the organs damages as side effects of nsaids
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NSAIDs side efects
Muhamed Al Rohani, MDAug. 2014
NSAIDs calcification and physiologyGroup 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
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
• 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
COX-2: RegulatedCOX-1: Constitutive
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.
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 arthritis2. Osteoarthritis 3. Acute Gout 4. Dysmenorrhea 5. Headache and migraine 6. Postoperative pain 7. Fever 8. Pain and inflammation
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%.
NSAIDs - Gastric Irritant Effects: Molecular Mechanisms
PGs reduce H+ secretion and increase mucous productionConsequently, NSAIDs cause some degree of gastric upset due to inhibition of PG synthesis
NSAIDS: GIT
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
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:
PerforationsBleeding
Hepatic Rare side effectElevation 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 riskDiclofenac showed higher rate of toxicity Liver cirrhosis associated with impairment of coagulation
Risk factors Hepatic failure or cirrhosis Hepatitis C
Peptic Ulcer Hospitalization RatesPeptic Ulcer Hospitalization Rates
Kurata JH. Kurata JH. Semin Gastrointest DisSemin Gastrointest Dis 1993:4 1993:4
RateRate per per
100,000100,000
Gastric UlcerGastric Ulcer Duodenal UlcerDuodenal Ulcer
70 75 80 85 900
20
40
60
80
100
Uncomplicated Uncomplicated
HemorrhageHemorrhage
Perforation Perforation
70 75 80 85 900
20
40
YearYear YearYear
30
10
Uncomplicated Uncomplicated
HemorrhageHemorrhage
Perforation Perforation
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
Cardiovascular1. 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).
NSAIDS: Cardiovascular
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
NSAIDs and Platelets/Endothelial Cells
3. Pharmacodynamic Effects of NSAIDs
- 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
NSAIDs and Platelets/Endothelial Cells
Note: Selective inhibition of COX-2 will inhibit the production of PGI2 but not of thromboxaneA2, which is produced by COX-1.
NSAIDs Selectivity
PGs: Controlling renin release Regulating vascular toneControlling tubular function
COX-1: role in hemodynamic regulation
Vascular endothelium Collecting ducts Loop of Henle
COX-1: role in hemodynamic regulation
Vascular endothelium Collecting ducts Loop of Henle
COX-2:Macula densaEpithelial cellsAscending loop of HenleModularly interstitial cells
COX-2:Macula densaEpithelial cellsAscending loop of HenleModularly interstitial cells
1. Increase renal perfusion 2. Dilation of vascular bed
1. Increase renal perfusion 2. Dilation of vascular bed
NSAIDS: RENAL
Afferent arteriole
Efferent arteriole
ACEI/ ARB
NSAIDS, Low
volume Poor renal
perfusion
normal
NSAIDs – Effects on Renal Function
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
Post operative use of NSAIDs: - Reduction in RF (drop of CrCl about 16 ml/min
- Fluid correction
- Lithiasis and or coexisting diseases (DM, HTN)
- No case needs HD
Renal injury:
• ATN or AIN leading to AKI or ARF,
• Hyperkalemia Risk Risk Heart failure
HTNHeart failure
HTN
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 NSAIDsCNS:
Reversible tinnitus Psychosis Cognitive changesAseptic meningitis Confusion, depression, dizziness
NSAIDS
Patients with Events (Rates per 100 Patient-Years)
Event CategoryRofecoxibN=4047
NaproxenN=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)
VIGOR - Confirmed Thrombotic Cardiovascular Events
Source: Data on file, MSD
Effect of Celecoxib & Rofecoxib on PGIM
* p<0.05 vs. placebo.
0
40
80
120
160
200
PlaceboN=7
Celecoxib 400 mg
N=7
Ibuprofen 800 mg
N=7
Urin
ary
PG
I-M
(pg
/mg
crea
tinin
e)
(Mea
n ±
SE
)
***
PlaceboN=12
Rofecoxib50 mg QD
N=12
Indomethacin50 mg TID
N=10
****
Single Dose Rx† Two Weeks Rx††
0
40
80
120
160
200
† Proc. Natl. Acad Sci. USA 1999;96:272-277.
Urinary 2,3 dinor-6-keto-PGF1(PGIM)
†† J. Pharmacol. Exp. Ther. 1999;289:735-741.**p<0.01 vs. placebo.
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
NSAIDS: pregnancy and lactation
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