Non-steroidal anti-

inflammatory drugs(NSAIDs)
Learning objectives
At the end of the session the students should be able;
• Recall the role of prostaglandins in inflammation, fever and pain
• Identify the role of cyclooxygenase enzyme in the synthesis of
prostaglandin
• Classify NSAIDs
• Describe the mechanism of action of aspirin as analgesic,
antipyretic, anti inflammatory and antiplatelet
• Identify the therapeutic uses and adverse effects of aspirin in
relation with its mechanism
• Briefly describe the unique pharmacological properties of important
NSAIDs

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HORIZONTAL INTEGRATION
PATHOLOGY
  Prostaglandins are chemical messengers
of • Inflammation
• Fever
• Pain

Prostaglandins, prostacyclin and thromboxane are

collectively called Prostanoid

They are biologically active lipids that are derived from

the action of cyclooxygenases or prostaglandin
synthases upon the twenty-carbon essential fatty acids
or eicosanoids, primarily arachidonic acid.

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• Constitutive • Inducible (Cytokines, IL-
I,IFN-γ & growth factors)
• House keeping
• Stress, inflammation, cancer,
(hemostatic) injury & ischemia
 Mucosal protection COX-3
• Constitutive (brain, kidney,
(stomach) reproductive organs & bone)
 Platelet aggregation • Macrophages, leukocytes,
(blood) fibroblasts & endothelial
 Regulation of renal cells
blood flow (kidney)

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 CYCLO-OXYGENASE ENZYME

6
Inflammation
• Acute
• Chronic
• Immune response
Inflammation
• Response of vascular and supporting tissue to
injury
Acute inflammation
• Increased permeability leads to outpouring from vessels,
leading to edema and release of various mediators.
• Histamine
• Serotonin
• Bradykinin
• Prostaglandins
• Leukotrines
Chronic inflammation
• Uncontrolled infection leads to chronic inflammation
• Residual damage takes place
e.g.Rheumatoid arthritis damage to joints
Mediators
• Interleukins
• Tumor necrosis factor
• Interferons
• Platelet derived factors
Immune response
• Neutrophils and lymphocytes to control the infection
Mediators
• Prostaglandins
• Leukotriens
Prostaglandin
Biosynthesis,
Function, and
Pharmacologic
Inhibition.
 CORE
PHARMACOLOGY
Classification of NSAIDs
A.Non-Selective COX Inhibitors. (Inhibitors of
both COX I & II)
1. Drugs with Analgesic & Marked Anti-
inflammatory Effects:
a. Salicylic Acid Derivatives
 Aspirin (Acetylsalicylic acid)
 Diflunisal
 Sodium Salicylate
 Magnesium Choline salicylate
 Salicylsalicylate
b. Pyrazolon Derivatives
Apazone, Phenylbutazone , Oxyphenbutazone
c. Acetic Acid Derivatives
Diclofenac , Tolmetin , ketorolac
Indomethacin , Etodolac , Sulnidac
d. Oxicams ( Enolic acids)
Piroxicam , Tenoxicam
e. Naphthylacetic Acid Prodrug:
Nabumetone
2.Drugs with Analgesic & Moderate
Anti-inflammatory Effect:
a. Propionic acid derivatives
Ibuprofen, Fenoprofen, Flurbiprofen ,
Ketoprofen , Naproxen, oxaprozin , carprofen ,
Tiaprofen
b. Fenamates
Mefenamic , Meclofenamic & Flufenamic acid
3. Drug with Analgesic & no Anti-
inflammatory Effect:
Para aminophenol Derivative
Acetaminophen
B. Selective Cyclooxygenase II (COX II)
Inhibitors.
Celecoxib , Roficoxib , Etoribcoxib
Valdecoxib, Meloxicam ,Nimesulide
Aspirin (acetyl salicylic acid)
• Prototype drug
• Salicylic acid—pKa 3.5
• Source -----willow bark
Pharmacokinetics
• Absorption:
Well absorbed from stomach &upper small
intestine
• Distribution:
wide , crosses placental barrier
PPL: In 1-2hrs. t1/2: 15 min.
• Metabolism:
Rapid hydrolysis by Esterases in blood &
tissues in to Salicylate & Acetic Acid.
Salicylate is 80-90-% PPB
Salicylate is metabolized in liver into:
1.Salicyluric acid (glycine conjugate)
2.Glucuronide conjugate
3.Salicylate-----Oxidized to--- Gentisic acid
when dose is small (600mg/d) ---- First order kinetics &

t1/2 is 3-5hrs
-when dose is large (>3.6g/d) ---- Zero order kinetics &
t1/2 is 12—16 hrs

•
Excretion:
-25 % excreted unchanged & 75 % as
-metabolites in urine ,
-enhanced by ALKLINIZATION.
Mechanism of action of Aspirin
As Anti-inflammatory:
Inhibit biosynthesis of PGs, by irreversibly
acetylating cyclo-oxygenase enzyme ,
both isoforms i.e.COX-I & COX-II
As Analgesic:
Reduced production of PGs in injured tissue may ↓
activation of pain sensors.
Inhibits pain stimuli at a subcortical site.
As Antipyretic:
• Block the production of prostaglandins, which are
responsible for resetting the hypothalamus at a higher
levels
• Thus they reset back to normal
AS Antiplatelet:
• In low doses irreversible acetylation of COX-1 enzyme in
platelets ,so action lasts for 8-10 days (life span of plt).
• Low doses < 300mg/ d inhibit TXA2 synthesis in
platelets
• higher doses inhibit prostacycline also.
VERTICAL INTEGRATION
MEDICINE
Therapeutic Uses of Aspirin
1. Analgesic :
Aspirin is one of the most frequently used
analgesic
Severe pain is not controlled by aspirin
a. used alone in pain like.
• : Headache, Myalgia, Arthralgia, Neuralgia
• osteomyelitis, osteoarthritis. Toothache
Dysmenhoea
b. With opioids – synergistic action
In pain of cancer metastases in bone
Post operative pain-  requirement of opioids.
 2.Anti pyretic :↓ body temp in fever, not effective
in raised body temp→ due to heat stroke or
malignancy
3. Acute rheumatic fever
4. Rheumatoid Arthritis, Osteoarthritis
5.Anti Platelet :
Post myocardial infarction & post stroke
patients.
↓ incidence of Transient ischemic attacks,
Unstable angina,
Coronary artery thrombosis with myocardial
infarction
Thrombosis after coronary artery bypass grafting.
6. Pregnancy induced hypertension & pre-
eclampsia.
an inherited renal tubular disorder caused by a defective
7. In Bartter’s syndromesalt reabsorption in the thick ascending limb of loop of
Henle, resulting in salt wasting, hypokalemia, and
metabolic alkalosis

8. Chemoprophylaxis of cancer of colon

9. Closure of PDA
10. Diarrhoea after Radiation & Cholera.
11. Prophylaxis of Cataract.
12. Systemic Mastocytosis with antihistamines.
13. With Niacin to improve compliance– ↓ flushing
Dosage of Aspirin

• Three dosage range

• Low dose
<100mg/d (81-325mg) ↓ Platelet Aggregation
• Intermediate dose
325-1000mg/d Analgesic, Antipyretic
• High dose
4000mg/d Anti-Inflammatory
Adverse Effects of Aspirin
At therapeutic doses
1. Gastric Intolerance:
The most common & serious is gastritis,
Gastric ulceration or Exacerbation of PU
 Dyspepsia& Heart burn , Abdominal Pain
 Nausea & Vomiting, Hematemesis
 Fecal blood loss
 Iron deficiency Anaemia
 CORE
PHARMACOLOGY
Special Prep. Of Aspirin to decrease gastric
intolerance:
• Aloxiprin (Enteric coated aspirin)
• Benorylate (Aspirin paracetamol ester)
• Buffered Aspirin
• Aspirin with Misoprostol
2. Impaired haemostasis: ↓ Platelet
Aggregation & Hypoprothrobinaemia:
3 . Hepatotoxicity
4. Decreased renal function
5. Allergic / Hyper sensitivity Reactions:
Bronchial asthma , Skin rashes , Rhinitis
7. Effects on CNS:
In large doses: Salicylism--- Vomiting ,tinnitus, ↓
hearing ,vertigo.
Still larger doses: Hyperpnea due to direct
effect on medulla
In Toxic Doses: Resp.Alkalosis , followed by
metabolic Acidosis , Repiratory depression ,
Hyperpyrexia , Cardiotoxicity
Glucose intolerance.
9. ↑ Risk of Reye’s syndrome
10. Drug Interaction:
Drug Interactions
• Corticosteroids , NSAIDs: ↑ GIT A/E.
• With ACE inhibitors. ↓ Antihypertensive effect
• With warfarin & Alcohol: ↑ GIT bleed.
• Probenecid & sufinpyrazone: Aspirin antagonizes
uricosuric action, inhibits tubular secretion of uric
acid (in low doses).
• Aspirin displaces Sulfonylureas, methotrexate,
warfarin, indomathacin , naproxen , ketoprofen,
fenoprofen from PPB sites.
• Aspirin ↓ diuretic action of fursemide, thiazides,
spironolactone.
• Aspirin blocks the active transport of penicillin from
CSF to blood.
Contraindications & Precautions
• Peptic ulcer.
• Hemophilia.
• Aspirin hypersensitivity
• Children with a viral illness.
• Chronic liver disease.
• Aspirin should be stopped one week before
elective surgery.
• Avoid high doses in G-6-PD deficient.
• Consider drug interactions.
Management of Aspirin Poisoning
1. Gastric Lavage
2. Activated Charcoal
3. Correct fluid, electrolyte & acid base balance.
4. Maintain high urine out put.
5. Keep airway patent.
6. Decrease body temperature by cold sponging.
1. Vit. K, I/V to correct hypopthrombinemia.
8. Diazepam I/V for convulsions.
9. Promote excretion by NaHCO3 I/V to alkalinize
urine, maintain pH at 8.o.
10. Haemodialysis in severe acidosis & coma.
11. Ventilatory assistance in severe cases.
Topically used Salicylates
• Methyl salicylates
Inflammatory bowel disease:
• Mesalamine ---
Suppository & rectal suspension enema.
Drugs with only Analgesic Effect

• Acetaminophen/Paracetamol
Para-aminophenol derivative
MOA:
• Selective COX-III Inhibitor in CNS
• Analgesic ,antipyretic.
• No anti-inflammatory
• No effect on platelet aggregation
• No effect on uric acid excretion.
Pharmacokinetics
• Oral
• Peak blood conc. 30—60 min
• Poorly bound to PP
• Metabolism
• Half life—2 -3 hrs
Therapeutic uses
1. Mild to moderate pain like Aspirin
2. Antipyretic
3. Preferred to Aspirin
▫ In pt. with Peptic ulcer, Haemophilia
▫ Pt. allergic to Aspirin.
▫ Concomitantly with Probenecid
▫ In children with viral infections
Toxicity of Acetaminophen
At therapeutic doses
• Rash & Allergic reactions.
• Drug fever.
• Mild increase in hepatic enzymes.
With over dosage:
Doses above 4G may be toxic. 15G may be fatal.
• Hepatic necrosis.
• Renal tubular necrosis.
• Hypoglycemic coma.
• Mechanism: Due to hepatotoxic metabolite N-
Acetyl-p-benzoquinone/ N- Acetyl
benzoquinoneimine
Management of Toxicity
• Gastric Lavage
• Activated Charcoal
• Correct fluid, electrolyte & acid base balance
• Antidote
• Precursers of Glutathion
• Antidote
1. N-Acetylsysteine by I/V infusion
2. Methionine & cysteine--orally
Selective COX II Inhibitors
• Selective COX-2 inhibitors.
• Have analgesic, antipyretic, & anti-inflammatory
effects similar to non selective NSAIDs
• GIT A/E (mediated by COX-1) less than non
selective NSAIDs
• No inhibition of platelet aggregation,
• So no cardioprotective effects.
• High incidence of CV thrombotic events ,MI &
stroke , (Rofecoxib).
• Renal toxicities similar to non selective NSAIDs: Not
recommended in severe renal inefficiency.
• Specially useful in osteoarithritis & Rh. Arthritis.
• Also used in Primary familial adenomatus polyposis
(celecoxib)
• Dysmenorrhea
• Acute gouty arthritis
• Acute musculoskeletal pain & ankylosing
spondylitis.
• Useful in patients undergoing bone repair /
operation.
Celecoxib: Sulfonamide
• Long half life: 11 hrs
• May cause rashes.
• Metabolized by CYPC29 -- interaction with
warfarin.
Etoricoxib:
Valdecoxib:
Meloxicam:
Nimesulide:
Acetic Acid Derivatives
Diclofenac
Phenylacetic acid derivative.

MOA: Non-selective Cox inhibitor.

Less Gastric irritation
Good anti-inflammatory.
Uses & dosage forms
• Prevention of postoperative ophthalmic
inflammation after intraocular lens
implantation: 1% Eye drops
• Solar keratoses: 3% gela treatment that involves administering pain medication before a surgical
procedure or tissue injury to reduce or prevent postoperative pain
• Choice for Preemptive analgesia with nausea --
rectal suppository.
• Oral mouthwash & intramuscular Injection.
• Also available in combination with misoprostol
& omeprazole.
Adverse effects

• Nephrotoxic– Impaired renal blood flow & GFR

• ↑ Liver enzymes
Etodolac:
• 10 times more selective Cox-2 inhibitor.
• Good for post-operative relief after coronary
artery by pass operation.
• Less gastric intolerance.
Indomethacin:
• Indole derivative.
• Potent non selective COX inhibitor.
• May also inhibit Phospholipase- A2 & C.
• ↓ neutrophil migration also ↓ T & B cell proliferation.
Therapeutic Uses:
• Gout, ankylosing spondylitis
• PDA.
• Conjunctival & gingival inflammation.
a condition that causes chronic pain
• Post laminectomy syndrome-- epidural inj. and other symptoms after a
laminectomy, a type of spinal surgery
A/E of Indomethacin:
• GIT adverse effects
• Pancrentitis
• Headache
• Hyperkalemia.
Rare:
• Renal papillary necrosis.
• Psychosis with hallucination
• Hepatic abnormalities
Oxicams ( Enolic acids)
• Piroxicam (feldene)
• Tenoxicam
 Piroxicam:
Oxicam derivative.
MOA:
• Non-selective Cox inhibitors
• Inhibition of chemotaxis
• Inhibits lymphocyte function
• ↓ O2 radical production
• Long t ½ - once daily dosage
• Metabolized in liver
• A/E:
• peptic ulcer & bleeding (at higher dose > 20
mg/d ) 9.5 times higher than other NSAIDs.
Propionic acid derivatives:
• Less Gastric irritation
MOA
• like Aspirin & Also Inhibit leukocyte migration.
• Good anti- inflammatory
• Do not potentiate effect of oral anticoagulants /
Hypoglycemics
• Nephrotoxic —
• Ac. renal failure , Interstitial nephritis.
Nephrotic syndrome.
Ibuprofen: – prototype
• 2400 mg = 4 g of aspirin.
• More effective in closure of PDA
• Prep. Oral tablet, liquid , topical cream , I/V.
• t ½ : 2 hrs
Adverse effects
• Aseptic meningitis in SLE patients
• Interaction with anticoagulant
• Rare agranulocytosis
• Aplastic anaemia
• Fenoprofen: interstitial nephritis
• Ketoprofen: Also inhibits lipooxygenase, not
superior to other NSAIDs.
• Naproxen:
• More Toxic
• Rare allergic pneumonitis, vasculitis,
pseudoporphyria.
• Oxaprozin: t ½: 50-60hrs.
• Tiaprofen: t ½ : 1-2 hrs, in elderly: 2-4 hrs,
inhibits renal uric acid reabsorption
Fenamates
Mefenamic acid, Meclofenamic
Flufenamic acid
Inhibit both COX & Phospholipase A2.
 Non selective NSAIDs VS COX-2 SELECTIVE NSAIDs

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RESEARCH, FUTURE
DEVELOPMENTS AND BIOETHICS
• Santos-Gallego, C.G. and Badimon, J., 2021. Overview of aspirin and platelet
biology. The American Journal of Cardiology, 144, pp.S2-S9.

• Walsh, S.W. and Strauss III, J.F., 2021. The road to low-dose aspirin therapy
for the prevention of preeclampsia began with the placenta. International
Journal of Molecular Sciences, 22(13), p.6985.

• Cornu, C., Grange, C., Regalin, A., Munier, J., Ounissi, S., Reynaud, N.,
Kassai-Koupai, B., Sallet, P. and Nony, P., 2020. Effect of non-steroidal anti-
inflammatory drugs on sport performance indices in healthy people: a meta-
analysis of randomized controlled trials. Sports Medicine-Open, 6(1), pp.1-11.

• Zhang, M., Xia, F., Xia, S., Zhou, W., Zhang, Y., Han, X., Zhao, K., Feng, L.,
Dong, R., Tian, D. and Yu, Y., 2022. NSAID-associated small intestinal
injury: an overview from animal model development to pathogenesis,
treatment, and prevention. Frontiers in Pharmacology, 13.