Pharmacognosy

PHARMACOGNOSY - SOURCES AND COMPOSITION OF DRUGS

Pharmacognosy is the study of the source of drugs. It also deals with the physical and chemical properties of drugs. It provides the tools to identify, select and process natural products destined for medicinal use.

Introduction

For thousands of years, natural products have played an important role throughout the world in treating and preventing human diseases. Natural product medicines have come from various source materials including terrestrial plants, terrestrial microorganisms, marine organisms, and terrestrial vertebrates and invertebrates. The value of natural products in this regard can be assessed using 3 criteria: (1) the rate of introduction of new chemical entities of wide structural diversity, including serving as templates for semisynthetic and total synthetic modification, (2) the number of diseases treated or prevented by these substances, and (3) their frequency of use in the treatment of disease.

An analysis of the origin of the drugs developed between 1981 and 2002 showed that natural products or natural product-derived drugs comprised 28% of all new chemical entities (NCEs) launched onto the market. In addition, 24% of these NCEs were synthetic or natural mimic compounds, based on the study of pharmacophores related to natural products. This combined percentage (52% of all NCEs) suggests that natural products are important sources for new drugs and are also good lead compounds suitable for further modification during drug development. The large proportion of natural products in drug discovery has stemmed from the diverse structures and the intricate carbon skeletons of natural products. Since secondary metabolites from natural sources have been elaborated within living systems, they are often perceived as showing more “drug-likeness and biological friendliness than totally synthetic molecules”, making them good candidates for further drug development.

Drugs are obtained from many sources. Many inorganic materials, such as metals, are chemotherapeutic; hormones, alkaloids, vaccines, and antibiotics come from living organisms; and other drugs are synthetic or semisynthetic. Currently most drugs are synthetics produced in the laboratories with few from natural extractions. Synthetics are often more effective and less toxic than the naturally obtained substances and are easier to prepare in standardized units. The techniques of genetic engineering are being applied to the production of drugs, and genetically engineered livestock that incorporate human genes are being developed for the production of scarce human enzymes and other proteins

Primitive Medicine; Folklore, witchcraft, dreams, trances etc. Also from observing the reaction of some animals to particular herbs. Through primitive medicine quinine was discovered from Africa; used for malaria and limejuice for Ascorbic acid/Vitamin C and this is used for scurvy and gum bleeding.

Traditional Medicine

In the past, traditional peoples or ancient civilizations depended greatly on local flora and fauna for their survival. They would experiment with various berries, leaves, roots, animal parts or minerals to find out what effects they had. As a result, many crude drugs were observed by the local healer or shaman to have some medical use. Although some preparations may have been dangerous, or worked by a ceremonial or placebo effect, traditional healing systems usually had a substantial active pharmacopoeia, and in fact most western medicines up until the 1920s were developed this way. Some systems, like traditional Chinese medicine or Ayurveda were fully as sophisticated and as documented systems as western medicine, although they might use different paradigms. Many of these aqueous, ethanolic, distilled, condensed or dried extracts do indeed have a real and beneficial effect, and a study of ethnobotany can give clues as to which plants might be worth studying in more detail. Rhubarb root has been used as a purgative for many centuries. In China, it was called "The General" because of its "galloping charge" and was only used for one or two doses unless processed to reduce its purgative qualities. (Bulk laxatives would follow or be used on weaker patients according to the complex laxative protocols of the medical system.^[3]) The most significant chemicals in rhubarb root are anthraquinones, which were used as the lead compounds in the design of the laxative dantron.

The extensive records of Chinese medicine about response to Artemisia preparations for malaria also provided the clue to the novel antimalarial drug artemisinin. The therapeutic properties of the opium poppy (active principle morphine) were known in Ancient Egypt, were those of the Solanaceae plants in ancient Greece (active principles atropine and hyoscine). The snakeroot plant was well regarded in India (active principle reserpine), and herbalists in medieval England used extracts from the willow tree (salicin) and foxglove (active principle digitalis - a mixture of compounds such as digitoxin, digitonin, digitalin). The Aztec and Mayan cultures of Mesoamerica used extracts from a variety of bushes and trees including the ipecacuanha root (active principle emetine), coca bush (active principle cocaine), and cinchona bark (active principle quinine).

It can be challenging to obtain information from practitioners of traditional medicine unless a genuine long term relationship is made. Ethnobotanist Richard Schultes approached the Amazonian shamans with respect, dealing with them on their terms. He became a "depswa" - medicine man - sharing their rituals while gaining knowledge. They responded to his inquiries in kind, leading to new medicines. On the other hand Cherokee herbalist David Winston recounts how his uncle, a medicine priest, would habitually give misinformation to the visiting ethnobotanists. The acupuncturists who investigated Mayan medicine recounted in Wind in the Blood had something to share with the native healers and thus were able to find information not available to anthropologists. The issue of rights to medicine derived from native plants used and frequently cultivated by native healers complicates this issue.

Isolation and purification

If the lead compound (or active principle) is present in a mixture of other compounds from a natural source, it has to be isolated and purified. The ease with which the active principle can be isolated and purified depends much on the structure, stability, and quantity of the compound. For example, Alexander Fleming recognized the antibiotic qualities of penicillin and its remarkable non-toxic nature to humans, but he disregarded it as a clinically useful drug because he was unable to purify it. He could isolate it in aqueous solution, but whenever he tried to remove the water, the drug was destroyed. It was not until the development of new experimental procedures such as freeze drying and chromatography that the successful isolation and purification of penicillin and other natural products became feasible.

Synthesis

Not all natural products can be fully synthesized and many natural products have very complex structures that are too difficult and expensive to synthesize on an industrial scale. These include drugs such as penicillin, morphine, and paclitaxel (Taxol). Such compounds can only be harvested from their natural source - a process which can be tedious, time consuming, and expensive, as well as being wasteful on the natural resource. For example, one yew tree would have to be cut down to extract enough paclitaxel from its bark for a single dose. Furthermore, the number of structural analogues that can be obtained from harvesting is severely limited.

A further problem is that isolates often work differently than the original natural products which have synergies and may combine, say, antimicrobial compounds with compounds that stimulate various pathways of the immune system:

Many higher plants contain novel metabolites with antimicrobial and antiviral properties. However, in the developed world almost all clinically used chemotherapeutics have been produced by in vitro chemical synthesis. Exceptions, like taxol and vincristine, were structurally complex metabolites that were difficult to synthesize in vitro. Many non-natural, synthetic drugs cause severe side effects that were not acceptable except as treatments of last resort for terminal diseases such as cancer. The metabolites discovered in medicinal plants may avoid the side effect of synthetic drugs, because they must accumulate within living cells.

Semisynthetic procedures can sometimes get around these problems. This often involves harvesting a biosynthetic intermediate from the natural source, rather than the final (lead) compound itself. The intermediate could then be converted to the final product by conventional synthesis. This approach can have two advantages. First, the intermediate may be more easily extracted in higher yield than the final product itself. Second, it may allow the possibility of synthesizing analogues of the final product. The semisynthetic penicillins are an illustration of this approach. Another recent example is that of paclitaxel. It is manufactured by extracting 10-deacetylbaccatin III from the needles of the yew tree, then carrying out a four-stage synthesis.

Sources of Drugs There are several sources from which medications are derived. Drugs are derived from the following four main sources:

I. NATURAL SOURCE

A. Organic drugs. Organic drugs are mainly obtained from

1. Vegetable source

2. Animal source

3. Microorganisms.

B. Inorganic drugs. These are mainly obtained from

1.  Metallic source

2.  Non-metallic source.

II. SYNTHETIC SOURCE

(I) NATURAL SOURCES OF DRUGS

Active principles of drugs are mainly present in crude form in minute amounts. These active principles are separated by various techniques or may be used as such in some cases.

Natural product

A natural product is a chemical compound or substance produced by a living organism - found in nature that usually has a pharmacological or biological activity for use in pharmaceutical drug discovery and drug design. A natural product can be considered as such even if it can be prepared by total synthesis.

These small molecules provide the source or inspiration for the majority of FDA-approved agents and continue to be one of the major sources of inspiration for drug discovery. In particular, these compounds are important in the treatment of life-threatening conditions.^[2]

Natural sources

A large number of drugs are used in the clinics for the cure of various ailments. These drugs are diverse in chemical structure and are obtained from a wide variety of sources. In earlier days, simple chemical substances and different parts of plants were employed as medicinal agents, but most drugs currently used in therapeutics are synthetic in nature. However, natural sources are still used for obtaining some drugs mainly because their synthesis is difficult and uneconomical. Drugs are mainly obtained from following sources.

Natural products may be extracted from tissues of terrestrial plants, marine organisms or microorganism fermentation broths. A crude (untreated) extract from any one of these sources typically contains novel, structurally diverse chemical compounds, which the natural environment is a rich source of. Chemical diversity in nature is based on biological and geographical diversity, so researchers travel around the world obtaining samples to analyze and evaluate in drug discovery screens or bioassays. This effort to search for natural products is known as bioprospecting.

Screening of natural products

Usually, the natural product compound has some form of biological activity and that compound is known as the active principle - such a structure can act as a lead compound (not to be confused with compounds containing the element lead). Many of today's medicines are obtained directly from a natural source.

On the other hand, some medicines are developed from a lead compound originally obtained from a natural source. This means the lead compound:

• can be produced by total synthesis, or
• can be a starting point (precursor) for a semisynthetic compound, or
• can act as a template for a structurally different total synthetic compound.

This is because most biologically active natural product compounds are secondary metabolites with very complex structures. This has an advantage in that they are extremely novel compounds but this complexity also makes many lead compounds' synthesis difficult and the compound usually has to be extracted from its natural source - a slow, expensive and inefficient process. As a result, there is usually an advantage in designing simpler analogues.

(A) Organic drugs: Main natural sources of organic drugs are vegetable, animal and microorganisms.

The plant kingdom

Plants have always been a rich source of lead compounds (e.g. morphine, cocaine, digitalis, quinine, tubocurarine, nicotine, and muscarine). Many of these lead compounds are useful drugs in themselves (e.g. morphine and quinine), and others have been the basis for synthetic drugs (e.g. local anaesthetics developed from cocaine). Clinically useful drugs which have been recently isolated from plants include the anticancer agent paclitaxel (Taxol) from the yew tree, and the antimalarial agent artemisinin from Artemisia annua.

Plants provide a large bank of rich, complex and highly varied structures which are unlikely to be synthesized in laboratories. Furthermore, evolution has already carried out a screening process itself whereby plants are more likely to survive if they contain potent compounds which deter animals or insects from eating them. Even today, the number of plants that have been extensively studied is relatively very few and the vast majority have not been studied at all.

Vegetable source: Roots, bark, sap, leaves, flowers, seeds were sources for drugs e.g. Reserpine from Rauwolfia Vomitora, Digitalis from foxglove, opium from the poppy plant. many drugs available from plants are even today used in treatment of pathological conditions. With the increasing tendency for the use of alternate medicine, this source has gained more importance in the recent past. The pharmacological activities of plants are attributed to certain active principles in plants. They are alkaloids, glycosides, fats, oils, tannins, saponins etc. Substances obtained from obtaining several important these :

It is very old and important source of drugs, various parts of the plants are still used for drugs. The following table summarizes some of

Part of the plant           Name of the plant         Active Principle                        Use

Root                             Rauwolfia                      Reserpine                     Antihypertensive

                                    pecacuanha                  Ipecac                          Emetic

Bulbs                           Urginea                         Squill                            Emetic, rodenticide

Bark                             Cinchona                      Quinine                         Antimalarial

Rhizome                      Ginger                          Gingerol                        Carminative

Wood                           Sandal wood                 Sandal wood oil                        Urinary antiseptic

                                    Quassia                        Quassin                        Stomachic

Leave                           Belladona                     Atropine                        Anti-muscarinic

                                    Digitalis                                    Digitoxin                       Cardiac stimulant

Flower                          Clove                            Eugenol                        Local anaesthetic, rubefacient

                                    Pyrethrium                    Pyrethrin                       Insecticide

Fruit                             Senna                           Senegrin                       Purgative

                                    Anise                            Anethole                       Carminative

Seed                            Nux vomica                   Strychnine                     Rodenticide

                                    Physostigma                 Physostigmine              Anti-glaucoma

Corn                             Colchicum                     Colchicine                     Anti-gout

The following is the short description of the active constituents of crude drugs.

(a) Alkaloid: These are complex, alkaline, nitrogenous compounds mostly obtained from plants and also animals. Their properties are as follows:  They are nitrogenous organic compounds. They are alkaline in reaction (so named alkaloids). They combine with acids to form crystalline salts without production of water. They are readily soluble in alcohol but sparingly soluble in water. But their salts are soluble in water. A few of them are liquid, which nearly contain C, H and N only. The solid alkaloids contain oxygen   in addition and are colourless crystalline in nature. Most of the alkaloids are closely related to pyridine and some may be prepared synthetically from pyridine bases. They are mostly bitter in taste. In higher concentration they are potent poisons. Their names mostly end with -ine.

Alkaloids - Alkaloids are nitrogenous substances obtained from various parts of the plant. Alkaloids containing oxygen are solids and comparatively non volatile (cocaine) while those that do not contain oxygen are liquids and volatile (nicotine, lobeline and coniine). Alkaloids are insoluble in water while their salts (atropine sulphate, caffeine citrate) are soluble in water. Alkaloids are bitter to taste. They are incompatible with the alkalies, tannic acid and heavy metals. Alkaloids represent the waste products of plant metabolism and their names end with 'ine'. Alkaloids should be administered in small quantities and when given in excess they may produce death without much postmortem changes for diagnosis.

Examples :

Solid alkaloid:              Atropine, morphine, quinine, etc.

Liquid alkaloid:            Arecholine, nicotine, lobeline

Semi-synthetic/synthetic:         Apomorphine, homatropine.

Animal alkaloid:           Adrenaline.

(b) Glycosides: They are mostly non-nitrogenous bodies mainly occurring in plants. They are non-nitrogenous compounds having sugar attached to non-sugar part by ether linkage. They are neutral in reaction.  They mainly contain C, H and O. Some may have in addition N and few S. They do not combine with acids to form salts.  They are mostly soluble in alcohol, less soluble in water and insoluble in ether. Some are highly active, while others are practically inert. These are hydrolysed by acids and liberate aglycone (non-sugar part). Their names usually end with -in. Sugar helps in the dissolution of the preparation while the pharmacological action rests with the 'aglycone'. When the sugar molecule is glucose, the glycoside is known as glucoside. Cardiac glycosides digitalis, strophanthus and squill play a major role in the treatment of congestive cardiac failure.

Examples : Digitoxin, scillarin, digoxin, etc.

(c) Saponins : These are plant glycosides which have distinctive property of frothing.  They are a group of non-nitrogenous substances usually glycosides. They are soluble in water and form froth when shaken.  On hydrolysis they split up into sugar and aglycone (sapogenin).  Toxic saponins are called sapotoxins.

Examples : Digitonin, senegin, glycyrrhizin, etc.

(d) Resins : These are rosin-like substances which are oxidative products of volatile oils. They are produced by some plants. They are invariably composed of a large number of substances which may be acid, alcohol or ester in chemical composition. They are secretions of plant tissues. They are bitter and amorphous solids. These are solid brittle substances formed from terpenes by oxidation.They are insoluble in water, but soluble in alcohol, ether, etc. They are soluble in alkalies forming non-detergent resin soaps.

Examples : Resin of Jalap, podophyllin.

Oleo-resins : They are natural plant exudates which are semisolid mixtures of resins and volatile oils, e.g. crude turpentine.

Gum-resins : They are mixture of resins and gums, e.g. asafoetida.

Balsams : They are oleoresins containing benzoic acid or cinnamic acid, e.g. benzoin, balsam of Peru, etc.

(e) Tannins:  Tannins  are  non-nitrogenous  phenol  derivatives characterised by their astringent action on the mucous membrane. They mainly occur in leaves and barks of the plant. They have irritant or astringent action. They react with iron to form blue colouration. They precipitate metallic salts, alkaloids and proteins. Some are glycosides, i.e. occur in combination with sugar.

Tannins - These are non-nitrogenous phenol derivatives found especially in leaves and bark. They are astringent in nature and form inky solutions with ferric salts. Catechu a tannic acid is used in the control of diarrhoea.

Example : Tannic acid obtained from nut galls.

(f) Gums : Gums are secretory products of plants which are used as emulsifying agents for oils and, suspending agents for insoluble substances. Gums are dried exudates obtained by incision on stems of various paints.They are amorphous, colloidal, complex polysaccharides. They dissolve in water forming viscid adhesive fluid known as mucilage. They form a jelly with water.

Examples : Acacia, tragacanth.

 (g) Oils : Oils are obtained from vegetable, animal and mineral sources. Oils are of 3 types: Volatile, fixed and mineral.

Oils - There are two types of oils namely fixed oils and volatile oils. Volatile oils are also known as essential oils. Castor oil, coconut oil etc. are fixed oils while turpentine oil, eucalyptus oil etc. are volatile oils. Fixed oils are obtained by expression while volatile oils are obtained by distillation.

Volatile oils: These are also called as essential, ethereal, aromatic or flavouring oils as they are responsible for the aroma and odour of plants and flowers. They are composed of diverse chemical compounds such as alcohols, aldehydes, ketones, esters, sulphur compounds, etc. They are mainly present in the flowering parts of plant, leaves and fruits and give characteristic smell to plants. They are mainly obtained by a process of distillation without being decomposed. They do not form soap with alkalies. They are less soluble in water but more soluble in organic solvents. Alcoholic solutions of these oils are known as essences and are used in perfumery. They do not leave a grease spot on paper. On exposure to air and light, they tend to oxidise and turn rancid.

Examples : Liquid volatile oil : Eucalyptus oil, clove oil. Solid volatile oil : Camphor, menthol, thymol.

Fixed oils : They are esters of higher fatty acids (oleic, palmitic, stearic acids) and glycerines. They are obtained from fruits, seeds and some other parts of the plants. They are non-volatile and as such cannot be distilled without decomposition, so obtained by process of expression. They are insoluble (immiscible) in water, sparingly soluble in alcohol and freely soluble in ether. They are liquid at ordinary temperature. They leave a permanent grease spot on paper. They turn rancid on heating. They form soap with alkalies.

Examples : Vegetable oils : Olive oil, castor oil, mustard oil. Animal oils : Cod liver oil, shark liver oil.

Fats : These are also oils containing more of palmitin and stearin making them solid at ordinary temperature, e.g. lard, lanolin, butter. Mineral oils : These are obtained by boring the earth and do not belong to organic class. Some are used in medicinal preparations and contain only C and H, e.g. liquid paraffin.

(h) Waxes : They are esters of higher fatty acids and higher monohydric alcohols. They are firmer in consistency and have higher melting , points, e.g. Yellow and white bees wax.

2. Animal sources : From animal source relatively few but important drugs are obtained. Following are some useful drugs: Animal sources

1. Animals can sometimes be a source of new lead compounds. For example, a series of antibiotic peptides were extracted from the skin of the African clawed frog and a potent analgesic compound called epibatidine was obtained from the skin extracts of the Ecuadorian poison frog.

Animal sources; Glandular products from animals are used, such as insulin and thyroid.; gave us hormones for replacement in times of deficiencies e.g. Insulin from the pancreases of pigs and cattle, Liver extracts for anemia etc Extracts of porcine pancreas were used in the preparation of insulin. However, now latest tools like biotechnology are used for the production of insulin.

Venoms and toxins

Venoms and toxins from animals, plants, snakes, spiders, scorpions, insects, and microorganisms are extremely potent because they often have very specific interactions with a macromolecular target in the body. As a result, they have proved important tools in studying receptors, ion channels, and enzymes. Many of these toxins are polypeptides (e.g. α-bungarotoxin from cobras). However, non-peptide toxins such as tetrodotoxin from the puffer fish are also extremely potent.

Venoms and toxins have been used as lead compounds in the development of novel drugs. For example, teprotide, a peptide isolated from the venom of the Brazilian viper, was the lead compound for the development of the antihypertensive agents cilazapril and captopril.

The neurotoxins from Clostridium botulinum are responsible for serious food poisoning (botulism), but they have a clinical use as well. They can be injected into specific muscles (such as those controlling the eyelid) to prevent muscle spasm. These toxins prevent cholinergic transmission and could well prove a lead for the development of novel anticholinergic drugs.

Hormones        :   Insulin, thyroxin, gonadotropins, etc.

Vitamins           :   Cod liver oil (vit. A).

Vaccines/serra :   Anti-rabies vaccine (A.R.V), antitetanic serum (A.T.S),,anti-diphtheric serum, etc.

Replacement therapy : Liver extract.

3. Microorganisms: Microorganisms such as bacteria and fungi have been invaluable for discovering drugs and lead compounds. These microorganisms produce a large variety of antimicrobial agents which have evolved to give their hosts an advantage over their competitors in the microbiological world.

Fungi:   Penicillin G from Penicillium notatum.

Actinomycetes: Streptomycin from Streptomyces griseus

Bacteria: Bacitracin from Bacillus subtilus.

The screening of microorganisms became highly popular after the discovery of penicillin. Soil and water samples were collected from all over the world in order to study new bacterial or fungal strains, leading to an impressive arsenal of antibacterial agents such as the cephalosporins, tetracyclines, aminoglycosides, rifamycins, and chloramphenicol.

Although most of the drugs derived from microorganisms are used in antibacterial therapy, some microbial metabolites have provided lead compounds in other fields of medicine. For example, asperlicin - isolated from Aspergillus alliaceus - is a novel antagonist of a peptide hormone called cholecystokinin (CCK) which is involved in the control of appetite. CCK also acts as a neurotransmitter in the brain and is thought to be involved in panic attacks. Analogues of asperlicin may therefore have potential in treating anxiety. Other examples include the fungal metabolite lovastatin, which was the lead compound for a series of drugs that lower cholesterol levels, and another fungal metabolite called ciclosporin which is used to suppress the immune response after transplantation operations.

The marine world

In recent years, there has been a great interest in finding lead compounds from marine sources. Coral, sponges, fish, and marine microorganisms have a wealth of biologically potent chemicals with interesting inflammatory, antiviral, and anticancer activity. For example, curacin A is obtained from a marine cyanobacterium and shows potent antitumor activity. Other antitumor agents derived from marine sources include eleutherobin, discodermolide, bryostatins, dolostatins, and cephalostatins.

(B) Inorganic Sources: Drugs obtained from inorganic sources have been simply classified into metals and non-metals. Metalloids which show intermediate properties are usually discussed along with metals. The elements either occur in native state or combined state.

Minerals; This includes drugs like sodium chloride, copper sulphate, magnesium sulphate, potassium permanganate etc. They are used in the purified form as drugs.

1. Metals : Minerals are the main source of metals.

Agent                           Use

Magnesium sulphate      Purgative

Calcium carbonate         Astringent

Copper sulphate            Emetic

Ferrous sulphate           Haematinic

Zinc sulphate                Astringent

Bismuth subnitrate         Antiseptic

Lead acetate                 Local sedative, antiseptic

2. Non-metals : These are also used for various purposes.

Agent                                       Use

Iodine (Pot. iodide)                    Expectorant

Bromine (Pot. bromide)                         Sedative

Hydrogen peroxide                    Antiseptic

Sulphur                                     Insecticide, disinfectant

Carbon (charcoal)                      Adsorbant

(II) SYNTHETIC SOURCES OF DRUGS

Synthetic drugs are prepared in the laboratory with the help of inorganic and organic drugs. Today majority of drugs are obtained synthetically or semi-synthetically. Numerous drugs which were originally obtained from plants are now prepared synthetically. For example, ether and chloroform (Volatile anaesthetics), sulfonamides and quinolones (antimicrobial drugs), paracetamol (analgesic), pentobarbital and thiopental (hypnotic and parenteral anaesthetics), etc.

Synthesis of Substances; from natural products in the laboratory. Laboratories duplicate natural processes. Frequently this can eliminate side effects and increase the potency of the drug. Examples include barbiturates, sulfonamides, and aspirin. A number of drugs synthesized in the laboratory are used in the day to day practice. Drugs like hormones, antimicrobials etc. are synthesized in the laboratory.

Happy Chance; Discovery is by chance not by any premeditated effort.