Transcript NSAIDs
NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS
(NSAIDS)
Dr Sasan Zaeri
(PharmD, PhD)
Department of Pharmacology
Inflammatory cascade
Triggers
Infection
Tissue and/or
vessel damage
Inflammatory
Mediators
Acute Inflammatory Response
Note this is a common & non-specific response
- Redness
- Heat
- Swelling
- Pain
Drugs block production or effect of
inflammatory mediators
Tissue and/or
vessel damage
Infection
Inflammatory Mediators
o
o
o
o
o
Vasoactive peptides:
Histamine,serotonin
The kinin system
Coagulation cascade
The complement system
Arachidonic Acid
metabolites
NSAIDs
Corticosteroids
Inflammatory Enzymes: PLA2 & COX
3. Zileuton
Montelukast,
zafirlukast
1. Steroids
Phospholipase A2
2.NSAIDS
Arachidonic acid (AA)
Lipoxygenase
Lipoxygenase products
(leukotrienes)
Inflammatory effects
(esp. in asthma)
Cyclooxygenase (COX)
Prostaglandins & thromboxanes
Inflammatory effects
(inducible)
Homeostatic
Functions
(stomach mucus)
COX-1 vs. COX-2
NSAIDS- MECHANISM OF ACTION
Non –Selective NSAIDs inhibit both COX-1
& COX-2 reversibly
Ibuprofen, Diclofenac, Indomethacin,
Naproxen, Mefenamic acid etc.
Aspirin (irreversible COX inhibitor)
Selective NSAIDs inhibit only COX-2
reversibly
Celecoxib
Pharmacological Actions of NonSelective NSAIDs
Analgesic
Antipyretic
(Drug that lowers the
elevated body temperature to normal)
Anti-inflammatory
Anti-platelet
Exceptions: celecoxib, non-acetylated
salicylates
THERAPEUTIC USES SHARED BY NSNSAIDs
Fever
Analgesic
Headache
Migraine
Dental pain
Common cold
THERAPEUTIC USES SHARED BY NSNSAIDs
Rheumatoid
arthritis
Osteoarthritis
Myositis
or other forms of inflammatory
conditions
Dysmenorrhea
ADVERSE EFFECTS SHARED BY
NS-NSAIDS
GIT upsets ( nausea, vomiting)
GIT bleeding & ulceration
Bleeding
Hypersensitivity reaction
Inhibition of uterine
contraction
Salt & water retention
DOSE DEPENDENT
THERAPEUTIC EFFECTS OF ASPIRIN
Antithrombotic
0
Antipyretic,
Analgesic
1
2
Anti-inflammatory
3
Daily dose of aspirin (g)
4
5
Blood Vessel Wall
Endothelial Cell (COX-2)
Arachidonic acid
PGH2
Prostacyclin (PGI2)
cAMP/vessel smooth muscle relaxes
Ca2+/vessel smooth muscle constricts
Platelet (COX-1)
Arachidonic acid
PGH2
Thromboxane (TXA2)
Ca2+ aggregation
cAMP aggregation
Normal physiologic interaction between PGI2 and TXA2
in platelet and endothelial cell biology
ADDED CLINICAL USES
Antiplatelet/Antithrombotic
effect
Decreases platelet production of TXA2 by
COX-1 irreversibly to limit platelet
aggregation and vasoconstriction
Cardioprotective (reducing the risk of
MI)
Acute
rheumatic fever
Prevention
Chronic
Chronic
of pre-eclampsia
gouty arthritis with
large doses
use of small doses , reduce
the incidence of cancer colon
Adverse Effects Related to :
(A) Therapeutic Doses Of Aspirin
Aspirin asthma
Reye's syndrome
Syndrome of hepatic injury &
encephalopathy in kids treated with
aspirin after a viral illness
Aspirin-induced
asthma
Adverse Effects Related to
( B) LARGE DOSES OR PROLONGED
USE OF ASPIRIN
Salicylism ( ringing of ear( tinnitus) ,
vertigo)
Hyperthermia
GI ulcer and bleeding
Metabolic acidosis
ADVERSE EFFECTS RELATED TO HIGH
DOSES
CONTRAINDICATIONS
Children
with viral infections
Patients with GI ulcer or upper GI
bleeding
Patients with hemophilia
Patients
with Aspirin-induced asthma
PARACETAMOL
(acetaminophen)
Commonly used as analgesic
antipyretic drug
CLINICAL USES OF PARACETAMOL
Can be used safely in patients with:
Peptic or gastric ulcers
Bleeding tendency
Allergy to aspirin
Viral infections in children
Pregnancy
ADVERSE EFFECTS
Mainly on liver due to its active metabolite
( N-acetyl-p-benzoquinone)
Large doses cause liver necrosis
Treatment Of toxicity of paracetamol:
N- acetylcysteine : SH- donor to
neutralize the toxic metabolite
ACETAMINOPHEN TOXICITY
Acetaminophen
UDP glucuronosyltransferase
Sulfotransferase
glucuronide
sulfate
CYP2E1
induction
alcohol
Acetylcysteine
(antidote)
Glutathione-Stransferase
glutathione
Live r failure
protein
DICLOFENAC
Clinical uses
o
o
o
o
o
Treatment of rheumatoid arthritis ,
osteoarthritis (accumulates in
synovial fluid in Long-term use )
Analgesic
Antipyretic
Acute gouty arthritis
Locally to prevent post-operative
ophthalmic inflammation
SELECTIVE COX-2 INHIBITORS
General advantages :
o Adverse effects are slighter than other
NSADs
o
o
No effect on platelet aggregation (COX-1)
Long-term studies of the incidence of
clinically significant gastrointestinal
ulcers and bleeding are not yet completed
ADVERSE EFFECTS
Renal
toxicity
Cardiovascular
(high risk of MI)
Rofecoxib and valdecoxib were withdrawn
STILL ON THE MARKET
GENERAL CLINICAL USES
Rheumatoid
arthritis
Osteoarthritis
Acute musculoskeletal pain
Dysmenorrhea
They can also be used in patients with
gastric ulcer , haemophilia for the above
indications