this lecture was done in the East Coast Activity

1. NSAIDs side efects
Muhamed Al Rohani, MD
Aug. 2014

2. NSAIDs calcification and physiology
Group 1 Non selective inhibit both COX-1, COX-2 Ibuprofen, diclofenac,
piroxicam, naproxen
Group 2 NSAIDs both COX, but 10 fold more for COX-2 Celecoxib, meloxicam,
nimesulide, etodolac
Group 3 NSAIDs strongly inhibit COX-2 and weak COX-1
inhibitors
Rofecoxib, NS-398
Group 4 NSAIDs weak for both COXs Sodium salicylate, nabmetone

3. ROLE OF PROSTAGLANDINS
PHYSIOLOGIC
Temperature control
Bronchial tone
Cytoprotection
Intestinal mobility
Myometrial tone
PATHOLOGIC
Fever
GIT ulcers and diarrhea ASTHMA
Asthma
Dysmenorrhea
Inflammation
Vasodilatation
Inhibition of platelet aggregation
Bronchodilatation
Pain
Bone erosion
Increase risk of mortality

4. COX-1: Constitutive COX-2: Regulated
• Homeostatic
– Protection of gastric
mucosa
– Platelet activation
– Renal functions
– Macrophage
differentiation
Pathologic
– Information
– Pain
– Fever
– Dysregulated
proliferation
• Tissue Repair
• Physiologic
– Reproduction
– Renal functions
– Other (see text)
• Development
– kidney
Exists in the tissue as constitutive isoform (COX-1).
At site of inflammation, cytokines stim the induction of the 2nd isoform (COX-2).
Inhibition of COX-2 is thought to be due to the anti-inflammatory actions of NSAIDs.
Inhibition of COX-1 is responsible for their GIT toxicity.
Most currently used NSAIDs are somewhat selective for COX-1, but selective COX-2
inhibitors are available.

5. Clinical and chemical effects of NSAIDs
Inhibition of :
– Cyclooxygenase enzymes
– Lipoxygenase enzymes
– Superoxide generation
– Lysosomal enzyme release
– Neutrophil activity
– Lymphocyte function
– Cytokine release
– Cartilage metabolism
Use in:
1. Rheumatoid arthritis
2. Osteoarthritis
3. Acute Gout
4. Dysmenorrhea
5. Headache and migraine
6. Postoperative pain
7. Fever
8. Pain and inflammation

6. Selective COX-2 Inhibitors
• The highly selective COX-2 are: celecoxib, rofecoxib, valdecoxib
– 2004 withdrawal of rofecoxib due to risk of MI and ischemic strocks
– 2005 FDA concluded that all COX-2 inhibitors due to increased CV events
– European Medicine Agency (EMA) concluded that all COX-2 inhibitors are C/I in patient with
IHD or stroke
• Anti-inflammatory with less adverse effects, especially GI events.
• Potential toxicities: kidney and platelets - ? increased risk of thrombotic
events.
• Assoc with MI and stroke because they do not inhibit platelet aggregation.
Thus,.. should not be given to patients with CV disease
But the GIT side effects decreased by ~50%.

7. NSAIDS: GIT
NSAIDs - Gastric Irritant Effects: Molecular Mechanisms
PGs reduce H+ secretion and increase mucous production
Consequently, NSAIDs cause some degree of gastric upset due to inhibition of PG synthesis

8. Figure 1 Prostaglandins’ (PGs’) role in the gastrointestinal tract (GI) in health, disease, and
effects of ns-NSAIDs and s-NSAIDs.
Radi Z A Toxicol Pathol 2009;37:34-46
Copyright © by Society of Toxicologic Pathology

9. Gastrointestinal
PGs (generated via COX-1)
1) inhibit stomach acid secretion,
2) stimulate mucus and HCO3
- secretion, vasodilation and therefore,
3) cytoprotective for the gastric mucosa.
Gestation
PGs (generated from COX-2) are involved in the initiation and progression of labor
and delivery.
Inhibition of PGs:
Dyspepsia, abd. Pain and discomfort 8 – 20%
 Gastric ulcers 15-30%
 Duodenal ulcer 10% also diverticulitis and bleedings
 Complications:
Perforations
Bleeding

10. Hepatic
Rare side effect
Elevation of transaminases with NSAIDs including aspirin
Acute liver injury or failure (1.1 to 3.7 / 100000
Sulindac hepatic injury 27/ 100000
Long period of therapy like RA or OA associated with higher risk
Diclofenac showed higher rate of toxicity
Liver cirrhosis associated with impairment of coagulation
Risk factors
Hepatic failure or cirrhosis
Hepatitis C

12. Peptic Ulcer HHoossppiittaalliizzaattiioonn RRaatteess
100
70 75 80 85 90
40
30
20
10
0
UUnnccoommpplliiccaatteedd
HHeemmoorrrrhhaaggee
PPeerrffoorraattiioonn
KKuurraattaa JJHH.. SSeemmiinn GGaassttrrooiinntteesstt DDiiss 11999933::44
RRaattee
ppeerr
110000,,000000
GGaassttrriicc UUllcceerr DDuuooddeennaall UUllcceerr
80
60
40
20
0
UUnnccoommpplliiccaatteedd
HHeemmoorrrrhhaaggee
PPeerrffoorraattiioonn
70 75 80 85 90
YYeeaarr YYeeaarr

13. Figure 2 Severe indomethacin-induced gastric mucosal hemorrhage and ulceration at the
gastro-duodenal junction (arrows) in a dog.
Radi Z A Toxicol Pathol 2009;37:34-46
Copyright © by Society of Toxicologic Pathology

16. NSAIDS: Cardiovascular
Cardiovascular
1. Risk of MI, recurrent of MI, (second heart attack) with COX-2 (rofecoxib and
valdocoxib) but less with celebrex
2. Risk of HF,
3. Risk of stroke
4. Risk of atrial fibrillation
5. Risk of HTN
Mechanisms:
 COX-1 and COX-2 inhibition by non selective and selective NSAIDs
 Imbalance of vasodilatory prostacyclin and PGE2 versus vasoconstrictive thromoxane
A2 leading to thrombosis.
 Na and water retention exacerbates HF, HTN and Edema
• NSAIDs use in pts with CHF associated with significant increase of mortality and morbidity
Atherosclerosis
Inhibition of COX-2 can destabilize atherosclerotic plaques (due to its anti-inflammatory actions)
Blood vessels/smooth muscle
COX-2 derived PGI2 can antagonize catecholamine- and angiotensin II-induced vasoconstriction (NSAIDs
can elevate BP).

17. Anti-platelet effects:
Inhibition of platelet COX-1-derived TxA2 with the net effect of increasing bleeding
time (inhibition of platelet aggregation)
Endothelial COX-2 derived PGI2 can inhibit platelet aggregation (inhibition augments
aggregation by TxA2).
To avoid in
Perioperative setting in general
Cardiac operations
Continue aspirin
 combination with anticoagulants

18. 3. Pharmacodynamic Effects of NSAIDs
NSAIDs and Platelets/Endothelial Cells

19. NSAIDs and Platelets/Endothelial Cells
- Reduces platelet aggregation
- Most of these drugs will potentiate the action of oral anticoagulants such as coumadin,
by their effects on platelet aggregation
- An 80 mg dose will increase bleeding time for 2 folds
Note: Selective inhibition of COX-2 will inhibit the production of
PGI2 but not of thromboxaneA2, which is produced by COX-1.

20. NSAIDs Selectivity

21. PGs:
NSAIDS: RENAL
Controlling renin release
Regulating vascular tone
Controlling tubular function
COX-2:
COX-2:
Macula densa
Epithelial cells
Ascending loop of Henle
Modularly interstitial cells
Macula densa
Epithelial cells
Ascending loop of Henle
Modularly interstitial cells
COX-1:
role in hemodynamic regulation
COX-1:
role in hemodynamic regulation
Vascular endothelium
Vascular endothelium
Collecting ducts
Loop of Henle
Collecting ducts
Loop of Henle
1. Increase renal perfusion
2. Dilation of vascular bed
1. Increase renal perfusion
2. Dilation of vascular bed

22. NSAIDs – Effects on Renal Function
Afferent
arteriole
Efferent
arteriole
ACEI/
ARB
NSAIDS,
 Low
volume
 Poor renal
perfusion
normal
PGs not participated
PGs vasodilator
when angiotensin II
or catercholamines
elevated
Risky patients
• Dehydrated patients
• Patients with CHF
• Patients using diuretics or RAS blockers
• CLD patients with low renal perfusion
• Patients with fluid overload

23. Renal injury:
• ATN or AIN leading to AKI or ARF,
• Hyperkalemia
Post operative use of NSAIDs:
RRisiskk
- Reduction in RF (drop of CrCl about 16 ml/min
- Fluid correction
- Lithiasis and or coexisting diseases (DM, HTN)
- No case needs HD
Heart failure
Heart failure
HTN
HTN

24. NSAIDS
Respiratory system
 Rarely induce pulmonary problems
 Bronchospasm in pts with aspirin or other
 Asthma aspirin – induced asthma (0.07% in general population, 21% in asthmatics
 Acute attacks as SOB mostly allergic reaction
 Nasal congestion and recurrent sinusitis
 Aspirin-exacerbated respiratory disease
Most of the side effects are related to non-selective NSAIDs
CNS:
Reversible tinnitus
Psychosis
Cognitive changes
Aseptic meningitis
Confusion, depression, dizziness

25. VIGOR - Confirmed Thrombotic
Patients with Events (Rates per 100 Patient-Years)
Event Category
Rofecoxib
N=4047
Naproxen
N=4029
Relative Risk
(95% CI)
Confirmed
CV events
45 (1.7) 19 (0.7) 0.42
(0.25, 0.72)
Cardiac
events
28 (1.0) 10 (0.4) 0.36
(0.17, 0.74)
Cerebrovascular
events
11 (0.4) 8 (0.3) 0.73
(0.29, 1.80)
Peripheral
vascular events
6 (0.2) 1 (0.04) 0.17
(0.00, 1.37)
Cardiovascular Events
Source: Data on file, MSD

26. Effect of Celecoxib & Rofecoxib on
PGIM
200
160
120
80
40
0
Urinary 2,3 dinor-6-keto-PGF1a (PGIM)
Placebo
N=7
* p<0.05 vs. placebo.
Celecoxib
400 mg
N=7
Ibuprofen
800 mg
N=7
Urinary PGI-M (pg/mg creatinine)
(Mean ± SE)
**
*
Placebo
N=12
Rofecoxib
50 mg QD
N=12
Indomethacin
50 mg TID
N=10
**
**
Single Dose Rx† 200
Two Weeks Rx††
160
120
80
40
0
† Proc. Natl. Acad Sci. USA 1999;96:272-277.
†† **p<0.01 vs. J. Pharmacol. Exp. Ther. 1999;289:735-741.
placebo.

27. NSAIDS: pregnancy and lactation
 NSAIDs are not known to be teratogenic in human
 NSADs generally considered safe in pregnancy (low doses, intermittent,
discontinued 6 -8 weeks before term)
 When NASIDs used:
 Prolonged gestation and labor
 Increased peripartum blood loss
 Anemia
 Fetus:
 Cutaneous and intracranial bleeding
 Pulmonary hypertension
 Impaired renal function
Lactation
Risk of bleeding and intoxication salycilate in neonate
Avoid of aspirin in breastfeeding mothers

28. TThhaannkk yyoouu