NSAIDs

Dr. Sarker Hafiz Mahmud

MBBS, [Link]
AssistantProfessor
[Link] Pharmacology& Therapeutics
• Immuneandinflammatory reaction
occurin responseto a variety stimuli
including physical damage,microbial
infection, hypersensitivity,
autoimmunity,malignancyandorgan
transplantation.
Pharmacological intervention aimedto
- managesystemic features of
inflammation e.g. pain ,swelling
- minimize tissuedysfunction,permanent
damage.
 NSAIDS
• drugs with diversechemical
structure ,share common
pharmacological properties;
• haveanalgesic ,antipyretic,
anti-inflammatory action , somehas
anti-platelet effect.
 NSAIDs
• differ in pharmacokinetic characteristics
e.g. potency, efficacy, duration of action
andadverseeffects.
• Manydrugs have been developed in
attemptto improve efficacy and
minimizeadverseeffects of aspirin, the
original NSAIDs.
 Classification:chemically
[Link] acidderivatives: Aspirin,Choline-
magnesium salicylate, benorylate,
diflunisal
B. acetic acid derivative:Indomethacin,
etodolac ,Sulindac,Diclofenac, tolmetin,
ketorolac
C. Fenamic acidderivatives :mefenamic
acid, meclofenamic acid, tolfenamic acid
[Link]: Ibuprofen,
ketoprofen,fenoprofen,naproxen,
flurbiprofen,oxaprozin
E..Enolic acidderivatives: Oxicams:
Piroxicam, meloxicam,tenoxicam,
azapropazone
F. Alkanones: Nabumetone
[Link]-acidNSAIDs : Coxibs:Celecoxib,
rofecoxib,etoricoxib,valdecoxib,
 Basedon anti-inflammatory effect:
[Link] anti-inflammatory
Salicylic acidderivative,diclofenac,
indomethacin,phenylbutazone,
piroxicam, meloxicam
[Link] anti-inflammatory :ibuprofen,
ketoprofen, mefenamicacid, nabumetne
[Link] anti-inflammatory: Paracetamol,
ketorolac
 According to their COX specificity
1. Aspirin,ibuprofen, indomethacin, piroxicam,
sulindac are COX1 > COX2
2. Ibuprofen , mefenamic acid equally inhibit
COX 1 = COX 2
3. Indomethacin, diclofenac, naproxen inhibit
both PGs and LTs
4 More selective COX 2 inhibitors are( 5 times
COX 2 selective than COX 1) : Celecoxib,
rofecoxib,valdecoxib,etoricoxib , .
 Common kenetic properties:
• well absorbedorally,not undergo
hepaticfirst pass biotransformation,
food does notaffect absorption and
bioavailability,.
• Arehighly plasma protein ‒bound(>
98%),lowvolumeof distribution.
• NSAIDs are weekacids,are localized in
synovial tissue of inflamedjoint.
• They undergoes enterohepatic
recirculation to varying degree.
• GITirritation correlatewith
entero-hepatic recirculation .
Urinaryexcretion of
• indomethacin is 16% ,of ketorolac is
58% ,of Piroxicamis 5- 10% ,of
naproxen is <1 %;
• Drugs with short half life remains longer
in sinovial fluid than with long half life.
 Common mechanism of action:
• By inhibiting COX 1 at theinflammatory
site ,inhibit PGs (esp.PGE2andPGI2 )
synthesis. Someinhibit LTs
• Inhibit calcium ‒mediated releaseof
mediators.
• Decrease production of interleukins,and
freeradicals
• Decrease chemotaxicproperties
• Decreaasesensitivityof
bradykinin,histamine.
• Decrease free radical production
• decreasesensitivity of vessels to
bradykinin andhistamine
• All (except selective COX2inhibitors )
inhibit platelet aggregation
• ManyNSAIDs reducerisk of colon cancer
 Common adverse effects:
• [Link]: headache,tinnitus,dizziness
• [Link]: Fluidretention, hypertension,
edema,may provoke CCF
• [Link]: dyspepsia,ulceration, bleeding,
aggravate pepticulcer;
• [Link] : Thrombocytopenia,
neutropenia,rarely apastic anemia.
• [Link] dysfunction
• [Link] : interfare autoregulation of renal
bloodflow, may cause hyperkalemia,
proteinuria.
Analgesic nephropathy;
Decrease renal perfusion in CCF,CRF, cirrhosis.
• [Link] system : bronchospasm
• 8. Hypersensitivity : vasomotor rhinitis,
urtecaria,
 SelectiveCOX II inhibitors
• may increaseincidence of edema and
hypertension.
• SelectiveCOX2 inhibitors decrease COX
2mediated PGI2 synthesis ,allow
production of COX-1 derived TxA2
• alter balance between PG I2andTXA2 in
favour of TXA2, therebymay increase
riskof cardiovascular events..
• Rofecoxiband valdecoxib increased
incidenceof cardiovascular thrombotic
events associatedwith COX2inhibition.
 Drug Interaction
• 1. NSAIDs + ACEIs /ARB :→ riskof renal
impairment and hyperkalemia
• [Link] + fluroquinolones : →increase
riskof convulsion
• [Link] + Warfarin , antiplatelets →:
increaserisk of bleeding
• [Link] + sulfonylurea Oral
hypoglycemicagents :→increaseaction
andduration
• [Link] + antihypertensives : →decrease their
action
• [Link] + diuretic : →decrease diuretic effects;
increase potassium retaining action of
potassium sparing diuretics
• [Link] + ciclosporin /tacrolimus :→increase
nephrotoxic effect
• [Link] + aspirin → increase CV risk ,
decrease total anti-inflammatory effect
 Uses of NSAIDs
[Link]
[Link]-inflammatory
[Link]
[Link]-platelet (low doses of aspirin)
[Link] of gestation
[Link] patentductus arteriosus in
neonates
[Link] cancer (by inhibition of COX2).
Several NSAIDs decrease incidence of
colonic cancer .
8. Systemic mastocytosis
 COX 1 COX 2
[Link] most of theCells. [Link] inflammatory cells
inducedby Cytokines,Growth
factor.
[Link] GIT, Kidney & [Link] in inflammatory &
Platelets. immune cells with early
responce.
[Link] stimulation [Link] with growth
increasesCOX-1level (2-4) factor,cytokinesetc. COX-2
folds. increases(10-18)folds.
[Link],PCs producedby COX 1 [Link],PCs producedby COX 2
participatein Physiological participatein inflammatory
function. reactions.
[Link] causes- GI [Link] causes- Cardio
ulceration &Renal function toxicity.
impairment.
 Salicylates:
Willow bark→Salicin →hydrolysis →
salicylic acid.
• Aspirin is acetyl salicylicacid.
• Aspirin,pK 3.5,un-ionized ,lipidsoluble,
well absorbedfrom stomach andupper
GIT.
• Different bufferedpreparation with
higher pH ,
• <600mg doses elimination follow 1st
order kinetic (t ½ is 3-5hs), whileat
higher doses( >3.6 grams) follow zero
order kinetic with t ½ ~15 hours .
• Excretedas free~ 10to 20% as freeand
water soluble metabolites.
• Renal elimination of freesalicylic acid
can be increasedby alkalization of urine.
 [Link]-inflammatory action:
• By inhibition of COX,inhibit
prostaglandin synthesis→oppose PGE2
andPGI2‒induced vasodilatation,
edema and pain.
• opposeeffect of kallikrein system,
stabilize lisosom
 [Link] effect:
at usual doses 300to 2400g daily ,
mediatedbyinhibition ofPGs.
• inhibit pain sensation at subcortical level.
• increases pain threshold,
• inhibit sensitivityto receptors
 [Link] effect:
• endotoxin →on macrophages →release
IL-1 →induce COX1→PG E in
hypothalamus → elevateʻSet point’ to a
higher level →pyrexia.
• NSAIDs →inhibiting PG production
return elevatedʻsetpoint’ to normal
→ dissipateheat
 [Link]-plateletaction:
• Aspirin at doses of 75 to 300 mg daily
irreversibly inhibit cycloxygenase
enzyme through acetylation. In
platelets aspirin at lowerdoses inhibits
TxA2
• Anti-platelet action maypersists through
lifeof theplatelet e.g. ~7days.
• Non-acetylated salicylates (magnesium
choline salicylate,sodium salicylate)are
less analgesic ,no anti-platelet
effect,areaffective anti-inflammatory.
 Ibuprofen
• at doses < 2400 mg daily exertanalgesic
action .
• Co-adminstration
antagonize of ibuprofen
irreversible plateletwith aspirin
inhibition
inducedby aspirin.
• Aspirin should
ibuprofen. be taken 2 our before of
• may cause
reactivity. fluid retention ,bronchospastic
• Ibuprofen topical
osteoarthritis, gel
liquid is
gelusedin
in knee
post- surgical
dental pain.
 Indomethacin
• Is a non-selective COXinhibitor ;also
inhibit phospholipase A andC.
• Use: Gout, ankylosing spondylitis,
Juvenile rheumatoidarthritis ,pleurisy ,
nephriticsyndrome, diabetes incipidus,
to accelerate closure of PDA.
• It shouldbeusedforshort ‒term.
• Adverse effects :common with other
NSAIDs , Maycause pancreatitis,
headache(15 -25%),
dizziness,hematological
toxicities(Thrombocytopenia, aplastic
anemia), ;
 Diclofenac
• GIulceration less than other NSAIDs.
• Daily useof >150 mg impairrenal blood
flow ,GFR,increases hepatic
transaminases.
• 0.1% ophthalmicsolution is usedin post-
operative ophthalmicinflammation,3%
topical gel is usedin solarkeratosis.
Ketoprofen
• Inhibit both cyclo-oxygenase
isoenzymes andlipoxygenase
• SE: GITandCNSrelated adverseeffects
of other NSAIDs.
 Ketorolac
• Is a more analgesic than anti-inflammatory.
• Ketorolac replaces morphine in mild to
moderate post-operative pain.
• decreased opioid requirement by 25-50 %.
• used for short-term management of moderate
pain, post-operative pain in dental surger.
• Renal toxicity is more common with chronic
use
• recommended for short-term (< 5 days) use.
Nabumetone
• is a non-acid NSAIDs and ketone pro-drug;Its
plasma half life 24 hours.
Naproxen
• Is a potentinhibitor of COX, t1/2 is 14 hours.
• SE: allergic pnemonitis, GI adverse effects are
more than ibuprofen.
• Oxaprozin
• Has long plasma half life of 50 -60 hours.
• Sulindac:is a prodrug ,undergo
enterohepatic re-circulation , duration of
action 12-16hours , is renal sparing.
• SE: Stevens-Johnsons syndrome,
nephriticsyndrome, thrombocytopenia,
• Tolmetin : has short half life
 COX-ibs
• Celecoxib is 10-20times COX 2selective
than COX1.
• Celecoxib decreasedrisk of colon cancer.
• As a sulfonamidecelecoxibmay cause
rash.
• coxibs favor TxA2 →increases relative
riskof cardiovascularevents.
• Coxibs causerenal toxicity
(COX2is constitutively activein kidneys)
• Coxibs reducedupper GI adverse effects
by50% , while 4times increased risk of
non-fatal MI.
• Rofecoxib,Valdecoxib increased
carviovascular risk →withdrawn from
market.
Parecoxib
• is pro-drug of valdecoxib, is given im /iv
• Usedin short-term treatment of
post-operativepain
Meloxicam
• inhibits COX2 over COX1 at lowest
dose7.5 mg/day;
• It is not as selective as celecoxib. exerts
fewer GIadverseeffects.
Piroxicam
• Mechanism is commonwith other
NSAIDs, appearedto decrease
polymorpho-nuclear leukocites ,
decreasefree radical formation. GI
bleeding is 10 times higherthan others.
 Paracetamol:
• Inhibit PG synthesis in thebrain ,hardly in
theperiphery.
• It inhibits COX3 ,which mediate pain,
fever; little effect on COX1 andCOX2 →
minimum anti-inflammatoryaction.
• Minor metabolite is N-acetyl ‒
p-benzoquinoneimine, is a high reactive
product.
• In acute over doses >150mg/kg→
quinone intermediate →conjugate with
glutathione→ deplete glutathione
reserve →increasedfreeradicals →
hepaticandrenal necrosis
• Treated by N-acetylcysteine and
methionine which donate -SH group.