B.Pharm. Class Notes and Handouts

• Conservation is the process of management of biosphere in order to obtain the greatest benefit for the present generation and maintaining the potential for future. • Conservation of medicinal plant resources is of global concern because we don't know what we are losing and what we will need in future.

DRUG METABOLISM

Presented by Saroj kanta Bisoyi Asst.Professor RCPHS, BAM INTRODUCTION

 Biotransformation: Chemical alteration of the drug in body that converts nonpolar or lipid soluble compounds to polar or lipid insoluble compounds.

 Drug metabolism may be defined as the biochemical modification of one chemical form to another, occurring usually through specialised enzymatic systems.

 It often involves the conversion of lipophilic chemical compounds (drugs) into highly polar derivatives that can be easily excreted from the body. FUNCTION OF BIOTRANSFORMATION 1) It causes conversion of an active drug to inactive or less active metabolite(s) called as pharmacological inactivation. Example of drug follow by this mechanism. Phenobarbitone P-hhdroxy phenobarbitone Phenytoin P-Hydroxy phenytoin Procaine P-amino benzoic acid 2) It causes conversion of an active to more active metabolite(s) called as bioactivation or toxicological activation.

Codeine Morphine

Halothane Trifluoro acetic acid

paracetamol N –Hydroxylation derivative

3) It causes conversion of an Inactive drug active metabolite. Ex of drug follow by this mechanism. Levodopa- dopamine SITE/ORGANS OF DRUG METABOLISM

 The major site of drug metabolism is the liver (microsomal enzyme systems of hepatocytes).

 Secondary organs of biotransformation

➢ kidney (proximal tubule)

✓ lungs

➢ testes

➢ skin

➢ intestines LIVER

 The primary site for metabolism of almost all drugs because it is relatively rich in a large variety of metabolising enzymes.

 Metabolism by organs other than liver (called as extra- hepatic metabolism) is of lesser importance because lower level of metabolising enzymes is present in such tissues.

 A few drugs are also metabolised by non-enzymatic means called as nonenzymatic metabolism.

 The drug metabolising enzymes can be broadly divided into two groups: microsomal and non-microsomal enzymes. TYPE OF DRUG METABOLISM

 The metabolism of drug in the body is achieved by two types of reactions .these reactions are

1) Phase-I reaction

2) Phase-II reaction

Phase 1 reaction. (Non synthetic phase).

➢ a change in drug molecule. generally results in the introduction of a functional group into molecules or the exposure of new functional groups of molecules. PHASE –I REACTION

❖ In this reaction a functional polar group (ie-OH,COOH,NH2,SH) is introdused to drug or in xenobiotics to convert them into more water soluble compounds so they are easily excreted out from the body. Phase-1 reaction convert the parent drug into polar metabolites by three ways. a) Oxidation reaction b) Reduction reaction C) Hydrolysis reaction A) OXIDATION REACTIONS

 Addition of oxygen/ negatively charged radical or

removal of hydrogen/ positvely charged radical.

 Reactions are carried out by group of enzyme

monooxygenases in the liver.

 Fianl step: Involves cytochrome P-450 haemoprotein,

NADPH, cytochrome P-450 reductase and O2 CYTOCHROME P FAMILY

Multiple CYP gene families have been identified in humans, and the categoriezed based on protein sequence homology

 Most of the drug metabolizing enzymes are in CYP 1, 2, & 3 families .

CYP3A4 is very common to the metabolism of many drugs. CYTOCHROMES: METABOLISM OF DRUGS CYP Enzyme Examples of substrates

1A1 Caffeine, Testosterone, R-Warfarin 1A2 Acetaminophen, Caffeine, Phenacetin, R-Warfarin 2A6 Estradiol, Testosterone 2B6 Cyclophosphamide, Erythromycin, Testosterone 2C-family Acetaminophen, Tolbutamide (2C9); Hexobarbital, SWarfarin (2C9,19); Phenytoin, Testosterone, R- Warfarin, Zidovudine (2C8,9,19); 2E1 Acetaminophen, Caffeine, Chlorzoxazone, Halothane 2D6 Acetaminophen, Codeine, Debrisoquine 3A4 Acetaminophen, Caffeine, Carbamazepine, Codeine, Cortisol, Erythromycin, Cyclophosphamide, S- and R Warfarin, Phenytoin, Testosterone, Halothane NON-CYP DRUG OXIDATIONS

 Monoamine Oxidase (MAO), Diamine Oxidase (DAO)

➢ MAO (mitochondrial) oxidatively deaminates endogenous substrates including neurotransmitters’

➢ Dopamine, serotonin, norepinephrine, epinephrine

 Alcohol & Aldehyde Dehydrogenase

➢ Non-specific enzymes found in soluble fraction of liver

➢ Ethanol metabolism TYPES OF DRUG METABOLISM OXIDATION REACTIONS

 Aromatic and side chain hydroxylation.

 Oxidation of benzylic carbon atom

 Oxidation of allylic carbon atom

 Oxidation at the carbon alpha to carbonyl and imino group.

 Oxidatiive N and O-dealkylation

 N- oxidation and sulphur oxidation.

 Desulphuration 1) AROMATIC AND SIDE CHAIN HYDROXYLATION.

 Hydroxylation means addition of –OH group to the aromatic ring.

 The reaction involves the formation of an epoxides as an intermediate and under goes rearrangement to form phenolic products 1) AROMATIC AND SIDE CHAIN HYDROXYLATION.

5) OXIDATIVE N AND O-DEALKYLATION

 oxidative N and O-dealkylation involves hydroxylation of

alpha carbon adjecent to amino group and oxygen to form

carbinolamine or hemiactal as an intermedite than

undergoes clevage to release the alkyl group and the drug

metabolites. 5) OXIDATIVE N AND O-DEALKYLATION

REDUCTION

 Nitro,azo and carbonyl group containg drug are easily redused by various enzyme present in the body (reductase enzyme). reduction of aromatic nitro group reduced to primary amine as metabolites. AZO GROUP CONTAINING DRUGS UNDERGOES ENZYMATIC REDUCTION GIVE TWO AMINES. CARBONYL CONTINING DRUG ON ENZYMATIC REDUCTION GIVES ALCOHOL AS METABILITES. HYDROLYSIS REACTION

 Drugs containing ester or amide functional group undergoes metabolism by this pathways. HYDROLYSIS

 Drugs containing ester or amide functional group undergoes metabolism by this pathways. AMIDE DRUGS LIKE LIGNOCAINE UNDERGOES HYDROLYSIS TO FORM AMINE

 Hydrolysis of amide is very slow as compared to esters.  The drug produced by hydrolysis get easily excreted as compared to parent drugs.  These products have high polarity and easily show conjugation reactions. PHASE-II DRUG METABOLISAM

 These are also called conjugation reaction.

 Last step in detoxification reactions and almost always results in loss of biological activity of a compound.

 May be preceded by one or more of phase I reaction .

 The products formed after phase-II reactions are generally inactive.

 It involve conjugation with various endogeneous substances like glucuronic acid,amino acids,glutathion etc. PHASE –II METABOLISM OCCURS BY FOLLOWING PATHWAYS

 1) Glucuronidation

 2) Glutathione conjugation

 3) Sulphate conjugation

 4) Methylation

 5) Acetylation

 6) Aminoacid conjugation 1) GLUCURONIDATION

 Also known as glucuronic acid conjugation.

 Phase-1 metabolites having free alcoholic or phenolic groups cojugates with glucuronic acid to form ether or ester glucuronides.

 This process is done by the help of the enzyme glucuronyl transferase. 1) GLUCURONIDATION

 The transfer of glucuronyl group to the drug takes place by the coenzyme UDPGA (uridine diphospho-α-d-glucuronic acid).

 Glucuronides formed are normally non toxic,highly polar and easily excreted in the urine or biles.

 It mainly occurs in many tissues like kidney,skin,intenstine,lungs and brain. 4-HYDROXY PHENYTOIN FORM IN PHASE-1 REACTION FORM PHENYTOIN –O- GLUCURONIDE MORPHINE PRODUCES MORPHINE GLUCURONIDES. GLUTATHIONE CONJUGATION

 Also known as mercaptouric acid is a thiol containing tripeptide.γ-glutamyl cysteine glycine

 Electron deficient metabolites like alkyl aryl halides,sulphates,sulphonates,nitrates produced by phase-I metabolism conjugates with glutathione.

 That catalysed by the enzyme glutathione transferase. METABOLISM OF ETHACRYNIC ACIDS SULPHATE CONJUGATION

 Drug having hydroxy groups,phenols and aromatic amines under goes sulphate conjugation.

 It occurs by the enzyme sulphotransferase and coenzyme PAPS(Phosphoadenosine phosphosulphate).

 Mostly the steroidal drugs undergoes by this reaction

 The proces occurs mostly in the liver ,kidney and intenstine.

 Ex-Estrone on metabolism produces estrone sulphate. ESTRONE METABOLISM METHYLATION

 Most of the endogeneous amine are metabolise by this methylation conjugation.  Mostly methyl group is attached with the help of coenzyme SAM(S-adenosyl methionine) and enzyme methyl transferase. ACETYLATION

 Acetylation inlvoves conjugation reaction with acetyl coA by using the enzyme N-Acetyl transferase present in liver ,lngs,spleen and gastric cell and red blood cells.  Drug contains Hydrazino functional group undergoes acetylation.  Ex- Isoniazid gets acetylted to form acetyl isoniazid AMINO ACIDS CONJUGATION

 Drugs having aromatic acids and aryl alkyl acids as functional group undergoes conjugation with amino acids like glycine and glutamic acids.  Metabolites of phase-I reaction having carboxyl group also conjugates with glycine.  Ex-Benzoic acid conjugates with glycine to form hippuric acid DIPHENHYDRAMINE METABOLISM FACTROR AFFECTING METABOLISM

 Some physical,chemical and biological factors affects the metabolism of a drugs. These are

 1) Physiochemical properties of the drug molecules.

✓ physiochemical properties like size,,shape,acidity and basicity,lipophilicity,solubility,pka value of drugs molecules affects drug metabolism. 2) CHEMICAL FACTORS

 Various chemical affects the metabolism of the drugs.

these are a) Enzyme inducer b) Enzyme inhibitors A) ENZYME INDUCER

 These are the chemical which increases metabolism.

 Ex-3-methyl cholanthrene and cigarette smoke increases

the metabolism of some drugs.

 Alcohol increases the metabolism of coumarins and

phenytoin.

 Barbiturates increases metabolism of oral contraceptives ENZYME INHIBITORS

 The chemicals and drugs which decreases the activity of metabolism.

 MAO inhibitors decreases metabolism of barbiturates .

 coumarins dccreases the biotransformation of phenytoin.

 Various halogenated pesticides like DDT,organophasphate insecticides,heavy metals like mercury,tin ,nickel,cobalt and arsenic decreases the metabolism of various drugs. 3.ENVIROMENTAL FACTORS

 Enviromental factors like pressure,temperatue and humudity also affects the metabolism. 4. Biological factors. Various biological factors which affect metabolism of drug are a) Age of the patient b) Sex of the patient c) Diet d) Altered physiological state like pregnancy,diseases state and hormonal imbalance. STERIOCHEMICAL ASPECTS OF THE DRUG MOLECULES.

 Steriochemistry of the drug also affcets the metabolism.  Metabolising enzymes have different preference for one enantiomer than the other.  Ex- 1. (–) Quinine treat the malaria fever but (+) quinine does not. 2. D (+) get easily metabolised in the body to give CO2 and water but L (-) glucose is not metabolised and excreted as such. REFERENCES

 Goodman and Gilman, Pharmacological basis of Therapeutics, 12th edition, Laurence L Bruton  Essential of Medical Pharmacology, K D Tripathi, 5th Edition, JP publishers, New Delhi.  Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry 11th ed. Lippincott, Williams & Wilkins ed  Drug metabolism by S.P. Markey, NIH, accessed on internet on 02-03-2013 from www.cc.nih.gov/.../ppt/drug_metabolism_20062007.ppt  Drug metabolism and pharmacokinetics in drug discovery: a primer for bioanalytic study: chandrani gunaratna, current separations, 19:1, 2000

• Edible Vaccine involves, introduction of selected desired genes into plant and then inducing these altered plants to manufacture the altered protein. Antigen in transgenic plant Ingestion Delivered by bio-encapsulation Taken up by Microbial cell Pass on to the Macrophage IgG,IgE responses Local IgA response & Memory cells Neutralize the attack by the real infectious agent ADVANTAGE AND DISADVANTAGE OF DIFFERENT PLANTS Potato Advantage Disadvantages • Easily transformed. • Spoils readily. • Easily propagated. • Need cooking • Stored for long periods without which denature refrigeration. antigen • Grow quickly. • Cultivate broadly. • High content Vitamin-A may boost immune response. ADVANTAGE AND DISADVANTAGE OF DIFFERENT PLANTS BANANA Advantage Disadvantages • Do not need cooking. • Trees take 2-3 to • Protein not destroyed even after mature years. cooking. • Spoils rapidly after • Inexpensive . ripening. • Grown widely in developing countries. RICE Advantage Disadvantages • Commonly • Grows slowly. used in baby • Requires glasshouse condition. food. • Do not need cooking. • High • Protein not destroyed even after cooking. expression of • Inexpensive . antigen. • Grown widely in developing countries. Clinical Trial on

• First human trials of potato-based vaccine against Hepatitis B have reported encouraging results. Hepatitis • The amount of HBsAg needed for one dose could - B be achieved in a single potato. • Levels of specific antibodies significantly exceeded the protective level of 10mIU/mL in human.

• 11 Volunteers were feed raw transgenic Potatoes ETEC expressing LT-B. • 10 (95%) of these individuals developed neutralizing antibodies and 6 (55%)develop mucosal response.

• 20 people fed with transgenic potato. Norwalk Virus • 19 (95%)of them expressing Norwalk virus antigen showed seroconversion. ADVANTAGES OF DISADVANTAGES OF EDIBLE VACCINES EDIBLE VACCINES • Cost effective. • Transgenic • Easy to administer. contamination can • Easy to store. occur. • Acceptable to poor developing country. • Antibiotic resistance • Fail safe marker genes can • Activate both mucosal and spread from GM food to systemic immunity. pathogenic Bacteria. • Heat stable. • Difficulty in dose • Do not required cold chain maintenance. maintenance. • No fear of contamination. FUTURE OF EDIBLE VACCINE CONCLUSION: Edible plant • Resistance to GM foods may derived vaccine may lead to affect future of Edible Vaccine. a future of safer and more effective immunization. • Edible Vaccine involves, introduction of selected desired genes into plant and then inducing these altered plants to manufacture the altered protein. Antigen in transgenic plant Ingestion Delivered by bio-encapsulation Taken up by Microbial cell Pass on to the Macrophage IgG,IgE responses Local IgA response & Memory cells Neutralize the attack by the real infectious agent ADVANTAGE AND DISADVANTAGE OF DIFFERENT PLANTS Potato Advantage Disadvantages • Easily transformed. • Spoils readily. • Easily propagated. • Need cooking • Stored for long periods without which denature refrigeration. antigen • Grow quickly. • Cultivate broadly. • High content Vitamin-A may boost immune response. ADVANTAGE AND DISADVANTAGE OF DIFFERENT PLANTS BANANA Advantage Disadvantages • Do not need cooking. • Trees take 2-3 to • Protein not destroyed even after mature years. cooking. • Spoils rapidly after • Inexpensive . ripening. • Grown widely in developing countries. RICE Advantage Disadvantages • Commonly • Grows slowly. used in baby • Requires glasshouse condition. food. • Do not need cooking. • High • Protein not destroyed even after cooking. expression of • Inexpensive . antigen. • Grown widely in developing countries. Clinical Trial on

• First human trials of potato-based vaccine against Hepatitis B have reported encouraging results. Hepatitis • The amount of HBsAg needed for one dose could -B be achieved in a single potato. • Levels of specific antibodies significantly exceeded the protective level of 10mIU/mL in human.

• 11 Volunteers were feed raw transgenic Potatoes ETEC expressing LT-B. • 10 (95%) of these individuals developed neutralizing antibodies and 6 (55%)develop mucosal response.

FACTORS INVOLVED IN THE PRODUCTION OF CRUDE DRUGS I. P. Padhy

• Time of collection • Season of collection • Ontogenic (age) factor • Methd of of collection • Other conditions Altitude: Height from sea level • Altitude is a very important factor in cultivation and crude drug production. • Tea, Cinchona, eucalyptus requires high altitude. • In case of Cinchona succirubra the plant grow well at low levels but practically produce no alkaloids.

Temperature: • Temperature is a major factor controlling the development and metabolism of plants. Although each species has become adapted to its own natural environment, plants frequently able to exist in a considerable range of temperature. • Variation in night and day temperature must also be considered • The variation often being considerable, the extent to which such variation can inﬂuence growth • Hyocyamus muticus.

Rain fall: • Except the xerophytes like aloe, acacia, most of the plants need sufficient rain fall or proper irrigation for their favorable development. • The important effects of rainfall on vegetation need to be considered in relation to the annual rainfall, its distribution through out the year. • Continuous rain can lead to a loss of aqueous soluble substances from leaves and roots by leaching. Day length and radiation characteristics: • Plants growth vary much in both the amount and intensity of the light which they require. • In wild state the plant will be found where its shade requirements are met, and under cultivation similar shade must be provide. • It is observed that light is a factor which helps to determine the amount of glycosides or alkaloids produced with Belladonna, Stramonium anCd inchona ledgeriana. • Full sun shine gives a higher content of alkaloids than shade. • Type of radiation has been studied in respect to morphological development of the plants. Many plants initiate flowers only in certain day lengths, and where flowering is essential this factor must be care fully considered before panting in a new region. Soil and its fertility:

Different plant species vary enormously in their soil and nutritive requirement, and this aspect has received considerable attention with medicinal plants. Three basic properties of soils are: i. Physical ii. Chemical iii. Microbiological.

A) Physical Properties: Depending upon the Depending upon the size of the mineral matter percentage covered by clay, the following names are given soil is classiﬁed as given to soil (It is one factor which below. inﬂuence the water holding capacity and mechanical strength) Particle size Types of soil Types of Percentage Soil Less than 0.002 Fine clay Clay More than 50.0% of mm clay 0.002 to 0.02 mm Course clay or Loamy 30 to 50% of clay slit 0.2 to 2.00 mm Course sand Slit loam 20 to 30% of clay

Sandy soil More than 70% sand Calcareous More than 20% of soil lime • A soil is good for plant growth should have half of the pore spaces filled with water and the rest with air, since good aeration is essential for root development. • The commonly known soil is shallow upper layer and is the friable material in which plants find foot hold and nourishment. • Clay is one of the highly weathered portions of the soil, consisting of finest particles. This provides to the soil adhesive and cohesive properties and also holds plant nutrients. B) Chemical properties: • Any type of soil containing not less than 0.5% of organic matter is described as rich. • The highest availability of plant nutrients is in between the PH range of 6.5 to 7.5. • To bring the PH to the normal, acidic soils can be limed or alkaline soils can be reclined by application of gypsum. • Soil containing more humus and little lime are inclined to become acid and those with abundant lime are alkaline. • All plants require calcium as their nutrition but plants known as calciphobous cannot be grown on chalky soil. • In some cases different varieties of the same species may grow on different soils.

C) Microbiological properties: Little work appears to be performed on the microbiology of soil with respect to secondary metabolism.  Soil fertility is the capacity of the soil to provide nutrients in adequate amount and in balanced proportion to plants.  Soil fertility can be maintained by addition of animal manure, nitrogen ﬁxing bacteria or by application of chemical fertilizers.

 For vegetative growth, plants need Sunlight, Co2, water, mineral matter.  Plants need 16 nutrient elements for synthesizing various compounds. • Primary nutrients: Nitrogen, Phosphorous, and Potassium. • Secondary Nutrients: Magnesium, calcium and sulphur. • Trace elements: Copper, Manganese Iron Boron, Molybdenum and zinc.

Fertilizers • Any deﬁciency from the above nutrients characterized by certain symptoms. • Various parts of plants are used in pharmaceutical industry for their active constituents. Some of the nutrients are responsible for growth of particular parts of the plant body and hence their usefulness and deﬁciency need to be described systematically. • NPK fertilizer: • Manure: • Bio-fertilizer: Propagation Medicinal plants can be propagated by using following methods as applicable to non-medicinal plants. These are: A. Sexual method B. Asexual Method C. Aseptic methods of Micro propagation D. By inoculation for fermentation.

A) Sexual Method: In this method plants are raised from seeds and such plants are known as seedlings.

A)Asexual method: i. Vegetative propagation: In case of asexual method of vegetative propagation, the vegetative part of a plant is placed in such an environmental that it develops into a new plant. • From stem, bulb(squill, garlic) • From corm (colchicom) • From tuber (potato, aconite) • From root, rhizome (ginger, turmeric) • From runner(peppermint) • From sucker (mint, chrysinthemum) • From offset (aloe) or stolon (liquorice) etc.

ii. Grafting or budding: Stock with scion

C) Aseptic methods of Micro propagation: • It is novel method for the propagation of medicinal plants. • In micro propagation the plants are developed in an artiﬁcial medium (provided with nutritional and hormonal requirements) under aseptic condition from very ﬁne pieces of plants like single cell, callus, seed, embryos, root tips, shoot tips, pollen grains etc.

D) By inoculation for fermentation: • This process applies particularly to the production of moulds and the bacteria and is extensively used in the manufacturer of antibiotics.

Collection Crude drugs are collected suitably when they contain maximum concentration of active constituents. Various factors for collection of crude drugs are: (I) Time of collection: Time of collection plays an important role for the crude the collection. E.g. Jasmine at morning time (in low temperature). (II) Season of collection: The season at which crude drug is collected is usually a matter of considerable important, since the amount and some times the nature of the active constituents not constant though out the years. • Barks are generally collected in the spring or in the early summer when the cambium is active as it is easy to detach from the stem, some time they are collected in autumn or in rainy season (cinnamon) • The roots are collected in spring before vegetative process stops. (III) Ontogenic variation (age factor): The age of the plant is also a factor for consideration as ontogenic variation. E.g. Turpentine oleo-resin and balsam of peru are collected when the plants is about 8-10 years old.

(IV) Other conditions: • The drugs which are leaf and the flowering tips of the plants, are collected just before they reach their flowering stage or maturity; example - Senna, digitalis, etc. • Flowers are collected just before pollination or before their full expansion e.g. clove. • Fruits are collected when these are fully grown and ripe, but in some case when partially ripe fruits are collected as per requirement. Generally fruits are collected just before their dehiscence. • Leaves, flower fruits should not be collected when covered with dew, and rain. • Rhizomes are collected when they store ample of reserve food material and also contain maximum content of chemical constituents. • Unorganized drugs are preferably collected in dry weather • Drugs such as resins gums, lattices are collected as soon as they are out of the plants e.g. acacia gum is collected when it is sufficiently hard after oozing out from the bark.

Drying Drying consists of removal of moisture content of the crude drugs. The slicing and cutting into smaller pieces is done to enhance drying. Drying should be carried out as soon as possible after collection (necessary in case of glycoside containing drugs). Drying facilitates to: – Improve the quality and make the drug resistance to the growth of microorganism. Before marketing a crude drug. It is necessary to process it properly. – Preserve it for a longer time and also to acquire better pharmaceutical elegance. – Process of grinding. – Prevents partially the enzymatic reaction. If enzymatic reaction to be bounced, drying

• Depending upon the type of chemical constituents a method of drying can be adopted which are as the following types; (I) Natural Drying (Sun Drying): (A) Drying under sun: If the contents of the drug are quite stable to the temperature and sun light can be dried directly in sunshine (gum acacia, seeds and fruits). (B) Drying in shade: If natural colour of the drug and the volatile principles of the drug are to be retained then it is dried under shed, in dry weather.

(II) Artificial drying: Drying by artificial means includes, drying of a drug in (A) Oven dryer (Tray dryer): Non volatile drugs such as belladonna, cinchona bark etc. (B) Vacuum dryer: Drugs which are sensitive to higher temperature e. g. digitals, tannic acid etc. (C) Spray dryer: Drugs which are highly sensitive to atmospheric condition such as leaves herbs, flowers are dried at 20’ to 40’ c. When delicate structures are over dried, they become brittle and tend to break in transit.

Packing • The morphological and economical nature of the drugs, their ultimate use, the effects of climatic conditions during transportation and storage should be taken into consideration while packing the drugs. • Drugs are packed in sacks, bales wooden cases, card boards, boxes and paper bags.

– Aloe is packed in goat skin.

– Colophony and tolu balsam in kerosene tins.

– Asafoetida in well closed containers.

– Cod liver oil in light resistant air tight container.

– Senna, vinca are pressed and baled. Storage

• Usually drugs are stored in dark place to prevent light. • Drugs sometimes absorb moisture in the time of storage, are often termed as air dry and for these, air tight containers are recommended; example - air in the container is released before storing ﬁxed oils. • Drugs are always liable to attack of insets and other pests, so they should be frequently examined during storage and any showing mould, worm or insect should be either rejected or treated. • Fungal growth can be prevented by using fumigants. • Temperature control should be done during storage. • Volatile oils in well ﬁlled and sealed containers.

TYPES OF PESTS

1. Fungi: Ascoclyta atropae (necrosis of leaves).

2. Viruses: Mosaic virus, ring spot virus

3. Weds:

4. Insects: Flea beetle, Heliothis armigera.

5. Non insects: i. Vertebrates - Rat, Monkeys, birds ii. Invertebrates - Nematodes, Mites.

1. Rodenticides: Red Squill, Strychnine.

2. Insecticides: Rotenoid, Peyrethroids.

3. Acaricides (Miticides): Tetradion.

4. Fungicides : Antibiotics, Chlorophenols.

5. Herbicides: 2, 4-dichlorophenoxy acetic acid. Insecticides are applied to vegetative parts for protective or eradicant activity.

Act either by: • Nerotoxication • Inhibition of acetyl cholinesterase • Inhibition of photosynthesis • Inhibition of chlorophyll synthesis • Hormone analogs Classiﬁcation

• These are used in the form of aerosol, spray, solution, suspensions, ﬁne dust and fumigation etc. DESIRED CHARACTERS: 1. Should non toxic, non Injurious to medicinal plants and human being. 2. Should be selective in action and highly toxic to the insects in low concentration. 3. Pesticides should be stable under ordinary condition of storage. 4. It should not be inﬂammable, corrosive. 5. Should be free from obnoxious odour. 6. Should be non–cumulative in soil.

Source Macroscopy Chemical Use Constituent Pyrethrum: Insect The closed Pyrethrum owes its Insectici flower flowers heads insecticidal property to -dal Biological Source: are about 6-9 Easters. (Contact Pyrethrum flowers mm. in diameter 1. Esters of Poison). Chrysanthemum acid. are the dried flower and the open • Pyrethrum-I heads of ones about 9-12 • Jasmoline – I Crysanthemum mm in diameter. 2. Esters of purethric cinerarifolium Colour–Cream to acid (Family: Composite). • Pyrethrin-II straw coloured, Geographical Source: • Jasmoline – II Odour- Aromatic , Indigenous to • Cinerine-II are.

It also contains Balkans. Taste – Acrid Leaves: Imparipinnate,, 1. Isoprenoids or Nimbine: Neem- alternate opposite. terpenoids Antiviral, Shape: ovate to A) Di- terpenoids Salanin: (Margosa, Indian lilac) laceolate. Antifeedant. B) Tri-terpenoids Margin-serrate Nimbidine: Biological Source: It Colour- green, 2. Norterpenoids Antiviral, consists of dried Taste - bitter. A) Nor-tri- Azadirechtin: leaves, root bark, Bark: Moderately thick, terpenoids: Insect stem bark and other Rough; colour- starchy repellant, 3. Limonoids - parts of Azadiracta white, laminated. Meliantrol: Odour-characteristic, Bitter principles Antifeedant, indica (Meliaceae). Taste-bitter. (Nimbine, nibibin, Nimbosterol: Large evergreen tree Flower: Numerous in nimbidine, salanin, Insecticidal, of height 12 to 18 mt. axillary panicles. Colour- azadirechtin, Margolone & with a straight bole white or pale yellow. margolonone: nimbolin-B etc.). and long spreading Fruit: Drupaceous, Antibacterial branches. colour- green turning 4. Other yellow on ripening. constituents: Other uses: Geographical Source: Seed: Single seed. meliantrol, spermicidal, Found through out Neem oil (margosa oil): antimalarial, quercetin, the drier parts Fixed oils expressed anti- myrecetin, (Pakistan, from seed carnels. Inflammatory margolone, Bangladesh, Srilanka, Colour- pale yellow. and anti- Odour- garlic like, margolonone, and tumor etc. Thailand, Malaysia, Taste- bitter. nimatone, Fiji south Africa East b l Source Chemical Constituents Use Derris and Lonchocarpus The roots of many species of Insecticidal properties Insecticidal Derris D- erris elliptica which are usually but not (Contact poison). (Leguminosae) and dried roots invariably due to the Powder of one or Loofn chocarpus utilize, presence of Rotenone. mixture of both. (Leguminosae). Nicotine Nicotine is the characteristics In addition to Nicotine Insecticidal. alkaloid obtained from the alkaloids the leaves of genus Nicotiana, homologous, Anabasine Nicotiana tobacum (solanaceae) is also having and is prepared commercially insecticidal properties. from waste materials of the Source Chemical Use Constituents Strychnine The occurrence of strychnine in Alkaloid - Strychnine The alkaloid Strychnine is a Strychnus species, dried ripe seeds CNS stimulant and used Soft rychnus nuxvomica as Rhodenticide. (Loganiacea). Ryania Insecticidal properties It consists of roots and stem of Contain 0.6 to 0.2% of (control various alkalioids (Ryanodine). Ryania speciosa (Flacourtriaceae). lepidopterous larval, eurepean corn cores). Citronella oil Deep yellow volatile oil obtained by Geranial, Citronellal. Citronellal is Insect distillation of C ymbopogon- repellant. nardus ( Gramineae). Source Chemical Use Constituents Sevadilla Seed Seeds contain about 2-4% The powdered seeds and Sabadilla or Cevadilla of mixed alkaloids: preparations of vertrine consists of the Cevadine, Veratridine, are used as a dust or dried ripe seeds of Sabadine, Sabadiline spray to control thrips and Schoenocaulon known as veratrine various true bugs which officinale (Liliaceal). alkaloids. attack vegetables. Red Squill In addition to other cardio Unlike other mammals, Red Squill and white squill are active glycosides the bulb rodent donot regurgitate both varieties of of the red squill also the squill bulb, and death Drimia maritima (Liliacea). contains other glycosides follows convulsion and like: scillirodise Scilliroside respiratory failure. Plant Growth Regulators • Plant growth regulators are the organic compounds, other than nutrients which affect the morphological structure and physiological process of plants in low concentrations. • Plant growth regulators include both the native (endogenous) and the synthetic (exogenous) substances. • Phytohormones or plant hormones are naturally occurring plant growth regulators. • Auxins, gibberlines, cytokinins, absicic acid and ethylene are five major plant growth regulators. • Auxins, gibberlines, cytokinins, are plant growth enhancers • Absicic acid and ethylene are plant growth inhibbitors. • Auxins, gibberlines and cytokinins are multiple forms of endogenous forms of plant growth regulators. • Plant growth regulators established their status specifically in enhancing the size of the plant and production of secondary metabolites used as drug.

Auxins • Auxin is a general term used to indicate substances that promote elongation of coleptile tissue. • These have similar properties to Indole-3-acetic acid (IAA) which is a major auxin of plants and found particularly in actively growing tissues. • Other natural auxins are: o Indole-3-acetonitrile, o 4-chloro indole-3-acetic acid (IAA) o Phenyl acetic acid. • The synthetic auxins are: Physiological effects: o Indole-3-butyric acid (IBA) • Cell elongation o α-napthyl acetic acid (NAA) • Root initiation o 4-dichloro phenoxy acetic acid (2,4-D)• Prevention of abscission • Induction of o 2-napthyl oxy acetic acid (NOA) parthenocarpy o 1-napthyl acetamide (NAD) etc. • Stimulates respiration • Callus formation Mechanism of action: The proposed mechanism of action of IAA is it’s interaction with one or more components of biochemical synthesis involved in the protein synthesis.

Practical uses: • In low concentration it accelerates the rooting of woody and herbaceous cuttings. • In higher concentration act as herbicide and weed killer.

Pharmaceutical applications: When seedlings ofM entha piperita are treated with auxins, 40% increase in volatile content is observed.

GIBBERELLINS • They are a class of endogenous plant growth regulators. • At present over 50 gibberellins are known. • About 40 of them are present in green plants, while other are present in some fungi. • They are present in different organic and tissue like roots shoots, buds, leaves ﬂoral apices root nodules, fruits and callus tissues. • Gibberellins are synthesized in leaves and they accumulate in relatively large quantities in the immature seeds and fruits of some plants.

• Gibberellins are referred to as GA1. GA2, GA 3, GA4, GA7 and GA9.

• GA3 is termed as gibberlic acid. • All of them are the derivatives of gibbane ring skeleton. • GA has not yet synthesized but can be produced by large Functions: The commercial formulations of gibberellins are used currently for promoting: • vegetative and fruit growth • breaking dormancy, ﬂower initiation • induction of parthenocarpy • internode elongation.

Pharmaceutical applications: The applications of gibberellins are extended to various medicinal plants: • The use of gibberellins in lower dose has shown increased yield of digitalis per shoot. The hormone tried with leaf and root culture of digitalis, showed higher production of digoxin. • It is observed that GA treatment can cause an increase in height of castor plant up to 5 times but does not show any change in ﬁxed oil content. • The treatment signiﬁcantly causes reduction in alkaloid content in vinca, datura.

Mechanism of action: • The growth effect of gibberellins arises by cell elongation in the sub-apical meristem region where young internodes are developing. • The effect of gibberellins and Auxins appear complimentary. • The full stimulation of elongation by either hormone necessitating an adequate presence of the other.

CYTOKININS • Auxins and gibberellins are concerned largely with cell enlargement and though they inﬂuence cell multiplication process • Cytokinines have a more speciﬁc effect on cell division (Cytokinesis). • Cytokinines are found in young and actively tissues like embryos, seed lings and apical meristems.

• Natural occurring cytokinins are zeatine (N6-dimethyl amino Purin) and (N6-S2 –Isopentyl aminopurine. • The synthetic cytokinins are kinetin, adenine, 6-benzyl adenine, benzimidazole and N, N1 diphenyl urea.

Mechanism of action: • In plant metabolism, it is proposed that some t-RNA contain cytokinin like activity. • They have an action on some enzymes responsible for formation of certain amino acids. • Functions: – Promotion of cell division. – Participation in orderly development of embryos during seed development inﬂuencing the expansion of cells in leaf discs and cotyledons. – Delaying senescence (the ageing process of the leaves usually accompanies with loss of chlorophyll i.e. yellowing and rapid breakdown of protein). – Cell enlargement (Induces cell enlargement). – Initiation of infrastructure cambium. – Cause morphogenetic change. – Dormancy of seeds. – Counteraction of apical dominance. – Cytokinins have been much employed in tissue culture work in which they are used to promote the formation of adventitious buds and shorts from undifferentiated cells. Pharmaceutical applications: • Cytokinins are reported to increase marginally sennoside content in Tirnnevally senna leaves and also enhance the dry weight of shoots. • In opium they cause formation of elongated capsule and reduced alkaloid content. • Kinetins are reported to play a role in nucleic acid metabolism and protein synthesis.

ETHYLENE (PLANT GROWTH INHIBITORS) • It is a simple organic molecule present in the forms of volatile gas. • Shows profound physiological effects on plants. • It is present in ripening fruit, ﬂower, stem, roots, tubers and seeds. • It is present in very less quantity in plant (normally about 0.1 PPM). • Possibly its quantity is increased in local areas during the time of growth and development. • Ethylene produced by one plant may inﬂuence the growths of the other plants near to it.

Functions: • Fruit ripening. Pharmaceutical applications: • Stimulate leaf abscission. • At low concentration has • Causes inhibition of root growth. been shown to increase the • Stimulates formation of adventitious sennoside concentration in roots. Cassia angustifolia. • Post harvest maturation of freshly fruit•s.Stimulates production of • It stimulates fading of some flowers. the stress compounds • It stimulates epinasty of leaves. (phytuberin and phytuberol) in tobacco leaves. ABSICIC ACID (PLANT GROWTH INHIBITORS) • A diffusible abscission accelerating substances was found by Osborne in senescent leaves. • Carns et. al. isolated several abscission accelerating substances from cotton plants and named as absicisin-I and abscisin- II (ABA). • In an inhibitory way ABA interacts with other plant growth substances in many seeds and helps in seed dormancy. • ABA concentration are found to be enhanced in stress condition like mineral deficiency, injury, draught and flooding. • ABA serves an important as potential anti- transpirant by closing the stomata when applied to leaves. HYBRIDIZATION “The process through which the hybrid is produced is called hybridization.”

•A hybrid is an organism which results from the crossing of two species or verities differing at least in one set of characters. •The resultant hybrids are: omonohybrid (have one pair of different character) odi-hybrids (two pairs of different characters) opolyhybrids more than two pairs of characters. •Hybrids helps in inducing the favorable characters of other varieties or species •Some times hybrids produce new and favorable characters in a single variety which are not present in both the parent. Example: The hybridization of Withania somnifera Israeli chemo type - II and W. sominefera South African chemo type has lead to formation of a new hybrid which contains 3 new withanoloids. •A recent development in hybridization is through the medium of tissue culture (protoplasts fusion through protoplast cultures) are employed for this purpose. MUTATION “Mutation is represented as variation in the character of the species.” • This is signiﬁcant for the medicinal plants. • The changes caused due to mutations included: o morphological and anatomical changes o changes in the chemical composition of the plants; this is signiﬁcant for the medicinal plants. o Change in the yield o Mutations may cause building resistance of a medicinal plant towards certain diseases and form resistance. But in all cases the plant may become susceptible to climate conditions and certain other diseases. These effects are to be eliminated by breeding and selection.

Cause of Mutation 1. Due to the environmental changes: o The variations are observed but the original traits are restored when the changes in environment are withdrawn or disappeared. o This type of change and re-storage is not heritable and also not built into the genotype. o They are termed only as phenotypic variations and commonly called as modiﬁcation.

2. Due to the changes in hereditary constitution.

Mutation is distinguished Spontaneous mutation: into two types: o Mutation which occurs due to some unknown reason 1.Chromosomal Mutation: from nature. o This leads to change o This has been observed in in amount or position some plants, bacteria of genetic material. viruses etc.

o The chromosomal, Artificial mutations: mutation is also called chromosomal o Mutation can also be aberration. induced by artificial means. o Those which are induced 1.Point mutation: artificially in the living o The changes with a organism by exposing them gene or cistron of the to mutagens (abnormal DNA molecule. environment) o It is permanent and o Mutagens (mutagenic heritable. agents): Radiations, chemicals etc. Mutagens or mutagenic agents:

1. Radiation mutagens: The electromagnetic waves of short wave length of U.V. light, X-ray, gamma ray, α-ray and β- ray are the radiation mutagens. • The X- ray and gamma rays are called ionizing radiation and also include α particle and β rays. • Ionizing radiation causes: o Water molecule in a biological system releases into H+ - + and OH radicals. H reacts with O2 and produces Hydroperoxils (HO2) radical. o Both these radicals viz. hydroperoxyl and hydroxyl are potent oxidizing agents. o When chromosomes and their DNA are struck by such radicals, they react due to which sugar phosphate part of DNA may be impaired leading to chromosomal mutation like breaks, deletions, additions, inversions and Mutagens or mutagenic agents: 2. Chemical mutagens: i. Nitrogen mustard, formaldehyde, nitrous acid and ethyl ethane sulphonate alter the chemical constituents of DNA bases and cause transitional substitution in DNA. ii.2-aminopurine, urethan, 5-bromouracil, caffeine, phenol and certain other carcinogens act as base analogs and bring out copy error mutation in DNA.

• The artiﬁcial production of mutation in medicinal plants is an important mile stone in the development of cultivation technology.

Chemical races

“Chemical races are group plants which have similar morphological characters but differs in type and quantity of chemical constituents”

Example: The hybridization of Withania somnifera Israeli chemo type - II and W. sominefera South African chemo type has lead to formation of a new hybrid which contains three new withanoloids.

GABA AND OTHER TYPES OF NEUROTRANSMITTER

INTRODUCTION TO SECONDARY METABOLITES: IDEFINITION, CLASSIFICATION, PROPERTIES AND TEST FOR IDENTIFICATION OF ALKALOIDS, GLYCOSIDES, FLAVONOIDS, TANNINS, VOLATILE OIL AND RESINS

Dr. I. P. Padhy • Phytochemicals are chemical compounds that contains naturally in plants. • The prefix “phyto” generated from Greek word which means plant. • Phytochemicals are of two types: 1. Primary phytochemicals or primary metabolites 2. Secondary phytochemicals or secondary metabolites

Alkaloids (alkal = alkali like + Oids = group of compounds)

“Typical alkaloids are organic plant products of natural origin which are basic in nature and contain one or more nitrogen atoms in its heterocyclic ring”.

These are optically active and possess specific physiological action on human or animal body, when administered in small quantities. Properties • Basic, crystalline substances which unite with acids to form salts. • Generally solid, exception is Nicotine (liquid). • Generally white coloured, exception is Barberin (yellow). • Odourless. • Bitter or intensely bitter taste. • Optically active • Free bases are frequently sparingly soluble in water, but soluble in organic solvents, with salts theses being usually soluble in water but sparingly soluble in organic solvents. Example- strychnine Hcl. is much more soluble in water than is strychnine base. Exception - Caffeine (base) is readily extracted from tea leaves with water and alkalodal salts like quinine sulphate is only soluble to the extent of 1 part in 1000 parts of water. • Nitrogen atoms of alkaloids are may be of primary (Mescaline), secondary (Ephedrine), tertiary (Atropine) of nature or quaternary ammonium compounds (Tubarcuranine Cl.) Effects of Alkaloids on Humans

• 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 – may be fatal • In small doses, many have therapeutic value • Generally used as muscle relaxants, tranquilizers, pain killers, mind altering drugs, chemotherapy. Types of alkaloids

• True alkaloids: Present in plants as salts of organic acids. • Proto alkaloids or amino alkaloids: Lack one or more properties of typical alkaloids like nitrogen atom is not present in its heterocyclic ring. Example: Mescaline. • Pseudo alkaloids: Steroidal or terpenoidal alkaloids (not derived from amino acids). Example: Caffeine. • Other alkaloids: These are not conforming to the general definition, are those synthetic compounds, not found in plants, but very closely related to the natural alkaloids. Example: Homoatropine. Source • There are about 6000 alkaloidal compounds identified yet. • Present in 15% of all vascular plants from 150 plant families. • Nearly 300 alkaloids belonging to more then 24 classes, are known to occur in the skin of amphibians. Some reptiles and mammals also possess alkaloids (The Alkaloids, 1993, 43, 119). • Synthetic alkaloids.

ALKALOIDS BIO-SYNTHESIS • Most alkaloids are synthesized from a few common amino acids (tyrosine, tryptophan, ornithine or argenine, aspartic acid and lysine). • Nicotinic acid is the precursor for part of nicotine. • Purine is the precursor for caffeine. • Some alkaloids synthesized from terpenes - along the mevalonic acid pathway. Classification Taxonomic method for classification of alkaloids: This method of classification is based on the taxonomical position of plant which contains the alkaloidal compounds. • Solanaceous alkaloids. Example: Atropine. • Rubiaceous alkaloids. Example: Quinine. Biosynthetic method for classification of alkaloids: This method of classification is based on their precursors. • Alkaloids synthesized from Tryptophane. Example: Indole alkaloids. • Alkaloids synthesized from Ornithine. Example: tropane alkaloids. Pharmacological method for classification of alkaloids: This method of classification is based on the pharmacological action. • Alkaloids acting as analgesic. Example: Morphine. • Alkaloids acting as antitussive. Example: Codine. • Alkaloids acting as antimalarial. Example: Quinine, chinchonine. Classification Chemical method for classification of alkaloids: Generally classified by the predominant ring structure and/or carbon skeleton.here are two broad divisions. I. Non heterocyclic alkaloids. II. II. Heterocyclic or typical alkaloids. 1. Pyrrole and pyrolidine alkaloids. Example: Hygrine. 2. Pyrolizidine alkaloids. Example: Symphitine. 3. Pyridine and piperidine alkaloids. Example: Nicotine. 4. Tropane(Piperidine / n-methyl-pyrolidine) alkaloids. Example: Atropine, cocaine. 5. Quinoline alkaloids. Example: Quinine, chinchonine, cinchonidine etc. 6. Isoquinoline alkaloids. Example: Morphine, codine, papaverine etc. 7. Aporphine (Reduced Isoquinoline / naphthalene) alkaloids. Example: Boldine. 8. Norlupinane alkaloids. Example: Spatein. 9. Indole or benzopyrrrole alkaloids. Example: Ergotamine, reserpine, vinblastin, vincristin, strychnine, brucine etc. 10. Indolizidine alkaloids. Example: Castanospermine. 11. Imidazole alkaloids. Example: Pilocarpine. 12. Purine alkaloids. Example: Caffine. 13. Steroidal alkaloids (some combined as glycosides). Example: Solanidine. 14. Terpenoid alkaloids. Example: Aconitine.

Chemical tests for alkaloids Tests with following reagents (precipitation tests) are carried out to detect the presence of alkaloids. Alkaloidal extracts (organic solvent) are treated with dilute acid and aqueous portion is separated. To few ml. of this solution, in sepatrte test tubes, a drop of following reagents for general tests are added from the side wall. General tests: 1) Mayer’s reagent test: (Potassium mercuric chloride) → Cream coloured precipitate. 2) Dragendroff’s reagent test: (Potassium bismuth iodide) → Reddish brown coloured precipitate. 3) Wagner’s reagent test: (Iodine in potassium iodide) → Brown coloured precipitate. 4) Hager’s reagent test: (Saturated solution of picric acid) → Yellow coloured precipitate. 5) Kraut’s reagent test (modified dragendroff’s reagent) → Reddish brown coloured precipitate. Chemical Tests for Alkaloids Specific tests: Murexide test for purine alkaloids: To 3 - 4 ml of test solution, add small amount of potassium chlorate and a drop of HCl. Evaporate to dryness and expose to ammonia vapour → purple colour is observed. Vitali’s test for tropane alkaloids: Mix a drop of fuming nitric acid with solid alkaloidal sample (as less as 1µg.) and evaporate to dryness at 100°C. Add 0.5 ml of 3% solution of alcoholic KOH solution to the residue → A bright purple colour which changes to red and subsequently fades to colourless. Thalleioquin test for quinoline alkaloids: Few drops of bromine water + 2-3 ml of a weakly acidic solution of a quinine salt + 0.5 to 1 ml of strong ammonia → a characteristic emerald green colour is produced. Van Urk reagent (Ehrlich reagent) test for indole alkaloids: Indole alkaloids + Van Urk reagent (p- dimethylaminobenzaldehyde) → a characteristic deep blue colour. GLYCOSIDES

“Glycosides may be defined as the organic compounds from plants or animals which is comprising of a sugar portion linked to a non sugar moiety in a particular manner (through glycosidic bond) and on enzymatic or acid hydrolysis produces the same.” Hydrolysis

• Sugar moiety of a glycoside is known as glycone or genin. • Non sugar moiety of a glycoside is called the aglycone or aglycogenin. • Sugars in glycosides are most commonly D-glucose, others are galactose, mannose, rhamnose, digitoxose or cymarose etc. • Number of sugar moieties in glycosides are one or more. • The linkage between glycone and aglycone is a hemiacetal formed by reducing group (usually aldehyde or keto group) of the sugar and an alcoholic or phenolic hydroxyl group of the aglycon (glycosidic linkage). Properties: • Crystalline or amorphous substances. • Soluble in water, dilute alcohol, insoluble in organic solvents like chloroform and ether. • Optically active. • Easily hydrolyzed by water, mineral acids and enzymes. • Do not reduce Fehling's solution until hydrolyzed. General Uses: • Glycosides are used as cardio tonic, purgative, anti rheumatic and expectorant etc. • Believed to participate in growth regulation and protection of the plants. General Chemical Tests: 1. Sugar content test: Determine free sugar content of the extract. Hydrolyse the extract with mineral acid ( dilute HCl / dilute H2SO4 ) and again determine the total sugar content of the hydrolised extract. Increase in sugar content indicates presence of glycoside in the extract. 2. Baljet test: A thick section of crude drug shows yellow to orange colour with sodium picrate. Classification I) Based on the types of linkage:

• C - Glycoside: Aloe.

Glycone – OH + HC – aglycone → Glycone –C-glycone + H20 • O - Glycoside: Senna

Glycone –OH + HO- aglycone → glycone-O-aglycone + H20 • S – Glycoside (Isothocyanate glycosides): Sinigrin

Glycone – OH+ HS –aglycone → Glycone -S-aglycone + H20 • N - Glycoside: Nucleosides

Glycone –OH + HN –aglycone → Glycone –N-aglycone + H20 ……Classification

II) According to the sugar moiety: • Glycosides with glucose. • Glycosides with rhamnose. • Glycosides with ribose. • Glycosides with digitoxose etc.

III) According to therapeutic action: • Glycosides as cathartics • Glycosides as analgesics • Glycosides as expectorant • Glycosides as cardio tonics etc. ……Classification Chemical Classification (according to chemical nature of aglycone moiety): 1. Anthraquinone glycoside: Senna 2. Cardiac glycosides: Digitalis 3. Saponin glycosides: Liquorice 4. Cyanogenetic or cyanophoretic glycosides: Bitter almond 5. Isothiocyanate glycosides: Black mustard 6. Flavonol glycosides; example: Citrus fruits 7. Coumarin and furauno-coumarin glycosides: Tonka bean camphor 8. Aldehyde glycosides: Vanilla 9. Phenolic glycosides: Bear berry 10. Steroidal glycosides: Solanum 11. Glycosidal biters or miscellaneous glycosides: Saffron Gold beater’s skin test for condensed tannins: • An intestinal membrane of ox or sheep is treated with HCl • Rinsed with distilled water • Treated with tannin solution for 05 minutes • Washed with distilled water

• Treated with ferrous sulphate solution → a brown or black colour is developed on the skin due to tannin.

Extraction of Tannins: Tannins can be Extracted using solvents like alcohol or acetone in a soxhelator. Resins and Resin Combination

“Resins are amorphous products of complex chemical nature and are mixtures of essential oils, oxygenated products of terpens and carboxylic acids containing large no of carbon atoms, found as exudations from the trunk of various trees.”

❖ In many instances resin in plants are formed in special passages or tubes called resin ducts, schizogenous and schizolysigenous glands as a product of metabolism, thus a single incision may drain the resin from a considerable area of the plant. Properties Extraction Methods: • Heavier than water 1. Extracted with alcohol and • Insoluble in water; soluble in then precipitated with alcohol, volatile oils, fixed oils water; Example – Ipomoea. and other non-polar organic 2. Distillation for separation of solvents oils; Example – Copaiba, • Non conductive to electricity Colophony. • These are Transparent or • Obtained as plant exudates translucent solids, semisolids or by incision; Example – liquid substances Myrrh, Asafetida etc. • These are hard, when heated • Heating Plant parts often and ultimately melt • Resins burn with a characteristic smoky flame • Chemically they contain organic acids, alcohols and esters Classification Depending upon the type of constituents, resins are classified as: 1) Acid Resins (resin acids or resinolic acids): These are of high molecular weight and very complex compounds usually occur as free; example: Abiatic acid, Commiphoric acid etc in Colophony. 2) Easter Resins: These consist mostly of resin alcohols combined with aromatic acids like benzoic and cinnamic acids; other aromatic acids are less frequently found, e.g. ferulic acid (in asafetida). There are two principal kinds of resin alcohols in combination with these acids: e.g. Benzoin, storax etc. 3) Resin alcohol (Resinols): The contents are the complex high molecular weight alcohols: Balsams of peru. 4) Resin phenols (Resinotannols): Occurs combined with benzoic and cinnamic acids eg. resinotannol in balsam of Tolu is called toluresinotannol. 5) Resens (Insert compounds): The chemical nature of these compounds are unknown. They are very stable, being unaffected by most chemical reagents or by exposure to moisture and light,Gum Copal, sandarac etc. Examples of resins and resins combinations • Resins (consisting principally of resin and other esters, together with free aromatic acids): Colophony and Cannabis etc. • Oleoresins (Resins and volatile oils in homogenous mixture): Copaiba, capcicum and ginger etc. • Oleo-gum-resins (Homogenous mixtures of volatile oils, gums and resins): Asafoetida and myrrh etc. • Glycoresins (Made up of resins and sugars): Jalap and ipomoea etc. • Balsams (resinous mixtures that contain large proportions of cinnamic acid, benzoic acid or both or esters of these acids): Balsam of Tolu, balsam of Peru etc. VOLATILE OILS Essential oil is a concentrated hydrophobic liquid containing volatile aroma compounds obtained mainly from plants and are volatile in steam. Latin ‘essentia’ meaning a liquid easily changed to a gas. Essential oils are also known as volatile oils, ethereal oils or aetherolea. “Volatile oils or essential oils are generally mixtures of hydrocarbons and oxygenated compounds derived from these hydrocarbons.” • They differ entirely in both chemical and physical properties from fixed oils. Properties • These are generally colorless liquids (exception chamomile which is violet) or solids with pleasant smell. • Volatilize in steam. • Practically in-soluble in water. • Soluble in alcohol, ether and other lipid solvents. • Usually lighter then water. • Possesses high refractive indices. • Most of them are optically active. • Many a times associated with other substances such as gums and resins and them selves tend to resinfy on exposure to air. • Terpeneless volatile oils are prepared by removing hydrocarbons and undesired components using fractional distillation or any other method, to make the oil stable. • The odour and taste of volatile oils is mainly due to oxygenated constituents, which are to some extent soluble in water but more soluble in alcohol. Source: • Volatile oils are biosynthesized from phenyl propane • Secreted from specially structures such as duct cells, schizogenous glands, lysoschizogenous glands and glandular trichomes etc. • Volatile oils present either in entire plant or in part of the plant. • Plants from families like labiatae, rutaceae, piperaceae, zinziberaceae, umbeliferae, myrtaceae and lauraceae etc. possesses volatile oils. • There are about 100 commercially valuable volatile oils directly derived from plants.

Uses: Volatile oils are generally used as flavoring agent, carminative and antiseptic (oils with a high phenol content, e.g. clove and thyme) etc. Classification On the basis of composition volatile oils are classified as following. 1. Terpenes and sesqui-terpenes (hydrocarbons) volatile oil example: turpentine. 2. Alcohol volatile oil, example: peppermint, cardamom. 3. Aldehyde volatile oil, example: cinnamic aldehyde in cinnamon, geraniol in citronella. 4. Ester volatile oil, example: lavender. 5. Ketone volatile oil, example: camphor, caraway. 6. Oxide volatile oil, example: eucalyptus. 7. Phenolic ether Alcohol volatile oil, example: anise, anethol in fennel. 8. Phenol volatile oil, example: eugenol in clove. 9. Peroxide volatile oil, example: ascaridol in chenopodium. 10. Volatile oils which are non terpenoids and derivatives of glycosides, example: glucosinolates in mustard and methyl salicylate in gaultheria. Chemical tests (volatile oils):

– Filter paper is not permanently stained with volatile oil.

– Solubility test: Volatile oils are soluble in 90% alcohol.

– Add alcoholic solution of sudan-III to the thin section of crude drug containing volatile oil → Red colour formed by globules.

– Add a drop of tincture alkene to the thin section of crude drug containing volatile oil → Red colour formed.

Classification

Dr. I. P. Padhy INTRODUCTION • In the domain of drugs and medicine, it is some what contradictory to note that most of them are obtained by synthesis or from terrestrial organisms. • About 5 lakhs of species of marine organisms have been reported from the oceans and seas from various parts of the world. • Some of these organisms are antimicrobial, antiviral, antibiotics, enzyme inhibiters, anti-inflammatory, neurophysiological, cardiovascular, anticancer/cytotoxic agents. • Many of the species contain toxic compounds. • In western medicine some established products from marine origin are; agar, alginic acid, spermaceti, carragenin, cod liver oil, shark liver oil, halibut liver oil, cephalosporines and protamine sulphate etc. CLASSIFICATION: ON THE BASIS OF ORGANISM ON THE BASIS OF THEIR ACTIVITY 1.Sea cucumber 1. Cardiovascular active compounds (Stichopus japonicus) 2. Cytotoxic/ anticancer compounds 1.Brown algae 3. Antimicrobial compounds (Dictyopteis zonaroids) 4. Antibiotics 1.Red algae 5. Anthelminitics (Bonnemaisonia hemifera) (Stichopus japonicus) 1.Sponge (Verongia aerophoba) 1. Anticoagulants 2.Sea hare (Aplysia californica) 2. Insecticides 3.Gorgonian corals 3. Anti-inflamatary (Eunicia mammosa) 4. Antispasmodics 1.Fungus 5. Vitamines (Cephalosporium acremonium) 6. Miscellaneous and other 1.Marine bacterium principles (Pseudomonas bromutillis) 7. Marine toxines 2.Marine bacterium (Pseudomonas bromutillis) CARDIOVASCULAR COMPOUNDS Active Source Use Compounds Anthopleurines Anthopleurines are groups of peptides Cardio tonic effect (35 obtained from colenterates viz. times higher as compared Anthropleura xanthogramica. to digoxin and less toxic). Laminine Laminine is a marine algae Laminaria Hypotensive effect. angustata. Eptatretin Eptatretin is found in the aneural Potent cardiac stimulant bronchial hearts of pacific hog fish, on mammalian Eptatretus stoutii. myocardium. d-octopamine D-octopamine is obtained from octopus Produces adrenergic and macropus and Octopus vulgaris. cardiovascular response. Saxitoxin Saxitoxin is obtained from Saxidomus Hypotensive effect. giganteus. Automonium Automonium is obtained from Verongia Produces adrenergic and fistularis. cholinergic activity. Spongisine Spongisine is a nucleoside obtained by Reduces both force and extracting Caribbean sponge rate of contraction of Cryptotethia crypta. heart. ANTICANCER DRUGS Active Source Use Compounds Ara-C Ara-C is 1- α – D- Arabinofuranosyl In acute cytosine obtained from the myelogenous Caribbean sponge viz. spongosine leukemia. and spongouridine. Cracin Cracin acetate is a cyclic di-terpene Cytotoxic acetate obtained from soft corals Caribbean gorganian. Asperidiol It is a gorgonian coral. Cytotoxic Aplisistatin It is obtained from sea hare Aplisia Anti leukemic. angasi. Halitoxin It is obtained from a sponge Antitumor Helielona viridis. activity. ANTIMICROBIAL AGENTS Marine organism Antimicrobial principle Sea cucumber (Stichopus Holotoxin-A, B & C japonicus) (steroidal glycoside)- antifungal. Brown algae (Dictyopteis Zonarol and isozonarol. zonaroids) Red algae (Bonnemaisonia Tetrabroheptanone. hemifera) Sponge (Verongia aerophoba) Aeroplysinin-1(+) and Aeroplysinin-1(-) Sea hare (Aplysia californica) Debromol aurenterol. Gorgonian corals (Eunicia Eunicin. mammosa) ANTIBIOTICS

Marine organism Antimicrobial principle

Fungus (Cephalosporium Cephalosporin-C acremonium) Sponge (Ircinia strobillina) Ircinine-1 Marine bacterium 2, 4-dibromo-6-(3, 4, 5- (Pseudomonas bromutillis) tribromopyrrol-2-4, 1) phenol. MISCELLANEOUS Source Active Compounds Use Eucheuma chondrus Laminarine Antilipimics Plexaura homomalla Prostaglandins(PGA-2, Used in asthma, peptic PGE-2) ulcer and in birth control. Obtained from marine Ara-A Antiviral agent sponge Tethya crpta Rhodactis howesii Anticoagulant Flustra foliaceae Flustramine A and B Muscle relaxant (antispasmodics) Cod liver oil, shark liver oil, Vitamine – A and D halibut liver oil Extract of various marine Vitamine – C, folic acid, algae niacin and B-complex. Sponge (Luffariella Monoalide Anti-inflammatory variabilis) Red algae (Digenia simplex) Anthelminitics Dominic acid Chondria armata Anthelminitics Dr. I. P. Padhy INTRODUCTION • In the domain of drugs and medicine, it is some what contradictory to note that most of them are obtained by synthesis or from terrestrial organisms. • About 5 lakhs of species of marine organisms have been reported from the oceans and seas from various parts of the world. • Some of these organisms are antimicrobial, antiviral, antibiotics, enzyme inhibiters, anti-inflammatory, neurophysiological, cardiovascular, anticancer/cytotoxic agents. • Many of the species contain toxic compounds. • In western medicine some established products from marine origin are; agar, alginic acid, spermaceti, carragenin, cod liver oil, shark liver oil, halibut liver oil, cephalosporines and protamine sulphate etc. CLASSIFICATION: ON THE BASIS OF ORGANISM ON THE BASIS OF THEIR ACTIVITY 1.Sea cucumber 1. Cardiovascular active compounds (Stichopus japonicus) 2. Cytotoxic/ anticancer compounds 1.Brown algae 3. Antimicrobial compounds (Dictyopteis zonaroids) 4. Antibiotics 1.Red algae 5. Anthelminitics (Bonnemaisonia hemifera) (Stichopus japonicus) 1.Sponge (Verongia aerophoba) 1. Anticoagulants 2.Sea hare (Aplysia californica) 2. Insecticides 3.Gorgonian corals 3. Anti-inflamatary (Eunicia mammosa) 4. Antispasmodics 1.Fungus 5. Vitamines (Cephalosporium acremonium) 6. Miscellaneous and other 1.Marine bacterium principles (Pseudomonas bromutillis) 7. Marine toxines 2.Marine bacterium (Pseudomonas bromutillis) CARDIOVASCULAR COMPOUNDS Active Source Use Compounds Anthopleurines Anthopleurines are groups of peptides Cardio tonic effect (35 obtained from colenterates viz. times higher as compared Anthropleura xanthogramica. to digoxin and less toxic). Laminine Laminine is a marine algae Laminaria Hypotensive effect. angustata. Eptatretin Eptatretin is found in the aneural Potent cardiac stimulant bronchial hearts of pacific hog fish, on mammalian Eptatretus stoutii. myocardium. d-octopamine D-octopamine is obtained from octopus Produces adrenergic and macropus and Octopus vulgaris. cardiovascular response. Saxitoxin Saxitoxin is obtained from Saxidomus Hypotensive effect. giganteus. Automonium Automonium is obtained from Verongia Produces adrenergic and fistularis. cholinergic activity. Spongisine Spongisine is a nucleoside obtained by Reduces both force and extracting Caribbean sponge rate of contraction of Cryptotethia crypta. heart. ANTICANCER DRUGS Active Source Use Compounds Ara-C Ara-C is 1- α – D- Arabinofuranosyl In acute cytosine obtained from the myelogenous Caribbean sponge viz. spongosine leukemia. and spongouridine. Cracin Cracin acetate is a cyclic di-terpene Cytotoxic acetate obtained from soft corals Caribbean gorganian. Asperidiol It is a gorgonian coral. Cytotoxic Aplisistatin It is obtained from sea hare Aplisia Anti leukemic. angasi. Halitoxin It is obtained from a sponge Antitumor Helielona viridis. activity. ANTIMICROBIAL AGENTS Marine organism Antimicrobial principle Sea cucumber (Stichopus Holotoxin-A, B & C japonicus) (steroidal glycoside)- antifungal. Brown algae (Dictyopteis Zonarol and isozonarol. zonaroids) Red algae (Bonnemaisonia Tetrabroheptanone. hemifera) Sponge (Verongia aerophoba) Aeroplysinin-1(+) and Aeroplysinin-1(-) Sea hare (Aplysia californica) Debromol aurenterol. Gorgonian corals (Eunicia Eunicin. mammosa) ANTIBIOTICS

Marine organism Antimicrobial principle

1. The nerve action potential (AP) consists of a transient self-propagated reversal of charge on the axonal membrane. The internal potential Ei goes from a negative value, through zero potential, to a slightly positive value primarily through increases in Na+ permeability and then returns to resting values by an increase in K+ permeability. When the AP arrives at the presynapticterminal, it initiates release of the excitatory or inhibitory transmitter. Depolarization at the nerve ending and entry of Ca2+ initiate docking and then fusion of the synaptic vesicle with the membrane of the nerve ending. 2. Combination of the excitatory transmitter with postsynaptic receptors produces a localized depolarization, the excitatory postsynaptic potential (EPSP), through an increase in permeability to cations, most notably Na+. An inhibitory transmitter causes a selective increase in permeability to K+ or Cl–, resulting in a localized hyperpolarization, the inhibitory postsynaptic potential (IPSP).

3. The EPSP initiates a conducted AP in the postsynaptic neuron; this can be prevented, however, by the hyperpolarization induced by a concurrent IPSP. The transmitter is dissipated by enzymatic destruction, by reuptake into the presynapticterminal or adjacent glial cells, or by diffusion. Depolarization of the postsynaptic membrane can permit Ca2+ entry if voltage-gated Ca2+ channels are present.

Parasympathomimetic drugs

Presented By Saroj kanta Bisoyi Asst. Professor RCPHS, BAM Introduction  The parasympathetic nervous system is also known as cholinergic nervous system.  Acetylcholine is the major neurotransmiter at post ganglionic synapses of cholinergic nervous system.  Acetylcholine was ﬁrst reported by Reid Hunt and Taveau in 1900.  Dale (1914) reported two receptor Muscarnic and Nicotinic Acetylcholine bind with the receptor shows their physiological activity.

Biosynthetic pathway of Acetylcholine.

The biosynthetic pathway of acetylcholine involve in sequential six step. 1) Synthesis of Acetylcholine 2) Storage of Acetylcholine in vescicle. 3) Release of Acetylcholine 4) Binding of Acetylcholine to Receptor 5) Degradation of Acetylcholine. 6) Recycling of Choline. Biosynthetic pathway of Acetylcholine. (1) Synthesis of Acetylcholine Choline is transported from extracellular ﬂuid into the cytoplasm of cholinergic nerve by energy depedent carrier cotransport system sodium channel. The uptake of Choline is the rate limiting step for Acetylcholine and is block by the drug Hemicholinium. Choline Acetyl transferase enzyme catalysed the reaction of choline with Acetyl Coenzyme-A to form an ester in the cytosol. Acetyl Coenzyme-A is derived from the mitochondria and is produced by the kerb cycle and fatty acid oxidation.

(2) Storage of Acetylcholine Newly formed Acetylcholine is transported into Cytosolic storage vesicle present in the presynaptic nerve ending.

It is present along with ATP and with calcium and magnesium ion until it is release. (3) Release of the Acetylcholine  When an action potential propagated by the action of voltage sensitive sodium chanel arrives at nerve ending that causes inﬂux of calcium into thee cell.  Elevation of calcium level promote the fusion of synaptic vesicle with the cell membrane and release of theire content into the synatic space and it bind to either of two postsynaptic receptor on the target cell.  The postsynaptic cholinergic receptor on the surface of effecttor organ are divided in to two classes. (i) Muscarnic receptors (ii)Nicotinic receptors. 4.Degradation of Acetylcholine Acetylcholine in the synapse can bind with cholinergic receptor on postsynaptic membrane to produced a responces.

The free Acetylcholine Hydrolysed to choline and acetate by enzyme Acetylcholine estarase.

(5)Degradation of Acetylcholine (6) Recycle of Choline Choline may be recaptcured by sodium coupled high aﬃnity uptake system that transport the choline back into the neuron. It is acetylted and stored until released by a subsiquent action potential. Actylcholine Receptors after releasing in the synapse Acetylcholine acts on two receptors

these are 1. Muscarnic receptors (M-Receptors) 2. Nicotinic receptors (N-Receptors) Muscarnic receptors Muscarnic receptors are G-Proteins coupled receptors which activates other ion channels. Muscarinic receptors are more sensitive to Acetylcholine than to nicotine receptors. Acetylcholine when bind to muscarnic receptor its causes a conﬁrmational changes in the receptors. Drug with muscarnic action potentially stimuates muscarnic receptors on those tissue but at high concentration they may shows some activity at Nicotinic receptors.

Muscarnic receptors M1 receptors are found in gastric periatal cell M2 receptors on cardiac cell and smooth muscles M3 receptors on bladder,exocrine gland and smooth muscle. M4 and M5 present in certain area of brain and regulates other neurotransmiter. However till today M1,M2 and M3 are major one present in effector cell and prejunctional nerve ending in CNS.

Mechanisam of Acetylcholine signal tranduction

When M1 and M3 receptors activated the receptor undergoes conﬁrmational changes and interact with a G- Proteine –Gq

Activated phospholipase

Hydrolysis of phosphatidylinositol(4,5)-bisphosphate.

Yield Diacylglycerol and ionsitol (1,4,5)triphosphate

Intracelular increase in calcium

Ths cation interact to stimulate or inhibit enzyme cause hperpolarization contraction

Mechanisam of Acetylcholine signal tranduction M2 subtype cardiac muscle stimulate a G- protein (Gi)

that inhibit adenyl cyclase

increase K+ condution to which heart respond to dcrease in rate and force of contraction

Parasympathomimetic agents These are the agents or compounds which directly or indirectly mimic the action of acetylcholine.

These are the drugs which produced action similar to that of Acetylcholine either by directly ineracting with cholinergic receptors.

 Acetylcholine is a major neurotransmiter of parasympathetic nervous system.

 Ssssssss (1)The quaternary ammonium group  Quaternary ammonium group is essential for activity.  Replacement of nitrogen with sulphur(S) ,Arsenic(As) or selenum(Se) produces less active compounds.  Primary ,Secondary or quaternary amine are less active than acetylcholine.  The methyl group of quaternary ammonium group can be replaced by alkyl group. Ex. Dimethyl ethyl derivatives of acetylcholine is more active than the parent drug.

The replacement of more than one methyl group of quaternary ammonium group leads to complete loss of cholinergic activity. (2) The ethylene bridge  As the chain length increased from 2-carbon to more than 2-carbon atom the activity is rapidly reduced. Branching in the chain i.e replacement of hydrogen atom of ethylene bridge by methyl group leads to equal or greater acetylcholine activity.

The α or β-methyl substituted derivative affect selectivity of receptors. Acetyl β-methylcholine act selectively on muscarnic receptors which Acetyl α-methylcholine chloride has greater nicotinic action than muscarnic activity. (3) Acetyl group/Aceloxy group The higher homologus of methyl group propionyl or butyryl group are less active than Acetylcholine. Ester of aromatic or higher molecular weight acid possess cholinergic antagonist activity. Acetate group of Acetylcholine may be replaced by carbamate. Ex. Carbachol is more active and more stable than parent drug.(Degradation is inhibited by enzyme Choline esterase )

Mechanism of action: Acetylcholine is directily acting drug act by bind to the Muscarnic receptor and shows their action. Uses  Mostly used as a topical Opthalmic eye drop.  It is used to redused the intraocular pressure associated with cataract surgery , ridectomy and anterior surgery.  It is also used as a vasodilator and cardiac depresant. It is also increases lachrymal ,salivary secretion.

Methacholine

Mechanism of action:  It is a Quaternary ammonium Parasympathomimetic agent with muscarnic action of acetylcholine.  It is more resistant to hydrolysis by the enzyme Choline esterase.  Its shows prolong action. Uses:  Used in treatment of Glaucoma and reynaud syndrome.

 it is used in the treatment of asthma by inhalation route.

 Also used in the treatment of peripheral vascular disorder.

Carabachol

IUPAC Name: 2-[(Aminocarbonyl)oxy]-N N, N, -trimethylethanaminium chloride

Carbachol MOA  It act by both muscarnic and nicotinic receptor and shows action of acetylcholine.  Its duration of action is increased due to inhibition degradation of by the enzyme cholinesterase.

Uses

 It is used in the treatment of Glaucoma to reduce intraocular pressure .  It is also used for treatment of decreased gastrointenstinal motility. Bethanechol

MOA Bethanechol is a choline ester mainly act on muscarnic receptor and shows their action. . It is not inactivated by cholinesterase. . It also have some nicotinic activity. USES . it is used in the relief of urinary retention and abdominal distention after surgery. . It also has prolong effect than Acetylcholine.  MOA Pilocarpine has mostly bind to M3 receptors in smooth muscle to cause contraction in the eye and trachea. . USES  Treatment of Glaucoma.  Treatment of dry eye or drymouth.

Anticholinesterases These are the agent which inhibt or protect acetylcholine from hydrolysis. Acetylcholine accumulates in the cholinergic terminals and increases the biological responces. These are of two types 1) Reversible inhibitores: These drug binds reversiblly to the enzyme. Ex- Physostigmine and Neostgmine 2)Irreversible inhibitors: These drug produses irrevesible inactivation of Acetylcholine estrase. ex: Organophosphorus compounds. They form a irreversible covalent bond to the active site of the enzyme. Ex: Parathion and Malathion MOA Physostigmine is a reversible tertiary amine inhibitor of enzyme Cholinestrase. Uses Treatment of Glucoma Also used parenterally for reversal the effects caused by anticholinergic and tricyclic antidepresant.

Neostigmine Neostgmine MOA  Indirectly stimulates both muscarnic and nicotinic receptors.  It binds to the anionic and esteric site of cholinesterase and block the activity of acetylcholinesterase. Uses  Treatment of myasthenia gravis.  treatment of postoperative urinary retention.  Used to lower intra-ocular pressure in the management of guaucoma. Pyridostigmine

 IUPAC Name:3-[(Dimethylamino carbonyl)oxy]-1-methyl pyridinium bromide.  Mechanism of action Pyridostigmine block acetyl choline esterase enzyme and inhibit the destruction of release acetylcholine. . Uses: It is mainly uesed in the treatment of myasthenia gravis. Also used as prophylaxis against the neurotransmiter effects of nerve gas poisoning.

 MOA  It is a reversible inhibitor of cholinesterase.  Uses:  It is mainly used in the treatment of Myasthenia gravis.  also used in the treatment of snake bite.

IUPAC Name: 1,2,3,4-Tetrahydroacridin-9-amine MOA:  Tacrine is a centrally acting anticholinesterase. . USES It is used in the treatment of mild to moderate dementia in alzhemer’s disease. Also used as an analeptic agent to promote mental alertness.

MOA: It produses irreversible inactivation of acetylcholinesterase. . USES: It is used as mitotic agent in treatment of glaucoma. Used in the treatment of organo phosphate toxicities.

MOA: It is an irreversible acetylcholine inhibitors. It covalently bind to cholinesterase and permanatly inactive the enzyme. . Uses Treatment of chronic Glaucoma.

 MOA:  It indirectly acts on the acetyl choline esterase enzyme.

 USES Used as insecticide in agriculture. Mostly applied by spraying to cotton rice and fruit tree. Malathion

IUPAC Name: Diethyl-2[(Dimethoxy phosphorothioyl) sulfanyl] butanediote. MOA: It act by binding to the serine residue on the cholinesterase enzyme and irreversibly deactivates the enzyme choline esterase. . Uses: . At low doses (0.5%) it is used in the treatment of head lice and body lice. . Also used in the treatment of scabies. . Mostly used in the treatment of insecticides. Cholinesterase reactivator These are the drugs which causes reactivation of choline esterase. These agent are react with alkylphosphorylated form of cholinesterase to free the active part of the enzyme. Mostly these drug are used in the treatment of organophosphorus poisoning. Ex: Pralidoxime chloride. IUPAC Name:2[(hydroxyimino)methyl]-1-methylpyridinium chloride. MOA:  It reactivates the Acetyl cholineserase enzyme rapidyl by binding to the anionic site of enzyme and displace the phosphate from the serine residue. . Uses  Mostly used in case of organophosphorus poisoning.  Also used for the treatment of overdose by anticholinergic drugs.