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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