Production of pharmaceuticals
Raw materials and their purity.
Pharmaceutical raw materials may be plant, animal, or other biologic products; inorganic elements and compounds; or organic compounds.
If the raw material is official - that is, if it is the subject of a monograph in pharmacopoeia or national formulary - then the minimum acceptable degree of chemical purity is specified. Very often, however, because some raw materials at specified levels may begin to decompose after a time, purification far exceeds these minimum requirements. If extra purification is inconvenient, a preservative may be added. If the raw material is not the subject of an official monograph, then physical or chemical specifications or both are drawn up by the manufacturer in accordance with the pharmaceutical requirements of the finished product, on lines similar to the official monographs.
Crude drugs
The term crude drugs is usually applied to plant or animal organs or whole organisms or exudations of these, either in the fresh state of dried and either ground or unground. Some crude drugs such as acacia, belladonna, and starch are official; for these, rigid specifications are available. Plant-derived crude drugs may come from cultivated sources or may be collected in the wild. Cultivation and collection are carefully planned to obtain drugs with the highest possible therapeutic activity or content of active constituents. The harvested drug plant must then be cleaned to remove matter such as sand and dirt. Next, unwanted plants or plant parts are carefully removed. Some crude drugs, such as belladonna, undergo curing, a process that consists either of slow drying or sweating, during which enzymes bring about chemical changes whereby the content of active ingredients is increased. Alternatively, as with cascara sagrada, the drug is carefully stored for a year, during which time unwanted constituents slowly decompose. The final stage in crude - drug production consists of drying, accomplished in air or with artificial heat. Drying aids preservation, stops various chemical reactions that might weaken or destroy the substance, facilitates subsequent grinding, and reduces weight and bulk. Drugs containing volatile constituents are dried at temperatures near freezing. After drying, some drugs (such as belladonna and ipecac) are reduced to a fine powder.
Known as «Hoffman’s drops», ether was first employed as an anesthetic in 1842; chloroform followed soon afterward in 1847. Alkaloid compounds were also isolated from plant sources during this period. Narcotine was obtained from opium by a French pharmacist in 1803 and was followed by morphine in 1806, emetine and strychnine (around 1817), brucine and piperine (1819), colchicines and quinine (1820), nicotine ( 1828 ), atropine ( 1833 ), cocaine (1860 ), and physostigmine ( 1867 ). Isolation of these potent compounds was a milestone in pharmaceutical progress for three reasons. First, accurate doses could now be administered; this had been impossible previously with crude drugs of unknown and variable composition. Second, toxic effects due to impurities in crude drugs could now be eliminated if pure compounds were used; and third, knowledge of the chemical structure of these drugs led to attempts at laboratory synthesis, whish led in turn to discovery of valuable related compounds.
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The modern pharmaceutical industry began in the 19th century with the discovery of highly active medicinal compounds that could most efficiently be manufactured on a large scale. As these compounds replaced herbal medicines of earlier times, the occurrence and severity of such diseases as pernicious anemia, rheumatic fever, typhoid fever, lobar pneumonia, poliomyelitis, syphilis, and tuberculosis were greatly reduced. Pharmaceutical industry research has greatly aided medicinal progress; of the 66 most valuable drugs introduced since aspirin in 1899, 57 were discovered and then produced in industrial laboratories.
Preparation from natural sources
The alkaloids
As mentioned above, the first pure pharmaceuticals isolated from natural sources were the alkaloids. Though the methods adopted for their extraction from plants vary in detail, all are based on three general characteristics of these compounds. First, most alkaloids are only slightly soluble in water but readily soluble in certain organic solvents such as benzene, chloroform, ether, and light petroleum. Second, alkaloids combine with acids to form salts that are usually freely soluble in water but only slightly so in organic solvents. Third, alkaloids are liberated from their salts by alkalies.
Application of these general principles can be seen in the following generalized outline of extraction methods. The crude drug, ground to a suitable state of subdivision, is mixed with water, a water-soluble alkali such as lime, and some organic solvent that does not mix with water. The mixture separates into two layers: one contains water, lime, and impurities and is discarded; the other contains the alkaloids dissolved in the organic solvent. Fresh water and dilute acids are now added to the mixture. Again there are two layers, but the acid has caused the alkaloids to pass from the organic layer into the aqueous layer. The aqueous layer is now separated, and the alkaloidal salt or salts may be crystallized out by cooling or concentrating the solution. The process described above is used to obtain quinine sulfate from cinchona bark.
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Glycosides
Glycosides such as digoxin are another important group of drugs obtained from plants. Generally, the glycoside is extracted from the crude drug with alcoholic extract that causes the impurities to fall to the bottom. After being poured through a filter, the alcoholic extract is concentrated, and the glycosides may crystallize out. Often, however, concentration of the extract is not sufficient to cause crystallization, and more complicated procedures must be employed.
Volatile, or essential, oils
Volatile, or essential, oils, also obtained from plants, may be extracted by distillation, steam distillation, expression, or by extraction with fats or organic solvents. In steam distillation, the most common method, the crude drug - either fresh or dried - is used in powder form. Water is mixed with the powder, serving the double purpose of preventing decomposition of plant material by excessive heat and of facilitating volatilization of the essential oil. The powder-water mixture is usually placed in a basket through which the steam penetrates. The distillate consist of a water-oil mixture; the oil forms a separate layer, which is run off. Anise, cinnamon, clove, coriander, fennel, and peppermint oils are all obtained by this method, as is the pharmaceutical substance camphor from camphor wood.
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Fixed, or fatty, oils cannot be obtained by distillation, but only by expression or extraction. Castor, olive, and sesame oil, for example, are all obtained by expression. Cod-liver and halibut-liver oils, rich sources of vitamins A and D, are both extracted by passing steam into tanks containing the livers suspended in water, until the temperature reaches 70-80 ºC (158-176 ºF). The tissues disintegrate, and the oils float to the surface and are skimmed or centrifuged off.
Ginseng
Ginseng is used throughout the Orient as a tonic for general weakness and extra energy. There are many types of ginseng: Eleuthrococcus senticosus
(Siberian ginseng), Panax quinquifolium (American ginseng), Panax ginseng ( Chinese or Korean ginseng ), and Panax japonicum ( Japanese ginseng ). Panax ginseng is the most widely used species.
Ginseng contains thirteen different ginsenosides (triterpenoid saponins ). The most important constituents include: panacaene, B-elemene and panaxinol, low-molecular weight starches, pectin, vitamins (B1, B2, B3, B5, B12 and biotin), choline, minerals, simple sugars, traces of germanium, and flavonoids.
The American Indians were familiar with ginseng. They called it gisens and used it for stomach and bronchial disorders, asthma, and neck pain.
Russian scientists claim that the ginseng root stimulates both physical and mental activity, improves endocrine glandular function, and has a positive effect on the sex glands. Today it is being used for fatigue because ginseng spares glycogen utilization in muscle by increasing the use of fatty acids as an energy source. It is also used to enhance athletic performance, to rejuvenate and to increase longevity, and to detoxify and normalize the entire system.
Many supplement combinations add ginseng to their products, but they contain such low amounts that it may not be effective. Lower doses of ginseng seem to raise blood pressure, while higher amounts lower the blood pressure. Research suggests that higher amounts may be effective for inflammatory diseases such as rheumatoid arthritis, without the side effects of steroids, and they also protect against the harmful effects of radiation. The hypoglycemic should avoid using large amounts of ginseng. Ginseng will benefit the diabetic, however, because it decreases serum cortisol levels. (Cortisol antagonizes insulin.)
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We advise following the Russian approach: use ginseng for 15-20 days, followed by a rest period of two weeks. Avoid long-term usage of high amounts of ginseng, even though studies have shown no side effects. The root is sold in many forms: as a whole root, root pieces, or tails, which are either untreated or blanched; as a powder or powdered extract; as a liquid extract or concentrate; in granules for instant tea; as a tincture, in an oil base, and in tablets and capsules. These products should not contain sugar or added color, and should be pure ginseng.
Wakunaga of America Company distributes several high-quality Korean and Siberian ginseng products:
- ENAX PG1. High quality Korean ginseng that is processed according to the ancient method.
- ENAX EG1. Siberian ginseng powder made from wild, fully matured plants that have been harvested in a remote pollution-free northern Pacific islands.
ENAX EG2. Siberian ginseng extract and powder made from the same high quality plants as ENAX EG1, but of greater potency.
Essential oil
Chemical composition
Terpenes, organic compounds consisting of isoprene units (containing five carbon atoms), are by far the most dominant constituents of essential oils. Individual oils, however, may contain appreciable quantities of straight chain, aromatic, or heterocyclic compounds. Thus allyl sulfides are characteristics of oil of garlic, traces of indole and anthranilic acid esters are found in orange oil, straight chain alcohols and aldehydes are recognized in oil of violets, and phenols and other aromatic compounds are common to many oils.
Terpenes are built up from units of the simple five-carbon molecule isoprene. Both hydrocarbons and oxygenated compounds such as alcohols, aldehydes, ketones, acids, esters, oxides, lactones, acetals, and phenols are responsible for the characteristic odours and flavours.
In some oils one or only a few components predominate: thus oil of wintergreen contains about 98 percent of methyl salicylate; orange oil, about 90 percent of d-limonene; bois de rose, 90 percent of linalool; and cassia, up to 95 percent of cinnamaldehyde. In most oils there is a mixture of anywhere from a few dozen to several hundred individual compounds. Trace components are very important, since they give the oil a characteristic and natural odour.
Essential oils are generally expensive, with prices ranging from several U.S. dollars per kilogram on the low side to several thousand dollars per kilogram. The high price of the natural oils coupled with their limited availability has encouraged a search for substitutes. Great progress has been made in the synthesis of individual components such as geraniol, citral, linalyl acetate, and the like. These synthetics have been combined with natural oils to extend supplies, and they have also been blended together in attempt to duplicate the oils themselves. Such reconstituted oils usually lack certain of the odour notes of the natural products, because of absence of trace ingredients, often unidentified, that may be present in the natural oils. They also tend to have a more « chemical » odour, because of trace impurities in the synthetics that are different from the components of natural oils.
Methods of production
The first step in the isolation of essential oils is crushing or grinding the plant material to reduce the particle size and to rupture some of the cell walls of oil-bearing glands. Steam distillation is by far the most common and important method of production, and extraction with cold fat (enfleurage) or hot fat ( maceration) is chiefly of historical importance.
Three different methods of steam distillation are practiced. In the oldest and simplest method a vessel containing water and the chopped or crushed plant material is heated by a direct flame, and the water vapour and volatile oil are recovered by a water-cooled condenser. This original method is being replaced by a process in which the plant material is suspended on a grid above the water level, and steam from a second vessel containing the plant material on a grid is heated to prevent condensation of steam, so that dry distillation is attained.
In southern France essential oils were extracted with cold fat long before the introduction of extraction with volatile solvents. This process is applied to flowers that do not yield an appreciable quantity of oil by steam distillation or whose odour is changed by contact with boiling water and steam. In this process, flowers are spread over a highly purified mixture of tallow and lard and are left for a period varying from 24 hours to 72 hours. During this time most of the flower oil is absorbed by the fat. The petals are then removed (defleurage), and the process is repeated until the fat is saturated with oil. The final product is called pomade (e. g. pomade de jasmine).
In most cases, it is possible to shorten the long enfleurage process by extracting the essential oils using molten fat for one to two hours at a temperature ranging from about 45 ºC to 80 ºC (110 ºF to 175 ºC). The fat is filtered after each immersion, and after 10 to 20 extraction cycles the pomade is sold as such, or it may be extracted with alcohol to yield the oil residue.
Since both enfleurage and maceration are rather expensive processes, some essential-oil specialists have shifted almost completely to using volatile solvents for the recovery of essential oils from plant materials that could not be processed by steam distillation. Petroleum naphthas, benzene, and alcohol are the primary solvents.
A procedure called expression is applied only to citrus oils. The outer coloured peel is squeezed in presses, and the oil is decanted or centrifuged to separate water and cell debris. The method is used for oil of sweet and bitter orange, lemon, lime, mandarin, tangerine, bergamot, and grapefruit. Much oil is produced as a by-product of the concentrated-citrus-juice industry.
Antibiotics
Antibiotics are an extremely important group of drugs isolated from natural sources. Penicillin was originally produced by growing the Penicillium notatum mold in small containers; the mycelium, or vegetative portion, formed a mat on the surface of the medium that contained the penicillin in solution. The process was difficult to operate and required a large labour force to inoculate and harvest the containers.
Penicillin production was revolutionized by the discovery that a strain of Penicilium chrysogenum mold ( isolated from an overripe cantaloupe ) would produce high yields when grown in deep culture. The growth of a mold is aerobic (it requires air), and in surface culture the growth and consequent production of antibiotic is limited by the rate at which air can diffuse into the medium. In submerged or deep culture, the mold is grown in large tanks supplied with a continnous flow of sterile air.
Though the medium used in fermentation varies for the particular antibiotic being produced, all contain a source of carbon (which may be lactose or glucose); nitrogen (in the from of ammonium salts ); and trace elements ( such as phosphorus, sulfur, magnesium, iron, zinc, and copper ). If phenylacetic acid is added, the mold will utilize it and produce benzylpenicillin ( penicillin G ), whereas, if phenoxyacetic acid is added, phenoxymethylpenicillin ( penicillin V ) is obtained. In addition, corn-steep liquor may be added for penicillin production, and soybean meal and dried distiller’s residues for streptomycin; these help increase the yield of product. (Corn-steep liquor is prepared by steeping cleaned corn grain in water for about 40 hours at about 48 ºC [118 ºF]; the liquor is drawn off and evaporated at reduced pressure to a suitable concentration - about 55 percent solids. Corn-steep liquor stimulates penicillin formation due to certain amino acids, minerals, and precursors that it contains.) Before use the medium - as well as the fermenter and associated equipment - is steam sterilized, as bacterial contamination can destroy the antibiotic.
A large volume of concentrated, actively growing fungal suspension is required for the main fermenting tanks, to keep the fermentation time to a minimum. This is obtained in three stages. First, the selected culture is transferred from cold storage to a culture medium (agar) to produce an initial inoculum. This inoculum is then cultured in shake flasks to give a suspension. Finally, the suspension is grown in seed tanks in the plant for 24-28 hours to the desired volume and concentration before transfer to the main fermenters. Fermentation is continued for three to five days, during which the vessel is cooled - to keep the temperature between 23-27 ºC (73-81 ºF) - and stirred and aerated with sterilized air. The introduction of large volumes of air causes frothing, whish is controlled by the addition of antifoams such as lard oil, octadecanol, or silicones. When fermentation is complete, the mycelium is removed on a rotary filter and the penicillin extracted into an organic solvent (such as butyl acetate or methyl isobutyl ketone), after acidification. The free acids of penicillins are generally unstable and are converted into a metal salt by extraction with alkali, followed by freeze-drying of the extract, or by addition of a concentrated solution of a metal salt such as potassium acetate, whereby the potassium salt of the penicillin is precipitated. All products that are to be administered by injection are sterilized by passage through a sterilizing filter, followed by freeze-drying, precipitation, or crystallization under sterile conditions.
Antioxidants
There is a group of vitamins, minerals, and enzymes called antioxidants that help protect our body from the formation of free radicals. Free radicals are atoms or groups of atoms that can cause damage to our cells, impairing our immune system and leading to infections and various degenerative diseases. There are three known free three radicals-the superoxide, the hydroxyl, and peroxide. They may be formed by exposure to radiation and toxic chemicals, overexposure to the sun’s rays, or though the action of various metabolic processes, such as the use of stored fat molecules for energy.
The way in which free radicals are normally kept in check is by the action of free radical scavengers that occur naturally in the body. These scavengers neutralize the free radicals. Certain enzymes serve this vital function. Four important enzymes that neutralize the free radicals naturally are superoxide dismutase (SOD), methione reductase, catalase, and glutathione peroxidase. The body makes these as a matter of course. In addition, the work of these scavenger enzymes can be supplemented by a diet rich in antioxidants such as vitamins A, E, and C, the mineral selenium, and other nutrients. These antioxidants are also scavengers, gobbling up the free radicals particles.
If the diet is inadequate in the appropriate antioxidants, or if the system is overwhelmed by free radicals, you can take the following supplements to aid the body in destroying free radicals.
Vitamin A is necessary for healthy mucous cells and promotes germ-killing enzymes. Beta-carotene and vitamin A destroy carcinogens (cancer-producing substances).
In addition to increasing interferon production, vitamin C is a potent stimulator of T- effector cell activity and is also a very powerful antioxidant. Vitamin C reduces lipid production in the brain and spinal cord, which frequently incur free radical damage. These sites can be protected by significant amounts of vitamin C, which is needed to cross the blood-brain barrier. Vitamin C acts as a more potent free radical scavenger in the presence of a bioflavonoid called hesperidin.
Vitamin E is a powerful antioxidant that prevents fat and cell membrane rancidity and protects the coating around each cell. Vitamin E improves oxygen utilization and enhances immune response. New evidence suggests that zinc is needed, to maintain normal blood concentrations of vitamin E.
GLA is a key regulator of T- lymphocyte function in the body. GLA can be made from linoleic acid, which is found in vegetable oils, but if zinc, magnesium, and vitamins C, B6 (pyridoxine), B3 ( niacin ), and A are deficient, the conversion may be blocked. Hydrogenated vegetable oils, margarine, or a high-fat diet can also inhibit this important conversion to GLA. Evening primrose oil, black currant seed oil, and borage oil are the main sources of pre-formed GLA.
The sulphur - containing amino acid glutathione is used by the liver and the lymphocytes to detoxify chemicals and germ poisons. Cysteine is a powerful detoxifier of alcohol, tobacco smoke, and environmental pollutants, all of which are immune suppressors. This powerful antioxidant rids the body of free radicals, protecting it from the harmful effects of metals, drugs, cigarette smoke, and alcohol.
A partner/ synergist with vitamin E, selenium is essential for the key enzyme, glutathione peroxidase (each enzyme molecule contains four selenium atoms). It stimulates increased antibody response to germ infection.
SOD is an enzyme. A healthy body produces nearly 5 million units of SOD and its partner catalase daily. SOD revitalizes the cells and reduces the rate of cell destruction. It removes the most common free radical, superoxide. SOD also aids in the body’s utilization of zinc, copper, and manganese. Free radical production increases with aging, while SOD levels are reduced. The potential of SOD to slow the aging process is currently being explored. The SOD supplement in pill form must be enteric coated, that is, coated with a protective substance that allows the SOD pill to pass intact through the stomach acid into the small intestines to be absorbed. A supplement should be able to provide a daily amount of about 5 million units or higher. SOD naturally occurs in barley grass, broccoli, Brussels sprouts, cabbage, wheatgrass, and most green plants.
This product contains large amounts of antioxidants to aid the body in destroying free radicals.
Bee By-Products
Bee Pollen and Honey
Pollen is a fine powderlike material produced by the anthers of flowering plants, and gathered by the bee. Bee pollen contains the B-complex vitamins, vitamin C, amino acids, polyunsaturated fatty acids, enzymes, carotene, calcium, copper, iron, magnesium, potassium, manganese, sodium, and protein (10-35 percent). Bee pollen, bee propolis, and honey have an antimicrobial effect. Honey is produced by the bee when plant nectar, which is a sweet substance secreted by flowers, is mixed with bee enzymes.
Honey varies in color and taste depending on the origin of the flower and nectar. It contains 35 percent protein (one-half of all the amino acids), and is considered to be a complete food. It is a highly concentrated source of essential nutrients, containing large amounts of carbohydrates (sugars), the B-complex vitamins, vitamins C, D, and some minerals. It is used to promote energy and healing. Two tablespoons daily is sufficient. It is twice as sweet as sugar and, therefore, not as much is needed. Only unfiltered, unheated, unprocessed honey should be purchased.
Diabetics and hypoglycemics should be careful when consuming honey and its by-products. The blood sugar reacts to these substances as it would to refined sugars. However, tupelo honey contains more levulose than any other honey and is absorbed at a slower rate so some hypoglycemics can use this type sparingly. If you are hypoglycemic, check with your health care provider.
Do not feed honey to infants under one year of age, as they are more prone to develop botulism.
Bee Propolis
Propolis is a resinous substance collected from various plants by bees; it is not made by bees. It is used together with beeswax in the construction of hives. As a supplement, it is an excellent aid against bacterial infections. A Soviet scientist stated that bee propolis stimulates phagocytosis, which helps the white blood cells to destroy bacteria. Soviet surgeons often fed honey to their patients before surgery as a precaution against infection.
Bee propolis is also good as a salve and for abrasions and bruises because of its antibacterial effect. Reports proclaim good results against inflammation of the mucous membranes of the mouth and throat, dry cough and throat, halitosis, ulcers, and acne, and for the stimulation of the immune system.
Be sure that all products from the bee are fresh and tightly sealed. It is best to purchase these products from a manufacturer who specializes in bee products. When used for allergies, it is best to obtain bee products that are produced within a ten-mile radius. This way, those with allergies get a minute dose of pollen to desensitize them to the local pollen in the area.
Iron
Perhaps the most important of its functions is its production of hemoglobin and oxygenation of red blood cells. Iron is the mineral found in the largest amounts in the blood. This mineral is essential for many enzymes, and is important for growth in children and resistance to disease. Iron is also required for a healthy immune system and for energy production. Vitamin C can increase iron absorption as much as 30 percent.
Iron deficiency symptoms include brittle hair, nails that are spoon-shaped or that have ridges running lengthwise, hair loss, fatique, pallor, dizziness, and anemia.
Sufficient hydrochloric acid (HCI) must be present in the stomach in order for the iron to be absorbed. Copper, manganese, molybdenum, vitamin A, and the B-complex vitamins are also needed for complete iron absorption.
According to Journal of Orthomolecular Medicine, iron utilization is impaired by rheumatoid arthritis and cancer and will result in anemia despite adequate amounts of iron stored in the liver, spleen, and bone marrow. The journal also states that iron deficiency is more prevalent in those suffering from candidiasis and chronic herpes infections.
Excess iron build-up in the tissues has been associated with a rare disease known as hemochromatosis, a disorder that causes bronze skin pigmentation, cirrhosis, diabetes, and heart disorders.
Sources
Iron is found in eggs, fish, liver, meat, poultry, green leafy vegetables, whole grains, and enriched breads and cereals. Other food sources include almonds, avocados, beets, blackstrap molasses, brewer’s yeast, dates, egg yolks, kelp, kidney and lima beans, lentils, millet, parsley, peaches, pears, dried prunes, pumpkins, raisins, rice and wheat bran, sesame seeds, and soybeans.
Warning
Excessive amounts of zinc and vitamin E interfere with iron absorption. Those who engage in strenuous exercise and who perspire heavily deplete iron from the body. Because iron is stored in the body, high iron intake can cause problems. Increased iron in the tissues and organs leads to the production of free radicals and increases the need for vitamin E, an important antioxidant (free radical scavenger).
An iron deficiency may result from intestinal bleeding, excessive menstrual bleeding, a diet high in phosphorus, poor digestion, a long-term illness, ulcers, prolonged use of antacids, excess coffee or tea consumption, and causes other than a nutrient deficiency. A doctor should investigate these symptoms before prescribing iron supplements. In some cases, doctors have discovered that a vitamin B6 or B12 deficiency is the underlying cause of the anemia.
According to a 1988 issue of Journal of Orthomolecular Medicine, you should not take extra iron if you have an infection. Because bacteria require iron for growth, the body stores iron and does not utilize it when there is an infection.
Antiinfective drugs
Antibiotics
Antibiotics are substances produced by microorganisms that at low concentrations kill or inhibit other microorganisms. They are produced commonly by soil microorganisms and probably represent a means by which organisms in a complex environment, such as soil, control the growth of competing microorganisms. The microorganisms that produce antibiotics useful in preventing or treating disease include bacteria (Bacillus and Streptomyces) and fungi (Penicillium, Cephalosporium, and Micromonospora). Antibiotics can inhibit microbes by inhibiting the synthesis of the cell wall.
Other antibiotics, such as the aminoglycosides, chloramphenicol, erythromycins, and clindamycin, inhibit protein synthesis in bacteria. The basic process by which bacteria and animal cells synthesize proteins is similar, but the proteins involved are different. Those antibiotics that are useful as antibacterial agents ( selectively toxic ) utilize these differences to bind to or inhibit the function of the proteins of the bacterium, thereby preventing the synthesis of new proteins and new bacterial cells. Antibiotics such as polymyxin B and colistin bind to phospholipids in the cell membrane of the bacterium and interfere with its function as a selective barrier; this allows essential macromolecules in the cell to leak out, resulting in the death of the cell. Because other cells, including human cells, have similar or identical phospholipids, these antibiotics are somewhat toxic. One antibiotic, rifampin, interferes with RNA synthesis in bacteria by binding to a subunit on the bacterial enzyme responsible for duplication of RNA. Since the affinity of rifampin is much stronger for the bacterial enzyme responsible for duplication of RNA. Since the affinity of rifampin is much stronger for the bacterial enzyme than for the mammalian enzyme, the mammalian cells are inaffected at therapeutic dosages.
Bacteria, unlike animal cells, have a cell wall surrounding a cytoplasmic membrane. Production of the cell wall involves the partial assembly of wall components inside the cell, transport of these structures through the cell membrane to the growing wall, assembly into the wall, and finally cross-linking of the strands of wall material. Antibiotics that inhibit the synthesis of a cell wall have a specific effect on one or another phase. The result is an alteration in the cell wall and in shape of the organism and the eventual destruction of the bacterium.
The penicillins and cephalosporins both have the unique structure, a ß-lactam ring, that is responsible for their antibacterial activity. The ß-lactam ring interacts with proteins in the cell responsible for the final step in the assembly of the cell wall. Thus, the mechanism of action is identical for both antibiotics; however, the basic chemical structure of the penicillins and cephalosporins differs in other respects, resulting in some difference in pharmacokinetics and the spectrum of antimicrobial activity.
The penicillins can be divided into two groups: the naturally occurring penicillins (penicillin G and penicillin V) and the semisynthetic penicillins. The semisynthetic penicillins are produced by growing the mold Penicillium under conditions whereby only the basic molecule (6-aminopenicillanic acid) is produced. By adding certain chemical groups to this molecule, several different semisynthetic penicillins are produced that vary in resistance to degradation by B- lactamase (penicillinase), an enzyme that specifically breaks the B-lactam ring, thereby inactivating the antibiotic. In addition, the antimicrobial spectrum of activity and pharmacological properties of the natural penicillins can be changed and improved by these chemical modifications.
The naturally occurring penicillins are important chemotherapeutic agents. Even after 40 years of use they are still the drugs of choice for treating streptococcal sore throat, tonsillitis, pneumococcal pneumonia, endocarditis caused by some streptococci, syphilis, gonorrhea, meningococcal infections, and infections caused by some anaerobic organisms. Several microorganisms, most notably the staphylococci, developed resistance to the naturally occurring penicillins, which led to the production of the penicillinase-resistant.
To extend the usefulness of the penicillins to the treatment of infections caused by gram-negative rods, the broad-spectrum penicillins (ampicillin, amoxicillin and carbenicillin) were developed. These penicillins are sensitive to penicillinase, but they are useful in treating urinary tract infections caused by gram-negative rods as well as in treating typhoid and enteric fevers.
The extended-spectrum agents ( mezlocillin, azlocillin, and piperacillin ) are unique in that they have greater activity against gram- negative bacteria, including Pseudomonas aeruginosa. They have decreased activity, however, against penicillinase-resistant Staphylococcus aureus.
The penicillins are the safest of all antibiotics. The major adverse reaction associated with their use is hypersensitivity, with reactions ranging from a rash to bronchospasm and anaphylaxis. The more serious reactions are uncommon.
The cephalosporins are produced by Cephalosporium acremonium. Modification of the basic molecule (7-aminocephalosporanic acid ) has resulted in three generations of cephalosporins. The first-generation cephalosporins have a range of antimicrobial activity similar to the broad-spectrum penicillins. The second-generation cephalosporins have greater ß-lactamase stability than the earlier cephalosporins, and their antibacterial spectrum has been extended to include greater activity against additional species of gram-negative rods. They have decreased activity, however, against gram-positive bacteria. Like the penicillins, the cephalosporins are relatively nontoxic. Because the structure of the cephalosporins is similar to that of penicillin, hypersensitivity reactions can occur in penicillin-hypersensitive patients.
Cycloserine, an antibiotic produced by Streptomyces orchidaceus, is a structural analogue of the amino acid D-alanine, and it interferes with enzymes necessary for incorporation of D-alanine into the bacterial cell wall. It is rapidly absorbed from the gastrointestinal tract and penetrates most tissues quite well; high levels are found in urine. It is used in the treatment of tuberculosis and in some urinary tract infections.
Bacitracin is produced by a special strain of Bacillus subtilis. Because of its toxicity its use is limited to the topical treatment of skin infections caused by streptococci and staphylococci and for eye and ear infections. Vancomycin, an antibiotic produced by Streptomyces orientalis, is poorly absorbed from the gastrointestinal tract and is usually given by intravenous injection. It is an excellent antibiotic for the treatment of serious staphylococcal infections caused by strains resistant to the various penicillins.
The aminoglycosides (streptomycin; neomycin; paromomycin; kanamycin and its derivative, amikacin; tobramycin; netilmicin; and spectinomycin) are produced by Streptomyces species. Gentamicin is produced by the molds Micromonospora purpurea and M. echinospora. All of the aminoglycosides inhibit protein synthesis, although spectinomycin, which has a different structure, does so by a mechanism different from the other aminoglycosides. The aminoglycosides are poorly absorbed from the gastrointestinal tract, so, with some exception, they are given by intramuscular injection. Neomycin is toxic and is used topically. Because it is poorly absorbed from the gastrointestinal tract, paromomycin is used in the treatment of protozoal infections of the intestinal tract.
Streptomycin was the first of the aminoglycosides to be discovered and the second antibiotic used in chemotherapy. One of its more important uses had been as part of the combined therapy for tuberculosis. It still has some use in combination with penicillin for treating infections of heart valves (endocarditis) and with tetracyclines in the treatment of plague, tularaemia, and brucellosis.
Kanamycin is used in the treatment of septicemia (blood poisoning ), meningitis, and urinary tract infections caused by gram-negative bacteria. Because many organisms are resistant to its effects, however, kanamycin is now being replaced by other drugs. Gentamicin, tobramycin, netilmicin, and amikacin are similar in their range of antimicrobial activity. They are effective against infections caused by staphylococci and gram-negative bacteria, including Pseudomonas aeruginosa.
Dermatological pharmacology
Introduction
The skin consist of layers called the epidermis and certain appendages such as sweat glands, sebaceous glands (which secrete an oily substance), hair, and nails. There also exists a subcutaneous layer beneath the dermis. The outermost layer of the epidermis is termed the stratum corneum. It consist principally of dead epithelial cells that are filled with a protein, keratin, which waterproofs and toughens the skin. Underlying the stratum corneum are layers comprising granular spinous cells, keratinocytes, melanocytes, and Langhan¢s cells. The dermis, which is below the epidermis, comprises connective tissue and a number of different cell types, it maintains and nourishes the epidermis through its network of capillaries and lymphatic vessels, sweat glands and hair follicles, which originate in the dermis and penetrate the stratum corneum of the epidermis, a potential route of penetration by drugs or chemicals. The subcutaneous layer is the innermost layer and is composed of loose connective tissue and many fat cells. It provides some degree of insulation and is a location for food storage and the site for subcutaneous injection.
Few chemicals or drugs are absorbed rapidly from intact skin. In fact, the skin effectively retards the diffusion and evaporation even of water except through the sweat glands. There are, however, a few notable exceptions (e.g., certain types of nerve gases, as well as insecticides, scopolamine, and nitroglycerin), and instances where a penetration enhancer (e.g., dimethyl sulfoxide) serves as a vehicle for the drug.
Several factors affect the transport of drugs through the skin (percutaneous) once they are applied topically. The absorption of drugs through the skin is enhanced if the drug is highly soluble in the fats (lipids) of the subcutaneous layer. The addition of water (hydration) to the stratum corneum greatly enhances the percutaneous transport of corticosteroids (anti-inflammatory steroids) and certain other topically applied agents. Hydration can be effected by wrapping the appropriate part of the body with plastic film, thereby facilitating dermal absorption. If the epithelial layer has been removed (denuded) by abrasion or burns, or if it has been affected by a disease, penetration of the drug may proceed more rapidly. A drug will be distributed (partitioned) between the solvent and the lipids of the skin according to the solubility of the solvent in water or lipids. Topical absorption of drugs is facilitated when they are dissolved in solvents that are soluble in both water and lipids. Highly water-soluble polar molecules, which have a lesser tendency to solubility in lipids, essentially cannot be absorbed percutaneously. Thus, a drug penetrates the skin at a rate determined primarily by its tendency to dissolve in water, or lipids, or both.
Topically applied drugs
Topical application of drugs provides a direct, localized effect on a specific area of the skin. When drugs are applied topically to the skin, they may be dissolved in a variety of vehicles or formulations, ranging from simple solutions to greasy ointments. The particular type of dermal formulation used (powder, ointment, etc.) depends, in part, on the type of skin lesion or disease process.
Topically applied medications can relieve itching, exert a constricting or astringent action on the pores, or dissolve or remove the epidermal layers. Other pharmacologic effects from topically applied drugs include antibacterial, anti-inflammatory, antifungal, and antiparasitic actions. Analgesic balms (e.g., wintergreen oil or methyl salicylate) have been used topically to relieve minor muscle aches and pains.
Drugs may also be applied to mucous membranes, including those of the conjunctiva, mouth, nasopharynx, vagina, colon, rectum, urethra, and bladder. They may either exert a local action or be absorbed into the bloodstream to act elsewhere, Examples include nitroglycerin, which is absorbed from under the tongue (sublingually) to act on the heart and relieve anginal pain, and trifluoperazine, which is a tranquilizer sometimes taken in suppositories. Nasal insufflation, or inhalation, involves the local application of a drug to the mucous membranes of the nose to achieve a systemic action. This represents an effective delivery route of antidiuretic hormone and its analogues in the treatment of diabetes insipidus. Relatively unsuccessful efforts have been made to get hormones of larger weight, such as insulin or growth hormone, to penetrate the mucous membranes of the nasal cavity, thereby avoiding the need to inject such hormones. Although certain medications can be applied successfully to mucous membranes, the topical application of drugs to the skin represents a more widespread and therapeutic method of administration. Although certain antibiotics are used topically, their use should be restricted to the most superficial skin infections. Antibiotics are more often administered systemically. The tetracyclines have been used topically for the treatment of acne. Skin disorders caused by fungi can be treated with either antibiotics or antifungal drugs.
Cardiovascular disease
In cardiac failure, cardiac glycosides are used for their inotropic effect on the heart, but vasodilators and drugs that increase urine flow are also helpful. The reduced cardiac output resulting from heart failure leads to an increase in pressure in the veins and also to accumulation of tissue fluid (edema). Vasodilators, such as the calcium antagonist nifedipine, dilate the veins and thus lower the venous pressure, and they also increase the cardiac output by reducing the resistance of the arterial system. Diuretic drugs are used to reduce the amount of tissue fluid, but they can also have a beneficial vasodilator effect. These drugs are used in treating high blood pressure as well.
High arterial blood pressure, which is produced by excessive constriction of small arteries, is often treated with drugs. Some drugs that lower blood pressure (hypotensives) inhibit the function of the sympathetic nervous system in various ways. Hypotensive drugs include methyldopa and clonidine, which probably work at the level of the central nervous system; reserpine and guanethidine, which prevent the release of norepinephrine by sympathetic nerves; adrenoceptor-blocking drugs (e.g., propranolol, which lowers blood pressure by reducing the cardiac output; and prazosin, which blocks the vasoconstrictor action of norepinephrine). Calcium antagonists also have a use in treating hypertension, as do other vasodilators such as hydralazine. A different approach, developed in the late 1970s, consists of using an inhibitor of adrenocortical extract (captopril), thus blocking the formation of angiotensin II. This is very effective in certain types of hypertension in which rennin secretion is increased. Most antihypertensive drugs have a variety of unwanted effects, such as drowsiness, dizziness on standing (due to an excessive postural fall in arterial pressure), impotence, and allergic reactions. Though fairly often, side effects are a serious problem because of the long-term nature of antihypertensive therapy, and better drugs are constantly being sought.
Migraine is a common condition associated with severe headaches that are believed to result from excessive dilation of the arteries in the membranous covering (meninges) surrounding the brain. The cause is not known, but it is believed to involve the local release of a substance called serotonin. Ergotamine, which comes from a fungus (ergot) that infests cereal crops and has a powerful vasoconstrictor effect, is widely used to treat migraine. Accidental poisoning with the ergot fungus produces many symptoms associated with excessive vasoconstriction, including brain disturbances and gangrene, but they do not generally occur when it is used therapeutically. Other antimigraine drugs include propranolol and calcium antagonists. Tests have shown them to be effective, but it is not clear how they work.
Partial occlusion of the coronary vessels by fatty deposits (atheroma) or blood clots may result in angina pectoris, a pain that occurs when the blood supply to the heart is inadequate for its needs. Vasodilator drugs, particularly nitroglycerine tablets and calcium antagonists, are often used to relive this condition. They work in part by dilating arteries and veins, which reduce arterial blood pressure and cardiac output, thereby lowering the work and oxygen consumption of the heart. They also have some effect on the coronary vessels themselves and may direct blood toward the regions in which the flow is impaired. Propranolol is also effective because it reduces the rate and force of the heart, thus lowering its oxygen requirement.
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