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Nonsteroidal Anti-Inflammatory Drugs: DR Tarek M Nasrallah Al - Azhar
Nonsteroidal Anti-Inflammatory Drugs: DR Tarek M Nasrallah Al - Azhar
ANTI-INFLAMMATORY
DRUGS
Dr TAREK M NASRALLAH
AL - AZHAR
NSAIDs
Large and chemically diverse group
of drugs with the following
properties:
Analgesic
Anti inflammatory
Antipyretic
1) The decrease in vasodilator
prostaglandins (PGE2, PGI2) means less
vasodilatation and, indirectly, less edema.
2) The inhibition of activity of adhesion
molecule.
(3) Accumulation of inflammatory cells is also
reduced
decreased prostaglandin generation means
less sensitization of nociceptive nerve
endings to inflammatory mediators such as
bradykinin and 5-hydroxytryptamine.
Relief of headache is probably due to
decreased prostaglandin-mediated
vasodilatation
This is partly due to a decrease
in the mediator prostaglandin
that is responsible for elevating
the hypothalamic set-point for
temperature control in fever.
Prostaglandins were isolated from human semen in
1936 by Ulf von Euler. He named them Prostaglandins
because he believed they came from the prostate gland.
The Swedish scientist received the Nobel Prize in
medicine in 1970 for this work.
Since his work in this area it has been determined that
they exist and are synthesized in almost every cell of the
body.
They are synthesized in the same cell on which they act.
COX Expression Function Inhibitors
constitutively organ pain, platelet
function, stomach NSAIDs
COX-1 throughout the
including aspirin
body protection
NSAIDs, COX 2
Inducible: inflammati
Inducible and inhibitors
on, pain, fever
COX-2 constitutively in including
Constitutive: synaptic
brain, kidney celecoxib
plasticity
(Celobrex )
PHYSIOLOGIC PATHOLOGIC
TEMPERATURE FEVER
CONTROL ASTHMA
BRONCHIAL TONE ULCERS
CYTOPROTECTION DIARRHEA
INTESTINAL DYSMENORRHEA
MOBILITY INFLAMMATION
MYOMETRIAL TONE BONE EROSION
SEMEN VIABILITY
PAIN
PGE2, PGI2
VASODILATION,
ACT SYNERGISTICALLY WITH OTHER
MEDIATORS
HISTAMINE, COMPLEMENT,
BRONCHODILATATION
INHIBITION OF PLATELET AGGREGATION
TXA2
PROMOTION OF PLATLET AGGREGATION
COX-2
INDUCIBLE
INFLAMMATORY AND
NEOPLATIC SITES ALSO
PRESENT IN KIDNEY,
UTERUS. OVARY
BRAIN, SMALL INTESTINE
Act as :
1. Cytokine inhibitors ( IL-1, TNF, IL-8),
antibodies or antibody fragments.
Antagonists to various peptides that
contribute to cytokine-mediated responses
(e.g., substance P, bradykinin).
2. Inhibitors of cell adhesion molecules : these
include soluble fragments of receptors to
bind cell adhesion molecules and use of
antibodies, peptides, and carbohydrate
moieties to block cell adhesion molecules.
3. phospholipase A2 inhibitors -
glucocorticoids but whose toxicity will
be less frequent and severe than that
of the steroids.
4. Inhibitors of lipoxygenase and
leukotriene receptors
5. Isoform specific inhibitors of
cyclooxygenase (meloxicam).
6. Reduction of superoxide radicals,
7. Induction of apoptosis,
8. Inhibition of adhesion molecule expression,
9. Decrease of nitric oxide synthase,
10. Modification of lymphocyte activity,
11.Alteration of cellular membrane functions
NSAIDs can be classified based on their
chemical structure or mechanism of action.
Older NSAIDs were known long before their
mechanism of action was elucidated and
were for this reason classified by chemical
structure or origin.
Newer substances are more often
classified by mechanism of action
Ibuprofen
Dexibuprofen
Naproxen
Fenoprofen
Ketoprofen
Dexketoprofen
Flurbiprofen
Oxaprozin
Loxoprofen
Indomethacin
Tolmetin
Sulindac
Etodolac
Ketorolac
Diclofenac Safety alert by FDA
Nabumetone drug itself is non-acidic but the
active, principal metabolite has a carboxylic acid
group
Lysine clonixinate
Piroxicam
Meloxicam
Tenoxicam
Droxicam
Lornoxicam
Isoxicam
Natural
Hyperforin
Figwort
Mefenamic acid
Meclofenamic acid
Flufenamic acid
Tolfenamic acid
(Celecoxib( FDA alert
)Rofecoxib( withdrawn from market
(Valdecoxib( withdrawn from market
Parecoxib FDA withdrawn, licenced in the EU
Lumiracoxib TGA cancelled registration
Etoricoxib FDA withdrawn, licenced in the EU
Firocoxib used in dogs and horses
(Nimesulide( systemic preparations are banned by
several countries for the potential risk of
hepatotoxicity
Others
Licofelone acts by inhibiting LOX (lipooxygenase) &
COX and hence known as 5-LOX/COX inhibitor
Lysine clonixinate
• Analgesic, no anti‐inflammatory
effect.
• Can replace morphine in mild to
moderate postsurgical pain.
• IM, IV.
• Similar toxicities. Renal toxicity
common with chronic use.
Peak Cp 30-60
Dose <65 years: 20 mg (orally), then 10 mg every 4-6 hours
not to exceed 40 mg/24 hours
>65 years 10 mg every 4-6 hours not to exceed 40 mg/24 hours
Commonly given parenterally (60 mg IM followed by 30 mg every
6 hours, or 30 mg IV every 6 hours
Potent analgesic, poor anti inflammatory
Protein binding 99%
Metabolites glucuronide conjugate (90%)
t1/2 4-6 hours
Analogue of indomethacin and similar
profile; anti-inflammatory mainly with
analgesic and antipyretic activity and
uricosuric action.
It is used for RA, OA and as a post-operative
analgesic.
It may cause GI ulceration and hemorrhage
at high doses. This drug is well absorbed
Peak Cp 1 hour
Dose 200-400 mg 3-4 times/day
Some COX-2 selectivity
Protein binding 99%
Metabolites Hepatic metabolites
T 1/2 7 hours
• Half‐life of 45 hrs. Once‐daily dosing.
Delay onset of action.
• High doses inhibits PMN migration,
decrease oxygen radical production, inhibits
lymphocyte function.
• Used in osteoarthritis, ankylosing
spondylitis and rheumatoid arthritis.
• Adverse effects: GI symptoms, dizziness,
tinnitus, headache, rash. Peptic ulcer (9.5
higher).
• Short half life (1‐2 hrs), high 1st pass
metabolism accumulates in synovial fluid after oral
administration
• GI S/E : in about 20% pt. Severe effects like GI
distress, GI bleeding, gastric ulceration less
frequent than other NSAIDs and similar to
celecoxib.
• High doses impairs renal function. Elevates liver
enzymes.
• CI : children, pregnant women and nursing
mothers
Most potent inhibitor of prostaglandin synthesis (COX ‐1)
May also inhibit phospholipase A ,C
• Orally absorbed, highly bound to plasma proteins, half
‐life 2hrs.
• Metabolized in liver, excreted in bile and urine.
• A/E : GI, severe migraine (20 ‐25%), dizziness,
confusion and depression, risk of fluid retention,
hyperkalemia and blood dyscrasias.
• Contraindicated in pregnancy and in patients with
psychosis.
•Uses : Treatment of patent ductus arteriosus in
premature babies.
GOOD ABSORPTION
HEPATIC METABOLISM
HIGHLY PROTEIN BOUND
BOTH ENTEROHEPATIC AND RENAL
EXCRETION
VARIABLE HALF LIFES
SHORT HALF LIFE-MORE RAPID EFFECT AND
CLEARANCE
IBUPROFEN,DICLOFENAC,INDOMETHACIN,
Aspirin 65 – 325 mg 4-6 Available as rectal, liquid, and sustained-release forms. Do not use in
Max: 3600mg children <12 years
old with suspected viral infection, due to potential of Reye’s
syndrome. Causes irreversible
inhibition of platelet aggregation. Anti-inflammatory effects start at
3600mg/day.
Acetaminophen 65 – 325 mg 4-6 No peripheral anti-inflammatory or antiplatelet properties. Available as
Max: 4000mg ER:8 rectal, liquid, and
sustained-release forms
Fenoprofen 100 - 300 mg 6–8
Max: 3200mg
Ibuprofen 200 - 400 mg 6–8 May inhibit anti-platelet effect of aspirin if administered
Max: 3200mg concomitantly. Take aspirin 30
minutes before ibuprofen or take ibuprofen 8 hours after
aspirin.Lowest incidence of GI side effects. Weaker anti-inflammatory
properties
Flurbiprofen 100 mg 6 - 12
Max: 300mg
Meloxicam 7.5 – 15 mg 24
Max: 15mg
Piroxicam 10 – 20 mg 24 High risk of GI side effects. Doses> 20mg daily associated
Meclofenamate sodium 50 – 100 mg 6-8
Max: 400mg