NSAIDs

Analgesics .. 1Classifications2Antipyretic analgesicsParacetamol(para-acetylaminophenol andpara-acetylaminophenol)Fever and pain , paracetamol + caffeine treatment of tension or migraine headache.Mechanism unclear: COX-3??Metabolism??phenacetintoxicAcetanilide toxic

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http://pharmaxchange.info/press/2012/08/metabolism-of-paracetamol-acetaminophen-acetanilide-and-phenacetin/4Pyrazolone and Pyrazolidinedione derivatives pyrazolone -toxic 3,5-pyrazolidinedione (uricosuric agent) antigout anti-rhumatoid arthritis acidic protonSulfinpyrazone n-butyl phenylbutazone 2-(phenylsulfinyl)ether acidic proton pKa 2.8 H

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n-butyl2-(phenylsulfinyl)ether antiinflamantigoutAnti-inflammatory analgesics (NSAIDs)Salicylic acid derivativesPropionic acid derivativesArylalkanoic acid or Acetic acid derivativesEnolic acid (Oxicam) derivativesAnthranilic acid derivatives (Fenamates )Selective COX-2 inhibitors (Coxibs)Sulfonanilides

6Salicylic acid derivativesSailicin salicylic acidsalicylic acid analgesic, antipyretic, anti-inflammatory Aspirin anti-thrombotic agent(81mg, baby ASA) thromboxane A2 platelet aggregation SE: GI irritation

(Aspirin, ASA)7Mechanism of ASAsuppression of theexpressionof COX enzyme

http://quizlet.com/25895153/drugs-and-diseases-skin-and-connective-tissue-talele-flash-cards8Methyl SalicylateLess analgelsic activityContain in ointment analgesic balmExternal useSalsalateDimer of salicylic acidsoluble in small intestine partially hydrolyzed to two molecules of salicylic acid absorbedless GI blood loss

9Diflunisaldifluorophenyl salicylic acid 5 salicylic acid lipophilicity longer duration of action Mild , moderate painOsteoarthritis(OA) Rheumatoid arthritis (RA) SE: GI bleeding, heart attack, stroke

10Arylalkanoic acid or Acetic acid derivativesIndomethacin, Tolmetin(sodium), Ketorolac, Diclofenac, Etodolac, Nabumetone

Mechnism of arylalkanoic acid derivatives: competitive with arachidonic acid to bind with enzyme cyclooxygenase Less reaction of arachidonic acid and enzyme cyclooxygenase Low production of Prostaglandin

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IndomethacinsulindacKetorolacDiclofenac

arylalkanoic acid anthranilic acid indene ring -Cl non-co planar , twistng effect important for binding to the active site of COX12SARindole ring(indomethacin) indene ring (sulindac) N-p-chlorobenzoyl benzylidine analgesic activity -F OCH3 analgesic activitysulfinyl group sulindac crystal urea(Z)-isomer indomethacin sulindac anti-inflammatory (E)-isomer

13Anthranilic acid derivatives (Fenamates )fenamic acid active site arachidonic acid cyclooxygenase : prostaglandin mefenamic acid, meclofenamic acid, flufenamic acid , tolfenamic acid14

anti-inflammatory Meclofenamic acid>Flufenamic acid>Mefenamic acid15SARStubstitution on Anthranilic acid ring reduce activityStubstitution on N-aryl ring increase activityAnti-inflammatory substitution of 3-CF3 (Flufenamic acid) at position, increasing of activity 3>2>>4 Substitution of both C-2,3 increase anti-inflammatory activity

16Propionic acid derivativesIbuprofen, Fenoprofen, Ketoprofen, Naproxen, Flurbiprofen, Ketorolac naproxen selective COX-2

O P mPhenoxy group

1718SAR of Ibuprofen

18 arcus adiposus SAR of Ibuprofen alphaCH3 acetic acid part 1 chiral carbon stereoisomer S- R-enantiomer Anti-inflammatory S-enantiomer > R-enantiomer R-enantiomer isomerization S-enantiomer racemic mixture

1920SAR of Naproxen

S(+)isomer123456(+)6-Methoxy--methyl-2-naphthaleneacetic acidEnolic acid (Oxicam) derivativescontain avinylogous carboxylic acid that exhibits a form ofketo-enol tautomerism Piroxicam, Meloxicam (= selective COX-2), TenoxicamVinylogous carboxylic acids = cpd. That contain carbonyl gr. which is separated from hydroxyl gr. from vinyl group. similar to carboxylic acid

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SAR

R1 is methyl group optimum activityR = aryl or heteroaryl (pyridine) good activityIf R= alkyl lost activityEnolic group; pKa ~ 4-64-hydroxy-1,2-benxothiazine carboxamides3-Carboxamide and 2-CH3-group are important structure for anti-inflammatory activity.Substution of N-Heterocyclic carboxamide (R) more acitivity than substitution of N-aryl carboxamide more stability of enolate anion by pyridine nitrogen atom of R.

2 amine enhance the stabilization of the enolate anion 22

PiroxicamMeloxicamPrimary carboxamidePrimary carboxamide2-pyridyl group2-(5-methtyl)thiazolyl groupPiroxicam & Meloxicam=4-hydroxy-2-methyl-N-(5-methyl-2-thiazoyl)-2H-1, 2-benzothiazine-3-carboxamide-1, 1-dioxidemeloxicam(Mobic) = partial COX-2 specificityVery long acting,(T1/2 50h) Dose - 20 to 30mg once daily.indometacin 25g or ibuprofen 40mg 3 times a day.23Stabilization of Enolate Aniontautomer B is more stable. Has N-H bond = enolate anion more potent and stable substitution of aryl group at Ortho- and Meta- stronger than substitution at para-m-Cl substituent highest activity

+ H+BAtautomer A and tautomer Bpiroxicamketo-enol tautomerism24Selective COX-2 inhibitors (Coxibs)Structure and Chemistrycox-2 inhibitor has core structure as diaryl-5-membered heterocycles

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PharmacophoreEx: Celecoxib, Rofecoxib, Valdecoxib, ParecoxibMost traditional NSAIDs are nonselective inhibitors of both COX 1 and COX 2. Nimesulide, a selective COX-2 inhibitor, celecoxib, and rofecoxib, two highly selective COX-2 inhibitors, have been in use for sometime now. They have at least a 200 to 300 fold selectivity for inhibition of COX-2 over COX 1. These agents provide analgesia comparable to the nonspecific NSAIDs among patients with rheumatoid arthritis and osteoarthritis and claimed to have several unique benefits, particularly a marked reduction in gastroduodenal toxicity (since COX 1 is involved in gastric cytoprotection) and renal safety. In addition, COX 2 inhibitors have been found to reduce the risk of colonic malignancy. Thus far highly selective COX-2 inhibitors have been extensively used in clinical practice and studies, conferring important benefits with regard to gastrointestinalside effects. But renal safety of these compounds has not been the focusof interest in the available large clinical trials.37Need for Selective COX 2 inhibitorsThe differences in the effectiveness with which a particular NSAID inhibits an isoform of cyclooxygenase may affect both its activity and toxicity. It has been proposed that the perfect NSAID would inhibit the inducible COX-2 isoform (thereby decreasing inflammation) without having any effect on the constitutive COX l isoform (thereby minimizing toxicity). Such an agent would maximize effectiveness, without inducing toxicity, particularly gastroduodenal erosions and nephrotoxicity.

25The differences in the NSAID binding sites of COX1 and COX2. 26

Note that the COX2 binding site is more accommodating and is characterized by a 'side pocket' that can accommodate bulky groups such as the methyl sulphonyl moiety of DuP697. COX, cyclooxygenase; NSAID, non-steroidal anti-inflammatory drug.27

http://www.atom.rmutphysics.com/charud/oldnews/0/275/medicine/drugs.htmArachidonic acid COX-1 COX-2 NSAIDs COX Arginine 120 hydrophobic channel active site hydrophobic channel hairpin loop Arg 120 523 COX 2 isoforms COX-1 Isoleusine COX-2 Valine isoform cyclo-oxygenase activity Tyr 385 arachidonic acid prostaglandin Tyr 385 prostaglandin Iso 523 COX-1 (steric hindrance) Val 523 COX-2 (side pocket) 523 COX-2 COX-1 salt bridge Arg 120 Iso 523 COX-2 side pocket salt bridge Arg 120 Val 523 COX-2 COX-1 COX-1 side pocket COX-2 COX-1 COX-2 COX-1 COX-2 side pocket COX-2 NSAIDs carboxyl group(-COOH) piroxicam COX-2 thromboxane A2(TxA2) neutrophils adherence half-life 30 inactive thromboxane B2 thromboxane A2 PGE2, PGD2 PGI2 PGE2 PGI2 permeability PGE2 tone arachidonic acid 5-lipoxygenase ()http://www.atom.rmutphysics.com/charud/oldnews/0/275/medicine/drugs.htm27Example of COXIB drugsCelecoxib(FDA alert)Rofecoxib(withdrawn from market)Valdecoxib(withdrawn from market)ParecoxibFDA withdrawn, licenced in the EULumiracoxibTGA cancelled registrationEtoricoxibnot FDA approved, licenced in the EU2829Celecoxib(Celebrex)structureName: 4-{5-(4-methylphenyl)-3-(trifluromethyl)-1H-pyrazole-1-yl} benzene sulfonamide

Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) It is marketed by Pfizer under the brand name Celebrex.

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has Pyrazole ring in middle, 2 phenyl substitutedone Phenyl contains Methyl group and the other contains sulfonamide moiety (sulfonamide bind with hydrophilic region in Cox-2 but not in Cox-1)Celecoxib is metabolited at benzylic methyl through oxidation Complete conjugation occure at this position inactive excrete Celecoxib

31Side effects:

less than 2% Gastrointestinal ADRs, sulfonamide moiety and may cause allergic reactions , increased risk for heart attack and stroke often foundheartburn, stomach ache, diarrhea

Indications: use for 1. Osteoarthritis 2. Rheumatoid arthritis 3. Acute pain 4. painfulmenstruation and menstrual symptoms 32Etoricoxib(Arcoxia )Chemical name : 5-chloro-2-(6-methylpyridine-3-yl)-3-(4-methylsulfonylphenyl) pyridineFrom Merck & Co. Mechanism:Inhibit COX-2 COX-2 selectivity 106 timesreduces the generation of prostaglandins (PGs) from arachidonic acid. approved in more than 70 countries worldwide but not approve in the US (FDA)indications are: treatment ofrheumatoid arthritis,psoriatic arthritis,osteoarthritis, ankylosing spondylitis(chronic, inflammatoryarthritisandautoimmune disease) , chroniclow back pain acute pain andgout. -increased incidence of adverse cardiovascular events

a new COX-2 selective inhibitor Parecoxib (Dynastat)

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Parecoxib is a water soluble and injectable prodrug of valdecoxib. It is marketed as Dynastat in the European Union.

administered as an intramuscular or intravenous injection.

Name:N-{[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]

brand name Dynastat from Pfizeronly injectable COX-2 specific inhibitor.Use for short term perioperative pain control with no effect onplateletfunction (unlike Ketorolac (Toradol)2005, FDA - non-approval for parecoxib in the United States with no reason??SulphonanilidesNimesulidea relativelyCOX-2 selective,non-steroidal anti-inflammatory drug(NSAID) withanalgesicandantipyreticproperties. Its approved indications are thetreatmentof acute painNot appoved in US SE: hepatotoxicity34

35Exercise(1)Which of the following drugs only relieve fever and pain,without antiinflammatoryMetamizole sodium

Aspirin

Paracetamol

Naproxen

Piroxicam 36Exercise (2)Whose activity in the following drugs is similar to the structure

Phenobarbital

adrenalin

Ibuprofen D. Diphenhydramine

E. Nifedipine 37Exercise (3)Which of the following items match IbuprofenBelong to NSAIDsBe used for goutPossesses a chiral carbon, and racemic body used in clinicContains isobutyl in its chemical structureUsed as an anti-ulcerative drug

38Exercise (4)Piroxicam Diclofenac CIbuprofen Paracetamol DNaproxen Indomethacin A

ABCDEFBFE39Case study (1)Six months ago, GZ began playing tennis ball during his lunch hour with one of his colleagues. Today, he visited his physician complaining of sore elbow.His physician has diagnosed the problem as bursitis, and wants to prescribe treatment for the problem. sore elbow bursitis39 40QWhich of the agents should not be used in the patient? Explain your answer using the chemistry of the compounds.

indomethacin NSAIDs ??paranaproxen41Case study (2)A two-year-old child is rushed to the emergency room of your hospital by his distraught mother. She tells the E.R. staff that her boy ate approximately half of a full bottle of Tylenol (acetaminophen) tablets.Along with gastric lavage, you recommend the po administration of a 5% solution of Cysteine

paracetamolN-acetylcysteinePO =per os (by mouth)4142Q1 and Q2How is acetaminophen normally metabolized? Based on this metabolic route, what medical emergency is facing this child?

What is the chemical rational for the administration of Cysteine43

N-acetyl-p-benzoquinone imine (NAPQI)Acetylcysteine, administered orally, is indicated as an antidote to prevent or lessenhepaticinjurywhich may occur following the ingestion of a potentially hepatotoxicquantity of acetaminophen. It isessentialto initiate treatment as soon as possible after the overdose and, in any case, within 24 hours of ingestion.44