NSAIDS - NPVS LECTURE.pdf. nn j

NSAIDs

1. Non-steroidalanti-inflammatory
drugs
EugeneLozinskyM.D.C.M.S.

2. Inflammation





itisapathologicalprocessthatarisesin
responsetodamagepathogenicstimulus
andeliminatedamageproducts,agents-
irritants-allcausativeagentsofthe
inflammatoryprocess.
3stagesofinflammation:
alteration-damagetocellsandtissues
exudation-thereleaseoffluidandblood
cellsfromthevesselsintothetissue
proliferation-growthofbodytissueby
celldivisiontheresultofwhichis
reparationofthetissueintegrity.

3. Pathogenesisofinflammation
Primaryalteration
Primaryinflammatory
mediators
Irritationofthe
neuroendocrinesystem
HematopoiesisactivationSecondaryalteration
Secondarymediators
Increased
vascular
permeability
Leukocytosis
Hyperemia Exudation
Leukocyte
migration
Chemotaxis
Proliferation

4. Anti-inflammatorydrugs-these
aredrugsthatsuppressthe
inflammatoryprocessduetothe
effectonthebiologicallyactive
substancesthatregulateit.
Definition

5. Mechanismoftheactionofanti-
inflammatorydrugs
Effectonthe
formationof
biologicallyactive
substancesfrom
phospholipidsofcell
membranes
Inhibitionof
phospholipaseA2
Inhibitionof
cyclooxygenase
Prostanoidreceptorblockade
5-lipoxygenase
blockade
Leukotrienereceptorblockade
Theblockadeof
PlateletsActivator
Factorreceptors

6. Pointsofapplicationofanti-
inflammatorydrugs

7. Nonsteroidalanti-inflammatorydrugs
(NSAIDs)


Agroupofdrugswithanalgesic,anti-
inflammatoryandantipyreticeffect.
Themainpharmacologicalactionof
NSAIDsisassociatedwiththe
suppressionofcyclooxygenase(COX)
activity.

8. Morethanthirtymillionpeoplein
theworldtakeNSAIDsdaily,and
40%ofthesepatientsareover60
yearsold.
About20%ofinpatientsreceive
NSAIDs.

9. EffectofNSAIDsonprostaglandin
synthesis
Prostaglandins
Arachidonicacid
Cyclic
endoperoxides
Phospholipid
s
Inflammation
Pain
Fever
cyclooxigen
ase
NSAID
-

10. Mechanismsofanti-inflammatoryaction
ofNSAIDs








Alterationandexudation:
SuppressionofCYCLOOXIGENASEactivity
Lipidperoxidationsuppression
Suppressionofneutrophilandmonocytechemotaxis
(suppressionofselectinexpression)
Suppressionofnon-immuneinflammationfactors
(amines,kinins,NO,thecomplementsystem)
Proliferation:
Uncouplingofoxidationandphosphorilation
processesinfibroblasts(urgentlackofenergy),which
leadstoadecreaseinthesynthesisof
mucopolysaccharides
Violationofproliferationandreparation

11. PHARMACOKINETICSOFNSAIDs
BIOAVAILABILITY-80-60%,forcoxibsupto99%.
DISTRIBUTION
Acidderivatives-penetrateintothesynovialfluid(indoleacetates
,oxycams).
Coxibsarelipophilic,canbedeposited,penetratethebrain-blood-
barrier
CONNECTIONWITHPROTEINS-80-99%,displacingotherdrugs
T½half-lifetimeforcoxibsis12-40hours
BIOTRANSFORMATION
liver-cytochromeP450-90-97%;indomethacin,sulindac,
meloxicamtransformedtoactivemetabolites(acetaminophenol,
metamizol,etc.)
EXCRETION
KIDNEYS-mostacidderivatives-90%tubularsecretion
BOWEL-somecoxibs(celecoxib)non-acidicNSAIDsoxicams

12. Non-steroidalanti-inflammatorydrugs

1.
2.
3.
4.



PHARMACOLOGICALEFFECTS
Anti-inflammatory-suppressinflammationof
anyorigin.
Analgesic
Antipyretic
Antiplatelet
EFFICIENCY-allNSAIDs(acidderivatives)are
equallyeffectiveinanti-inflammatoryaction.
DIFFERENCES:
activity
portability
preferredlocalaction

13. 
1.




2.
3.

1.
2.
3.
4.
5.
APPLICATIONOFNSAIDS
Withanalgesicandanti-inflammatorypurpose:
rheumaticdiseasesandotherdiseasesofthe
musculoskeletalsystem
Neurologicaldiseases-neuralgia,neuritis,radiculitis);
painsyndrome;
primarydysmenorrhea(painassociatedwithincreased
uterinetoneduetoprostaglandinimbalance).
Fever
Preventionofarterialthrombosis(ASA)
CONTRAINDICATIONS
Individualintolerance
Gastrointestinalerosionsandulcers
Pregnancy(withtheexceptionofASAasanantiplatelet)
Chronichepatitisandreducedrenalfunction
Leuco-andthrombocytopenia

14. GeneralindicationsforuseofNSAIDs



Rheumatoiddiseases(rheumatoid
arthritis,reactivesynoviitis,osteoarthritis,
ankylosingspondylitis)
Asanalgesics(painsyndromeofvarious
originswiththeinflammatorycomponent)
Asanantipyretic(feverwithinfectiousand
inflammatorydiseases)

15. Generalcontraindications





Gastrointestinalulcer
Severeabnormalliverandkidney
function
Hematomesis
Bronchialasthma
Individualintolerance

16. RisksofdevelopmentofNSAIDs-
gastropathy








ageover65years
smoking,
alcoholabuse
historyofgastrointestinaldiseases,
concomitantuseofglucocorticoids,
immunosuppressants,
anticoagulants,
long-termNSAIDtherapy,
takingtwoormoredrugsofthisgroupat
thesametime.

17. 

1.
NSAIDGASTROPATHY
Associatedwiththemainaction-
suppressionofthesynthesisof
prostaglandins
Gastrotoxicity.
NB!Associatedwithasystemiceffectonthe
synthesisofprostaglandins,andnotwitha
localirritanteffectonthegastrointestinal
mucosa,therefore,replacementofthe
dosageformisnoteffective.

18. Undesirablereactions(kidneys)




I.ByblockingthesynthesisofPG-E2andprostacyclin
inthekidneys,NSAIDscausevasoconstrictionand
deteriorationofrenalbloodflow.
Thisleadstothedevelopmentofischemicchangesin
thekidneys,reducedglomerularfiltrationandvolume
ofdiuresis.Asaresult,violationsofwaterand
electrolytemetabolismcanoccur:waterretention,
edema,hypernatremia,hyperkalemia,anincreasein
serumcreatininelevels,anincreaseofbloodpressure.
Indomethacinandphenylbutazone,butadione,ASA
havethemostpronouncedeffectontherenalblood
flow.
II.NSAIDscanhaveadirecteffectonthekidney
parenchyma,causinginterstitialnephritis(theso-
called"analgesicnephropathy").
Themostdangerousinthisregardarephenacetin,
butadioneanalginindomethacin

19. AdverseReactions:Hemotoxicity


Developmentofhypochromicmicrocyticanemia,
hemolyticanemia,thrombocytopenia,derivativesof
pyrazolone,indomethacinandaspirin.Terminationof
thedrugleadstonormalizationofthehemogram
within1-2weeks..???
Complicationsassociatedwithinhibitionofblood
formationinthebonemarrow(leukopenia,
agranulocytosis,thrombocytopenia).
Ahighriskofdevelopingthesecomplicationsis
associatedwithtakinganalgin,isolatedcasesare
describedwhentakingphenylbutazoneand
indomethacin.

20. AdverseReactions:
Hemorhagicsyndrome-
NSAIDsinhibitplateletaggregationand
haveamoderateanticoagulanteffect
duetoinhibitionofprothrombin
formationintheliver.
Asaresult,bleedingmaydevelop
sometimesfromthegastrointestinal
tract..

21. AdverseReactions:Hepatotoxicity



NSAIDsshowahepatotoxiceffectthatdevelops
throughanimmunoallergic,toxicormixed
mechanism.
Toxichepatitisdevelopsonthebackgroundof
long-termadministration(severalmonths)andis
usuallymanifestedbyjaundice.
Moreoften,thesecomplicationsdevelopwiththe
useofphenylbutazone,sulindacanddiclofenac
sodium;extremelyrarely-whentreatingwith
tolmetin,meclofenamicandmefenamicacids.

22. Undesirablereactions(Neurosensorysphere)





Theyaremainlymanifestedbydizziness,
headaches,fatigueandsleepdisorders.
Forindomethacinischaracterizedbythe
developmentofretinopathyandkeratopathy
(depositionofthedrugintheretinaandcornea).
Long-termuseofibuprofencanleadtothe
developmentofopticneuritis.
Mentaldisorderscanmanifestashallucinations,
confusion(upto1.5-4%ofcaseswithindomethacin)
,whichisassociatedwithahighdegreeof
penetrationofthedrugintothecentralnervous
system.
Perhapsatransientdecreaseintheseverityof
hearingwhentakingASA,indomethacin,ibuprofen
andpreparationsofthepyrazolonegroup.

23. AdverseReactions:Allergy


Thefrequencyofhypersensitivityreactions
duringNSAIDtherapydecreasesinthe
followingsequence:
diclofenac>naproxen>piroxicam>
ibuprofen>indomethacin>ketoprofen.

24. Undesirablereactions:Bronchospasm


Asarule,itdevelopsinpatientswithbronchial
asthmaandmoreoftenwhentakingaspirin
Itcanbecausedbyallergicmechanisms,
inhibitionofprostaglandinPG-E2synthesis,
whichisanendogenousbronchodilator,and
theprevalenceofanalternativearachidonic
acidresultingintheformationofleukotrienes
(LT-C4,D4,E4),causingbronchospasm.

25. Undesirablereactions(teratogenicity)


ASA(especiallyinthefirsttrimesterofpregnancy)
leadstothedevelopmentofsplittingoftheupper
palateinthefetus(8-14casesper100
observations).
TheuseofNSAIDsinthelastweeksofpregnancy
(especiallyindomethacin)provokesinhibitionof
labor.Indomethacincanleadtoprematureclosure
ofthearterialductinthefetus,whichcauses
pulmonaryhyperplasiaandhypertensioninthe
pulmonarycirculation.

26. Mutagenicity,carcinogenicity–adverse
effects



Casesofthedevelopmentofacuteleukemiahave
beendescribedin0.8%ofpatientswhohavetakena
butadioneoveradailydoseofmorethan0.45gfor6
-12months.
Frequentandseriouscomplicationsledtothe
prohibitionoftheuseoffluphenamicacid,indoprofen,
benoxaprofen,zomax,oxyfenbutazone,isoxicamina
numberofcountries.
Amidopyrineisexcludedfrommedicalusedueto
possiblecarcinogenicity.Carcinogenicproperties
(developmentofbladdercancer)havealsobeen
identifiedinphenacetin.Inmanycountries,phenacetin
isbanned.

27. Adversereactions(prolongationof
pregnancyanddelayoflabor)
Thiseffectisduetothefactthat
prostaglandins(PG-E2andPG-F2a)stimulate
themyometrium.

28. Classification
Group1-NSAIDswithpronouncedanti-
inflammatoryactivity








a)acetylated:
-acetylsalicylicacid(ASA)-
(aspirin);
-lysinemonoacetylsalicylate
(aspizol,laspal);
b)non-acetylated:
-sodiumsalicylate;
-cholinsalicylate(sakhol);
-salicylamide;
-Dolobid(diflunisal);
-disalcide;
-trilisat.

29. Classification
2.Pyrazolidines




-azapropazone(reimox);
-klofezon;
-phenylbutazone(butadion);
-hydroxyphenylbutazone.

30. Classification
Group1-NSAIDswithpronouncedanti-inflammatoryactivity
3.Indoleacetic
acidderivatives



-indomethacin
(metindol);
-Sulindac
(klinoril);
-etodalak(lodin)
;

31. Classification
4.Phenylaceticacid
derivatives:



-diclofenacsodium
(ortofen,voltaren);
-Diclofenacpotassium
(voltaren-Rapid);
-fentiazak(donorest);

32. 5.Oxycams




-piroxicam(roxicam);
-Tenoxicam(tenoctin)
;
-Meloxicam(Movalis);
-Lornoxicam
(Ksefokam).

33. Classification
NSAIDswithpronouncedanti-inflammatory
activity
6.Alkanones -nabumeton
(relifex).

34. Classification
 7.Propionicacidderivatives







-naproxen(naprosyn);
-sodiumnaproxen(apranx);
-Ketoprofen(Kanavon,profenid,oruvel);
-flurbiprofen(flugaline);
-Fenoprofen(fenopron);
-fenbufen(lederlen);
-tiaprofenicacid(Surgam).

35. Group2-NSAIDswithanti-inflammatoryactivity
Anthranilicacid
derivatives
(fenamata)





-Mefenamicacid
(pomstal);
-meclofenamic
acid(meklomet);
-niflumicacid
(donalgin,nifluril);
-Morniflumate
(nifluril);
-tolfenamicacid
(clotam).

36. Classification
Group2-NSAIDswithanti-inflammatory
activity
Pyrazolones



-Metamizole
(Analgin);
-minophenazon
e(amidopyrine);
-propifenazone.

37. Classification
Group2-NSAIDswithanti-inflammatoryactivity
Para-
aminophenol
derivatives


-phenacetin;
-paracetamol.

38. Paracetamol

39. Classification
Group2-NSAIDswithanti-inflammatory
activity
Heteroaryl
AceticAcid
Derivatives


ketorolak
-tolmetin
(tolectin).

40. Classification
Group2-NSAIDswithanti-inflammatoryactivity
Others 


-prokvazon
(biarizon);
-benzydamine
(tantum);
-Nimesulide
(mesulide);

41. FEATURES OF SOME NSAIDsFEATURESOFSOMENSAIDs
Indomethac
in
pronouncedanti-inflammatoryactivity
severenephrotoxicity


Ibuprofen
Naproxen
Diclofenac
bestefficacyandsafetyprofileamongnon-
selectiveNSAIDs

Metamizole weakanti-inflammatoryeffect
pronouncedanalgesiceffectwithacentral
component
antispasmodiceffect
severehematotoxicity




Paracetamo
l
weakanti-inflammatoryeffect
pronouncedantipyreticandanalgesiceffectwith
acentralcomponent
hepatotoxicity,nephrotoxicity



Ketorolac pronouncedanalgesiceffect

42. Anti-inflammatoryeffect




2.NSAIDssuppresspredominantlythe
exudationphase.Themostpowerful
drugs
indomethacin,
diclofenac
phenylbutazone
Theyalsoactontheproliferationphase
(reducingcollagensynthesisandthe
associatedtissuehardening),but
weakerthanattheexudativephase.
AtthephaseofalterationNPVSvirtually
havenoeffect.

43. Analgesiceffect




NSAIDsdonotaffectpainreceptors,butbyblocking
theexudation,stabilizingthelysosomemembranes,
theyindirectlyreducethenumberofreceptorsthatare
sensitivetochemicalstimuli.
TheanalgesiceffectofNSAIDsismorepronounced
forpainsoflowandmediumintensity,whichare
localizedinmuscles,joints,tendons,nervetrunks,as
wellasheadachesandtoothaches.Withsevere
visceralpainassociatedwithinjury,mostNSAIDsare
noteffective.
Thereisahypothesisaboutthestimulatingeffectof
NSAIDsontheproductionofendogenouspeptides
withanalgesiceffects(suchasendorphins)
Centralaction(Ketoprofen)

44. 



Indomethacin,butadione,naproxen,
ibuprofencauseaprimary
immunosuppressiveeffect.
Thesecondaryimmunosuppressiveeffect
isalsodetermined:
-adecreaseincapillarypermeability,
whichcomplicatesthecontactof
immunocompetentcellswiththeantigen,
antibodieswiththesubstrate;
-stabilizationoflysosomalmembranesin
macrophages,whichlimitsthesplittingof
antigens,necessaryforthedevelopment
oftheimmuneresponse.

45. Desensitizingeffect



ReducethecontentofPG-E2and
leukocytesinthefocusofinflammation,
whichinhibitsthechemotaxisof
monocytes;
Inhibittheformationof
hydroheptanotrenicacid,whichreduces
thechemotaxisofT-lymphocytes,
eosinophilsandpolymorphonuclear
leukocytesinthefocusofinflammation;
Inhibitlymphocyteblasttransformation,
whichrequiresPG.

46. COX-2inhibitors
Celecoxib(Celecoxib,Celebrex)
375timesmoreselectivelyblocksCOX-2,
comparedwithCOX-1
pronouncedanti-inflammatoryand
analgesiceffects
usedtotreatchronicinflammatory
lesionsofmusculoskeletalorgans

47. Rofecoxib
COX-2inhibitors
wellexpressed
analgesic,anti-
inflammatoryand
antipyreticeffects

48. ADVANTAGES AND DISADVANTAGES OF COX-2 SELECTIVE
INHIBITORS (COKSIBS)
ADVANTAGESANDDISADVANTAGESOFCOX-2SELECTIVE
INHIBITORS(COKSIBS)
PURPOSEOFCREATION-suppressionofinflammationand
painwithoutdisruptingtheregulatoryfunctionsof
prostanoids.
PROBLEM-COX-2-dependentprostanoidshaveanumberof
adaptivefunctions,thesuppressionofwhichincreasesthe
riskofdisturbanceofhomeostasis.
PRACTICE-increasedriskofvascularcomplicationsinthe
appointmentofcoxibswithanalgesicandanti-inflammatory
purposes(rofecoksib,celecoxib,valdecoxib).
TACTICS-short-termprescribingofminimumeffective
dosesforstrictindicationsandundermedicalsupervision.

49. CARDIOVASCULAR EFFECTS of COX-2 INHIBITIONCARDIOVASCULAREFFECTSofCOX-2INHIBITION
Inhibitionofthesynthesisofprostacyclinin
vesselsandthelackofeffectonthesynthesisof
thromboxaneinplatelets
Prostanoidimbalance
Prothromboticcondition
Increasedriskofthromboticembolic
cardiovascularevents

50. RECOMMENDATIONS OF THE EUROPEAN AGENCY ON DRUGS (EMEA) ON
THE USE OF COX-2 INHIBITORS
RECOMMENDATIONSOFTHEEUROPEANAGENCYONDRUGS(EMEA)ON
THEUSEOFCOX-2INHIBITORS





Contraindications:
Ischemicheartdisease
cerebralvasculardisease(stroke)
peripheralarterydisease
Precautions:
thepresenceofriskfactorsforheartdisease-
hypertension,hyperlipidemia,diabetes,smoking
inthepresenceofriskfactors,COX-2inhibitors
areusedintheabsenceofanalternativeinthe
lowestdoseovertheshortestperiodoftime.

51. ThedurationofsomeNSAIDs
DRUG Durationofaction,h
Acetylsalicylicacid 4-6
Diclofenac 8-12
Ibuprofen 6-8
Indomethacin 6-12
Meloxicam 24
Naproxen 12
Nimesulide 12
Piroxicam 24
Celecoxib 12-24

52. Meansthatmainlyaffectthelipoxygenase
metabolismofeicosanoids
I.
II.
5-lipoxygenaseinhibitors:zileuton
Ii.LeukotrienecysLT1receptorantagonists:
zafirlukast,montelukast,verlukast,pranlukast,
cinalukast,iralukast,pobilukast

53. Meansthatmainlyaffectthelipoxygenase
metabolismofeicosanoids
Zileuton(Zileuton,Zyflo)
Ithasanti-asthmaeffect.
Takingzileutonreduces
thesynthesisof
leukotrienesandasa
result,thelikelihoodof
developing
bronchospasm,edemaof
thebronchialmucosa
decreases.

54. Rulesofappointmentanddosingof
SAIDs



Dosage
Anynewpatientforthispatientshouldbe
prescribedfirstinthelowestdose.
Withgoodtolerancein2-3daysincreasethe
dailydose.
Restrictionsonmaximumdosesofaspirin,
indomethacin,phenylbutazone,andpiroxicam
remain.

55. RulesofappointmentanddosingofNSAIDs




Timeofintake
Withalongcourseassignment(forexample,
inrheumatology),NSAIDsaretakenafter
meals.
Butforaquickanalgesicorantipyretic
effect,itispreferabletoprescribethem30
minutesbeforeamealor2hoursaftera
meal,drinking1/2-1cupofwater.
Aftertakingfor15minutes,itisadvisable
nottogotobedinordertopreventthe
developmentofesophagitis

56. 11.ANTICYTICANIMALS
Cyclosporine-Tacrolimuspolypeptide-asyntheticanalogue
Themechanismofaction-reversiblysuppresstheproductionofIL-2and
FRTl
Highnephro-andhepatotoxicity
Basiliximab-chimericmouse/humanmonoclonalantibodies(IgG1k,
recombinantDNAtechnology).
Mechanismofaction-Reversiblyblockstheα-subunitoftheIL-2receptor
complex(IL-2Rα(CD25antigen))activatedbyT-landdisrupts
interactionwithhypertension.Doesnotcausecytokinereleaseand
myelosuppression.
Itiswelltolerated,sideeffectsfromthegastrointestinaltract,
cardiovascularsystem,OD,NS.
Areasofapplication-systemicdiseasesoftheconnectivetissue,
preventionoftransplantrejection

57. PHARMACOTHERAPY of GOUTSPHARMACOTHERAPYofGOUTS
Gout-ahereditarymetabolicdisease
characterizedbyrepeated
episodesofacutearthritisdueto
thedepositionofsodiumuratein
thejointsandcartilage.
Uratolithiasisispossible.
Thereasonisahighserumurealevel.
•
•
•
•
PATHOGENESIS
Depositionofurateinthe
joints
Infiltrationofthesynovial
membranebygranulocytes,
uratephagocytosis
PHdropinsynovialfluid
Furtherdepositionofurates
•
•
•
•
APPROACHES
Uricacidexcretion
PhagocytosisInhibition
Inhibitionofuricacidsynthesis
Suppressionofinflammationand
pain

58. PHARMACOTHERAPYofGout
1.
2.
1.
1.
2.
3.
Kolkhitsin
MECHANISMOFACTION:
Colchicine+intracellulartubulin→inhibitionofpolymerizationin
microtubules→suppressionofintracellulartransportandmigration
ofleukocytes→suppressionofphagocytosisandthereleaseof
inflammatorymediators
NSAID
NB!Acetylsalicylicacidinlowdosesretainsuricacid,inhibitingthe
secretioninthekidneys-iscontraindicatedinpatientswithgout.
URICOSURICDRUGS(probenecid,sulfinpyrazon)
ACTIONMECHANISM:inhibitsthereabsorptionofuricacidfromthe
proximaltubulesofthekidneys,increasestheexcretionwithurine.
NB!Maintainthevolumeofurine(atleast3l/day)andpH>6.0.

59. 4.



ALLOPURINOL
MECHANISMOFACTION:Purine
nucleotidesareconvertedtoxanthineor
hypoxanthineandareoxidizedtouric
acidwiththeparticipationofxanthine
oxidase(KO).AllopurinolinhibitsCO.
Tactics:
Reliefofacuteattack-colchicine,
NSAIDs.
Preventionofexacerbationsand
uratolithiasis
-colchicineallopurinoluricosuricdrugs

60. theEnd!!