phytoterapy and chem. of Nat.Produts Lectures.pdf

CHEMISTRY OF DRUGS Phytotherapy and chem. of natural products Dr. Khaled Tawaha The living organism may be considered → a biosynthetic laboratory not only for chemical compounds (carbohydrates, proteins,fats) that are utilized as food by hum...

CHEMISTRY OF DRUGS Phytotherapy and chem. of natural products Dr. Khaled Tawaha The living organism may be considered → a biosynthetic laboratory not only for chemical compounds (carbohydrates, proteins,fats) that are utilized as food by humans and animals. → but also for a multitude of compounds (glycosides, alkaloids, terpenes) that exert a physiologic effect. → These chemical compounds give plant and animal drugs their therapeutic properties. Phytotherapy and chem. of natural products Dr. Khaled Tawaha → Drugs are used as such in their crude form or they may be extracted, → the resulting principles (constituents) being employed as medicinal agents. → because the plant or animal is composed of many chemical compounds, it is common practice to single out those compounds that are responsible for the therapeutic effect and to call them → active constituents. Phytotherapy and chem. of natural products Dr. Khaled Tawaha These active constituents are differentiated from inert constituents(cellulose, lignin, suberin , and cutin) in addition, starch, albumin, coloring matters, and other substances may have no definite pharmacologic activity and also are considered inert constituents. → In animal drugs, keratin, chitin, muscle fiber, and connective tissue are regarded as inert. → Often the presence of inert substances may modify or prevent the absorbability or potency of the active constituents. → To eliminate the undesirable effects of inert matter in the crude drug or its preparations. Phytotherapy and chem. of natural products Dr. Khaled Tawaha → active principles are extracted, crystallized, and purified for therapeutic use. →These constituents have been referred to as “secondary” plant substances. Active constituents may be divided into two classes: → 1-pharmaceutically active 2-pharmacologically active. → Pharmaceutically active constituents may cause→ precipitation or other chemical changes in a medicinal preparation. Phytotherapy and chem. of natural products Dr. Khaled Tawaha →For instance, neither cinchona bark nor its extracts could be used in formulating preparations containing iron salts→because the cinchotannic acid would combine with these salts and cause precipitation. → Cinchotannic acid, then, is active constituent. → The use of quinine hydrochloride obviates this incompatibility →because it is a purified crystalline compound that does not contain the slightest trace of cinchotannic acid. Phytotherapy and chem. of natural products Dr. Khaled Tawaha Pharmacologically active constituents are responsible → for the therapeutic activity of the drug. →They may be either single chemical substances or mixtures of principles. → The single chemicals are exemplified by sugars, starches, plant acids, enzymes, glycosides, steroids, alkaloids, proteins, hormones, and vitamins. →The mixtures include fixed oils, fats, waxes, volatile oils, resins, oleoresins, oleo-gum-resins, and balsams. Phytotherapy and chem. of natural products Dr. Khaled Tawaha PRODUCTION OF CRUDE DRUGS Phytotherapy and chem. of natural products Dr. Khaled Tawaha CULTIVATED AND WILD PLANTS 1-Certain drugs are now obtained almost exclusively from cultivated plants:→ cardamoms, Indian hemp, ginger, and pepper mint and spearmint for oil production, fennel, cinchona and opium. I 2-Others are now grown because supplies of the wild plants are insufficient to meet the demand or because, owing to sparse distribution or collection is difficult. 3-Cultivation is essential in the case of drug such as Indian hemp and opium, which are subject to government control. Phytotherapy and chem. of natural products Dr. Khaled Tawaha 4-In many cases cultivation is advisable because of the improved quality of the drug which it is possible to produce. The improvement may be due the following: A) The power to confine collections to species, varieties which have the desired phytochemical characters (cinnamon, fennel, cinchona Labiate drugs and valerian. Phytotherapy and chem. of natural products Dr. Khaled Tawaha B)The better development of the plants owing to - improved conditions of the soil control of insect pests. fungi, etc C) The better facilities for treatment after collection. → For example drying at a correct temperature in the cases of digitalis, peeling of cinnamon and ginger. *For success in cultivation it is necessary to study the conditions under which the plant flourishes in the wild state and reproduce the conditions or improve on them. Phytotherapy and chem. of natural products Dr. Khaled Tawaha SOILS Phytotherapy and chem. of natural products Dr. Khaled Tawaha Three important basic characteristics of soils are the physical, chemical and microbiological properties. 1-Variations in partiele size result in different soils ranging from clay,via sand,to gravel 2-Particle size is one factor influencing water- holding capacity→ some plants (e.g. Althaea officillalis) which produce mucilage as a water- retaining material contain less mucilage when grown on soil with a high moisture content. Phytotherapy and chem. of natural products Dr. Khaled Tawaha 3-Although particular species have their own soil pH tolerances (Datura stramonium 6.0-8.2, Majorana hortensis 5.6-6.4), no marked influence of pH value within the tolerance range has been demonstrated for essential oils (Mentha piperita) and alkaloids (D. stramonium). -Nitrogen fertilization has been shown to increase the silymarin content of the fruits of Silybum marianum. Phytotherapy and chem. of natural products Dr. Khaled Tawaha PROPAGATION FROM SEEDS Phytotherapy and chem. of natural products Dr. Khaled Tawaha 1-To ensure success the seeds must be collected when perfectly ripe. If not planted immediately, they should normally be stored in a cool and dry place. 2-1 Some seeds such as cinnamon, coca and nutmegs rapidly lose their power of germination if allowed to dry or if stored for quite short periods, 2-2 Long storage of all seeds usually much decreases the percentage which germinate. Phytotherapy and chem. of natural products Dr. Khaled Tawaha 3-In some cases, however, immediate sowing of the fresh seed is advisable →For example, it has been shown that if the seeds of Colchicum autumnale are air-dried even for a few days, only about 5% germinate in 1 year and some may not germinate for 5 years; whereas if sown as soon as the capsules dehisce, 30% will germinate in the first year. Phytotherapy and chem. of natural products Dr. Khaled Tawaha *-With Erythroxylum coca and E. novogranatense the seeds stored at 4°C for 24 days gave, respectively, 29% and 0% germination. *-Seeds may, if slow germinating, be soaked in water or a 0.2% solution of gibberellic acid for 48 hrs before sowing Phytotherapy and chem. of natural products Dr. Khaled Tawaha  -Time of seed sowing may affect the active constituents, as illustrated by Chamomilla recutita for 17 cultivars investigated most gave a significantly higher yield of volatile oil if they were spring-sown rather than autumn-sown and the oil composition also varied Phytotherapy and chem. of natural products Dr. Khaled Tawaha COLLECTION Phytotherapy and chem. of natural products Dr. Khaled Tawaha 1-Drugs may be collected from wild or cultivated plants. 2-The season at which each drug is collected is usually is important → Rhubarb is reported to contain no anthraquinone derivatives in winter but anthranols which, on the arrival of warmer weather, are converted by oxidation into anthraquinones. Phytotherapy and chem. of natural products Dr. Khaled Tawaha 3- Time of the day (digitalis)?! 4-The age of the plant is also of considerable importance and governs not only the total quantity of active constituents produced but also the relative proportions of the components of the active mixture. A few examples are given in Table. Phytotherapy and chem. of natural products Dr. Khaled Tawaha Generally speaking, leaves are collected as the flowers are beginning to open, flowers just before they are fully expanded, and underground organs as the aerial parts die down. Leaves, flowers and fruits should not be collected when covered with dew or rain. Any which are discolored or attacked by insects of slugs should be rejected. -Seeds such as nux vomica and cocoa, which are extracted from mucilaginous fruits, are washed free from pulp before drying. Phytotherapy and chem. of natural products Dr. Khaled Tawaha DRYING Phytotherapy and chem. of natural products Dr. Khaled Tawaha 1-If enzymic action is to be encouraged, slow drying at a moderate temperature is necessary. Examples; 'Vanilla Pods', 'Cocoa Seeds'. 2-If enzymic action is not desired, drying should take place as soon as possible after collection. 3- Drugs containing volatile oils are liable to lose their aroma if not dried or if the oil is not distilled from them immediately 4- All moist drugs are liable to develop mould→ For these reasons, drying apparatus and still should be situated as near to the growing Phytotherapy and chem. of plants as possible. natural products Dr. Khaled Tawaha 5-The duration of the drying process varies from a few hours to many weeks 5-1 And in the case of open-air drying depends very largely on the weather. In suitable climates open-air drying is used for such drugs as clove, cardamom and cinnamon. 5-2 Drying by artificial heat is more rapid than open-air drying and in often necessary in tropical countries (e.g. West Africa, where the humidity is very high, and Honduras for drying cardamom fruits). 5-3 Freeze-drying was generally satisfactory for taxol recoveries but the recoveries for 10-deacetylbaccatin III was only 75-80% of those expected. 5-4 Rapid drying helps flowers and leaves to retain their colour and aromatic drugs their aroma. but the temperature used in each case must be governed by the constituents and the physical nature of the drug. 5-5 As a general rule, leaves, herbs and flowers may be dried between 20 and 40°C, and barks and roots between 30 and 65°C. Phytotherapy and chem. of natural products Dr. Khaled Tawaha STORAGE Phytotherapy and chem. of natural products Dr. Khaled Tawaha 1-The large-scale storage of drugs is a considerable undertaking. 2-Except in a few cases such as cascara bark, long storage, although often unavoidable, is not to be recommended. 3-Drugs such as Indian hemp deteriorate even when carefully stored. 4- It has been reported that the content of taxol in Taxus baccata leaves and extracts stored at room temperature for one year decreased by 30-40% and 70-80% respectively 5-Similarly the alkamides of the popular immunostimulant herb Echinacea purpurea decrease rapidly on storage; have shown that although drying has little effect on the quantity of alkamides, storage for 64 weeks at 24° produces an 80% loss, and a significant loss even at -18°. Phytotherapy and chem. of natural products Dr. Khaled Tawaha 6-Drugs stored in the usual containers-sacks, bales. wooden cases, cardboard boxes and paper bags-reabsorb about 10-12% or more of moisture. 7-Air- dry drugs are always susceptible to the attack of insects, so they should be examined frequently during storage and many showing mould or worminess should be rejected 8- Some plant materials may require sterilization before storage(reduce undesirable microbial contamination) Phytotherapy and chem. of natural products Dr. Khaled Tawaha PACKAGING, STORAGE AND PRESERVATION Phytotherapy and chem. of natural products Dr. Khaled Tawaha * The packaging of drugs depends on their final disposition, commerce, if transportation, storage, and ultimate use for manufacturing purposes are involved, it is customary to chose the type of packaging that provides ample protection to the drug and gives economy of space. Leaf and herb material is usually baled with power balers into a solid compact mass. Packaging is often characteristic for certain drugs. The standard package for all grades of aloe is a 55- gallon steel drum. Proper storage and preservation are important factors in maintaining a high degree of quality of the drug. Phytotherapy and chem. of natural products Dr. Khaled Tawaha *Hard-packed bale, barks, and resinous drugs usually reabsorb little moisture. But leaf, herb, and root drugs that are not well packed tend to absorb amounts of - moisture that reach 10, 15, or even 30% of the weight of the drug. * Excessive moisture not only increases the weight of the drug, thus reducing the percentage of active constituents, but also favors enzymatic activity and facilitates fungal growth. Phytotherapy and chem. of natural products Dr. Khaled Tawaha  -Light adversely affects drugs that are highly colored, rendering them unattractive and possibly causing undesirable changes in constituents. - Oxygen of the air increases oxidation of the constituents of drugs, especially, when oxidases are present. Therefore , the warehouse should be cool, dark, and well ventilated. The protection of drugs againts attacks by insects must not be overlooked. The insects that infest vegetable drugs belong chiefly to the orders Lepidoptera, Coleoptera, and Diptera. Phytotherapy and chem. of natural products Dr. Khaled Tawaha  For destruction of insects and prevention of their attacks a number of methods have been employed: The simplest methods is to expose‫ ﺗﻌﺮﻳﺾ‬the drug to a temperature of 65C??. This method is probably the most efficient??? not only in preventing insect attacks but also in preventing many other forms of deterioration. For the fumigation of large lots of crude drugs,such as those stored in warehouses and manufacturing plants, the use of methyl bromide has met with considerable success.  small lots of drugs may readily be stored it tight, light- resistant containers. Tincans,covered metal bins, or amber glass containers are the most satisfactory. * Drugs should not be stored in wooden boxes or in drawers and never in paper bags. Phytotherapy and chem. of natural products Dr. Khaled Tawaha Insect attack can be controlled by adding to the container a few drops of chloroform or carbon tetrachloride from time to time. *In the case of digitalis and ergot, whose low moisture content must be maintained at all times, a suitable cartridge or device containing a non liquefying, inert, dehydrating substance may be introduced into the tight container. Because high temperatures accelerate all chemical reaction, including those involved in deterioration, drug must always be stored at as low a temperature as possible. The ideal temperature is just above freezing, but since this is impractical in most cases, the warehouse or other storage place should be as cool as possible. Certain drugs, such as the biologics, must be stored at a temperature between 2 and 8C. Phytotherapy and chem. of natural products Dr. Khaled Tawaha ANIMAL DRUGS Animal drugs are produced from wild or domesticated animals. Wild animals must be hunted(whale, musk deer) or fished for (cod and halibut) (correspond to wild plants) Domesticated animals(sheep) (correspond to cultivated vegetable drugs). When drugs consist of insects, the drugs are either collected from wild insects (cantharides) or definite attempts are made to cultivate them,to furnish the insects with food and shelter and to maintain optimum conditions for their propagation (honeybee). Drugs such as lanolin and milk products, as well as hormones, endocrine products, and some enzymes, are obtained from domesticated hogs, sheep, or cattle. Phytotherapy and chem. of natural products Dr. Khaled Tawaha  EVALUATION OF DRUGS To evaluate a drug means to identify it and to determine its quality‫ ﺟﻮدة‬and purity. * The identity of a drug can be established by Its actual collection from a plant or animal that has been positively identified(drug gardens). The comparison of a representative unknown sample to a published description of the drug and to authentic drug samples. Phytotherapy and chem. of natural products Dr. Khaled Tawaha Quality refers to the intrinsic ‫ﺟﻮھﺮي‬value of the drug, which means the amount of medicinal principles or active constituents present. These constituents are classified into groups of nonprotoplasmic cell contents: (e.g. carbohydrates, glycosides, tannins, lipids, volatile oils, resins and resin- combinations, steroids, alkaloids, peptides hormones, enzymes and other proteins, vitamins, antibiotics, biologics, allergens, and others). Effort should be made to obtain and maintain this high quality of drug. HOW??? Evaluation Phytotherapy and chem. of natural products Dr. Khaled Tawaha  Evaluation Methods Of Evaluation: (1)organoleptic, (2) microscopic, (3) biologic, (4) chemical, (5) physical (1)Organoleptic (lit. `impression on the organs`) refers to evaluation By means of the organs of sense And includes the macroscopic appearance(shape, color) of the drug, Its odor and taste, Occasionally the sound or `snap` of its fracture Ears and the `feel` of the drug to the touch Skin Phytotherapy and chem. of natural products Dr. Khaled Tawaha (2)Microscopic: It is important for powdered drugs 1- Study of adulterants in powdered plant and animal drugs 2- Identification of the pure powdered drug. Powdered drugs possess few macroscopic features of identification (color, odor and taste) While the microscopic characteristics are important(key elements) (3)The pharmacologic activity: ( evaluation and standardization)Strength of the drug or its preparation by Assays on living animals (in vivo) as well as on intact or excised organs (in vitro). Because living organisms are used, the assays are called biologic assays or bioassays. Phytotherapy and chem. of natural products Dr. Khaled Tawaha 4- Chemical : For active constituents of many natural drugs activity Best methods of determining the official potency for crude drugs and their products 5- Physical: typical physical constants are rarely applied to crude drug. But extensively applied to the active principles of drugs, such as alkaloids, volatile oils, an others. Phytotherapy and chem. of natural products Dr. Khaled Tawaha The secondary constituents of drug plants are influenced → by 3 principal factors: 1-Heredity (genetic composition). 2-Ontogeny (stage of development). 3-Environment. Phytotherapy and chem. of natural products Dr. Khaled Tawaha  GENETIC EFFECTS → induce both quantitative and qualitative changes, → but those caused by environmental influences are primarily quantitative. →Perhaps the best-known pharmacognostic examples of chemical races are found in the ergot fungus (Claviceps purpurea). →Individual strains have been isolated representing chemical races that produce superior yields of single desired alkaloids, e.g., ergotamine → instead of the usual small concentrations of complex mixtures of alkaloids. Phytotherapy and chem. of natural products Dr. Khaled Tawaha  ONTOGENY also plays a significant role in the nature of the active constituents found in medicinal plants. Although it might be expected that the concentration of secondary metabolites would increase with the age of the plant. →The cannabidiol content of Cannabis sativa reaches a peak early in the growing season → then begins to decline. →When this decline occurs → the concentration of tetrahydrocannabinol begins to increase and continues until the plant approaches maturity. *→ In the opium poppy(Papaver somniferum), → the morphine content of the capsules is highest 2 to 3 weeks after flowering. →If the latex is harvested earlier, related alkaloids such as Theban and codeine predominate. → On the other hand, if harvesting is delayed too long. The morphine → decomposes. Phytotherapy and chem. of natural products Dr. Khaled Tawaha ENVIRONMENTAL CONDITIONS Phytotherapy and chem. of natural products Dr. Khaled Tawaha Plant growth and development, and often the nature and quantity of secondary metabolites, are affected →by temperature, rainfall, length of day (including the quality of light) and altitude. Example : seeds of cannabis, grown ih England →and rich in CBD and devoid of THC, →when cultivated in Sudan started to produce THC in the first generation and in the second generation contained up to 3.3% THC with a further decrease (down to 0% in some plants) of CBD. Phytotherapy and chem. of natural products Dr. Khaled Tawaha 1- Temperature →Temperature is a major factor controlling the development and metabolism of plants. → In general, the formation of volatile oils appears to be enhanced at higher temperatures, although very hot days may lead to an excess physical loss of oil. →The mean optimum temperature for nicotine production in Nicotiana rustica is 20°C (lower at 11-12°C and at 30°C). → fixed oils produced at low temperatures contain fatty acids with a higher content of double bonds than those formed at higher Phytotherapy and chem. of temperatures. natural products Dr. Khaled Tawaha 2- Rainfall - The annual rainfall, its distribution throughout the year. →Continuous rain can lead to a loss of water-soluble substances from leaves and roots by leaching; this is known to apply to some plants producing alkaloids, glycosides and even volatile oils. →This could account for low yields of some active constituents in wet seasons from plants whose general condition appears to be good. Phytotherapy and chem. of natural products Dr. Khaled Tawaha 3-Day-length and radiation characteristics →Datura stramonium var. tatula long exposure to intense light→ brought about a sharp increase in hyoscine content at the time of flowering. → long-day conditions peppermint leaves contain menthone, menthol and traces of menthofuran; →plants grown under short-day conditions contain menthofuran as a major component of the volatile oil. Phytotherapy and chem. of natural products Dr. Khaled Tawaha 4- Altitude →Tea, cocoa, coffee, medicinal rhubarb, tragacanth and cinchona require elevation. →In the case of Cinchona: succirubra the plants grow well at low levels but produce practically no alkaloids. Phytotherapy and chem. of natural products Dr. Khaled Tawaha