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Non-Opioid Analgesics the Most Common Non-Opioid Analgesics Are Derivatives Of

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Non-Opioid Analgesics the Most Common Non-Opioid Analgesics Are Derivatives Of Analgesics Non-opioid analgesics The most common non-opioid analgesics are derivatives of: aniline: paracetamol salicylic acid: acetylsalicylic acid propionic acid: ibuprofen pirazolone: phenazone, propyphenazone, metamizole These drugs also act antipyretically and some of them have anti- inflammatory action (acetylsalicylic acid, ibuprofen). New non-opioid analgesics include ketorolac, flupirtin and nefopam. The chemical structure and action of non-opioid analgesics Paracetamol, R = H O N-(4-Hydroksyphenyl)acetamid ACETAMINOPHEN, APAP, CODIPAR, PANADOL, HN CH3 PARACETAMOL Propacetamol, R = -CO-CH2-N(CH3)2 PRO-DEFALGIN OR Paracetamol is known to have analgesic, antipyretic and only slight anti- inflammatory action. Propacetamol is also used intravenously in patients who can not take paracetamol orally as an analgesic, for example after surgical procedures, or to relieve fever in infections and neoplastic diseases. COOH Acetylsalicylic acid, O CH3 Acidum acetylsalicylicum O ASPIRIN, POLOPIRYNA Acetylsalicylic acid (ASA) demonstrates the following kinds of action: analgesic (at low doses, two 300 mg tablets 4 times daily) antipyretic (at the above doses) anti-inflammatory/antirheumatic (at high doses only) prevention of platelet aggregation (at low doses, 160 mg daily) initiation of apoptosis and inhibition of angiogenesis. When administered orally, ASA reaches the small intestine through the stomach and after resorption it is directed to the liver through the portal vein. In intestinal mucus, in the potral vein and in the liver, ASA is partially deacetylated by non-specific esterases. The first metabolite of ASA is salicylic acid. The half-time of ASA in the stomach or in the intestinal fluid is 16- 17 hours, similarly to its half-time in a physiological buffer. In the pre-systemic circulation ASA inhibits the action of cyclo- oxygenase in the platelets by irreversible acetylation of serine 530 in the active center of COX-1. It prevents the formation of TXA2 from arachidonic acid. Only 45%-50% of unchanged ASA reaches the systemic circulation. In this system ASA inhibits COX-2 (induced by the blood flow) in the endothelium and inductive COX-2 in tissues by acetylation of serine 516 in COX-2. These reactions prevent synthesis of prostacyclin in the endothelium and prostaglandins in tissues. In plasma, further acetylation of ASA is caused by non-specific esterases. The half-time of ASA in plasma or in the whole blood is only 15- 20 min. ASA behaves like active acetic acid. - O O O O OH O O- CH + 3 O CH3 - H O CH3 O + O H+ O Its acetyl rest is transmitted to other functional groups, such as water (hydrolysis), other drugs (interactions), foods or enzymes (e.g. cyclo-oxygenase (mechanism of action). - O O CH3 OH + HO O H O (hydrolysis) 2 O - O - O O O O O CH HO NH HN 3 CH O CH3 3 OH (Interaction) + O CH3 XH (mechanism of action) O - O O O OH CH3 + X ASA is excreted with urine as salicylic acid (70-80%) and as its glucuronide and glycinate. This metabolism depends on pH and is partially limited by enzymatic capacity, which is responsible for the elongation of the half-time of salicylic acid from 2 to 3 and even 10 hours at higher doses (over 4 g). Salicylic acid also inhibits the activity of COX by blocking it competitively. O Ibuprofen, IBUPROFEN, ZUPAR H3C OH -Methyl-4-(2-methylpropyl)benzenacetate acid 2-(p-isobutylphenyl)propionic acid CH3 S(+)-Ibuprofen, SERACTIL CH3 Ibuprofen has strong analgesic, antipyretic and anti- inflammatory/ antirheumatic action. Unlike other non-opioid analgesics, ibuprofen has a chiral center. In therapy racemate and S(+)-ibuprofen are used. Only isomer S(+)is active and it also shows antiaggregative action. Ibuprofen is metabolized as a result of , and -oxidation and the conjugation of ibuprofen and its metabolites. The action of those metabolites is unknown. O H C Ar 3 OH Ar CH -2 hydroxylation -1 hydroxylation 3 CH3 OH _ CH3 CH OH CH3 2 oxydation CH3 IBUPROFEN Ar 3 hydroxylation CH3 Ar COOH CH3 -oxydation HO CH 3 Ar COOH Conjugation _ _ H2C O R(-)-Ibu _ _ I phase CoA-SH HC O R(-)-Ibu metabolites _ _ H2C O Ac R(-)-Ibu R(-)-Ibu-S-CoA Conjugation H C _ OH ( +- )-Ibu 2 _ + HC OH CoA-SH _ _ H2C O Ac Conjugation S(+)-Ibu S(+)-Ibu-S-CoA I phase _ _ metabolites H2C O S(+)-Ibu CoA-SH HC_ O _ S(+)-Ibu Conjugation _ _ H2C O Ac In the body, non-active R(-)-isomer is partially inverted to S(+)- isomer, but R(-)-isomer is not considered a pro-drug. The accumulation of non-active R(-)-isomer in the fatty tissue is significantly higher than the accumulation of S(+)-isomer. The above inversion of ibuprofen is catalysed by acetyl-CoA. The product of the reaction of ibuprofen with acetyl Co-A (R(-)- IBU-S-CoA) is converted to S(+)-IBU-S-CoA. The CoA-tioesters of R(-) and S(+)-IBU react with the OH groups of acylglycerol. The resulting ‘hybride-esters’ have very long half-time of elimination (approx. 150 hours) compared to ibuprofen (t1/2=2 hours) and increase the permeability of cell membranes. Phenazone, R = H 2,3-Dimethyl-1-phenyl-3-pirazolin-5-on CH3 N R = CH Propyphenazone, O N 3 CH3 CH3 Metamizol, PYRALGINUM R = N R CH3 _ CH2 SO3 Na Phenazone, propyphenazone and metamizol (the strongest non- opioid analgesic) act analgesically and antipyretically. At therapeutic doses they do not exhibit anti-inflammatory action. Recently the use of pirazolones has decreased because of their adverse effects. COOH N O Ketorolac is an analgesic that acts longer and more strongly than metamizol. It is used to relieve short-term pain. Ketorolac is contraindicated because of the many adverse effects it produces. It is not recommended in pregnancy or lactation and to treat pain in children and older patients. Caution should also be exercised when ketorolac is used in patients with liver and/or kidney dysfunction, heart failure and arterial hypertension, and also in patients receiving diuretics and/or NSAIDs. H2N H N O N CH3 Flupirtin O N H F In the treatment of pain caused by elevated muscle tone, analgesics together with drugs that relax muscles are used. In these cases flupirtin may be an alternative drug. Its action is centrally analgesic and spasmolitic. Flupirtin causes antinociception by stimulating the descending noradrenergic rout of modulating pain. It also increases the binding of GABA with GABAA- receptors. Nefopam H C 3 N O 5-Metylo-1-fenylo-1,3,4,6-tetrahydro-2,5- benzoksazocyna Nefopam (Acupan, Silentan, Nefadol and Ajan) is a centrally-acting non-opioid analgesic drug of the benzoxazocine derivative. It is used for the relief of moderate to severe pain as an alternative to opioid analgesic drugs. Animal studies have shown that nefopam has a potentiating (analgesic-sparing) effect on morphine and other opioids by broadening he antinociceptive action of the opioid and possibly other mechanisms, generally lowering the dose requirements of both when they are used concomitantly. 17 Side effects Nausea, nervousness, dry mouth, light-headedness and urinary retention; Less common side effects include vomiting, blurred vision, drowsiness, sweating, insomnia, headache, confusion, hallucinations, tachycardia, aggravation of angina and rarely a temporary and benign pink discolouration of the skin or erythema multiforme. Contraindications In people with convulsive disorders, those that have received treatment with irreversible MAO inhibitors within the past 30 days and those with myocardial infraction pain, mostly due to a lack of safety data in these conditions. Interactions It has additive anticholinergic and sympathomimetic effects with other agents with these properties. Its use should be avoided in people receiving some types of antidepressants (tricyclic antidepressants or MAO inhibitors) as there is the potential for serotonim syndrome or hypertensive crises to result. 18 The mechanism of action The analgesic action of non-opioid analgesics It is thought that the analgesic action of non-opioid analgesics involves the inhibition of transmission of pain stimuli in the spinal cord. Interneurons and glial cells are involved in the modulation of pain in the spinal cord, where the pro-analgesic transmitters of pain are glutamate, substance P and prostaglandins, while the transmitters inhibiting pain are enkephalins, GABA and glycine. The antinociceptive transmitters in the descending routes are 5-HT and NA. Afferent fibers: C, A Substance P Aff e r ent fibers CGRP A Glutamate Enkephalin Somatostatin NA > Glutamate Posterior horn A f ferent fibers of the spinal cord Brain stem A > GABA 5-HT Glycine Descending system stimulation inhibition The analgesic action of non-opioid analgesics It is believed that the mechanism of action of non-opioid analgesics is determined by selective inhibition of COX-3, which is present in the heart and the aorta. Isoenzyme COX-3 is fully inhibited by paracetamol and, probably, by other non-opioid analgesics. Other mechanisms of action may include reduction of the permeability of nerve cell membranes and the blocking of transmission in peripheral afferent nerve fibers. The analgesic action of non-opioid analgesics ASA also affects serotoninergic transmission. Research has shown a correlation between analgesia induced by ASA and the turnover of serotonine in the brain and between the influence of ASA on the synthesis of serotonine by removing tryptophane (precursor of serotonine) from its binding with the proteins of plasma. PGE2 sensitizes nerve ends to the action of bradykinin, histamin and other chemical mediators released locally in inflammation. Non-opioid analgesics inhibit the feeling of pain of low to moderate intensity. Compared to opioids, NSAIDs (ASA, ibuprofen) are more effective in the treatment of pain caused by inflammation. The analgesic action of non-opioid analgesics A pain stimulus increases the activity of peripheral receptors of pain.
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