NSAIDS

Benefits,risks,Cost

:_MAIN FEATURES
ANALGESICSANTIPYRTICSANTI-INFLMATORYSNON STEROIDALSNON NARCOTICS-

MECHANISM OF ACTION
Most NSAIDs act as non-selective inhibitors of the enzyme cyclooxygenase, inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. Cyclooxygenase catalyzes the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A2). Prostaglandins act (among other things) as messenger molecules in the process of inflammation.
This mechanism of action was elucidated by John Vane (1927-2004), who later received a Nobel Prize for his work

:_CLASSIFICATION

:_BENEFITS
NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and .inflammation are present NSAIDs are generally indicated for the symptomatic :_relief of the following conditions OSTEOARTHRITISRHEUMATOID ARTHRITISGOUTY ARTHRITISINFLAMATORY ARTHROPATHY (ANKYL;OSING SPONDYLITIS,REITERS(SYNDROME,PSORIATIC .METASTATIC BONE PAIN-

HEADACHE & MIGRAINEFEVERDYSMENORRHOEATISSUE INJURY & INFLAMMATIONILLEUSRENAL COLIC.POST-OPERATIVE PAIN-

They are also given to neonate infants whose ductus arteriosus is not closed within 24 hours of birth Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for inhibition of platelet aggregation. This is useful in the management of arterial thrombosis and prevention of adverse cardiovascular events. Aspirin inhibits platelet aggregation by inhibiting the action of thromboxane -A.

:_RISKS & ADVERSE EFFECT

The widespread use of NSAIDs has meant that the adverse effects of these relatively safe drugs have become increasingly prevalent. The two main adverse drug reactions (ADRs) associated with NSAIDs relate to gastrointestinal (GI) effects and renal effects of the agents.

:_GASTROINTESTINAL

NSAIDs cause a dual insult on the GIT: the acidic molecules directly irritate the gastric mucosa, and inhibition of COX-1 reduces the levels of protective prostaglandins. Inhibition of prostaglandin synthesis in the GI tract causes increased gastric acid secretion, diminished bicarbonate secretion, diminished mucous secretion and diminished trophic effects on epithelial mucosa. Nausea,vomiting,diarrhea,dyspepsia,ulceration bleedind are the most common git problems. Risk of ulceration increases with duration of therapy, and with higher doses. In attempting to minimise GI ADRs, it is advised to use the lowest effective dose for the shortest period of time, a practice which studies show is not often followed. Recent studies show that over 50% of patients taking NSAIDs have sustained damage to their small intestine. There are also some differences in the propensity of individual

Lo of ss ac of id PG se E cr 2 a et n d io P n an GI d 2m cy to edia pr ot ted ec i n tiv hi e e bi t ffe ion ct

NSAID
Loss of PGI2 induced inhibition of LTB4 mediated endothelial adhesion and activation of neutrophils

Leukocyte-Endothelial Interactions

Capillary Obstruction Ischemic Cell Injury

Proteases + Oxygen Radicals Endo/Epithelial Cell Injury

Mucosal Ulceration

RENAL

NSAIDs are also associated with a relatively high incidence of renal adverse drug reactions (ADRs). The mechanism of these renal ADRs is due to changes in renal haemodynamics (blood flow), ordinarily mediated by prostaglandins, which are affected by NSAIDs. Prostaglandins normally cause vasodilation of the afferent arterioles of the glomeruli. This helps maintain normal glomerular perfusion and glomerular filtration rate (GFR), an indicator of renal function. This is particularly important in renal failure where the kidney is trying to maintain renal perfusion pressure by elevated angiotensin II levels. At these elevated levels, angiotensin II also constricts the afferent ateriole into the glomerulus in addition to the efferent arteriole one it normally constricts. Prostaglandins serve to dilate the afferent arteriole; by blocking this prostaglandin-mediated effect, particularly in renal failure, NSAIDs cause unopposed constriction of the afferent arteriole and decreased renal perfusion pressure. These agents may also cause renal impairment, especially in combination with other nephrotoxic agents. Renal failure is especially a risk if the patient

Common ADRs associated with altered renal function include: Salt and fluid retention Hypertension (high blood pressure) Interstitial nephritis Nephrotic syndrome Acute renal failure Acute tubular necrosis

CARDIOVASCULAR

A recent meta-analysis of all trials comparing NSAIDs found an 80% increase in the risk of myocardial infarction with both newer COX-2 antagonists and high dose traditional antiinflammatories compared with placebo. NSAIDs aside from (low-dose) aspirin are associated with a doubled risk of symptomatic heart failure in patients without a history of cardiac disease. In patients with such a history, however, use of NSAIDs (aside from low-dose aspirin) was associated with more than 10-fold increase in heart failure. NSAIDs are estimated to be responsible for up to 20 percent of hospital admissions for congestive heart failure.

PHOTOSESETIVITYOTHERS :_ Common ADRs, other than listed above, include: raised liver enzymes, headache, dizziness. Uncommon ADRs include: hyperkalaemia, confusion, bronchospasm, rash.Rapid and severe swelling of the face and/or body. Ibuprofen may also rarely cause irritable bowel syndrome symptoms.

During pregnancy

NSAIDs are not recommended during pregnancy, particularly during the third trimester. While NSAIDs as a class are not direct teratogens, they may cause premature closure of the fetal ductus arteriosus and renal ADRs in the fetus. Additionally, they are linked with premature birth .Aspirin, however, is used together with heparin in pregnant women with antiphospholipid antibodies In contrast, paracetamol (acetaminophen) is regarded as being safe and well-tolerated during pregnancy.Doses should be taken as prescribed, due to risk of hepatotoxicity with overdoses In France, the country's health agency contraindicates the use of NSAIDs, including aspirin, after the sixth month of pregnancy.

COST

PRESCRIBE THE MOST ECONOMIC NSAID FOR THE SHORTEST PERIOD THAT YOU CAN. THINK ABOUT BALANCE IN COST BETWEEN PROTON PUMP INHIBITOR INTAKE WITH NON-SELECTIVE NSAIDS TO AVOID GIT MANIFESTATION AND SELECTIVE COX-2 NSAIDS.
Most NSAIDs are equally effective as analgesics and anti-inflammatory agents when administered in appropriate doses. New NSAIDs do not possess greater analgesic and anti-inflammatory activity than older NSAIDs.

NSAIDs differ in price ranging from $3.00 per month to $73.00 per month. If health care professionals were to prescribe the lower priced NSAIDs rather than the higher priced NSAIDs,we realize an annual savings of approximately $500,000.00.

If Sodium Naproxen 550mg were changed to Naproxen 500mg, it will save approximately $108,000.00 annually

Cost effectiveness & Cox selectiveness

OBJECTIVE: This study was designed to assess the costeffectiveness of cyclooxygenase-2 specific (COX-2) inhibitors (rofecoxib and celecoxib) over nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in high-risk arthritis patients from the perspective of the Veterans Health Administration (VA). METHODS: This literature-based economic analysis (with data summarized from MEDLINEindexed and other published sources, FDA reports, and data on file at VA San Diego Healthcare System) compared rofecoxib and celecoxib to NSAIDS in two arthritis patient populations considered at higher risk of developing clinically significant upper gastrointestinal events (CSUGIEs): (1) patients of any age with previous medical history of perforation/ulcer/bleed (PUB); and (2) patients 65 years and older (regardless of history of PUB). Two outcome measures were reported: (1) incremental cost per CSUGIE averted over 1 year; and (2) incremental cost per qualityadjusted life-year (QALY) gained, considering both the mortality and morbidity associated with gastrointestinal (including CSUGIEs) and cardiovascular-related adverse events. When possible, costs were modeled to reflect the

RESULTS: Compared to NSAIDS, rofecoxib and celecoxib increased costs but reduced the incidence of CSUGIE. Cost per CSUGIE avoided were $7476 and $16,379 (in patients with a PUB history) and $14,294 and $18,376 (in patients aged > or = 65 years) for celecoxib and rofecoxib, respectively. In both populations, celecoxib was associated with a cost per QALY less than $50,000. In contrast, rofecoxib was found to cost more and result in a net QALY loss, due in particular to the increase in the risk of cardiovascular complications, and was therefore considered costineffective. Results were most dependent on assumptions about the incidence of cardiovascular events and CSUGIE and the COX-2 inhibitors' acquisition price. CONCLUSIONS: This analysis suggests that COX-2 inhibitors may be costeffective from the perspective of the VA. However, cost-effectiveness appears to depend less on the

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