Analgesic agent

Tainter has divided the history of analgesic dmgs into four major eras, namely  

The period of discovery and u.se of naturally occurring plant drugs 

1 Isolation of pure plant principles (e.g.. alkaloids) from the natural sources and their irlcntirication with analgesic action. t. Development of organic chemistry and the first synthetic analgesics 

Development of modem phonnacological techniques, making It possible to undertake a systematic testing of new analgesics 

A new era has emerged with the discovery of opioid receptors and endogenous chemicals that have analgesic activity. 

Aminopyrine, indomethacin, acetoaminophen, and phenylbutazone have been reported to produce a variety of allergic manifestations affecting the skin including maculopapular and urticarial rashes, erythema multiforme, fixed drug eruptions, 

Even with the availabity of antibiotics the disease still carries a serious prognosis with death occurring in 5%-10% of affected individuals. Obviously neither aminopyrine nor phenylbutazone should be used when less toxic drugs such as aspirin produce an adequate symptomatic response. Once the diagnosis is supected, the drug should be discontinued and not readministered. 

The role of immunity in anemic or thrombocytopenic reactions produced by these drugs has been less well studied, in part because of their lower frequency. Oxyphenbutazone was recently reported to be the commonest cause of drug-induced aplastic anemia in Sweden (Bottiger and Westerholm 1973). A positive lymphocyte transformation test has been reported in a patient with phenylbutazone-induced aplastic anemia (Reidenberg and Caccese 1975), suggesting an immune response to the drug and conceivably immune suppression of erythropoiesis, but further studies are needed. 

Alkalay I, Zipoli T (1977) Levodopa-induced acute non-hemolytic anemia. Ann Allergy 39 191 

Angervall L, Bengtsson U, Lehmann L (1972) Renal diseases caused by drugs. In Samter M, Parker CW (eds) International encyclopedia of pharmacology and therapeutics. Sect 75 Hypersensitivity to drugs. Pergamon, Oxford Atkinson JP, Sullivan TJ, Kelly JP, Parker CW (1977) Stimulation by alcohols of cAMP metabolism in human lymphocytes. Possible role of cAMP in the anti-inflammatory effects of ethanol. J Clin Invest 60 284-294 

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Most of the time, the powerful analgesia suppHed by morphine and the other opioid analgesics is not needed. Rather, a mild analgesic, such as aspirin, the most commonly employed analgesic agent, can be used for the treatment of simple pain associated with headaches, minor muscle pain, mild trauma, arthritis, cold and flu symptoms, and fever. 

FIGURE 25.29 (a) The structures of several commou analgesic agents. Acetaminophen is marketed under the tradename Tylenol. Ibuprofen is sold as Motrin, Nuprin, and Advil, (b) Acetylsalicylate (aspirin) inhibits the cyclooxygenase activity of endoperoxide synthase via acetylation (covalent modification) of Ser ... 

Central and peripheral analgesic agents from kappa-opioid agonists 95E405. 

Hydrolysis of the nitrile in 130 (obtained by an alkylation analogous to that used to prepare 126) affords the acid, 131. esterification with ethanol affords the analgesic agent, norpipa-none (132). ... 

The popularity of aspirin has led to the preparation of a liost of relatively simple derivatives in the hope of finding a ilrug that would be either superior in action or better tolerated. i alicylamide (5), for example, is sometimes prescribed for pa-I Lents allergic to aspirin. It should be noted, however, that I his agent is not as active as the parent compound as an antiinflammatory or analgesic agent. This may be related to the fact I hat salicylamide does not undergo conversion to salicylic acid i 11 the body. 

The ring-contracted analog of alphaprodine is prepared by a variation of the scheme above. Alkylation of 109 with ethyl bromoacetate affords the lower homolog diester (115). Dieckmann cyclization followed by saponification-decarboxylation yields the pyrrolidine (116). Reaction with phenylmagnesium bromide leads to the condensation product (117) acylation with propionic anhydride gives the analgesic agent prolidine (118)... 

Many alkaloids have pronounced biological properties, and a substantial number of the pharmaceutical agents used today are derived from naturally occurring amines. As a few examples, morphine, an analgesic agent, is obtained from the opium poppy Papaver somnifemm. Cocaine, both an anesthetic and a central nervous system stimulant, is obtained front the coca bush Erythroxylon coca, endemic to upland rain forest areas of Colombia, Ecuador, Peru, Bolivia, and western Brazil. Reserpine, a tranquilizer and antihypertensive, comes from powdered roots of the semitropical plant Rauwolfia serpentina. Ephedrine, a bronchodilator and decongestant, is obtained front the Chinese plant Ephedra sinica. 

However, 4-amino-l,2-dihydro-5-(2-hydroxyphenyl)-3H-pyrazol-3-one and 5-amino-6-6-(2-hydroxyphenyl)pyrimidin-4(3H)-one appear to be interesting structures for developing new analgesic agents. 

Capsaicin-sensitive nerves sense bladder fullness and form the afferent limb of the micturition reflex [132]. In conditions of bladder hypersensitivity, TRPVl is up-regulated on these nerves (presumably via NGL [133, 134]) and deafferentation of the bladder by intravesical capsaicin or RTX was proven beneficial [135-137]. Parenthetically, intravesical RTX is also an effective analgesic agent during experimental cystitis in the rat [138]. By... 

Yohimbine (36) is a well-known and reasonably available alkaloid from Corynanthe yohimbe, inter alia. For this reason, and partly because of its intrinsic pharmacological activity (including reputed aphrodisiac activity), chemists have frequently studied its properties. Oppenauer oxidation is usually attended by saponification and decarboxylation in this series, and yohimbone (37) is the product. Wolf-Kischner reduction to yohimbane (38), followed by sodium hydride mediated alkylation, leads to the analgesic agent, mimbane (39). °... 

Opium and its derivatives have been employed for centuries for the treatment of pain. Morphine was first synthesized in 1805 and has proven to be one of the most effective analgesic agents available [1], Morphine and its analogs are particularly useful because they diminish pain sensation while maintaining consciousness. However, opiates induce severe side-effects including respiratory depression, nausea, bradycardia and constipation and long-term use of opiates can cause addiction [2]. 

W. Nerinckx, M. Vandewalle, Asymmetric Alkylation of a-Aryl Substituted Carbonyl Compounds by Means of Chiral Phase Transfer Catalysts. Applications for the Synthesis of (+)-Podocarp-8(14)-en-13-one and of (-)-Wy-16,225, A Potent Analgesic Agent , Tetrahedron Asymmetry 1990,1, 265-276. 

Anti-inflammatory and analgesic agents 1997FA42 2000EJM1021 2001MI1135 2005EJM155... 

There are also known cases of drug enantiomers that possess completely different therapeutic properties. The (+)-2/ ,35 -stereoisomer of propoxyphene (dextropropoxyphene) is marketed as an analgesic agent, whereas its enantiomer ( )-(25, 3/ )-propoxyphene (levopropoxyphene) is available as an effective anti-tussive agent [3]. The enantiomers of some chiral drugs are known to possess essentially identical qualitative and quantitative pharmacological activities, for example, the antihistamine promethazine, which is marketed as a racemate [5]. 

In the past, a number of discoveries have been made in the absence of any knowledge about the receptors or ligands. One of the earliest examples of this kind is morphine (65) which was used for many years as an analgesic agent (as a constituent of opium, extracted from the poppy plant, Papaver somniferum) without... 

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