Download Non-steroidal anti-inflammatory drugs

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