NSAIDs

I. Introduction
II. MOA
III. Non-steroidal Anti-inflammatory Drugs
IV. Case Study
Pain
A physiological and emotional experience characterized by
unpleasant feelings usually associated by trauma or disease.
Can be classified either as Acute or Chronic
Can also be classified according to source
• Injury to nerves- neuropathic
• Injury to tissues- nociceptors
Inflammation
• Plays a major role in the pathophysiology of a wide spectrum of disease. It is
primarily a protective response, but if excessive or inappropriately prolonged
can contribute adversely to the disease process.
• Inflammatory cells: neutrophils(e.g. in acute bacterial infections), eosinophils,
mast cells and lymphocytes (e.g. in asthma), monocytes, macrophages and
lymphocytes.
• Inflammatory mediators: prostaglandins, complement and coagulation-
cascade-derived peptides, and cytokines.

• Cardinal Signs of Inflammation

Rubor – redness
Calor – heat
Dolor – pain
Tumor - swelling
Pathway of Prostanoid Synthesis
Phospholipids
(cell membrane)

Phospholipase A2

Arachidonic acid
COX-1
COX-2

PGE2 Prostacyclin Thromboxane

PGD2 PGF2alpha
 Cyclooxygenase

• Is the enzyme that converts arachidonic acid into endoperoxide precursors of

prostaglandins

• Two Isoforms of COX

• COX-1 –(constitutive enzyme) is primarily expressed in noninflammatory cells
-present in platelets, stomach, kidneys, and other tissues.
• COX-2 –(inducible enzyme) is expressed in activated lymphocytes,
polymorphonuclear cells, and other inflammatory cells.
-present in lesser extent in healthy organs (Kidneys).
 PGE1 PGE2 PGF2alpha TXA2 Leukotrienes

Increased Endogenous Released in large Cause Comprise the

secretion of vasodilators amounts from the platelet important mediator of
bicarbonate and endometrium aggregation bronchoconstriction
mucus Natural during and SRS-A (LTC4, LTD4)
vasodilator that menstruation
Decreased acid maintains Leukotriene B4(LTB4)-
secretion patency of the Induced uterine chemotactic factor
ductus arteriosus contraction important in
Relaxed vascular during fetal inflammation
and other smooth development Reduces
muscle involved in the intraocular
ripening of the pressure
*Gastro- cervix at term
protectant
Maintains renal
blood flow
 Mechanism of Action of NSAIDs
Mechanical or chemical stimulation

Membrane Lipids Glucocorticoids

Phospholipase C Phospholipase A2
NSAIDs Lipoxygenase
Free Arachidonic Acid inhibitors

PGH synthase
Lipoxygenase
Cyclooxygenase

Prostaglandins Leukotrines
Thromboxanes
 NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
• Drugs of choice for mild and moderate pain especially with pain especially
with pain associated with inflammation.
NSAIDs
• Inhibit cyclooxygenase (COX). Examples: indomethacin, naproxen, and ibuprofen
Uses: Adverse Effect: Interactions:
• Short term: 1. Central nervous system: Headaches, tinnitus, and dizziness. • Antihypertensive drugs
analgesia/ anti- 2. Cardiovascular: Fluid retention, hypertension, edema, and (reduced effectiveness)
inflammatory; rarely, myocardial infarction, and congestive heart failure. • Diuretics (reduced
• Chronic: 3. Gastrointestinal: Abdominal pain, dysplasia, nausea, vomiting, effectiveness)
symptomatic and rarely, ulcers or bleeding.
relief in arthritis. 4. Hematologic: Rare thrombocytopenia, neutropenia, or even
aplastic anemia.
5. Hepatic: Abnormal liver function tests and rare liver failure.
6. Pulmonary: Asthma.
7. Skin: Rashes, all types, pruritus.
8. Renal: Renal insufficiency, renal failure, hyperkalemia, and
Proteinuria
 NSAIDs and Related Drugs
Cyclooxygenase Inhibitors (NSAIDS)
Nonselective COX-1, COX-2 inhibitors
Salicylates
Aspirin Aspilet ®
→3.2-4g/day- usual adult dose of Aspirin for its Anti-inflammatory effect.
→325mg/day, 1st line in the primary and secondary prevention of acute thrombotic events

→absorbed in the stomach & in the small intestines in the unhydrolyze form
EXCRETION: <600mg/d-1st order, >600mg/d-0th order
(its excretion, enhance with alkalination of the urine;
follows Michaelis Menten Elimination Kinetics
CLINICAL USES: analgesia, antipyretic(inh. CNS response to interleukin-1), anti-inflammatory
Antithrombotic; prevention of colon cancer
SE: GI discomfort, GI ulceration CNS salicylism, vertigo hypersensitivity reaction=RSA, Asthma
Reye's Syndrome- manifest as hepatic failure & encelopathy
- happen when there is a previous or current viral infection
ADMINISTRATION: Must be given w/ or after heavy meal or take PPI before taking Aspirin
RISK FACTORS: Taking multiple NSAIDS: causes Gastritis (blood in the stools)
Current use of Glucocorticoids: Increase inhibition of cytoprotectant action of COX
Pyrazolone derivatives
Phenylbutazone SE: Hematology toxicities – Aplastic anemia, Agranolocyte;
Oxyphenbutazone ATN(Acute tubular necrosis)
CI: Drug allergy, Blood Dyscrasias, Hypertension
Sulfinpyrazone Anturane® *Aromatic Hydrolation – involved in biotransformation of
Phenylbutazone to Oxybutazone
Indole derivatives
Indomethacin Infree® MOA: Inhibits COX-1 than COX-2 *50-70mg tid
VI-Gel® *Increase gastric ulcers
BENEFICIAL: PDA(Patent Ductus Arteriorus)
mx of pain of an acute attacks gout
mx of Barter’s Syndrome
Pyrolle alkanoic acid derivatives
Tolmetin Tolectin®-400mg qid C/I: Gout
Oxicam derivatives
Piroxicam Feldene® MOA: Inhibits COX-1 than COX-2 (represents a class of acidic inhibitors
of Prostaglandins synthetase, although it does not antagonize PGE2
directly)
Highest risk of GI effects. *20mg qd
Phenylacetic acid derivatives
Sulindac Clinoril® -sulfur containing drugs Indications: 0 Arthritis,
-causes SJS(Steven Johnson Syndrome Ostroarthritis
*200mg bid Ankylosing Spondylitis
Diclofenac Voltaren®, Cataflam®, Diclogen *50-75mg qid
Etodolac Etoflam® -has minimal anti-inflammatory activity that are primarily
indicated as analgesic especially in the mx of post-operative pain
Ketorolac -replace
*Etodolac-200-300mg qid
morphine
*Ketorolac-10mg qid
Nabumetone Relafen® *All known NSAIDS are weak acids, except Nabumetone
*1000-2000mg qd

Fenamates
Mefenamic acid Dolfenal®, -not anti-inflammatory *must be given for not more than 5 days
Gardan®, Ponsran® -not antipyretic *never give it to children
Flufenamic acid -but only an analgesic *more toxic than Aspirin
Meclofenamic
 Propionic acid derivative
Ibuprofen Advil®, Dolan FP® -is an arylacetic acid derivative
Medicol®, Midol® -appears comparable to aspirin in the tx of RA, with a lower incidence of
Nuprin®, Motrin® side effect
-also been approved for use in primary dysmenorrheal
-prescribed for Hemophiliac Patient for RA
*600mg qid -exists both as R- & S- enantiomers (S-enantiomer is the only active form
SE: Renal Failure
Ibuprofen+Paracetamol (Alaxan®), Ketoprofen (Orudis®), Flurbiprofen (Ocufen®)-ophthalmic solution
Naproxen (Flanax®, Naprosyn®) *Analgesic and Anti-inflammatory
Selective COX-2 inhibitor
Meloxicam Mobic® *7.5-15mg qd
Specific COX-2 inhibitor (Advantage: Less incidence of gastric irritation or ulceration)
Celecoxib Celebrex®, MOA: Selectively reversibly inhibits COX-2
*100- Celcoxx® CLINICAL USES: Analgesia, antipyretic, and anti-inflammatory
200mg TOXICITY: Nephrotoxicity; hypersensitivity due to increased leukotrines; less risk
bid of GI toxicity than nonselective NSAIDS; greater risk of thrombosis than
nonselective NSAIDS
Eteroxib Arcoxia® *Rofecoxib (Vioxx®) – have been withdrawn from the market or are marketed w/
“black box” warning because of its increase risk of Thrombosis & cardiac death
DMARDS

Disease modifying anti-rheumatic drugs

• NSAIDS provide symptomatic relief but do not alter the long-
term progression of joint destruction in rheumatoid arthritis.
• DMARDS produce long-term depression of the inflammatory
response even though they have little direct anti-
inflammatory effect. They all have a slow onset of action,
with many producing little improvement until about 3
months after starting treatment.
• Most of these agents are contraindicated in pregnant
women.
• DMARDS decrease inflammation, improve symptoms, and
slow the bone damage associated with rheumatoid arthritis.
Rheumatoid arthritis
• Is an immunologic disease that causes significant systemic effects,
shortens life, and reduces mobility and quality of life.
• In rheumatoid arthritis immune complexes are deposited in the
affected joints, causing inflammatory response that is amplified by
eicosanoids .
• Lymphocytes and macrophages accumulate in the synovium,
whereas leukocytes localize mainly in the synovial fluid. The major
eicosanoids produced by leukocytes are leukotrienes, which
facilitate T-cell proliferation and act as chemoattractants. Human
macrophages synthesize the COX products PGE2 and TXA2 and
large amount of leukotrienes.
 DMARDs- alters/ slow down joint destruction
-SAArTs (Slow-acting antirheumatic drugs
Abatacept MOA: inhibits the activation of T cells
AE: increased risk of infection of the upper respiratory tract; anaphylaxis
Azathioprine -metabolize into 6-mercaptopurine
(Imuran®) -2 mg/kg/d
AE: Bone marrow suppression; GI disturbance; increased lymphomas
Methotrexate -1st line DMARDS in RA
(Zexate®), -important to pyrimidine synthesis
(Altrex®) MOA: cytotoxic to rapidly dividing immune cells due to inhibition of dihydrofolate reductase
Inhibit AICAR (aminoimidazole carboxanide tribonucleotide)
Inhibits DNA transcription
CLINICAL USES: Anticancer, rheumatic disorders
SE: Hepatotoxicity (Folic acid-hepatoprotectant)
TOXICITY: Nausea, Mucosal ulcers, Hematotoxicity, Hepatotoxicity, Teratogenicity
ALTERNATIVE: Leflunamide
Leflunomide Arava® -alternative of Methotrexate
Penicillamine Cuprimine® -for copper toxicity/ Wilson’s -also useful in treating Lead poisoning & RA
-alter the function of WBC -is a degradation of product of
-for progressive rheumatoid Arthritis Disease penicillin-type antibiotics
Sulfasalazine -synthetic DMARD, metabolized to sulfapyridine and 5-aminosalicylic acid
INDICATION: RA and reduces radiologic disease progression
2-3g/d
SE: Nausea, vomiting, headache

Gold Compounds
Auranofin Ridaura®
Aurothiomalate Myochrysine® SE: hypersensitivity reaction
Aurothioglucose Solganal®

Biologic Agents
Adalimumab Humiral® *MAB (Monoclonal Antibodies)
Infiximab Remicade® *Inhibit TNF-alpha & also block inflammation
Etanercept Enbrel® -subjecting patients to
inflammation

ANTI-MALARIAL AGENTS MOA: Suppression of T-lymphocyte responses to mitogens; decreased

Chloroquine (Chloromax®) leukocyte chemotaxis; stabilization of lysosomal enzymes; inhibition of RNA
Hydroxychloroquine (Plaquenil®) and DNA synthesis
-6.4mg/kg/d for hydroxychloroquine, 200mg/d for chloroquine
Case Study
• A 48-year-old man presents with compliants of bilateral morning stiffness
in his wrists and knees and pain in these joints on exercise. On physical
examination, the joints are slightly swollen. The rest of the examination is
unremarkable. His laboratory findings are also negative except for slight
anemia, elevated erythrocyte sedimentation rate, and positive rheumatoid
factor. With the diagnosis of rheumatoid arthritis, he is started on a
regimen of naproxen, 220 mg twice daily. After 1 week, the dosage is
increased to 440 mg twice daily. His symptoms are reduced at this dosage,
but he complains of significant heartburn that is not controlled by
antacids. He is then switched to celecoxib, 200 mg twice daily, and on this
regimen his joint symptoms and heartburn resolve. 2 years later; he
returns with increased joint symptoms. His hands, wrists, elbows, feet and
knees are all now involved and appear swollen, warm, and tender. What
therapeutic options should be considered at this time? What are the
possible complications?
This patient had good control of his symptoms for 1 year but now
has a prolonged flare, probably denoting worsening disease (not
just a temporary flare). In addition to physical findings and
measurement of acute-phase reactants such as sedimentation rate
or C-protein, it would be wise to get hand and feet radiographs to
document whether he has developed joint damage. Assuming
such damage is found, the appropriate approach would be either a
combination of nonbiologic DMARDs (eg. Adding sulfasalazine and
hydroxychloroquinone) or adding a biologic medication, usually a
tumor necrosis factor inhibitor. Follow-up should be every 1-3
months to gauge response and toxicity. Adverse events requiring
caution are an increased risk of infection, possible appearance of
lymphoma and rare liver function test or hematologic
abnormalities. Importantly, close follow-up should ensue,
including changing medications every 3-6 months until full disease
control is achieved.