Drugs Containing Alkaloids 19.1, INTRODUCTION ‘One of the largest groups of chemicals produced by plants is the alkaloids. Many ot these metabolic by-products are derived from amino acids and include an enormous number fof bitter, nitrogenous compounds. More than 10,000 dif ferent alkaloids have been discovered in species from over 300 plant families. Alkaloids often contain one or more rings of carbon atoms, usually with a nitrogen atom in the ring, The position of the nitrogen atom in the carbon ring varies with different alkaloids and with different plant families. In some alkaloids, such as mescaline, the nitrogen atom is not within a carbon ring. In fact, itis the precise position of the nitrogen atom that atfects the properties ot these alkaloids. These compounds are renowned for their potent pharmacological activities. Whilst tiny amounts of some can immobilize an elephant or a thinoceros, others have important clinical use, such as analgesics, antimalarial, antispasmodics, for pupil dilation, treatment of hyperten- sion, mental disorders and tumours. ‘They are all nierogen heterocycles which occur mainly in plants as their salts of common carboxylic acids, such as citric, lactic, oxalic, acetic, maleic and tartaric acids as well as fumaric, benzoic, aconitic and veratric acids. Their amine character produce an alkaline solution in water and hence the origin of their name—alkaloids Although they undoubtedly existed long before humans, some alkaloids have remarkable structural similarities with neurotransmitters in the central nervous system (CNS) ot humans, including dopamine, serotonin and acetylcholine. ‘The amazing effect of these alkaloids on humans has led to the development of powerful painkiller medications, spiritual drugs, and serious addictions by people who are ignorant of the properties of these powertul chemicals. 15.2, DEFINITION An alkaloid is a nitrogenous organic molecule that has a pharmacological effect on humans and animals. They are CHAPTER 15 a class of compounds which typically contain nitrogen and hhave complex ring structures. They occur naturally in seed bearing plants and are foxind in berries, bark. fir, roots and leaves. Ofien, they are bases which have some physiological effect. The name derives from the word alkaline; originally, the term was used to describe any nitrogen-containing base (an amine in modern terms). Alkaloids are found as secondary metabolites in plants (eg. in Vinca and Datura), animals (e.g. in shellfish) and fungi, and can be extracted from their sources by treatment with acids (usually hydro- chloric acid or sulphuric acid, though organic acids, such as maleic acid and citric acid are sometimes used). Usually alkaloids are derivatives trom amino acids, Even though many alkaloids are poisonous (e.g, strych- nine oF coniine), some are used in medicine as analgesics (pain relievers) or anaesthetics, particularly morphine and codeine. Most alkaloids have a very bitter taste. 15.3. HISTORY Evidence suggests that alkaloids have been used by human- ity for thousands of years. The first civilizations to use them were probably the ancient Sumarians and Egyptians However, it was not until the early nineteenth century that these compounds were reproducibly isolated and analysed. Advances in analytical separation techniques, such as chromatography and mass spectroscopy; led to the clucidation of the chemical structure of alkaloids, The term for these compounds is thought to have originated from the fact that the alkaloid, morphine, had similar properties to basic salts derived from the alkali ashes of plants thus, it was called a vegetable alkali or alkaloid. Since the first alkaloids were isolated, thousands more have .been identi- fied and classified, Prior to approximately 300 years ago, malaria was the scourge of Europe, likely having been introduced throu the Midalle Bast. Malaria is caused by protozoa of the genusPlasmodium, contained as spores in the gut of the Anopheles ‘mosquito. which then spreads the spores to humans when it bites. As the Spanish and Portuguese explorers began to colonize South America, they discovered a cure for ‘malaria known to the native Indians. ‘This was the bark of the Cinchona trees. The use of Cinchona bark to treat malaria was first reported in Europe in 1633, and the first bark reached Rome about 12 years later. Teas made from the bark cured people suffering from malaria, one of the major scourges in Europe at that time, and the bark was known as Jesuit’s bark, Because of the philosophi- cal differences benween Protestants and Catholics, many Protestants refused to be treated with the bark. One of the most prominent Protestants of the time, Oliver Cromuell, reportedly died of malaria because of this stubbornness. ‘The French apothecary Derosne probably isolated the alkaloid afterwards known as narcotine in 1803 and the Hanoverian apothecary Serturner further investi~ gated opium and isolated morphine (1906 and 1916). Morphine is the principal alkaloid and was first isolated between 1803 and 1806. It was widely used for pain relief beginning in the 1830s, but was also recognized as being addictive. Isolation of other alkaloids, particularly by Pelletier and Caventou, rapidly followed: strychnine (1817), emetine (1817), brucine (1819), piperine (1819), caffeine (1819), quinine (1820), colchicine (1890) and conine (1826). Coniine was the first alkaloid to have its structure established and to be synthesized, but for others, such as colchicine, it was well over a century before the structures were finally elucidated. In the second half of the ewenticth century alkaloids featured strongly in the search for plant drugs with anticancer activity. A notable success was the introduction of catharanthus alkaloids and paclitaxel into medicine and there is much current interest in other alkaloids having anticancer properties as well as those exhibiting antiaging and antiviral possibilities, 15.4. CLASSIFICATION Alkaloids are generally classified by their common molec- ular precursors, based on the biological pathway used to construct the molecule, From a structural point of view, alkaloids are divided according to their shapes and origins. There are three main types of alkaloids: (1) true alkaloids, (2) protoalkaloids, and (3) pseudoalkaloids ‘Truc alkaloids and protoalkaloids are derived from amino acids, whereas pseudoalkaloids are not derived from these compounds. ‘True Alkaloids Thue alkaloids derive from amino acid and they share a heterocyclic ring with nitrogen. These alkaloids are highly reactive substances with biological activity even in low doses. PBMBBEIIIS 1611300x oF PuveMacocNosy AND PHYTOCHEMISTRY All trne alkaloids have a bitter taste and appear as a white solid, with the exception of nicotine which has a brown liquid. True alkaloids form water-soluble salts. Morcover, most of them are well-defined crystalline substances which cunive with acids w forum salts, Thue alkaloids nay occur it plants (1) in the free state, (2) as salts and (3) as N-oxides ‘These alkaloids occur in a limited number of species and families, and are those compounds in which decarboxylated amino acids are condensed with a nonnitrogenous structural moiety: The primary precursors of true alkaloids are such amino acids as L-ornithine, L-lysine, L-phenylalanine/L~ tyrosine, L-tryptophan and L-histidine. Examples of true alkaloids include such biologically active alkaloids as cocaine, quinine, dopamine and morphine Protoalkaloids Protoalkaloids are compounds, in which the N atom derived from an amino acid is not a part of the heterocyclic. Such kinde of allaloid include compounde derived from L ty rosine and L-tryptophan. Protoalkaloids are those with a closed ring, being perfect but structurally simple alkaloids, ‘They form a minority of all alkaloids, Hordenine, mesca~ line and yohimbine are good examples of these kinds of alkaloid, Chini eral, have found new alkaloids, stachydrine and 4-hydroxystachydrine, derived from Boscia angustifolia, aa plant helonging to the Capparidacea family. These alka- loids have a pyrroline nucleus and are basic alkaloids in the genus Boscia. The species from this genus have been used in folk medicine in East and South Africa, Boscia angustifolia is used for the treatment of mental illness, and occasionally to combat pain and neuralgia, Pseudoalkaloids Pseudoalkaloids are compounds, the basic carbon skeletons of which are not derived from amino acids. In reality. pseudoalkaloids are connected with amino acid pathways They are derived from the precursors or post-cursors (derwatives the mdegradation process) of amino acids. They ‘can also result from the amination and trans-amination reactions of the different pathways connected with precur- sors or post-cursors of amino acids. ‘These alkaloids can also be derived from nonaminoacid precursors. The N atom is inserted into the molecule at a relatively late stage, for example, in the case of stcroidal or terpenoid skeletons. Certainly, the N atom ‘can also be donated by an amino acid source across a trans-amination reaction, if there is a suitable aldehyde ‘or ketone. Pscudoalkaloids can be acetate and phenylala~ nine derived or terpenoid, as well as steroidal alkaloids. Examples of pscudoalkaloids include such compounds as coniine, capsaicin, ephedrine, solanidine, caffeine and theobromine.DRUGS CONTANING ALKALOIDS Alkaloids are mainly divided into two categories on the Table 15.2 Main types of alkaloids and theie chemical groups basis of their chemical structure, that is, heterocyclic rings ae (able 15.1). rosa Atypical alkaloids True homithine |Plidine [Pyridine |Cusconygrine These are also known as nonheterocyclic alkaloids and alkaloids alkaloids Hyarine contain nitrogen in aliphatic chain. Hropane [Tropane [Atropine i i stato Cocaine ‘Typical alkaloids Hyoscyamine “These are also known as heterocyclic alkaloids and contain Scopolamine! nitrogen in heterocyclic ring system, eect Pyrola |Pyrolzidine |Hlamine eee f sno a nici N-oxide Table 15.1 Classitication of alkaloids ae eae td oan Examph Uses a ee a iene Hysine |Ppendine [Pperdine [Anaerine 1. Nonheterocycic Alkaloids ue latatoids | PRERinna Phenyl Ephedine, | Ephedasp. [Asthma tobetine ethylamine | Mesaline, eee alkaloid | Hordenine Piperiine ' = - Piperine alkaloids 3. Sedamine Modified | Taxol Taxus p.__| Anicancer [Quinolizi-|Quinolizidine [Cyne sliterpene ine aka Lupanine TAR ods Sparteine 2, Heterocyclic Alkaloids 7 Mone-mcear Wetec Ve ANSI ee Pyridine | bobeline Lobelia sp. [Asthma ayosine|Phe- —_|Phenylethyl [Adrenaline Ppersine | Piperine Pipersp | Gonorthors, rylethyt. amine | Aahslarsine Anionidant Jamino Dopamine aalods Noradrenaline Pyrole Hiyine Coca sp.___| ENS Stimulant Co Pyrolidine | Nicotine ‘Tobacco [CNS Stimulant [simple ter Benayre- [Codeine 8. rahyckoiso- |rahykoiso- | Moephine Tmidazole | Piocarpine | Pilacarpus | Contraction of pupil lqunotine qunotine | orcoctaurine " an me [Akad Papaverine Paya sory said Himtatn Tsoquinoline | Morphine, J Opium | Narcotic analgesic Fubocuraine papaverine IHyrosine |Pheneth~ —[Amarylida- JAuturmaline o: Itsoquino- |coxe Icrinine Quinoline | Quinidine, | Cinchona | Antimalarial “ema: lle eee oe pining nine |alhaloids Galamthamtine Indole Ergotamine, | got, | Oxytacie An-HT, [Galamtine reserpine, | Rauwoa, | Anticancer, CNS Haemantamine vinerisine, | Vinea, | stimulant Lycorine Sirychnine | Nux Lycorenine vomica Martine |Oxomartdine Quinazsliws | Vashi rs Iviatine Tropane | Avopine, Datura, | Parasympatholytic ‘iy. indole [indole hyoscine | elladona tophan [alkaloids ce i sae GUTS Simple indole |Arundacine a Gi real CSsmay alkaloids |Arundmine Steroid Solaeodine | Solanum | steroidal precursor Psion #. Serotonin x Hryptamine fepenoid | Acontine | Aconite sp. | Newalgia eee Simple | Eleagnine The interrelationship between different ways of clas- pecarbotine | Harmine siffcations can be summarized by the Table 15.2 thaiTEXTBOOK OF PHARMACOGNOSY AND PHYTOCHEMISTRY frerpencid — JAjmalicine indole |Catharanthine Jatkaloids —_|Secologanin Tabersonine [Quinoline |Quinoline _|chloroquinine atkaloide Cinchonidine Quinine Quinine JPyrooin- indole ——[Yohimbine dole CChimonantheine atalouss ‘Chimonantheine Corynantheine Corynantheidine ieynantine Ergot Ergotamine alkaloids Ergocryptine| imidazole imidazole Histamine ataloids Pilocarpine Piles IManzamine [Restomanza- [Xestomanzamine alkaloids |mine A 8 arginine [Marine [Becaboline _[Saxitoxin ataloids eradotoxin [Anthranilic [Quinazo- |Quinazoline [Peganine lacid line alkaloids [Quinotine [Quinoline —[Acetyifolidine atkaloids Acute lBucharine Dictamine Dubunidine Kokusaginine IMaculosine Pesamsine Pesorine Palficine Stimmianine JAcridone [Acridine [Acronycine alkaloids Rutacridone Nicotinic [Pyridine [Pyidine? _[Anabasine lacid alkaloids |Pyroliine —|cassinine cena Evoline Evonoline Evorine IMaymytsine Nicotine Regelidine Willorine Proto [lyosine [Phe __[Phenylayl- [Hordenine stkaloids Javlety- —_farsine Mescaline akaloids [reyp-__[Terpenoid Indole ___|Yohimbine lophan indole alkaloids Fomithine [Pyrotiz- [Pyroiziine |$-hydroxy idine alka- stachydrine ide Stacliyeine Pseudo [Acetate [Piperidine [Piperidine [Contine alkaloids alkaloids Coniceine Pinidine [Sesquite|Sesqiterpene [Cassinine ei ered ois Evonine Evonoline Evorine Maymytsine Regelidine lwiterine Pyuvie Ephedra [Phenylc _ |cathine acid [alkaloids Icathinone pte Norephedrine Ferulic acid| Aromatic [Phenyl | Capsaicin alkaloids Geraniol [Texpenoid [Terpenoid | Aconitine allaloids Actinidine sine Gentian B-skytanthine Saponins [Steroid Icholestane alkaloids IConessine lerine Pregnenolone Protoveratine A Solanidine Solasodine ‘Adenine’ [Purine [Purine —|cafiene Guanine alkaloids Theobromine [Theophyline 15.5. OCCURRENCE IN NATURE ‘Alkaloids are substances very well known for their biological activity at the beginning of world civilization. They were ‘wed in shamanism, in traditional herbal medicine for the cure of diseases and in weapons as toxins during tribal wars and during hunting, They also had, and still have, socio-cultural and personal significance in ethnobotany. Moreover, they have been and continue to be the object of human interest conecrning new possibilities for their safe utilization and ensuing health benefits. OF all sec- ‘ondary compounds, historically and contemporaneously, only alkaloids are molecules of natural origin with highly important benefits and diagnostic uses. They can be char- acterized a the must useful and abso the must dangerous products of nature, Alkaloids are most abundant in higher plants. At least 25% of higher plants contain these molecules. In effect, this means that on average; at least one in fourth plants contains some alkaloids. In reality, it is nor impossible that alkaloids occur more commonly. Using the latest equip- ‘ment and technology, such slight traces of alkaloids may be detected (e.g. less than 10 gigagrams per kg of plant mass) that these have no real influence on biological receptors and activity. Generally these species are not considered asalkaloid species. Hegnauer has defined alkaloid plants as those species which contain more than 0.01% of alkaloids. This is right from the point of view of the classification. From the genetic point of view, and the genetic mechanism Of alkaloid synthesis, ies areal limitation, Paying attention to slight traces of alkaloids in plants, we see the members of the plant family which are relatives. They have a genetically determined alkaloid mechanism with a species expression. ‘Moreover, this expression is also on the hybrid level. ‘The distribution of alkaloids in nature is restricted 10 some specific plants, animals or lower plants. The pattern of distribution of compound and its pharmacological activ- ity have a great role in chemotaxonomical classification. Alkaloids are chiefly found to be distributed in angiosperms and to some extent in lower plants (mosses, liverworts) and animals. Nearly about 47-50% of various bacterial species also contain alkaloids, for example, pyocyanine from Pseudomonas aeruginosa. Alkaloids are commonly found in the families like, Chenopodiaceae, Lauraceae, Berberidace: aceae, Leguminosae, Papilionaceae, Rutaceae, Apocynaceae, Loganiaceae, Rubiaceae, Boraginaceae, Convolvullaceae, Solanaceae, Campanulaceae, Compositae, etc. They may be present in any part of the plant like, roots (reserpine from Rauwolfia), serial parts Tike (Ephedra), barks (quinine from cinchona), leaves (Cocaine from Coca), seeds (caffeine from Coca seeds) or even in entire plant (vinblastin from Vinca). 300 alkaloids belonging to more than 24 classes are reported to occur in the skins of amphibians. 15.6. PROPERTIES: Although numerous alkaloids exist, they have similar prop- erties when separated. In general, they are colourle crystalline solids which are hasie, have a ring structure, and have definite melting points. ‘They are also derived from plants and have a bitter taste. However, some exceptions are known. For instance, some alkaloids are nor basic and others are brightly coloured (betanidine, beriberine, sangui- narine) or liquid (nicotine). Other alkaloids are produced synthetically, Most alkaloids are also chiral molecules which ‘mean they have nonsuperimposable mirror images. This results in isomers that have different chemical properties. For example, one isomer may have a physiological function while the other does not. Generally free bases of alkaloids are soluble in organic solvents and insoluble in water, where as alkaloidal sats are soluble in water and partially soluble in organie solvents. For example, strychnine hydrochloride is much more soluble jn water than strychnine as a base. 15.7. EXTRACTION ‘The extraction of alkaloids is based on their basic character and solubility profiles. Generally alkaloids are extracted rninly using evo mneciods DRUGS CONTANING ALKALOIDS (EC Method A ‘The powdered material that contains alkaloidal salts is moistened with alkaline substances like sodium bicarbon- ate, ammonia, calcium hydroxide. etc.. which combines with acids, tannins and other phenolic substances and sets free the alkaloids bases. Extraction is then carried out with ‘organic solvents such as ether or petroleum spirit. The ‘concentrated organic liquid is then shaken with aqueous acid and allowed to separate. Alkaloid salts will be present in aqueous liquid, while many impurities remain behind in the organic liquid. Method B ‘The collected powdered material is extracted with water or aqueous alcohol containing dilute acid. Chloroform or ‘ther organic solvents are added and shaken to remove the pigments and other unwanted materials, ‘he tree alkaloxds are then precipitated by the addition of excess alkalis like, sodium bicarbonate or ammonia and separated by filtration or by extraction with organic solvents. Volatile liquid alkaloids (nicotine and coniine) are iso- lated by distillation. The powdered material that contains alkaloids is extracted with water and the aqueous extract is ‘made alkaline with sodium carbonate or ammonia and the alkaloid is distilled off in steam. This could be collected and purified. 15.8. CHEMICAL TESTS “The chemical tests are performed from neutral oF slightly acidic solution of drug, Dragendorff’s Test Drugsolution + Dragendroft’s reagent (Potassium Bismuth Iodide), formation of Orangish red colour. Mayer's Test Drug solution + few drops of Mayer's n igent (potassium ‘mercuric iodide), formation of creamy-whi precipitant Hager’s Test Drug solution + few drops of Hagers reagent (Saturated aq. Solution of Picric acid), formation of crystalline yellow precipitate. ‘Wagner's Test Drug solution + few drops of Wagner’s reagent (dilute Iodine solution), formulation of reddish-brown. precipi- tate Tannic Acid Test Drug solution + few drops of tannic acid solution, forma- Gon of bull'coloured precipitate.