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Chapter 6

Chapter 6. Antipyretic Analgesics & Nonsteroidal Anti-inflammatory Agents. Pei YU Rm. 623, College of Pharmacy. Key Word:. Anti pyretic Analgesics ( 解热止痛剂 ) Non steroidal ( 非类固醇类的，非甾体类 ) Anti- inflammatory （抗炎的）. Background informations.

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Chapter 6

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  1. Chapter 6 Antipyretic Analgesics & Nonsteroidal Anti-inflammatory Agents Pei YU Rm. 623, College of Pharmacy

  2. Key Word: • Antipyretic Analgesics(解热止痛剂) • Nonsteroidal(非类固醇类的，非甾体类) • Anti-inflammatory（抗炎的）

  3. Background informations Can induce a drop in temperature in feverish conditions. Some antipyretics were noted to be excellent analgesics for the relieve of minor aches and pains, and even survived to the present time on the basis of the analgetic, rather than the antipyretic.

  4. Background informations Fever is an outward symptom of inflammation. These drugs also used extensively in the symptomatic treatment (对症治疗) of rheumatic fever (风湿热),rheumatoid arthritis (类风湿性关节炎RA), and osteoarthritis (骨关节炎OA).

  5. Two comparisons • Analgesic effect in comparison with the morphine-type compounds • Anti-inflammatory effect in comparison with the corticosteroids(皮质激素) Low activity for a given dose Two principal features: Lack of addiction potential Long-term therapy with the corticosteroids often accompanied by various side effects.

  6. Section 1 Antipyretic Analgesics

  7. Request and Purpose • structure • chemical name • physico-chemical property • metablism in vivo • clinical application To master Aspirin and Paracetamol:

  8. Mechanism of action • Inhitbit the biosynthesis of prostaglandine(前列腺素)in several tissues such as hypothalamus(下丘脑). • The search for specific inhibitors of cyclooxygenase (环氧合酶) has opened a new area of research in this field. In vitro, all inhibit the prostaglandine epoxidase The effects of relieving fever and pain parallel their relative potency to inhibit the epoxidase

  9. COX-1 and COX-2 • Non-steroidal antiinflammatory drugs (NSAIDs 非甾体抗炎药) act by inhibiting the biosynthesis of prostaglandins(PGs) from arachidonic acid (AA 花生四烯酸). • Two enzymes catalyze the first step in biosynthesis of PGs, cyclooxygenase 1 and 2 (COX-1 and COX-2).

  10. COX-1 and COX-2 Although COX-1 and COX-2 catalyze the same biochemical reaction, they are distinctly in terms of amino acid content, tissue distribution, and physiological function. COX-1 is a constitutive enzyme and plays a role in the production of essential prostaglandins. COX-2 level is normal lower, it is induced in response to the release of several proinflammatory mediators. It become elevated at sites of inflammation. Leading to the inflammatory response and pain The selective COX-2 inhibitor emerged from this effort.

  11. Classification Salicylic acids Chemical structure Anilines More toxic Pyrazolones

  12. Development B.C. 5 century, chewing willow bark can relieve pain. In 1838, Salicylic Acid firstly isolated. In 1860, Kolbe firstly synthesize Salicylic Acid. In 1875, sodium salicylate clinically used as antipyretic analgesics. In 1886, phenol salicylate went on the market. In 1899, aspirin introduced into medicine, although it’s first prepared in 1853.

  13. Salicylic acid Salicylic acid is no longer used as an oral medicine since it is very irritating to the stomach and can cause serious gastrointestinal bleeding.

  14. Derivatives of salicylic acid • Type I: Modifying the carboxyl group (salts, esters, or amides). Hydrolysis takes place in the intestine. • Type II: Substitution on the hydroxyl group. Absorbed unchanged into the bloodstream.

  15. Derivatives of salicylic acid

  16. Aspirin Aspirin—Acetylsalicylic acid It is more potent, less irritating. Aspirin is named by taking “a” from acetyl and adding it to “spirin”. An old name for salicylic or spiric acid, derived from its natural source of spirea plants(绣线菊类).

  17. Development of Aspirin • Widely used during the flu epidemic in Europe in 1917-1918 because it effectively lowers dangerously high fevers. • By the 1950s aspirin became by far the most widely used painkiller globally. • Subsequent research indicated that aspirin inhibits blood clotting at low dosages (80-90mg per day) • Annual production of aspirin is in excess of 40,000 tons worldwide now.

  18. Physico-chemical property of Aspirin Nomenclature: Acetylsalicylic acid; 2-Acetoxy benzoic acid; (Aspro, Empirin) White crystal or white crystalline power

  19. Physico-chemical property of Aspirin • Slightly soluble in water (1:300). • Soluble in alcohol, chloroform and ether. • In the presence of moisture air, it is easy to decompositon and oxidation.

  20. Physico-chemical property of Aspirin • Its solution boiled and showed a violet color on the addition of ferric chloride solution. • When an aqueous solution of aspirin and sodium hydroxide is boiling, salicylic acid (white) will be crystallized out after being acidified. Hydrolyzed to form salicylic acid

  21. Physico-chemical property of Aspirin yellow Blue or brown-black Aspirin hydrolyzes into salicylic acid.

  22. Metabolic Pathway of Aspirin

  23. Pharmacologic action • Irreversible inhibition of cyclooxygenase, and used as an antipyretic, analgesic, and antirheumatic • Inhibit the synthesis of thromboxane A2(血栓素TXA2), and used as prophylaxis(预防)of heart attack and thrombotic(血栓)strokes in a low-dosage form. • Also prophylaxis of colon carcinoma(结肠癌). In clinic widely used for common cold, headache, neuralgia(神经痛), arthralgia(关节痛), acute and chronic rheumatalgia(风湿痛), etc.

  24. Side effects of Aspirin Gastric mucosa (胃粘膜) injury, even gastric and duodenal hemorrhage (十二指肠出血). The free carboxyl acid. To make its salt and derivatives.

  25. Aspirin Derivates

  26. Initiation of supersensitivity Impurity test ＜0.003% Precipitate from Na2CO3

  27. Aspirin • Dry dosage form such as tablets, capsules, or powders should be used, since aspirin is somewhat unstable in aqueous media. • All salts of aspirin, except those of aluminum and calcium, are unstable for pharmaceutical use.

  28. Synthesis of Aspirin Decompose • pKa for acetylsalicylic acid is 3.5 at 25ºC. Vinegar smell

  29. Paracetamol(对乙酰氨基酚) • N -(4-Hydroxyphenyl) acetamide; • Acetaminophen; • N-Acetal-p-aminophenol; • 4-Hydroxyacetanilide; • APAP It is Aniline and p-Aminophenol derivative.

  30. Synthesis of Paracetamol Method 1 • It is stable in the air. • When pH6, it is most stable. T1/2=21.8 year (25ºC)

  31. Synthesis of Paracetamol Method 2 Paracetamol

  32. Development Antifebrin(Acetanilide) Ferrihemoglobin(高铁血红蛋白)and jaundice(黄疸) Hydroxyl etherification, get Phenacetin APC Renal toxicity(肾毒性), gastric cancer(胃癌)and retina(视网膜)toxicity In 1893, Paracetamol launch Found: It is the metabolite of Phenacetin and Acetanilide after 50 years.

  33. Physico-chemical property of Paracetamol • White, odorless, slightly bitter crystalline powder. • Slightly soluble in water, and ether; soluble in boiling water, acetone, alcohol and sodium hydroxide. • Formation of a violet color on the addition of ferric chloride solution. • Mix its diluted HCl solution with sodium nitrite, then react with -naphthol, present red color. • Hydrolyzed to form primary amine.

  34. Metabolic Pathway of Paracetamol children adults

  35. Metabolism Paracetamol is metabolised primarily in the liver, into non-toxic products. Three metabolic pathways : • Glucuronidation is believed to account for 40% to 2/3 of the metabolism. • Sulfation may account for 20–40%. • N-hydroxylation and rearrangement, then GSH conjugation, accounts for less than 15%. • All three pathways yield final products that are inactive, non-toxic, and eventually excreted by the kidneys. • In the third pathway, the intermediate product NAPQI is toxic.

  36. Usage of Paracetamol : • Has analgesic and antipyretic activities(releving fever and pain). • It isn’t anti-inflammatory, different with Aspirin. • Exerts its effects by inhibiting the cyclooxygenase enzyme centrally but has very little effect peripherally. • It is considered safer. • Not to exceed the recommended dosages. • Risk of liver toxicity in chronic alcoholics.

  37. Paracetamol in Clinic • Chinese: 扑热息痛 • Is available in several nonprescription forms (that is OTC). • Is marketed in combination with aspirin and caffeine. (APC)

  38. Paracetamol in Clinic • Paracetamol is available in a tablet, capsule, liquid suspension, suppository（栓剂）, intravenous, and intramuscular form. • The common adult dose is 500 mg to 1000 mg. • The recommended maximum daily dose, for adults, is 4 grams. • In recommended doses, paracetamol generally is safe for children and infants, as well as for adults.

  39. Summary

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