Where do drugs come from? Sources of Drugs!

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Today we will discuss about the sources of drugs and where they come from! Shall we start?

Did you know that records of using drug is found dating back to 2,700 B.C. in the Middle East and China! The drugs most commonly used were laxatives and anti-emetics To relieve pain, Opium extract was used. Ephedrine was used for the treatment of respiratory tract disorders.

Until the beginning of twentieth century, the substances used for the treatment of diseases were obtained from natural sources. Natural sources include plants, animals, and minerals. Among the natural sources, plants were mainly used. Sometimes minerals and occasionally animals were used for the same purpose. Nowadays most of the drugs are manufactured in the laboratory, i.e. synthetic drugs. Microorganisms also serve as a source of a large number of drugs.

So, what are the sources of drugs?

I've already given you the answer in the above paragraph! ;). But simply speaking, the sources of drugs can be grouped according to the following:

1. Plant source:

• Alkaloid
• Glycoside
• Oil
• Gum and mucilage
• Carbohydrate and related compounds

2. Animal source

3. Mineral source

4. Laboratory source

5. Microorganisms

Now, let’s have a look at each of the drug sources individually.

Believe it or not, there used to be a time when the leaves that had the shape of the liver, were used for the treatment of liver diseases! Subsequently various parts of the plant such as root, bark, stem, leaf, seed and flower were used.

All parts of a specific plant do not equally contain a specific drug. For example, atropine, caffeine, cocaine, digoxin, and pilocarpine are obtained from the leaves of specific plants. Seeds some plants are used to extract castor oil, colchicine, morphine, strychnine and theobromine. Barks of some plants are used for the extraction of drugs like cinnamon, quinidine, and quinine. Roots of some plants are used to extract reserpine and atropine.

Nowadays plants that were used as drugs, with some expectation (digitalis, belladonna), are no longer considered for rational treatment. Rather the pharmacologically active constituents (e.g. atropine from the roots) are extracted and used.

The pharmacologically active constituents of different plants are grouped according to their physio-chemical properties and include:

A. Alkaloid
B. Glycoside
C. Oil
D. Gum
E. Mucilage
F. Carbohydrate and related compounds

Some of these active constituents can be extracted by soaking the plant in alcohol.

The purpose of extracting the active constituents are:

1. Identification of the active constituents.
2. Analysis of the pharmacodynamic and pharmacokinetic properties of the active constituents
3. Ensuring a precise and constant dosage in the therapeutic use of chemically pure constituents
4. The possibility of chemical synthesis

Now, let's discuss in details about each group of the active constituents obtained from plants.

The word alkaloid (alkali + oid) literally means alkali like substance.

Alkaloid is defined as a basic nitrogenous compound of plant origin which produces salt when combines with acid and is physiologically active in plant and animal.

The properties of alkaloids are:

1. White crystalline substance
2. Bitter taste
3. Insoluble in water but its salt preparation is highly soluble in water
4. Almost all aresoluble in alcohol, ether, chloroform, and oil.

Names of alkaloids end in –ine. For e.g. atropine, cocaine, morphine are all alkaloids.

The majority of the alkaloids are extracted from the flowering plants abundant in seeds and roots. Only a few alkaloids are obtained from the flowerless plants or produced synthetically. Synthetic alkaloids are apomorphine, homatropine, etc.

Classification of alkaloids:

Alkaloids are broadly classified according to their plant source, i.e. from which plant they are obtained. These are:

1. Belladonna
2. Cinchona
3. Cocaine
4. Ergot
5. Opium
6. Rauwolfia
7. Vinca
8. Xanthine

The word rauwolfa was originated from the name of a German physician and botanist of the 16^th century, Leonard Rauwolf.

1. Belladonna alkaloids:

Belladonna alkaloids include:

• Atropine
• Scopolamine (hyoscine)
• Hyoscyamine.

Atropine is an organic ester formed by the combination of tropine (an organic base) and tropic acid (an aromatic acid). On the other hand, scopolamine contains scopine and tropic acid.

Scopine differs from tropine by having an oxygen bridge between the carbon atoms designated on 6 and 7.

2. Cinchona alkaloids:

The important alkaloids of cinchona are;

• Quinine
• Quinidine
• Cinchonine
• Cinchonidine.

Quinine is present abundantly in the bark of cinchona tree. It was used as antimalarial, antipyretic and analgesic.

3. Cocaine alkaloids

Cocaine alkaloids include:

• Cocaine
• Cegonine

Cocaine (the first discovered local anesthetic) is obtained in large amount (0.6 to 1.8%) in the leaves of Erythroxylon coca. It is an ester of benzoic acid and a nitrogen-containing base.

4. Ergot alkaloids

Ergot alkaloids contain:

• Ergine
• Ergonovine
• Ergotamine

Ergot is the product of the fungus (Claviceps purpurea)that grows up on rye and other grains.

5. Opium alkaloids

Opium is obtained from the milky juice derived from the unripe seed capsule of the poppy plant (Papaver somniferum). This includes at least 20 alkaloids of which the ones having clinical importance are:

• Morphine
• Codeine
• Papaverine
• Noscapine
• Thebaine

6. Rauwolfia alkaloids:

The examples of rauwolfia alkaloids are:

• Reserpine
• Cevadine
• Germerine

7. Xanthine alkaloids

Xanthine alkaloids include:

• Caffeine
• Theophylline
• Theobromine

That's all about alkaloids for now. Now let's move on to Glycosides!

What is glycoside? Glycosides are non-nitrogenous, colorless, crystalline solids that splits up into sugar (one to four molecules) and non-sugar parts. They do not form salts. Some are poisonous.

The non-sugar part of glycosides is termed aglycone or genin. Aglycone is made of cyclopentanoperhydrophenanthrene nucleus (steroid nucleus) to which is attached an unsaturated lactone ring at C17 (17th number carbon atom). It is chemically related to bile acid, sterol and steroid hormones.

The pharmacological activity of glycoside resides in the aglycone part. However, the combination of sugar to the aglycone modifies the lipid/water partition coefficient, potency, and pharmacokinetic properties.

Aglycone can be separated from the sugar part of glycosides by adding an acid or enzyme.

Classification of glycosides

Glycoside is classified as glucoside, glalactoside, fructoside according to the presence of glucose, galactose and fructose respectively as sugar.

Glycoside is widely distributed in the bark, seed and leaf of the plant.

Some important glycosides are:

Digoxin and digitoxin (isolated from the leaves of purple foxgloves Digitalis purpurea) are called digitalis cardiac glycosides. They have powerful action on the myocardium.

Salicylic acid (orthohydrobenzoic acid) was obtained first from salicin, a glycoside bitter in taste found in the willow bark in 1838. On hydrolysis, salicin yields glucose and salicylic alcohol. Salicylic alcohol is then converted into salicylic acid.

The aminoglycosides contains glycosidic bond (-O-) in its structure but it is NOT considered as glycoside.

Oils used as drug are of two kinds: fixed and volatile.

Fixed oil

Fixed oil is a mixture of glycerol esters of high molecular weight aliphatic acid especially palmitic, stearic, and oleic acid. It is non-volatile and lighter than water as well as insoluble in water. But it is soluble in chloroform and ether. It is not dissipated by heat.

Examples of fixed oils are olive oil, castor oil, and chaulmoogra oil. Metabolites of castor oil irritate the mucosa of gastrointestinal tract producing peristalsis leading to evacuation and are used as cathartic.

Olive oil is usually edible and can be used as emollient.

Volatile oil

Volatile oil is the odorous principle found in various parts of plant. Since it evaporates when exposed to air at room temperature, it is called volatile or essential oil. The term essential is used because volatile oil represent the essence or odoriferous constituent of the plant.

Volatile oil is colorless when fresh, but on standing it may be oxidized and resinified, thus its color is converted to dark. So, it should be stored in cool, dry place in tightly stoppered, preferably amber glass container. Chemically, it usually contains the hydrocarbon tarpene or some polymer of it. The terpene fraction serves as diluent for the more active compound present.

Examples of volatile oils are Peppermint oil, spearmint oil, clove oil, wintergreen oil, and lemon oil.

The active portion of peppermint oil is menthol. In case of clove oil, the active component is eugenol. Clove oil relieves pain when applied locally (in case of toothache). Wintergreen oil is used locally in the relief of joint pain. Peppermint and spearmint oils are used as solvent and flavor in the compounding of prescription.

Gum is a secretory hydrocarbon product of plant origin. Chemically, it is anionic or nonionic polysaccharide or slat of polysaccharide which on hydrolysis produces sugar.

An effort has been made to distinguish between the gum and mucilage on the basis that gum readily dissolves in water, whereas mucilage forms slimy mass.

Examples of natural gums include Agar and psyllium seed. When they are swallowed, they absorb water to from bulk, and exert a laxative effect.

An example of mucilage isTragacanth, which is used as:

• A suspending agent for insoluble powder in mixture
• An emulsifying agent for oil and resin
• An adhesive

Carbohydrate constituents a major class of naturally occurring organic compound.

The carbohydrate sucrose and other sugars like dextrose and fructose are used in many circumstances. For example:

• Sucrose is used as a demulcent and nutrient
• Sucrose in sufficient concentration (65%) in aqueous solution, is bacteriostatic and preservative
• Dextrose is a nutrient and may be given by mouth or by intravenous injection as required.
• Dextrose is used as an ingredient in many preparation such as dextrose in aqua and dextrose in saline.
• Dextrose is used as an ingredient of anticoagulant such as dextrose citrate sodium, citrate phosphate dextrose solution, etc. These solutions are used for the storage of whole blood.
• Fructose is used for food for diabetic patients and may be of particular benefit in diabetic acidosis.
• A carbohydrate related compound, Alcohol (70%) is used as an antiseptic.

So there you go, I have discussed the whole of plant sources of drugs for you! Now, it's time to move on to the animal sources!

There was a time when the Chinese people used the dried skin of toad to treat toothache and bleeding in gum. Later it was found that toad skin contains adrenaline.

The liver of cod fish (cod liver oil) contains high levels of omega 3 fatty acids, vitamin A and vitamin D.

Insulin is extracted from the pancreas of bovine or porcine.

Immunoglobulin G is prepared by the injecting antigen into an animal and collecting the antibody formed as a reaction to the antigen. Immunoglobulin of animal origin (antisera) is frequently associated with hypersensitivity reactions which has led to its virtual abandonment. For example, horse globulin containing anti-tetanus and anti-diphtheria toxin has been extensively used at one time, but nowadays their use is more restricted as they give rise to complications like serum sickness.

So antisera is replaced by human immunoglobulin. Human immunoglobulin is prepared from pools of at least 1000 donations of human plasma containing the antibody to measles, mumps, hepatitis A and other viruses.

Injection of human immunoglobulin produces immediate passive immunity lasting for about 4 to 6 weeks.

Specific immunoglobulin (hepatitis B immunoglobulin, rabies immunoglobulin, tetanus immunoglobulin) are prepared by pooling the plasma of selected donors with high levels of the specific antibody required.

Human menopausal gonadotropins (hMG) is isolated from the urine of postmenopausal women and contains a mixture of follicle stimulating hormone (FSH) and luteinizing hormone (LH).

Human chorionic gonadotropin (hCG) is produced by the placenta and can be isolated and purified from the urine of pregnant woman. The hCG is nearly identical in activity to LH but it differs in sequence and carbohydrate content.

Heparin is commonly extracted from porcine intestinal mucosa or bovine lung.

The sword symbolizes strength and power, the early Greek physicians attempt to use iron therapy against weakness and anemia.

Various clay have been used for the treatment of diarrhea. One remedy, called for the powdering of the bowls with old clay pipes. The principal ingredients of such pipes would be kaolin and activated charcoal, both of which are used today for the treatment of diarrhea.

Calomel was used for the treatment of constipation. It contains mercury and subsequently found to have a diuretic effect and was used with digitals for the treatment of congestive cardiac failure. The diuretic effect of mercury was also observed following the used of that compound in the treatment of syphilis.

Iodine is used for the treatment of goiter.

Gold is used for the treatment for the arthritis.

Sulfur is used externally in skin diseases.

Aluminum hydroxide and magnesium trisilicate are widely used as antacids.

Magnesium sulfide is used to relieve constipation and to control eclamptic seizure.

Nowadays most drugs are produced artificially by combining two or more compounds or elements. It may be partially or totally synthesized. The structural alteration of the natural substance by the addition of a pure chemical substance leads to the production of a partially synthetic substance.

With the improvement of organic chemical industry, the synthesis of chemical substances in the laboratory has become extremely advanced. In most cases, drugs produced in laboratories are of high quality, less expensive, produced in large scale within short time, safer, and more effective than drugs extracted from plants or animals.

For example, 1 mg of digoxin produced in the laboratory has the same pharmacological effect as produced from 1000 mg of crude leaves of purple foxgloves. That is 1 mg synthetic digoxin is equivalent to 1000 mg of crude leaves of purple foxgloves.

Salicylates originally extracted from the plant source are nowadays produced in the laboratory.

The synthesis of sulfonamide began from protonsil dye. One of the adverse effects of sulfonamides was hypoglycemia, which led to the development of sulfonylurea drugs. Acetazolamide (carbonic anhydrase inhibitor), hydrochlorothiazide, and frusemide are also developed from sulfanilamide. Nowadays sulfonylureas are used to lower blood sugar level in non-insulin dependent diabetes mellitus.

Human insulin is produced by modification of porcine insulin or by bacteria using recombinant DNA technology. It is known to us that insulin contains 51 amino acids in two chains, A and B. A chain contains 21 amino acids and B chain contains 30 amino acids. Bovine insulin differs from human insulin at 3 amino acid sites whereas porcine insulin at 1 amino acid site. By changing the amino acids alanine or porcine insulin at position 30 of B chain with threonine, we can convert it to human insulin. Human insulin is absorbed more rapidly from the site of administration that re the bovine or porcine insulin. But the duration of effect of human insulin is shorter and doses must be adjusted.

The actual production of insulin (see the diagram below) involves the introduction of human insulin gene into a non-pathogenic strain of the bacteria Escherichia coli K12. Insulin gene is separated from the chromosome using restriction enzymes. Then bacteria containing human gene are cultured in huge vats of nutrients until they are ready to have the insulin extracted from them.

In 1948, the antibiotic 7-chlortetracycline was isolated from the Streptomyces aurefaciens. The catalytic removal of chlorine from 7-chlortetracycline gave tetracycline. Tetracycline is superior than 7-chlortetracycline and has replaced it. Studies on the structure and synthesis of penicillin led to the development of the naturally synthetic penicillin and later to cephalosporin.

Most of the currently used analgesics, chemotherapeutic drugs, hypnotics and local anesthetics are produced in the laboratory.

The natural source of caffeine is the tea or coffee. Large amount of caffeine is nowadays obtained as the byproduct of manufacturing decaffeinated coffee.

Theophylline can be produced by methylation of theobromine (partial synthesis) or from urea (total synthesis).

Well-known antibiotics produced by the actinomycetes are actinomycin, amphotericin, chloramphenicol, erythromycin, kanamycin, neomycin, gentamicin, streptomycin and tetracycline.

Aspergillate group of fungi produce antibiotics such as penicillin, griseofulvin and cephalosporin. Among the bacteria, genus Bacillus produces antibiotics such as polymyxin B and bacitracin.