicotine is an important insecticide, and large amounts are prepared from the parts of the tobacco plant which is not used for
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PHARMACOLOGICAL ACTION & USES

CNS Action: stimulants (caffeine) or depressants (morphine) ANS: sympathomimetics (ephedrine) or sympatholytics (yohimbine, ergot alkaloids), parasympathomimetics (pilocarpine), anticholinergics (choline), ganglioplegics (nicotine). Also: local anesthetics (cocaine), defibrillation (quinidine), antitumour agents (ellipticine), antimalarial (quinine), antibacterials (berberine), and amoebicides (emetine).

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These actions lead to the extensive use of alkaloid containing herbs and drugs. Although some are used as galenicals (belladonna, datura, and henbane), most are used as starting materials for industrial extraction (morphine from poppy straw or opium, and quinine from Cinchona bark.
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BIOGENESIS OF ALKALOIDS
Alkaloids are produced in plants by basic substances and reactions well-known in organic chemistry.

Biosynthetic origin cannot be discussed in general terms for all alkaloids, instead it has to be covered separately for each of the major groups of alkaloids
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True alkaloids are based on an amino acid (precursor). Only a few amino acids form the pre-cursors for all alkaloids: ornithine, lysine, phenylalanine, tyrosine, tryptophan, histidine and anthranilic acid. Alkaloid formation may require the involvement of only one molecule of amino acid, or 2 molecules of the same AA, or less commonly, 2 molecules of different AA or else several molecules of the same AA. The formation starts with the formation of a Schiff base or a Mannich reaction. When the alkaloid has additional C-atoms, these play important roles in other metabolic pathways.

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MAIN PRE-CURSORS FOR ALKALOIDS

a.

Group 1: Aliphatic AAs ornithine & lysine

* Pre-cursors to pyrrolidien, piperridine & tropane alkaloids

b.

Aromatic AA Phenylalanine, tyrosine, tryptophane

c. Precursors of terpenes, steroids & polyketides often together with the aliphatic or aromatic AAs result in alkaloids of mixed biosynthetic origin

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HETROCYCLIC ALKALOIDS
Pyrrolidine Alkaloids Piperridine/pyridine Pyrrolizidine Tropane Alkaloids Quinoline Alkaloids Isoquinoline Alkaloids Opium Alkaloids Aporphine Norlupinane Ipecac Alkaloids Indole Alkaloids Indolizidine Imidazole Purine Alkaloids Protoalkaloids Steroidal Terpenoid

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TROPANE ALKALOIDS
Derived from tropine and consist of mandelic, tropic or benzoic acid esters of tropine. Are very closely related to each other. All have pronounced physiological actions.
Natural alkaloids include Hyoscyamine Hyoscine Atropine Cocaine The above mentioned alkaloids occur within the Solanaceae family (except cocaine from Erythroxylaceae family)
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ATROPINE & HYOSCINE

Have the same structure differ only in their optical activity. Also have different physiological actions Atropine deadly nightshade, Atropa belladonna: dilates eye pupils, decreases sweating, produces stomach acid and saliva & relaxes smooth muscle (asthma and colic). Hyoscine black henbane, Hyoscyamus niger: Limited influence on the CNS. Sedative Cocaine: Narcotic properties & local anaesthetic action (e.g. used in eye drops).

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Hyoscine
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DATURA STRAMONIUM - SOLANACEAE

Definition: Stramonium Leaf consists of the dried leaves or dried leaves and flowering tops of Datura stramonium. The drug should contain at least 0.25% alkaloids calculated as hyoscyamine.

Common names: Stramonium leaf, Thornapple, Jimson or Jamestown weed

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DATURA STRAMONIUM - CONSTITUENTS

Main (Tropane) Alkaloids * Hyoscyamine Hyoscine (2:1) Younger plants: hyoscine predominant alkaloid Also contains Atropine

Larger stems contain little alkaloid, and drug should contain no more than 3% of stems with a diameter >5mm
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DATURA STRAMONIUM ALLIED DRUGS & ADULTERANTS

ALLIED DRUGS Datura innoxia Datura metel (dried leaves are also curled and twisted like D. stramonium), but are browner in colour. Datura sanguinea ADULTERANTS Xanthium, Carthamus and Chenopodium leaves (easily distinguished from original herb)

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USES OF DATURA STRAMONIUM

Atropine: Stimulant on CNS Depresses nerve endings on the secretory glands and smooth muscle

Hyoscine: lacks CNS stimulant action of atropine Sedative motion sickness

Atropine & Hyoscine: used in opthalmic practice to dilate the pupil of the eye.
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HYOSCYAMUS NIGER - SOLANACEAE

Definition: Hyoscyamus leaf consists of the dried leaves or dried leaves and flowering tops of Hyoscyamus niger. It should contain at least 0.05% alkaloids hyoscyamine. Common names: Henbane
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HYOSCYAMUS NIGER - CONSTITUENTS

Tropane Alkaloids Mainly Hyoscyamine Hyoscine (main constituent)

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HYOSCYAMUS NIGER ALLIED DRUGS

Hyoscyamus albus (petiolate stem-leaves and pale yellow, nonveined petals bottom left). Hyosycamus muticus (top right) Hyoscyamus pusillus Hyoscyamus aureus Hyoscyamus reticulatus (Indian henbane bottom right)

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HYOSCYAMUS NIGER - USES

Resembles belladonna and stramonium in action only weaker. Higher hyoscine content less likely to cause cerebral stimulation .

Used to relieve spasm of the urinary tract

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ATROPA BELLADONNA - SOLANACEAE

Definition: Belladonna herb consists of the dried leaves and flowering tops of Atropa belladonna, containing at least 0.3% alkaloids (hyoscyamine). Should not contain >3% stem >5mm in diameter. USP also allows A. acuminata in the Belladonna Leaf monograph.
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ATROPA BELLADONNA CONSTITUENTS

Main (Tropane) alkaloid Hyoscyamine Also contains Scopoletin Calcium oxalate

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ATROPA BELLADONNA
ALLIED DRUGS Indian belladonna (Atropa acuminata) yellow-brown flowers & brown-green leaves. Atropa baetica (yellow flowers and black berries) endangered species ADULTERANTS Phytolacca decandra Ailanthus glandulosa

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ATROPA BELLADONNA - USES

Used as a sedative To stop bodily secretions (e.g. saliva) Root preparations are used externally

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PYRIDINE ALKALOIDS
Also referred to as Pyrrolizidine alkaloids Include Lobeline (Lobelia herb) respiratory stimulant Used in anti-asthmatic preparations. Nicotine (Nicotiana tabacum and other Nicotina spp) toxic used as an insecticide Areca catechu or Areca nut
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Lobeline

LOBELIA INFLATA- LOBELIACEAE

Definition: Lobelia herb consists of the dried aerial parts of Lobelia inflata. Common Names: Lobelia, Indian Tobacco, Wild Tobacoo, Emetic herb, Asthma weed, Vomit wort

History: Traditionally used by the Native Americans for asthma.

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LOBELIA INFLATA CONSTITUENTS

Contains Pyrrolizidine Alkaloids Most important Lobeline The alkaloids of Lobelia are classified into three groups 1. Lobeline-l-lobeline. dllobeline, lobelanine, lobelanidine 2. Lelobine dl-lelobanidine, llelobanidine I&II 3. LobinineLobinine, isolobinine, lobinanidine & isolobinanidine
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LOBELIA INFLATA - USES

Asthma Chronic bronchitis Anti-smoking preparations Injection of lobeline hydrochloride is used in the resuscitation of newborn infants. Caution: Toxic doses the herb has a paralytic effect.
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Areca Nuts
Official Source: Areca catechu Constituents: Arecoline, Arecaidine, Guvacine, Guvacoline Use:

As anthelmintic Useful in urinary disorder As nervine(having a soothing effect on nerve) tonic and emmenagogue(hasten the menstruation)
The chewing of areca nut may cause mouth cancer

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QUINOLINE ALKALOIDS
Consist of alkaloids and alkaloid salts obtained from the bark of certain Cinchona species (Quinine, Quinidine, Cinchonine, Cinchonidine). The amount of alkaloids present depend on the species, environment of the tree, age, and method of bark collection. Quinine: Anti-malarial Synthetic alkaloids are now used as substitutes for quinine for malaria.
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CINCHONA BARK - RUBIACEAE

Definition: Cinchona bark consists of the various species races and hybrids of Cinchona, large trees indigenous to Colombia Equador, Peru & Bolivia INCLUDES C. Succirubra, C. calisaya, C. ledgeriana, C. officinalis
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CINCHONA - HISTORY
Historically played an important role in the treatment of malaria. This has now lessened with the introduction of synthetic drugs. Traditionally not used by the native South American Indians (bitter taste inspired them with fear). First used as a medicine in Peru in 1630 used to cure fevers.
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CINCHONA - CONSTITUENTS
Quinoline Alkaloids Mainly Quinine Quinidine

Also Quinicine Cinchonicine Cinchotannic acid Anthraquinones

Leaves contain Indole Alkaloids

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CINCHONA CHEMICAL TESTS

Colour reaction for quinine and quinidine alkaloids Use bromine and ammonia (the thalleioquin test)

Powdered cinchona is slightly moistened with glacial acetic acid & heated in an ignition tube
Red drops condense on the sides of the tube. Cinchona bark therefore gives reactions for phlobatannins.
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CINCHONA ALLIED DRUGS

Barks of certain species of Remijia e.g. R. pedunculata R. purdiena

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CINCHONA BARK - USES

Bitter tonics Stomachics Used as gargles (tannins in bark astringent) Malaria Prophylaxis of cardiac arrhythmias Treatment of atrial fibrillation

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ISOQUINOLINE ALKALOIDS
Drugs: Opium and Ipecac. Alkaloids of both these herbs are in the same group, yet they differ chemically and also in their pharmaceutical actions. Opium Alkaloids: morphine, codeine, ethylmorphine, thebaine, heroine, papaverine. Ipecac Alkaloids: emetine, cephaeline, psychotrine, methylpsychotrine

Emetine
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OPIUM ALKALOIDS OPIUM

Definition: Opium (Raw Opium) is the latex obtained by incision from the unripe capsules of Papaver somniferum, from the Papaveraceae Family. It is dried partially by spontaneous evaporation and partly by artificial heat. Commercially known as Indian opium. BP monograph: opium is intended only as a starting point for the manufacture of galenicals, and should not be dispensed as such.
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PAPAVER SOMNIFERUM CONSTITUENTS

30 Alkaloids 6 main ones Morphine Codeine Thebaine Noscapine Narceine papaverine

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TESTS FOR OPIUM ALKALOIDS

Morphine: soluble in sodium hydroxide (due to phenols) Codeine is precipitated by sodium hydroxide. Other chemical tests are found in pharmacopoeias.
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OPIUM - ADULTERANTS
Adulterated with sugary fruits, gums, powdered poppy capsules and other substances.

Adulteration is now useless (product is first analysed and the price is paid depending on the content of morphine and other alkaloids)
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PAPAVER SOMNIFERUM USES

Opium & Morphine: Relieve pain Hypnotics (affect the sensory nerve cells of the cerebrum). Opium (closely resembles morphine) exerts action more slowly preferable to morphine (e.g in diarrhoea). Opium: also a diaphoretic Codeine Milder sedative Relieve cough Habitual use may cause constipation Both Morphine & Codeine decrease metabolism Codeine was used to treat diabetes (before the introduction of insulin).

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CODEINE MAY BE NO CURE FOR COUGH

Researchers at the University of Manchester North West Lung Centre have found that codeine a standard ingredient in cough remedies could be no more effective than an inactive placebo compound at treating cough. Scientists at the Centre, which is based at Wythenshawe Hospital, studied a sample of patients with chronic lung disease. After coughing was induced with citric acid they were given either codeine or a placebo, and sent home wearing a lapel microphone to record their coughing during the day and night. Lead researcher Dr. Jacyln Smith said: "Codeine has long been considered the standard anti cough agent against which others are measured, but until now little has been known about its impact in patients with chronic lung diseases. After the placebo therapy the patients' coughing fell from an average of 8.27 seconds per hour to 7.22 seconds, and after codeine to 6.41 seconds. "Even though there was a significant reduction after codeine, from a statistical standpoint there was really no difference between codeine and placebo - despite the fact that the dose of codeine used far exceeds that in over-the counter cough remedies. The findings were reported in Journal of Allergy and Clinical Immunology, and seem to confirm some medics' view that reductions in coughing after codeine are attributable to a placebo effect

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IPECAC ALKALOIDS - IPECACUANHA

Definition: Ipecacuanha (Ipecacuanha Root) is the dried root or rhizome and root of Cephaelis ipecacuanha of the Rubiaceae family. It should contain at least 2% alkaloids

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IPECACUANHA COLLECTION
A pointed stick is used to lever the plant up from the ground. Most of the roots are then removed. The plant is replaced into the ground, where it will continue t produce more crops. Roots are dried in the sun or by fire and then transported.
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IPECACUANHA CONSTITUENTS
Ipecac alkaloids (isoquinoline) alkaloids Mainly Emetine Psychotrine Cephaeline Also Emetamine Psychotrine methylether Ipecoside (glycoside)
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IPECACUANHA - ADULTERANTS
Other ipecacuanhas, different roots said to have emetic properties. These are easily distinguished from the original root and are now very rarely imported.

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TEST FOR EMETINE

Mix 0.5g powdered herb with 20ml HCL and 5ml water. Filter To 2ml filtrate add 0.01g potassium chlorate Result: if emetine is present, a yellow colour appears. After standing for 1hr, changes to red.

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IPECACUANHA USES
Expectorant Emetic Amoebic Dysentry Emetine is more expectorant and less emetic in action than cephaeline

Psychotrine: selective HIV inhibotors (study could lead to therapeutically useful agents)
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INDOLE ALKALOIDS
These are found in Ergot & Nux Vormica Ergot alkloids: based on lysergic acid (LSD lysergic acid diethylamide) Nux Vormica: 2 important alkaloids: strychinine and brucine. Strychinine: CNS stimulant, lethal in large doses (uses as a poison)
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Other plants containing indole alkaloids Rauwolfia serpentina (Indian snakeroot) Hypertension Gelsemium sempervirens contains gelsemine, sempervine. Used as a CNS depressant used for migraines. Catharanthus roseus vinblastine, vincristine. Used for migraine

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ERGOT (ERGOT OF RYE)

Defintion: Ergot (Ergot of Rye) is the dried sclerotium of a fungus, Claviceps purpurea, arising in the ovary of the rye, Secale cereale.

Controlled field cultivation on rye is the main source of crude drug.

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ERGOT - HISTORY
World-wide, sporadic reports of ergot poisoning (ergotism) still appear in literature: 1992 an analysis of rye flour sold in Canada showed low levels of fungus contamination. Of 128 samples, 118 were contained the fungus.
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ERGOT - CONSTITUENTS
Ergot alkaloids (ergolines) Include Ergonovine (watersoluble) Alkaloids Ergotoxine & Ergotamine alkaloids (water-insoluble)
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ERGOT SUBSTITUTES & STORAGE

SUBSTITUTES Ergot of Wheat Ergot of Oats Ergot of Diss (reed)

STORAGE Liable to attacks by insects, moulds & bacteria. Dried after collection & stored in a cool, dry place. If powdered and not immediately defatted looses lots of its activity. If defatted can keep for an extended period.
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ERGOT - USES
Traditionally used in labour to assist the delivery Reduce post-partum haemorrhage Ergometrine produces oxyticic effects.

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NUX VORMICA - LOGANIACEAE

Definition: Nux vormica consists of the dried, ripe seeds of Strychnos nuxvormica, (a tree growing up 13m in India, Thailand, South Vietnam and Cambodia). History: in 16th Century it was sold in Europe, mainly used for poisoning animals.
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NUX VORMICA COLLECTION & PREPARATION

Fruit consists a berry about the size of a small orange. When ripe it has a hard orange-yellow pericarp and a white, pulpy interior containing 1-5 seeds. Seeds are washed to remove pulp and dried. Exported in small sacks known as pockets.

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NUX VORMICA - CONSTITUENTS

2-5% Indole alkaloids Mainly Strychine Brucine Strychine is more physiological active than brucine
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NUX VORMICA - USES

Action of the whole drug resembles the action of Strychnine Formerly used as a circulatory stimulant (e.g. in surgical shock) Now used mainly as a respiratory stimulant (in certain cases of poisoning) Bitter - used to improve appetite & digestion Commonly misused as a General Tonic

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NUX VORMICA ALLIED DRUGS

Ignatius beans (seeds of Strychnos ignatii) fruits are larger than those of Nux vormica & may contain up t 30 seeds. Also dark grey in colour.

Also S. potatorum and S. nux-blanda contai no strychnine or brucine

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RAUWOLFIA SERPENTINE APOCYNACEAE

Defintion: Rauwolfia consists of the dried rhizome and roots of Rauwolfia serpentiana.

(a small shrub found in India, Pakistan, Java and Thailand).

Common name: Rauwolfia, Indian Snakeroot
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RAUWOLFIA - CONSTITUENTS
30 Alkaloids Main alkaloid Reserpine Also Rauwolfine Serpentine Serpentinine New alkaloids continue to be isolated.

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RAUWOLFIA - USES
Essential Hypertension Malignant Hypertension Neuropsychiatric Disorders Cardiac arrhythmias Circulatory Disease

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RAUWOLFIA CAUTIONS!
Conflicting reports on the possible involvement of rauwolfia alkaloids in breast cancer. Suggested that the alkaloids do not initiate the carcinogenic process, but promote breast cancer from previously initiated cells. DEPRESSION
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PROTOALKALOIDS
Alkaloid-like amines. Have no nitrogen as part of the hetrocyclic ring.

Examples: ephedrine and adrenaline Both cause dilation of the bronchi (asthma), increase heart rate and peripheral vasoconstriction.

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EPHEDRA - EPHEDRACEAE
Definition: Various species of Ephedra are used as a source of the alkaloids Ephedrine and Psuedoephidrine. These include E. major, E. intermedia, E. sinica and E. equisetina. Common name: Ephedra, (Ma-huang)
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EPHEDRA - CONSTITUENTS
Alkaloids (protoalkaloids) Mainly Ephedrine Pseudoephidrine Also contains ephedradines hypotensive properties
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EPHEDRA - USES
Asthma, colds, flu and Hayfever medications (action is more prolonged than adrenaline. Additional advantage: need not be given by injection, but can be administered orally). Allopathic: Sinumed (dries a runny nose) TCM: Used as an antiinflammatory. Weight loss (increases metabolism, decreases appetite CNS stimulant acts on adrenergic receptors) Above ground parts are normally used, although the roots are better to use (less alkaloids)

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EPHEDRA - CAUTIONS
Above-ground parts contain higher amounts of alkaloids (increase BP) Side Effects: Causes tremors, nervousness, palpitations & tacchycardia. Full medical Hx of pt is required: contraindicated in DM, thyroid disease, glycoma, all cardiac conditions (including hypertension)

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KHAT OR ABYSSINIAN TEA

Consists of the fresh leaves of Catha edulis. Cultivated in Abyssinia and Arabian peninsula. Contains protoalkaloids

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KHAT USES AND ACTIONS

Traditionally: Fresh leaves are chewed (mental clarity) and used in the same way as cocoa. Used by students & labourers. Used as a tea: colds & flu, weight loss, menstrual cramps, asthma. Not addictive (leaves are chewed juice swallowed residue spat out) Toxic in high doses Males: headaches, insomnia, low sperm count, decreased fertility Females: jaundice and acute gastritis (Toxic effects differ in males and females)
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CNS stimulant
Used to treat depression (brings about a sense of well-being)

Alleviates sensations of hunger and fatigue.

Elevates mood, increases mental and physical alertness

COLCHICUM - LILIACEAE
Definition: Colchicum seed and corm are derived from the Autumn crocus or meadow saffron, Colchicum autumnale.

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COLCHICINE
Constituent in colchium seeds and corm. Amorphous, yellow-white alkaloid (darkens on exposure to light). Gives a strong yellow coloration with strong mineral acids. Dissolves readily in water, alcohol and chloroform, but only slightly in ether or petroleum spirit. Weak base

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COLCHIUM USES
Relieve gout (used with caution professional supervision) Also used in biological experiments to produce polyploidy (multiplication of the chromosomes in a cell nucleus)

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PURINE ALKALOIDS
Also known as non-alkaloids (xanthines) * synthetic origin does not contain an intact AA * Amphoteric Character * Peculiar solubility in warm water and in chlorinated solvents. Examples are caffeine (seeds of coffee plants, kola plants, tea leaves and guarana seeds), theobromine (Theobroma cocao) and theophylline (tea leaves & cola nuts). Beverages such as tea and coffee owe their stimulant action to the purine alkaloids.
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Caffeine: stimulates CNS and has a weak diuretic action. Theobromine: opposite action. Theophylline: relaxes involuntary muscles more effectively than caffeine or theobromine Caffeine does not precipitate like most alkaloids. A purple colour is derived from caffeine and other purine derivatives (murexide test).

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CNS activity, enhances alertness, facilitates thought formation, decreases the sensation of fatigue. Very high doses: induces nervousness, insomnia & tremors. Stimulates respiratory centre of the brain (increasing sensitivity to CO2). Cardiovascular activity: Positive inotropic action, causes tacchycardia, increases CO, slight peripheral dilation, mild diuretic action

PHARMACOLOGICAL ACTIVITY OF CAFFEINE

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CAFFEINE: USES
In combinations with antipyretics and analgesics, cold and flu medication. (increases the intestinal absorption of some of these drugs; or to counteract drowsiness). Ingredient in nonalcoholic beverages and energizing beverages
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CAFFEINE SIDE EFFECTS

Sinus tacchycardia Epigastric pain Nausea Vomiting Headaches Nervousness Insomnia tremors

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PHARMACOLOGICAL ACTION OF THEOPHYLLINE

bronchial smooth muscle relaxant Stimulates respiratory centre in the brain stem by increasing sensitivity to CO2. CNS stimulating Slightly inotropic. Diuretic activity is stronger than that of caffeine.
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THEOPHYLLINE - USES
Used for cough & asthmatic medication Reversible bronchospasm (chronic obstructive pulmonary disease).

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THEOPHYLLINE SIDE EFFECTS

Nervousness Sleeplessness Transient tacchycaridia Permanent tacchycardia Nausea Vomiting Headaches Tremors Diarrhoea
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THEOBROMA ACTIONS
Found in Cocoa Nutritive/food Nervous system stimulant Diuretic

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THEOBROMA - USES
Cocao butter is used as a base for suppositories and salves Heart and kidney tonic

Chocolate (flavouring)

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