Chapter Ten Autocoids and Antipyretic, Analgesic and Anti-inflammatory Drugs

Autocoids are the common name of materials that are widely spreaded and general biology (pharmacology) activity in the animal body, and are also called self-regulating medicinal agents. Under the normal situation, they exist in the form of their prosoma or stored, however, when they are activated or released on the influence of some factors, they would produce wide and intense biological effect. Autocoids are usually generated locally, and only active to neighborly histiocyte, and most of them have their own special receptors, and also called local hormone. Another difference to neurotransmitter and hormone is that organism has no special organ or tissue to generate them. Some autocoids are used as medicine directly to cure diseases, such as prostaglandin. People are interested in the fact that their functions can be adjusted by relative medicines, such as histamine. And some other autocoids, which take part in certain pathology processes, by modeling or rivalry their functions, or interrupting their metabolic conversion to make clear their physiology or pathology meaning, which will help to discover new medicines or interpret mechanism of action, such as PG. autocoids play an important role in medical contain endogenous amines (histamine, 5-HT), arachidonic acid derivative (PG, leukotriene), polypeptides(angiotonin, bradykinin, kallidin, p-material) and so on. At present, histamine and PG have some veterinary clinical significance. Antipyretic, analgesics and anti-inflammatory drugs is a large kind of medicines that can suppress PG synthesis, and can be regard as PG antagon, so they will be discussed in this chapter.

Section One Histamine and Antihistamine Drugs

Allergie is also called anaphylactic response, which a complex immunopathogenesis reaction process, with the nature of antigen- antibody response. Active histiocyte in animal body generate special antibody after recognition, reaction and dealing the foreign objects (such as antigen, chemical material or medicines). Antigen-antibody response will happen when the same antigen enters the body for the second time, and the sensitive animals will show serious allergies, even allergic shock. Anaphylactic response has four types, they are quick happening anaphylactic response ( type ), mainly show inflammatory medium released; cytotoxicity reaction (type ), mainly show histiocyte damage and dissolve; antigen-antibody complex reaction (type ), mainly show antigen-antibody complex deposit in tissues and late happening anaphylactic response (type ) mainly induced by allergize T-cell. In the veterinary clinic, there usually are four types of used antiallergic drugs, and each has their own actions and applications. Glucocorticoid can depress several processes of immunoreactive and are suitable for all kinds of anaphylactic response, however, its action does not always happen immediately. Adrenomimetic can be used to the anaphylactic response that accompany with the release of histamine and slow reacting substance of anaphylaxis, but it can induce pyknocardia or cardiac dysrhythmia. Calcium can lower blood capillary permeability, reduce leak, lighten subinflammation and dropsy, and usually be used as ancillary drug to cure

anaphylactic response. Antihistamine drug introduced in this section, can release or eliminate anaphylactic symptom by rivalry antihistamine action, and can be used to cure type anaphylactic response and relieve the symptom caused by type and type anaphylactic response, so it is a kind of important antiallergic drugs. However, this kind of medicines cant eliminate all the anaphylactic symptoms, and have no antagonism to anaphylactic response of animals releasing little histamine, such as cattle and rabbits.

ONE Histamine
Histamine is formed by histidine decarboxylation. Each organism has different ability in generating histamine. There are high histamine concentrations in skin, lung and intestinal mucosa that contact with outside. Most of histamine are in the form of calparine-proteinum compounds, and stored in granula of organizational mastocyte and hematological basicyte together with proteolytic enzyme and other autocoids, so this part of histamine renovate slowly. epidermal cell, gastric mucosa cell and neuron can also generate and store histamine, and this part can renovate quickly. Terminal metabolin of histamine in body is N- Methylimidazoleacetic, conjugate of imidazoleacetic acid and ribose phosphate and methylhistamine. The factors which can induce histamine to be released from storage granula include: the factors that can make Magnocellular cAMP depress and cGMP concentration increase, such as acetylcholine, -receptor agonist, -receptor antagonist; factors that destroy mastocyte membrane directly, such as the materials take positive charge (alkalinity): Exogenous material contains morphine, polymyxins, polypeptide, and endogenous compounds contains bradykinin, kallidin and some other basic polypeptide, some poison and toxin (such as snake venom) also can directly induce histamine release; immune induced type anaphylactic response. Histamine release always combines with Ca2+ concentration increase of mastocyte, and the other materials stored in granula release together with histamine, and these materials can also cause significant biological response. In addition, destroying Magnocellular cellular membrane can promote the generation of other autocoids with similar adverse effect (such as PG). in hence, histamine release is only part of physiologic reaction induced by mastocyte degranulation. Just as some drugs can induce mastocyte degranulation, the drugs used to cure or prevent type anaphylactic response, are always the ones that can lessen mastocyte degranulation. Ananaphylaxis function of glucocorticoids is based on its action to -receptor and anti-inflammatory action aimed directly on other inflammatory medium. Except for taking part in inflammation and anaphylactic response, histamine also has interactionwith some drugs. It can adjust gastral secretion. In central nervous system, it is a neurotransmitter; some foreign compounds have similar structure with histamine, and also have the function of expand small vessels, shrink SM except vessels, stimulate gastric follicles secretion. Histamine biology function is implemented by receptors on target cells and periphery tissues have two types of histamine receptors, that is H2 and H2 receptors. Distribution and biology functions of two types of receptor demonstrated in tab.10-1. central nervous system might have H3 receptor which needs further study in veterinary clinical.

Tab. 10-1 disposition and application of histamine receptor Acceptor type H1 critical organ smooth muscle: bronchus stomach intestine Uterus vasa sanguinea integumenti communis cardiac muscle Aschoff-Tawara knot Acceptor type H2 critical organ gastric wall gland blood vessel cardiac muscle atrionector physiological effect Shrink Shrink Shrink Expand shrink strengthen conduction step down physiological effect Secrete increased Broaden Cardiac shrink strengthen cardiac rhythm speed up pathology effect Convulsion, anhelation diarrhea Permeability increase,moisture content in blood vessel leak

pathology effect blood pressure descend, circulatory collapse

Medical histamine is artificial synthesis, and has been used in human medicine, but there is no reports in the veterinary clinic.

TWO Antihistamine Drugs

You can use many kinds of measures to prevent or treat cacoethic biology consequence caused by histamine, for instance, prevent or lessen Histamine released from cells, block up histamine combining together with receptors, antagonize the biological effect of histamine. Antihistamine drug only point at the drug which affect histamine receptor and block up Histamine combining together with receptor. Corresponded with histamine receptors, this kind of drug is divided to H1-blocker (traditionary Antihistamine drug) and H2-blocker (new-style antihistamine drug).

I. H1 receptor-blockers
The elementary structure of H1-blocker is ethylamine and is similar to that of histamine (as follows).This is the imperative structure which compete with specified receptor for histamine. The difference between X and side chain will decide drug's intensity of effect and type of side effect. This kind of drug can selectivity oppose the action of vasodilating agent, smooth muscle spasm and so on, which is resulted from the excitement of H1 receptor due to histamine, and it is used for allergic disorder of skin and mucous membrane, for instance, urticaria and contact dermatitis. In clinic, it is used to question negative abnormal disease which is related with histamine, such as eczema, trophicity or gravidity laminitis and emphysema. This kind of drug's absorption is good and it will be effective in 30min after medication. It is distributed extensively, and can get into the central nervous system and it has side effects of inhibiting the centre system. It may complete the metabolism in liver, the metabolite is excreted through urine and the effect will last 3~12h.

The commonly used drugs are diphenhydramine, promethazine, chlorphenamine maleate, chlorphenamine, tripelennamine, astemizole and so on. The intension and duration of antianaphylaxis action are chlorphenamine maleate promethazine diphenhydramine. The inhibition to the center system is promethazinediphenhydraminechlorphenamine maleate.

Diphenhydramine
Physico-chemical properties It is a man-made synthetic product. Its hydrochloric acid phlegmasia is crystallinity powder. It is extremely easy to be dissolved in water. The composite of diphenhydramine and Aminophylline is dimenhydrinate. Action and applicationThis product can contradict or weaken the action of Histamine expanding blood vessel, contracting stomach intestine and bronchus smooth muscle, and the action of calming, opposing choline, stoping throwing up and slightly anesthetizing. It will be effective quickly and the duration is short. It is used for anaphylactic disease of skin mucous membrane, for instance, skin tickling, oedema, neurodermitis which is resulted from urticaria, serum sickness, eczema and contact dermatitis; it is also used for dizziness and vomiting of transporting small animals; The disease of tissue damage accompanied with histamine release, for instance, burn, frostbite, eczema and septimetritis. It is also used for allergic shock, diarrhea and laminitis which is resulted from forage hypersensitiveness, adjunctive therapy drug for organophosphate poisoning. It also has determinate curative effect for irritability stomach intestine spasm and diarrhea but the effect for irritability bronchospasm is bad.

Promethazine (Phenergan)
Action and applicationThe effect of antihistamine is stronger than diphenhydramine, and will last more than 24h. It also has the effect of lowering body temperature, stopping throwing up and fairly doughty action of central inhibition. It may strengthen the effect of anesthetic, sedative and analgesic. The application is similar to diphenhydramine. It is stimulative but not suitable for hypodermic.

Chlorphenamine Maleate
Its name is chlortrimeton, too. Man-made synthetics. Its effect is stronger and longer than diphenhydramine, but the side effect is of central inhibition and lethargy is fairly light. The application is similar to diphenhydramine.

Astemizole (Hismanal)
It is a new type H1 receptor blocker. The effect of antihistamine is strong and durative, and the drug effect may last as long as 24h. It doesn't penetrate to blood-brain barrier, doesn't have the action of center calm but has strong effect for anti-choline. It is used for Sensitization dermatitis, anaphylactic conjunctivitis, urticaria and other anaphylactic treatment.

II. H2 receptor-blocker
Different from H1-blocker, H2-blocker retains Histamine's imidazole ring in structure and the change of side chain is big. Now it is used widely in veterinary clinic, and the fairly new drug are Cimetidine, Ranitidine, Famotidine and Nizatidine. The gastrin in stomach promotes the formation and release of Histamine. Histamine affects receptor H2 and increases production quantity of cAMP in cell. cAMP makes protein kinase activate carbonic anhydrase to catalysis CO2 and H2O to generate water. The latter decollements and releases H+ to increase the secretory volume of gastric acid. The H2-blocker has upstair selectivity to receptor H2 and it can effectually struggle for receptor H2 in gastric wall glandular cell to block up Histamine combining together with it. H2-blocker will restrain gastric acid secreting and restrain various kinds of factors which cause gastric acid secretion, for instance, gastrin, insulin, hydroxycholine drug's action. With the help of receptor H1, H2-blocker has puissant inhibitory action on foundational gastric acid and food revulsive gastric acid secretion(volume and acidity). Veterinary surgeon clinically this kind of drug is mainly used for gastritis; stomach, abomasum and duodenal ulcer; erosive gastritis which is resulted from stress or drug and so on. This kind of drug is absorbed quickly and cannot be affected by food completely(except for horse). But the first pass effect is big. Cimetidine and Ranitidine's bioavailability are 95% and 81% in order in dog's oral medication. This kind of drug's liposolubility is lower than H1-blocker and it can't reach through blood-brain barrier and doesn't have the side effect of central inhibition. It is mainly canceled by origin shape from kidney. The half life is about 2~3h.

Cimetidine
Its name is Tagamet, Altramet, too. This is man-made synthetics. Action and applicationThis product is fairly strong H2-blocker which can lower the secretory volume of gastric juice and the concentration of H+ in gastric juice. It also can restrain pepsin and trypsogen secreting and has no effect of opposing choline. It is mainly used to cure gastrointestinal ulcer, gastritis, pancreatitis and acute gastrointestinal (ahead of enteron)bleeding. This product can be used together with hepatic microsomal enzyme and restrain the activity of enzyme. It can lower hepatic blood flow and interfere with the absorption of other drugs.

Ranitidine
Its name is ran., zantac, too. This is man-made synthetics. The action of this product restraining gastric acid secretion is 5 times stronger than cimetidine and adverse effect is light and the duration of effect is longer. This product competes with other drugs for tubular secretion in kidney. The application is similar to cimetidine.

Section Two Prostaglandin

Prostaglandin is the derivant of prostanoic acid and belong to eicosanoids compound. It was first discovered from personal semen and was confirmed from sheep spermary. Eicosanoids is the generic name of a series of ramification of phospholipid and includes prostaglandins, leukotrienes and its analogue. Each kind of prostaglandin's denomination is to add English letter (representation type) and subscript number (express the number of double bond of side chain), some also have Greece character after figures (indicate the direction of side chain), for instance, PGF2.

I. Biosynthesis and decomposition

The eicosanic acid usually isnt stored in cell, but stimulated by the factors of machinery or chemistry injury, hormone, immunity, hypoxia and so on to be formed instantaneously. The raw material which generates eicosanoids comes from cell membrane's phospholipid and fatty acid is catalysised to release by the activatory phospholipases in cell membrane. Arachidonic acid is the most consequential eicosanoids's prosoma fatty acid. The arachidonic acid which is released from membrane gets into cell to generate prostaglandin or leukotriene by the action of enzyme. For instance, bacterial endotoxin ester polysaccharide (LPS) activate phospholipase A2 (PLA2) to release arachidonic acid from the acyl position of membrane phospholipid and at the same time also form one lysophosphatide (LPL). LPL is the raw material which form platelet activating factor (PAF). Arachidonic acid is metabolized into prostaglandin (PG), thromboxane (TX) and leukotriene (LT). The enzyme which catalysis prostaglandin's production is cyclooxygenase and resides in all cells of body. The enzyme which catalysis leukotriene's synthesis is lipooxygenase and mainly resided in platelet, white blood cell and lung cell. In the process of synthesis of prostaglandin, first arachidonic acid is metabolized into unstabilized intermediate cyclic endoperoxides PGG2 and PGH2 and the oxygen-derived free radicals which is harmful for tissue. Then cyclic endoperoxides is metabolized to generate end products quickly which are various kinds of prostaglandin. The different prostaglandins are respectively catalysised to form by different enzymes. For instance, prostaglandin isomerase is catalysised to form PGE2 and PGD2, prostaglandin reductases is catalysised to form PGF2, prostaglandin synthetase is catalysised to form prostacyclin PGI2 and thromboxane synthetase is catalysised to form thromboxane TXI2. Different tissue forms different prostaglandin. The medulla and cortex of lung, macrophage and kidney and the tissue of foetal pulmonary artery, lung, kidney, spermary, uterus and so on form PGE2. Vascular endothelial cell, kidney, lung and so on form PGI2. Cyclical platelet, lung and so on form TXA2. The catabolism of prostaglandin is very quick. In its generating local tissue, degradation and enzymolysis take place at the same time invariably. Liver is also a considerable metabolism location. Some dehydroxylase and reductases can change prostaglandin to slightly active or

inactive product. Except for PGI2, finally, all other prostaglandin are cleared from the cycle in lung. The half-life of prostaglandin is very short, for instance, TXA2's is only 30s, while other prostaglandins are no more than 5min. The effective duration of man-made prostanoid compound is longer than natural product, therefore it can be used for drug clinically.

II. Biologic action

Invariably prostaglandin plays a role through the accommodation of partaking other autoallergic active material, neurotransmitter and hormone. In many tissues, prostaglandin increase the production of cAMP by activating adenylate cyclase and it can adjust the concentration of Ca2+ in cells. It's extensional mechanism of action different from cell to cell on cellular level. Under physiological condition, prostaglandin mainly affects blood vessel and smooth muscle and participates in platelet agglutination, Inflammatory reaction, electrolyte affluxion, pain, febrile, nerve impulse, cell growth and so on. The action of prostaglandin to most body cell may be considered as protection. For instance, the prostaglandin of kidney can maintain the blood of kidney medulla and even does not scruple to cut down the filterability of glomerulus; the prostaglandin of gastrointestinal tract protects mucous membrane from being damaged by gastric acid; the prostaglandin of small intestine can cause looseness of bowels, which makes enteric cavity throw off noxious substances. Even pain and inflammation are also a kind of protective mechanism, Despite that it will be the healing target of many drugs when it is overaction. Many physiological (pharmacology) effect of the prostaglandin is often contradictory. Such as PGI2 and TXA2 are often generated at the same time, and their role is opposite to each other which is for balance physiological functions; the role of PGE2 and PGF2 is also antagonized each other, so that the environmental balance can be maintained. In general, PGF and PGEs tend to expand or chalasia smooth muscle, but PGD and TXA2 tend to anastole smooth muscle, see Table 10-2. Table 10-2 Major physiological action of prostaglandin in tissue organ uterus corepus luteum placenta prostaglandin PGF2 PGF2, PGE2 PGI, PGE action Musclecontraction of uterus Solution of corepus luteum vasodilatation Remaining blood current patefaction foetal blood vessel Hypotension,increasing blood flow of organ hypertension reduction blood flow of organ of to resist thrombosis effect abortionparturition

Artery (resistance vessel thrombocyte

PGEPGI PGF2

vasodilatation vasoconstriction

PGI TXA2

Inhibition coacervation thrombocyte

coacervation of thrombocyte ren stomach mucous membrane PGE PGE, PGI PGE vasodilatationdiuresis Depressing gastric acid secretion Increasing quantity of mucilage and ambi-carbonationpromotion form of epithelium Bronchi smooth muscle inflammation immunocyte nociceptive receptor hypothalamus PGE PGD, TXA2 PGE, PGD2 PGE PGE PGE chalasis contraction Increasing chemotaxis vasopermeability,

to promote thrombosis super-protection on hypotension Counteracting elcosis Counteracting elcosis

bronchodilatation bronchoconstriction inflammation immunoloregulation pain febrile

Stimulation or chemotaxis Depressing critical value Changing body temperature

III. Commonly used drugs

Prostaglandin has a wide range of hysiological (pharmacology) and pathology effects, which occupies an important position in medicine. It has been used to dissolve corepus luteum and shrink uterus in breeding and production of animals. In the small animal clinic, it plays an important role in expanding blood vessels, protecting platelets, expanding bronchus, safeguarding gastric mucosa and so on. The main drugs include dinoprost, alprostadil, dinoprostone, misoprostol, epoprostenol, fluprostenol, cloprostenol and so on.

DinoprostLutalyse
It is also called Luteolysin which is prostaglandin F2 (prostaglandinF2). Pharmacological actionIt has a wide range of functions for genital system, circulation system, systema respiratorium and other systems. For the genital system: It can dissolve corepus luteum, promote uterine contraction, promote the release of luteinizing hormone of the anterior pituitary, influence migration and occurrence of spermatozoa, interfere the activities of the fallopian tube and embryo implantation. Dinoprost may dissolve corepus luteum, and make it shrink, and the production of pregnendione decrease, even stop. The result shows that the luteal phase is shortened, resulting in the female animals rutting and ovulating on the same period, in favor of artificial insemination or embryo transplantation. There is a normal sexual cycle when inject it for cows, horses and sheep. The products have good results of oestrus and breeding for weaning young pigs at an earlier time. It can also shrink the corpus and promote ovulation and estrus for treating lutein cyst of ovaries or permanency ovaries.

This product can excite myometrium, have effects for uteruses of pregnancy and nongestational. Uterus is particularly sensitive at the end of pregnancy for it, which can increase the tension of uterus, relax the cervix, promote production, artificial labor and induced abortion. Clinical UsesTo be used for the synchronization of estrus. Horse, cattle, sheep after injection have a normal sexual cycle, the second injection, more accurately for synchronization of estrus. To be used in the treatment of persistent corpus luteum cyst and corpus luteum. For the persistent corpus luteum, cows of dioestrus are injected this production 30mg, the first heat began to 3d, ovulation after 4~5d. As to the corpus luteum cyst, ovulation on the 6~7d after the first injection. To be used flushing for horses, cattle, pigs. It can increase the amount of sperm injection and improve the effectiveness of artificial insemination for Sire. for oxytocin, induced abortion, stillbirth discharge, or pyometra, chronic endometritis.

Cloprostenol (Estrumate)
It is artificial synthetics and the homologue of prostaglandin F2. This product has the effect of dissolving yellow body and shrinking uterus primarily for cattle. The bovine serum half-life has only a few minutes. Non-pregnancy cattle are rut 2 to 4 days after using the drug. The cow from 1 week after mating to 5 months pregnancy, can outpour foetus and placenta after the injection of 4~5d. For the cow pregnant more than five months, their artificial labor ability will descend, and the chance of difficult labour will increase. To be used for the synchronization of estrus in cows, pyometra, breeding, property artificial labor, and flushing of female animals.

Fluprostenol (Equimate)
It is artificial synthetics and the homologue of prostaglandin F2. In the prostaglandins preparation, it has the max effect and minimal toxicity for luteolysis. For horses, most of the mares begin to rut on the sixth day after injection, ovulate about 24h before the termination of ovulation. It has no flushing effect for the mare that quiescent period of ovaries caused no sexual heat and a variety of reasons caused by the lack of pituitary function. It can be used for the efficient management of horses, so that the mare begin to rut effectively according to the plan and become pregnant in the breeding season. For the early embryo death or re-absorption of the mare, it can dissolve yellow body, so that there will be no lasting corpus luteum of the situation and the lack of infertility does not happen, and anembryonic pregnancy is terminated.

Section Three Antipyretic-analgesic and Anti-inflammatory Drugs

Antipyretic-analgesic and anti-inflammatory drugs are a class of drugs, which can be used to treat high fever and reduce the local dull pain, most of them have effects of anti-inflammatory and anti-rheumatic. Although their chemical structures are different, they have a common role of inhibiting synthesis of prostaglandin. This is a special role of the anti-inflammatory drug, different from steroids anti-inflammatory drugs, also known as non-steroidal anti-inflammatory drugs.

Antipyretic-analgesic and anti-inflammatory drugs have a total of 60 kinds, about 20 of them are used in the veterinary clinical. They have the following common effects. 1. Antipyretic effect The hypothalamus of animals at the rear of the central body temperature regulation, are affected by exogenous pyrogen such as bacterial toxin and ehdogenous pyrogen (now considered to be IL -1) released by leucocyte impact. Pyrogen effect to the original front of the hypothalamus, and promote prostaglandin E (PGE) to be released and synthesised. PGE can raise the set-point of body temperature, in order to increase heat production, dissipate heat production, and raise the temperature of body. Antipyretic-analgesic and anti-inflammatory drugs can reduce the synthesis of prostaglandins, in order to cut down the point, recover the balance of production and lose the heat of normal body. This kind of drugs can only make high body temperature to drop to the normal, instead of dropping the normal body temperature, which is different from chlorpromazine and other drugs. A fever is the body's defence reaction, and the tempreture is an important basis for the diagnosis of the disease. Therefore, the general fever, in particular caused by infectious diseases, do not rush to use the antithermic, instead of etiological treatment, to remove heat caused by the pathogeny. When the constant high fever consume physical strength, aggravate the disease, and even become life-threatening cases, the use of antipyretic drugs can reduce the body temperature to ease the complications caused by high fever. It should be noted that antipyretic drugs are only symptomatic treatment, so if it need to cure once and for all to bring under permanent control, and then it should focus on etiological treatment. 2. Antipyretic effect. Antipyretic effect of antipyretic-analgesic and anti-inflammatory drugs, mainly acted on the periphery of body. Tissue injury or inflammation, some parts of the body produce and release some of the pain induced by chemicals (or physical pain) in the case of bradykinin, histamine, 5-HT ammonia, prostaglandins and so on. Bradykinin and amine directly effect in the pain caused by pain receptors; prostaglandin can enhance the pain receptors on the bradykinin-induced pain, such as the sensitivity of the material in the course of inflammatory pain from amplification; some prostaglandins, such as prostaglandin E1, E2 and F2, also has a direct role for pain. Antipyretic analgesic and anti-inflammatory drugs inhibit the synthesis of prostaglandins, so it has antipyretic effect. This class of drugs have a good analgesic effect for the persistent dull pain caused by inflammation, such as neuralgia, joint pain, muscle pain, and so on, but there are invalid effect for the acute pain and visceral smooth muscle cramps null and void caused by direct stimulation of sensory nerve endings. 3. Anti-inflammatory effect. prostaglandin is also an active material to participate in inflammatory reaction, a large number of them exist in inflammation organizations, and have synergy with other inflammatory material. Antipyretic analgesic and anti-inflammatory drugs inhibit the synthesis of prostaglandins, which can ease the inflammation. There are positive effects to control and rheumatic arthritis symptoms, but it cannot not stop the development of the disease or complications. Antipyretic analgesics inhibit synthesis and release prostaglandin. Through acting on epoxidase, there are three ways: competitive inhibit enzymes, such as ibuprofen, mefenamic acid, indomethacin, and so on. irreversibly inhibiting enzymes, such as aspirin, difluorobiphenyl acid, a chlorine diclofenac, this role of the drug action is a better way. Aspirin is also the enzyme active site so that the serine residues acetylation. capture oxygen free radicals. Antipyretic and anti-inflammatory drugs are not dependent on the effects of epoxidase, but

also on many other factors. For example, it can interfere the drug of chematropism, the ability to swallow, destruction of neutrophil cell, and it has the best anti-inflammatory effects, no matter whether it is the irreversibility of the COX inhibitor. If arachidonic acid does not shift into prostaglandins then it will generate leukotrienes, bug leukotriene-induced inflammation is more difficult to control. It first Interferes neutrophil cells function, then inhibits leukotriene generation. Some of antipyretic analgesic and anti-inflammatory drugs could inhibit prostate-specific role (such as the type of salicylic acid and acid-fen) and the formation of renin (salicylic acid-type), which have a good anti-inflammatory effect. Most of antipyretic analgesic and anti-inflammatory medicine are weak acidic compounds, usually rapid absorbed in the front of the gastrointestinal tract, but it can be influenced by animal species, gastrointestinal peristalsis, stomach PH, chyme, and other factors. Antipyretic analgesic and anti-inflammatory drugs are mainly distributed in the extracellular fluid, permeate into acidic environment of inflammation and damnification organization. It has a high level of incorporation with plasma protein (some even more than 99%). If combined with the drug of big affinity, it can eliminate the extension. Combined with protein binding with the high rate of similar drugs and other drugs, it brings about displacement of binding site in order to cause poison. The elimination of this class of drug depends largely on the liver cytochrome P-450 enzymes, and metabolites are also subjected to metabolic responses but have different species. Metabolites mainly are eliminated with kidney filtration and the secretion of the initiative. The rate of renal excretion depends on the urine pH, and aciduria can increase this rate. The drug active secreted by renal tubular, have the phenomenon of competitive inhibition. Drugs are part of the glucuronide conjugates in the form of bile from the discharge, there is a clear cycle of liver, such as ibuprofen naphthalene in dogs. Due to the elimination of such drugs and organization of the volume, there is a lot of differences among the species,so it will be applied with the doses of great danger and sometimes death. For example, half-life of aspirin in the horses, dogs, cats are 1, 8, 38 hours, respectively. This calculation based on weight 1kg of the same dose in the horse may be null and void, but in the cat (as a result of a lack of glucose metabolism combined with acid) there are serious consequences. In accordance with chemical structures, antipyretic analgesic and anti-inflammatory drugs can be divided into the categories of aniline, pyrazole, and other types of organic acids and ketones. Organic acids are divided into categories of formic acid (salicylic acid category, that acid-fen), the type of acid (indole), acid-type (naphthalene and benzene in acid-type acid-type). Of the two types of drugs having analgesic effects, indole and fun acids have more importance than the types of pyrazolone and orthohydroxybenzoic acid for inflammatory pain. There are differences in the antipyretic and anti-inflammatory effects. The types of aniline, pyrazole ketones and salicylic acid-type have better role of the relieve fever effect. The types of aspirin, pyrazolon and indole ketones have stronger effect of the anti-inflammatory, anti-rheumatoid effects, but aspirin that have better curative effect and less adverse reaction, is the first choice of them for anti-rheumatic drug. Aniline have little effect for anti-rheumatism.

I. Salicylates
Salicylates are the derivatives of antipyrine benzoate, and salicylic acid is part of the biological activity of anion. It includes sodium salicylate and aspirin, but aspirin is more

commonly used. Physico-chemical propertiesIt is also known as acetyl salicylic acid, of white crystals or crystalline powder. It is no foul microstrip or acetic acid smell, and taste Micro. In the case of moisture, it is slow hydrolysis. Soluble in ethanol, chloroform or ether dissolved in water or water in micro-ether solution. In the solution of sodium hydroxide solution or sodium carbonate solution, but at the same time, it breaks down in. PharmacokineticsIt is absorbed in the front of the gastrointestinal tract after ad usum internum. Dogs, cats and horses can absorb it quickly, while cattle, sheep slowly. Ruminant bioavailability is 70%, carbinoxamine compound drops reach to the peak time for the 24h. This product is systemically distributed, which can enter the joint cavity, ncurolymph and fluid milk, through the placental barrier. Mainly in the liver metabolism, but also in the plasma, red blood cell and the organization are hydrolyzed for salicylic acid and acetic acid. They are excreted by the kidneys, urine alkalization in order to speed up its excretion. Aspirin has a very short half-life of only a few minutes, but generates salicylic acid with a long half-life. Action and applicationIt not only inhibits COX-goods, but also helps the production of thrombosis-synthase and renin. They have better effects of relieving fever and pain, and stronger effect for anti-inflammatory and rheumatism. It not only inhibits the association reaction between antibody formation and antigen-antibody, but also inhibit inflammatory exudation, at the same time it has special effects for acute rheumatism. Large doses can inhibit tubular reabsorption of uric acid and promote its excretion. It is often used for the treatment of fever, rheumatism, nerve, muscle and joint pain, inflammation of soft tissue and gout disease. Adverse effectsThis product can inhibit the synthesis of prothrombin, If the bleeding tendency happens in the course of its usage, then treated with vitamin K. It is irritating to the digestive tract, a larger dose can cause loss of appetite, nausea, vomiting and even gastrointestinal bleeding, so it is not appropriate medication on an empty stomach. Long-term use can cause gastrointestinal ulcers. Be cautious with Gastritis, gastric ulcer, bleeding, renal failure sick animals. And usage with the calcium carbonate can reduce the irritation of the stomach. The treatment of gout, can be combined with the equivalent of sodium bicarbonate to prevent the deposition of uric acid in the tubules. This medication is the ramification of Phenols, and has the large toxicity for cats.

II. Aniline derivatives

Utility mother nucleus of aniline derivatives is phenylamine, and commonly used drug are acetophenetidin and paracetamol.

Phenacetin (Acetophentidine)
PharmacokineticsIt is easy to be absorpt by usum internum, shows effects after 20-30min, and lasts for 5-6h. Most of them can rapidly take off the intrahepatic ethyl, generate paracetamol which have the effect of antipyretic analgesic, and are discharged through urine together with paracetamol glucuronide. A small number of them can change into p-aminophenetole by taking off acetyl, and further taking off eshyl to generate the N-ethyl phenol, which is oxidized into sub-quinone. Imino-

quinone could methemoglobin into hemoglobin and the capacity of carrying oxygen is lost, causing hypoxia, and red blood cell hemolysis dissolved, jaundice and liver damage, and so on. Under normal circumstances, the middle of toxic metabolites and glutathione rapid integrate into a non-toxic or acid sulfide (mercapturic acid), and are exhausted from urine. Toxicity occurs only if agents or excessive animal acid happens together with a lack of glucose metabolism in the way. Action and application It has stronger inhibitive effects for synthesising and the release of prostaglandin of hypothalamus, but has weak effects for periphery, so it has the better effect of antipyretic, but poor effects of analgesic and anti-inflammatory. Prototype and its metabolites have antipyretic paracetamol, and a considerable effect with aspirin, slow but long-lasting effect. Mainly used as antipyretic drugs. Adverse effectsIt can induce methemoglobinemia with long-term usage or excessive dose, resulting in hypoxia and cyanosis. It might have serious toxicity for cats, so it should not be given to cats.

Paracetamol Acetaminophen
Paracetamol Acetaminophen is also known as Para and paracetamol, which is the metabolin of acetophenetidin in vivo. Its chemical synthetics for medical are used because they have the effect of relieving fever and analgesic. As to relieve fever, it is the similar to aspirin, but weaker than analgesic and antiphlogosis. It has permanent effect with less side reaction, and mainly used as antipyretic analgesic for middle and small animals. It also has the same adverse effects to acetophenetidin.

III. Pyrazolones
Pyrazolones mainly contain amidopyrine, algopyrin, butalidon and oxyphenbutazone (crovaril), which are all derivated from anodynin, with the elementary structure of compounds ring with prolonged amidobenzene side chain. The drugs all can relieve fever, analgesia and antiphlogosis, while amidopyrine and algopyrin are good at relieving fever, butalidon works well in antiphlogosis.

Aminopyrine (Aminophenazone)
Also known as pyramidon, which is white crystal or crystal-like powder. Without foul, mildly bitter flavor. It can dissolve in water and aqueous solution is of alkalinity. It is easy to deteriorate in light, and oxidated by oxidant. The injection is made up of the mixture of Aminopyrine and barbital is called Compound Amidopyrine Injection. Effect and application quickly absorbed by oral medication and show analgesic effect immediately, with the half life of 1 to 4 hours. It has strong and permanent effect of relieving fever and analgesic, which is stronger than aminobenzenes. analgesic effect can be strengthened by combining with barbiturates. Has the similar effect to acute rheumatic arthritis with orthohydroxybenzoic acids. Widely used in neuralgia, courbature, arthralgia, acute rheumatic arthritis and colic of horse and mule. Long time continual use can cause granulocytopenia.

Phenylbutazone (Butazaolidin)
Phenylbutazone is white or light yellow crystallinity powder, mildly bitter flavor, difficult to be dissolved in water, while dissolved in alcoh and ether, easily dissolved in base and chloroform. Its character is stable. Pharmacokinetics is absorbed easily orally for dogs and cats, and the drug peak time in It blood is 2h. It can combine with musculin after intramuscular administration, absorbed slowly, and the drug peak time in blood is 610h. The plasma protein binding rate of therapeutic dose is 99%, and can replace other drugs from plasma protein. The half life in serum: horse (according to dosages), 3.56h; cattle, 40h; dogs, 2.56h; pigs, 26h; rabbits, 3h; goats, 14.5h. mainly metabolished into crovaril in the liver, which has significant anti-rheumatism and sodium retention activity. Crovaril is excreted from the kidney, and alkalify urine can accelerate its evacuation. Action and applicationThe reactive intermediate transformed in the body can inhibit synthetase of prostaglandin H and prostaglandin. Compared with amidopyrine, it has better anti-inflammatory action, and the effect of relieving fever and analgesic. It can promote excretion of acidum uricum. Mainly used in muscle and osseous system antiinflammatory of horse and dog, such as arthritis, rheumatism, tenosynovitis, bursitis, and gout, didymitis as well. Adverse effects The therapeutic dose cant cause toxicity. Forbidden to use in animals of abnormal blood, gastrointestinal ulcers, or animals with problems of heart, kidney or liver, food production animals, or milking cows.

Analgin Metamizole
It is also known as alginodia, which is the synthetics of sodium sulfite and Amidopyrine. Easily dissolved in water, aqueous solution gradually changes into yellow after short time standing. It is slightly dissolved in ethanol, almost not dissolved in ethylether. Quickly absorbed by intramuscular, the drug action lasts for 3 to 4 hours. It can significantly relieve fever, and analgesic effect as well, and it has certain effects of dephlogisticate and anti rheumatism. The application is the same as Amidopyrine. Long-term usage may cause granulocytopenia, suppress the serozyme formation, and aggravate hemorrhagic tendency.

VI. Indoles
Indoles belongs to anti-inflammatory agents with aryl radicalthanoic acid, with the characteristics or features of strong anti-inflammatory action, and significantly counter labor pains caused by inflammatory pain. The symbol drugs include Indomethacin, acemetacin, Arthrocine(Sulindac), Tolmetin and analogue benzydamine.

Indomethacin (Indocin)
It is white or slight yellow crystallinity powder. Nearly no foul or taste. It can dissolve in acetone, slightly dissolve in methanol, chloroform, ethanol and ethylether, dissoluble in water. Pharmacokinetics Given orally, it is absorbed quickly and thoroughly for single-stomach animals, while plasma peak hour is 1.5-2h. Plasma protein binding rate is 90%. It

is metabolized in the liver, then the metabolins and Indomethacin are excreted mainly by kidney in the form of binding with glucuronate. And still a part enter intestinal tract with bile and experience enterohepatic circulation, and a small part excrete with manure. Action and application Indomethacin is especially effective in anti-inflammatory, and the anti-inflammatory action is 84 times stronger than butalidon, and also stronger than dermacort. If combined together they both can lessen their dosage and side effect. And its another effect is to relieve the fever, which is lighter than its analgesic effect, but the effect for inflammatory pain is better than butalidon, Analgin and ortho-oxybenzoic acids. It has the best therapeutic effect to gouty arthritis, and hypertrophic arthritis. It is mainly used for chronic rheumatic arthritis, neuralgia, tendinitis, tenosynovitis and muscle injury. As to dogs and cats, it can cause enteron symptoms, such as nauseated, stomachache and alo laxata, and some show gastrointestinal ulcers. It also can cause liver damage and hematopoietic function. Be careful with the animals with degenerative nephritis and gastrointestinal ulcers.

Benzydamin (Benzyrin)
Benzydamin has stronger analgesic effect on inflammatory pain than antifani, the similar anti-inflammatory action to butalidon, and significant effect to acute inflammation, external injury and postoperative inflammatory. Mainly used for the inflammatory pain caused by operation, external injury and rheumarthritis. It has the adverse effect of poor appetite, and nauseated, vomitus sometimes.

V. Propionic acid
Propionic acid is a kind of new non-steroidal anti-inflammatory drugs. It is analogue of aspirin, which contains nandrolone derivatives(the drugs contain Brufen, ketoprofen, Phenoxy Ketoprofen). It has lighter stimulus to enteron than aspirin, and less adverse effect than butalidon.

Ketoprofen (Profenid)
It is extremely easily dissolute in methanol, almost not dissolute in water. It can be quickly absorbed by oral medication, and about 99% is combined with plasma protein, metabolized into inactive products in the liver and bound with glucuronate, then excrete from urine. It has strong depressive effect on epoxidase, and effectively suppresses leukotriene, bradykinin and some lipoxidase. Hence, its significant characteristics is strong anti-inflammatory, pain relief and antipyretic effect. It has better effect to human rheumarthritis than aspirin, naproxen, indomethacin, Brufen, diclofenac and piroxicam. It is more effective to postoperative pain than pentazocine and meperidine, and has longer drug effects than the combination of acamol and codeine. Compared with butalidon, it has less toxicity and adverse effect. In veterinary, it mainly used for horse and dog.

VI. Fenamates
Fenamates is also called fenamic acids, which is of anthranilic of anthranilic acid. People found it could relieve pain, fever and antiphlogosis since 1950. The drugs contain mefenamic acid, clofenamic acids, diclofenac, and so on.

Mefenamic Acid
Physico-chemical properties It is also called ponstan. It is white or non-white color crystallinity powder. It tasted lightly at beginning and then slight bitter. Cant dissolved in water, and slightly soluble in water. It may change dark for long time under light. Action and application It has relieve pain, dephlogisticate and relieve fever. analgesic effect is 2.5 times stronger than aspirin, anti-inflammatory effect is 5 times stronger than aspirin, 4 times than amidazophen, but is lighter than butalidon. It has permanent relieve fever. Mainly used to relax muscle and osseous system chronic inflammation and hypertrophic arthritis of dogs, active chronic inflammation of horse such as claudication. But long-term usage can cause drowsiness, nausea and diarrhea.

Meclofenamic Acid
Physico-chemical propertiesIt is also called acidum meclofenamicum. Mainly use its sodium, which is colorless crystalline powder. Easily dissolved in water, and the aqueous solution is alkalinity. Pharmacokinetics as to ruminants, plasma concentration achieve peak after oral 0.5h. Concentration-time curve has two summits caused by enterohepatic circulation. Its half time is 4h. plasma concentration peak shows in 0.54h, and effect is slow, which needs 3696h. Less than 15% of drugs is removed from urine, and bile is the main eliminate route. Action and application It has stronger antiphlogosis than aspirin, amidazophen, butalidon and indomethacin, and similar analgesic effect with aspirin, but inferior to amidazophen. It is mainly used to cure rheumarthritis, arthritis deformans and other skeleton, muscular system disorder. It has less gastrointestinal tract effects.