Dr.

Zienab Halem
Faculty of pharmacy
SCU
 Objectives
 What’s inflammation ?
 How does NSAIDs work ?
 Effect of NSAIDs on different organs
 Groups of NSAIDs
 Acetaminophen
 OVERVIEW :

Inflammation is a normal part of a complex

biological response of body tissues to harmful
stimuli caused by physical trauma , noxious
chemicals or microbiologic agents .

Inflammation is triggered by the release of

chemical mediators from injured tissues and
migrating cells .
 The specific chemical mediators vary with the
type of inflammation and include :

Amines : histamine and 5Hydroxytryptamine (serotonin )

Lpids : prostaglandines ( PGs ) , thromboxanes ( TXs ) and
leukotrienes ( LTs ) .
Small peptides : Bradykinin .
Larger peptides : interleukin 1 and tumor necrosis factor α
N.B
Anti inflammatory drugs act by interfere with the
action of specific mediator important in inflammation .
 Non Steroidal anti inflammatory drugs (
NSAIDs ) have analgesic ( pain killer ) , anti pyretic (
fever reducing ) and anti inflammatory effect .

 Steroidal anti inflammatory : Corticosteroids

Acetaminophen ( paracetamol ) isnot considered an

NSAID because it has a very weak anti inflammatory
activity .
 The NSAIDs act by inhibit the synthesis of PGs .

Biosynthesis of prostaglandines ( compound of

Eicosanoids )
Eicosanoids : oxygenation products of polyunsaturated
long chain fatty acids.
e.g : PGs , TXs and LTs .

PGs and TXs are called prostanoids

Eicosanoids arenot stored within cells , but are
synthesized as required .
 Two main pathways are involved in the biosynthesis of
eicosanoids .

1- PGs and TXs are synthesized by cyclic pathway .

2- LTs are synthesized by linear pathway .
 Inhibition of Eicosanoid synthesis :

Corticosteroids block all the known pathways of

eicosanoids synthesis .
NSAIDs block COX activity so block PGs ang TXs
formation .
5-LOX inhibitors (Montelukast ) are used in
bronchial asthma .
 Major rules of Eicosanoids :
PGs
Modulate pain , inflammation and fever .
Control acid secertion and mucus production in the GIT
Control renal blood flow .
Control uterine contraction .
Prostacyclin ( PGIs )
Inhibit platelet aggregation . Induce vasodilation .
TXs
Induce platelet aggregation . Induce vasconstriction .
LTs
Powerful bronchoconstriction .
Increase vascular permeability .
 Pharmacokinetics
Most are excreted renally .
 Pharmacodynamics
Inhibit of COX activity
Aspirin is an irreversibly inhibitor of COX enzyme
while other NSAIDs are reversible inhibitors .
pharmacological action :
1- Anti-inflammatory actions
PGs act as mediator for inflammation , NSAIDs decrease
PGs synthesis so inhibits inflammation .
N.B
COX 2 is expressed during inflammation and injury .
COX 1 is exist in gastric mucosa and kideny epithelial cells .

2- Analgesic
Reduce inflammation .

3- Anti pyretic action .

N.B NSAIDs have no effect on normal body temp .

  Effect of NSAIDs on different organs

bleeding and ulceration

Normally
NSAIDs inhibit COX 1

patients with high risk for GI events : NSAIDs

with PPI or Misoprostol ( PG analogue )

Patient counseling
 TXAs enhance platelet aggregation
 PGIs decrease platelet aggregation

Dose of aspirin ?
  Decrease renal blood flow .

Normally : PGE2 and PGI2 are responsible For

maintaining renal blood flow by vasodilation in the
kidney .

Mechanism of vasodilation in the kidney ???

 NSAIDs decrease sodium and water excretion may
cause edema in some patient .
(( patients with a history of heart failure or kidney
disease ))

 Selective COX2 inhibitors have less effect on renal

blood flow .
Normally : there is a balance between PGIs and TXA2

In heart cells
PGIs is mediated by COX2
TXA2 is mediated by COX1

SO
NSAIDs with a very high degree of COX1
selectivity such as ASPIRIN have a cardiovascular
protective effect .

NSAIDs with a very degree of COX2 selectivity

have a high risk for cardiovascular events ( MI and
strock )
 Aspirin in high dose ≥ 325 mg inhibit PGI2
production and may carry a risk for CVS events .

N.B
ALL NSAIDs aren’t without CVS risk

Naproxen appears to be the least CVS risk .

 There is balance between
COX pathway and LOX pathway .

NSAIDs cause shift from COX to LOX 21

bronchospasm may occur .
 High dose of NSAIDs may cause CNS
stimulation ( confusion and dizziness ) and
tinnitus .
NSAIDs should be used at
the lowest effective dose for
the shortest possible
duration of therapy .
Most NSAIDs are category C in
the 1st and 2nd trimester .
All NSAIDs are category D in 3rd
trimester .

NSAIDs block the synthesis of

PGE1 & PGE2 which are needed
to keep open the ductus
arteriosus

Pulmonary hypertension in
newborns due to premature
closure of ductus arteriosus.
 Persistent opening ductus arteriosus ( patent ductus
arteriosus ) after birth .
Giving emergency IBUPROFEN OR INDOMETHACIN
I.V

 Alprostadil is a PGE1 analogue is used to

maintaining a patent ductus arteriosus in newborns in
certain type of congenital heart disease until
correction surgery can be carried out
 Low dose of Aspirin may be beneficial in
pregnancies at risk for the development of
pregnancy induced hypertension , pre
eclampsia and in fetuses with
congenital heart disease
Most NSAIDs displace
bilirubin through protein
binding & they are
contraindicated when
breastfeeding a neonate
with Jaundice .

The American Academy of

pediatrics considers
Ibuprofen ,
Indomethacin and
Naproxen safe in
breastfeeding women .
 Aspirin ( acetyl salicylic acid )
 The only NSAID irreversibly inactivating COX .
 Rarely used as anti inflammatory .
 Anti platelet ( 75 – 325 mg / day )
 Alkalinization of urine occur increase free
salicylate excretion .
 At low dose of aspirin : uric acid secretion is decreased
 At high doses : Uric acid secretion is increased .
 Aspirin is avoided in gout or patients taking
Probenecid .
 Aspirin is contraindicated in children under 20
years with viral infections Reye’s syndrome .

 Aspirin is NOT given at least one week before

surgery
(( anti-platelet effect of Aspirin lasts 8-10 days .))
 Propionic acid derivatives
 Ibuprofen , dexibuprofen ,
ketoprofen , dexketoprofen ,
flurbiprofen , fenoprofen ,
loxoprofen , naproxen , oxaprozin .
 Used in chronic ttt. Of RA and OA .
 Their GI side effects are generally less than Aspirin.
 Ibuprofen has the lowest risk of causing GI bleeding , it
has about 4 times the analgesic potency of Aspirin .
 Ketoprofen inhibit both COX espicially COX1 and LOX , less
potent than indomethacin , MAX.dose 300 mg / day .
 Naproxen has lowest risk of CV effents , intermediate risk
of stomach ulcers compared to Ibuprofen , may used alone
in menstrual migraine prophylaxis , used for mild to
moderate pain and primary dysmenorrhea.
 Oxaprozin has rapid onset of action and prolonged
duration of action , has mild uricosuric properties and is
more useful in gout than other NSAIDs .
 Doses of ibuprofen
Adult
1200 – 1800 mg /day
Some patients maintance 600 – 1200 mg / day
Not exceed 2400 mg
Children
20 mg /kg / day in divided doses
In juvenile RA : up to 40 mg / kg / day
 100 mg / 5 ml
3 – 6 months ( 5-7 kg ) : 2.5 ml ( 50 mg ) / 3 times .
6-12 months ( 7 – 10 kg ) : 2.5 ml / 3times .
1 – 2 years ( 10 – 14.5 kg ) : 2.5 ml / 3-4 times .
3 – 7 years ( 14.5 – 25 kg ) : 5 ml / 3-4 times .
8 – 12 years ( 25-40 kg ) : 10 ml ( 200 mg ) /3-4 times.
 Acetic acid derivatives
Indomethacin , diclofenac ,
aceclofenac , ketorolac ,
etodolac , sulindac , tolmetin ,
nabumetone .
 Indomethacin very potent , non selective COX , more
antipyretic , 6 times analgesic of ibuprofen , has very high
GI complications and many CV effects .
 Diclofenac is the most anti-inflammatory than
indomethacin , inhibit LOX and higher COX2 selectivity .
First choice NSAID for renal colic .
Very high risk of CV events and moderate risk of GI
complications .
Diclofenac supp. Should be used with causion in children
younger than 3 years old.
 Diclofenac & sulindac cause elevation of liver enzymes so
increased risk for liver toxicity compared with other
NSAIDs
 Aceclofenac its GI complications is lower 2 folds
lesser than naproxen.

 Ketorolac is the most potent and most effective

analgesic
30 mg ketorolac = 10 mg of morphine .( used after
surgery )
Shouldn’t be used orally for more than 5 days or 2 days
for I.V OR I.M .
 Etodolac has low GI complications .

 Sulindac ( rudac ) is powerful anti inflammatory

like indomethacin , lesser inhibiting PGs synthesis
in the kidneys .
Safest NSAID for ttt. OA in older ppl .

 Nabumetone ( ruheumaton ) .. Its effect on BP

control in hypertensive patients on ACEIs is good.

 Dose of diclofenac
100- 150 mg / day in divided doses .
Milder cases 75 -100 mg / day .
Max.dose 200 mg / day .

In children
Supp . 0.5 – 2 mg / kg / day
In RA : 3 mg / kg / day in 2-3 divided doses for max. 4 days
 Catafly syp .
 Children aged 1 year or over should be given :
0.25 to 1 ml / kg / day divided in 2 to 3 doses .

Cataflam drops .
up to 1 year
0.5 – 2 mg / kg ( 1-4 drops ) daily
1 drop = 0.5 mg
 Enolic acid derivatives ( oxicams )
 Piroxicam , tenoxicam , lornoxicam ,meloxicam .
 Piroxicam is non selective COX inhibitor .
 Tenoxicam has long half life ( once daily ) , has a
very high GI complications .
 Lornoxicam has rapid onset of action .
 Meloxicam is higher COX2 selective , has fewer GI
complications with high risk of CV events
( once daily )
N.B
Long term use of Oxicams and ketorolac is
associated with an increased risk of chronic
kidney disease .
 Fenamic acid derivatives
 Mefenamic acid
Non selective COX inhibitor prostaglandins antagonist .
COX 2 >> COX 1
Used in ttt. Of primary dysmenorrhoea .
 Pyrazolone derivatives
 Metamizole ( dipyrone )
Non opioid analgesic , minimal anti inflammatory , anti
pyretic , anti spasmodic .
Selective COX2 inhibitors ( coxibs )
 Celecoxib ,etoricoxib .

Celecoxib is a reversible selective COX2inhibitor .

Less GI complications than other NSAIDs
Sulfonamide structure .

DDI
Fluconazole and fluvastatin elevate serum levels
of celecoxib
 Primary dysmenorrhea : Mefenamic acid ,
ibuprofen , naproxen
Other are effective
 High risk CV risk : IF MUST , NAPROXEN .
 High GI risk : IF MUST , ibuprofen and celecoxib
appear to be the least GI risk + PPI .
 Asthma : 8-20%
 Renal disease : IF MUST , sulindac , aspirin and
Ibuprofen less nephrotoxic .
 Children : Ibuprofen
 Paracetamol
acetaminophen
 Mechanism of action .
Paracetamol inhibit COX3 isozyme found active in the
CNS , rather than at site of inflammation in
peripheral.

Analgesic and anti pyretic .

 Uses :

Children with viral infections or chickenpox

Pregnancy & breastfeeding
Patients with CV risk or GI complications
Asthmatic patients
 Fever and paracetamol .

 Headache
Caffiene accelerate absorption and enhances the
analgesic effect of paracetamol
 Dose :
Adults : 500 mg – 1 g every 4 – 6 hours daily , not exceeding
4 gm daily .
Childern : the following doses may be given every 4-6 hours
< 3 months : 10 mg / kg (( reduce to 5 mg /kg if jaundiced )).
3 mon. – 1 year : 60 – 120 mg .
1-6 years : 120 mg – 250 mg .
6-12 years : 250 mg – 500 mg
 Severe hepatic impairment :
contraindicated .
 Mild to moderate hepatic impairment : use
with caution .
Reduce total daily dose and/or used in combination with
Mthionine . ( GSH analogue )