Introduction

• Definition of NSAIDS

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are a class of medications

widely used to relieve pain, reduce inflammation, and lower fever. They work
by inhibiting the activity of cyclooxygenase (COX) enzymes, which are
involved in the production of prostaglandins—chemical substances
responsible for pain, inflammation, and fever. Unlike steroids, NSAIDs are
non-hormonal and have a broad range of therapeutic applications, including
managing arthritis, headaches, and minor injuries.

Mechanism of Action

The primary mechanism of action of NSAIDs is the inhibition of

cyclooxygenase (COX) enzymes, which play a crucial role in the synthesis of
prostaglandins and thromboxanes. These are lipid compounds involved in
inflammation, pain, fever, and platelet aggregation.

1.​ Cyclooxygenase Enzymes

​ •​ COX-1: Constitutive enzyme responsible for producing

prostaglandins that protect the gastric mucosa, maintain renal blood flow, and
support platelet function.

​ •​ COX-2: Inducible enzyme produced in response to inflammatory

stimuli, leading to the production of prostaglandins involved in pain,
inflammation, and fever.

​ 2.​ NSAID Action

​ •​ NSAIDs block COX enzymes, reducing the production of

prostaglandins.

​ •​ By inhibiting COX-2, NSAIDs reduce inflammation, pain, and

fever.

​ •​ However, inhibition of COX-1 can lead to side effects such as

gastric irritation and impaired renal function.

​ 3.​ Selective and Non-Selective Inhibition

​ •​ Non-selective NSAIDs (e.g., ibuprofen, aspirin) inhibit both COX-1

and COX-2.
​ •​ Selective COX-2 inhibitors (e.g., celecoxib) preferentially block
COX-2, aiming to minimize gastrointestinal side effects while retaining
anti-inflammatory benefits.

Classification of NSAIDs

1.Non-Selective COX Inhibitors

• These NSAIDs inhibit both COX-1 and COX-2 enzymes without preference,
affecting prostaglandins involved in both physiological and inflammatory processes.

• Examples:

. Aspirin

• Ibuprofen

• Naproxen

• Diclofenac

• Indomethacin

• oxaprozin

• Aspirin is unique as it irreversibly inhibits both

COX-1 and COX-2, providing anti-inflammatory, analgesic, and

antiplatelet effects.

ASPIRIN

Aspirin's long use and availability without prescription diminishes its

glamour compared with that of the newer NSAIDs. Aspirin is now rarely
used as an anti-inflammatory medication and will be reviewed only in
terms of its antiplatelet effects

Mechanisms of Action: Aspirin irreversibly inhibits platelet

COX so that aspirin's antiplatelet effect lasts 8-10 days (the life of the
platelet). In other tissues, synthesis of new COX replaces the inactivated
enzyme so that ordinary doses have a duration of action of 6-12 hours.

Pharmacokinetics of Aspirin
​ 1.​ Absorption

​ •​ Rapidly absorbed from the stomach and upper small

intestine.

​ •​ Peak plasma concentration occurs within 1–2 hours after oral

administration.

​ 2.​ Distribution

​ •​ Widely distributed throughout the body.

​ •​ Binds to plasma proteins, primarily albumin (~90%).

​ 3.​ Metabolism

​ •​ Hydrolyzed to salicylic acid (active metabolite) in the liver

and plasma.

​ •​ Further metabolized in the liver via conjugation to form

water-soluble metabolites.

​ 4.​ Excretion

​ •​ Excreted mainly through the kidneys as metabolites.

​ •​ Excretion is pH-dependent: alkaline urine increases

salicylate elimination.

​ 5.​ Half-Life

​ •​ Aspirin: 15–20 minutes (short due to rapid hydrolysis).

​ •​ Salicylic acid: 2–3 hours (longer at therapeutic doses, but

can increase with higher doses).

Note: At high doses, metabolism becomes saturated, leading to

non-linear pharmacokinetics.

Clinical Uses:
Aspirin decreases the incidence of transient ischemic attacks, unstable
angina, coronary artery thrombosis with myocardial infarction, and
thrombosis after coronary artery bypass grafting

Adverse Effects:

aspirin's main adverse effects at antithrombotic doses are gastric upset

(intolerance) and gastric and duodenal ulcers.

Hepatotoxicity, asthma, rashes, GI bleeding, and renal toxicity rarely if

ever occur at antithrombotic doses.

Epidemiologic studies suggest that long-term use of aspirin at low

dosage is associated with a lower incidence of colon cancer, possibly
related to its COX-inhibiting effects.

Drug drug/ drug food interactions

1. Drug-Drug Interactions

​ •​ Anticoagulants (e.g., warfarin, heparin)

​ •​ Increased risk of bleeding.

​ •​ NSAIDs (e.g., ibuprofen, naproxen)

​ •​ Reduced cardioprotective effects of aspirin and higher

gastrointestinal risks.

​ •​ Corticosteroids

​ •​ Increased risk of gastric ulceration.

​ •​ Antihypertensives (e.g., ACE inhibitors, beta-blockers)

​ •​ Reduced antihypertensive efficacy due to sodium and water

retention.

​ •​ Methotrexate

​ •​ Increased toxicity (e.g., bone marrow suppression) due to

decreased renal clearance.
​ •​ Selective Serotonin Reuptake Inhibitors (SSRIs)

​ •​ Increased risk of gastrointestinal bleeding.

​ •​ Probenecid

​ •​ Reduced uricosuric effect of probenecid.

2. Drug-Food Interactions

​ •​ Alcohol

​ •​ Increased risk of gastrointestinal irritation and bleeding.

​ •​ High-fat meals

​ •​ May delay absorption of aspirin, reducing its onset of action.

Note: Always consult a healthcare provider to manage potential

interactions when using aspirin.

Contraindication

The antiplatelet action of aspirin contraindicates its use by patients with

hemophilia. Although previously not recommended during pregnancy,
aspirin may be valuable in treating preeclampsia-eclampsia.

• Ibuprofen

Mechanism of Action of Ibuprofen

Ibuprofen is a non-selective NSAID that works by inhibiting the activity of

both COX-1 and COX-2 enzymes. These enzymes are involved in the
biosynthesis of prostaglandins and thromboxanes, which mediate pain,
inflammation, and fever.

1. Inhibition of Cyclooxygenase Enzymes

●​ COX-1 inhibition:

​ • Reduces prostaglandins that protect the gastric mucosa and

regulate kidney function.

​ • May lead to gastrointestinal side effects and renal impairment.

​ • COX-2 inhibition:

​ • Reduces prostaglandins involved in the inflammatory response,

leading to decreased pain, swelling, and fever.

2. Reduction of Prostaglandin Synthesis

●​ Prostaglandins sensitize nerve endings, causing pain and

contributing to inflammation and fever.

​ • By reducing prostaglandin production:

​ • Pain relief (analgesic effect)

​ • Inflammation reduction (anti-inflammatory effect)

​ • Fever reduction (antipyretic effect)

3. Reversible Inhibition

●​ Unlike aspirin, ibuprofen causes reversible inhibition of COX

enzymes, meaning its effects are temporary and wear off as the
drug is cleared from the body

Pharmacokinetics

​ 1.​ Absorption

​ •​ Rapidly absorbed from the gastrointestinal tract.

​ •​ Peak plasma concentration occurs within 1–2 hours after oral

administration.

​ 2.​ Distribution

​ •​ Widely distributed in the body.

​ •​ Highly bound to plasma proteins (~98%).

​ 3.​ Metabolism

​ •​ Metabolized in the liver via cytochrome P450 enzymes

(CYP2C9).
​ •​ Converts to inactive metabolites through oxidation and
hydroxylation.

​ 4.​ Excretion

​ •​ Excreted primarily through the kidneys as metabolites

(~90%).

​ •​ Small amounts are excreted unchanged in urine.

​ 5.​ Half-Life

​ •​ 2–4 hours in adults, allowing for multiple daily dosing.

Note: Ibuprofen has a relatively short half-life, necessitating frequent

administration for sustained effects.

Clinical use

Clinical Uses of Ibuprofen

Ibuprofen is a widely used non-selective NSAID with analgesic,

anti-inflammatory, and antipyretic properties. It is prescribed for a variety
of conditions, including the following:

1. Pain Relief (Analgesic Use)

​ •​ Mild to moderate pain:

​ •​ Headache

​ •​ Toothache

​ •​ Back pain

​ •​ Post-surgical pain

​ •​ Menstrual pain (Dysmenorrhea): Effective in reducing

menstrual cramps by inhibiting prostaglandin production.

2. Inflammatory Conditions

​ •​ Arthritis:
​ •​ Rheumatoid arthritis

​ •​ Osteoarthritis

3. Fever Reduction (Antipyretic Use)

​ •​ Treatment of fever in adults and children, often used as an

alternative to paracetamol.

4. Post-Operative and Post-Trauma Inflammation

​ •​ Used to manage pain and swelling following surgery or

injuries.

5. Miscellaneous Uses

​ •​ Gout (acute attacks): Helps alleviate pain and

inflammation.Clinical Uses of Ibuprofen

• Migraine: Used to reduce the intensity of migraine-related pain.

Adverse effects

Adverse Effects of Ibuprofen

​ 1.​ Gastrointestinal

​ •​ Nausea, vomiting

​ •​ Stomach pain, dyspepsia

​ •​ Gastric ulcers, bleeding

​ •​ Perforation (rare but serious)

​ 2.​ Cardiovascular

​ •​ Increased risk of heart attack or stroke (especially with

long-term use or high doses)

​ •​ Hypertension

​ 3.​ Renal
​ •​ Kidney damage (nephrotoxicity)

​ •​ Fluid retention and edema

​ 4.​ Hematological

​ •​ Prolonged bleeding time

​ •​ Anemia (rare)

​ 5.​ Hypersensitivity

​ •​ Rash, itching

​ •​ Anaphylaxis (rare but severe)

​ 6.​ Central Nervous System

​ •​ Dizziness, drowsiness

​ 7.​ Liver

Drug drug/ drug food interaction

1. Drug-Drug Interactions

​ •​ Anticoagulants (e.g., warfarin, heparin)

​ •​ Increased risk of bleeding.

​ •​ Aspirin

​ •​ May reduce aspirin’s cardioprotective effects.

​ •​ Antihypertensives (e.g., ACE inhibitors, diuretics,

beta-blockers)

​ •​ Decreased antihypertensive efficacy due to sodium and

water retention.

​ •​ Methotrexate

​ •​ Increased methotrexate toxicity due to reduced clearance.

​ •​ Lithium
​ •​ Increased lithium levels and potential toxicity.

​ •​ Corticosteroids

​ •​ Higher risk of gastrointestinal ulcers and bleeding.

​ •​ SSRIs

​ •​ Increased risk of gastrointestinal bleeding.

2. Drug-Food Interactions

​ •​ Alcohol

​ •​ Increased risk of gastrointestinal irritation and bleeding.

​ •​ Food

​ •​ May delay absorption but does not significantly reduce

overall bioavailability.

Note: Always inform your healthcare provider about concurrent

medications and dietary habits when using ibuprofen.

Contraindications

Contraindications of Ibuprofen

Ibuprofen is contraindicated in the following conditions:

​ 1.​ Gastrointestinal Disorders

​ •​ Active peptic ulcers

​ •​ History of recurrent gastrointestinal bleeding or perforation

​ •​ Severe gastritis

​ 2.​ Hypersensitivity

​ •​ Allergy to ibuprofen or other NSAIDs (e.g., aspirin)

​ •​ History of NSAID-induced asthma, urticaria, or angioedema

​ 3. Cardiovascular Conditions
 ●​ Severe heart failure

​ • Recent coronary artery bypass graft (CABG) surgery

​ 4.Renal Impairment

2.Selective COX-2 Inhibitors

• These NSAIDs selectively inhibit COX-2, focusing on reducing pain

and inflammation with minimal effect on COX-1 activity, thus decreasing
gastrointestinal and renal side effects.

• Examples:

• Celecoxib

• Meloxicam

Celecoxib

MOA

Celecoxib is a selective COX-2 inhibitor, which works by:

1. Selective Inhibition of COX-2 Enzyme

• Blocks the activity of cyclooxygenase-2

(COX-2), an enzyme involved in the synthesis of prostaglandins during

inflammation.

• Reduces inflammation, pain, and fever without significantly affecting

COX-1, which helps protect the gastric mucosa and maintain renal
function.

2. Reduced Gastrointestinal Side Effects

• By sparing COX-1, celecoxio causes less gastric irritation and bleeding

compared to non-selective NSAIDs.

Pharmacokinetics

1. Absorption
• Well absorbed after oral administration.

• Peak plasma concentration occurs within 2-

4 hours.

2. Distribution

• Highly protein-bound (~97%).

• Distributes widely in tissues.

3. Metabolism

• Metabolized in the liver primarily by CYP2C9

into inactive metabolites.

4. Excretion

• Excreted mainly via feces (~57%) and urine (~27%) as metabolites.

• Minimal unchanged drug is excreted.

5. Half-Life

• -11 hours, allowing for once or twice daily dosing.

Clinical use

1. Rheumatic and Inflammatory Conditions

• Osteoarthritis

• Rheumatoid arthritis

• Ankylosing spondylitis

2. Acute Pain Management

• Postoperative pain

• Musculoskeletal pain

3. Dysmenorrhea
• Relief of menstrual pain and cramps.

4. Familial Adenomatous Polyposis (FAP)

• Reduces the number of colorectal polyps (adjunct therapy).

Adverse effects

1. Gastrointestinal

• Abdominal pain

• Dyspepsia

• Nausea, diarrhea (lower risk of ulcers compared to non-selective

NSAIDs)

2. Cardiovascular

• Increased risk of heart attack and stroke (especially with long-term use
or high doses)

• Hypertension

3. Renal

• Acute kidney injury

• Fluid retention, edema

4. Hypersensitivity

• Rash, itching

• Rare: Stevens-Johnson syndrome, anaphylaxis

5. Hepatic

• Elevated liver enzymes (rarely leading to liver injury)

6. Central Nervous System

• Headache, dizziness

Drug drug / drug food

1. Drug-Drug Interactions

• Anticoagulants (e.g., warfarin)

• Increased risk of bleeding.

• Antihypertensives (e.g., ACE inhibitors, diuretics)

• Reduced antihypertensive efficacy due to fluid retention.

• CYP2C9 inhibitors (e.g., fluconazole)

• Increased plasma levels of celecoxib (risk of toxicity).

• CYP2C9 inducers (e.g., rifampin)

• Reduced efficacy of celecoxib.

• Lithium

• Increased lithium levels and potential toxicity.

• Other NSAIDs or corticosteroids

• Higher risk of gastrointestinal side effects.

2. Drug-Food Interactions

• High-fat meals

• May delay absorption but does not significantly affect' overall efficacy.

Contraindication

1. Allergy or Hypersensitivity

• Allergy to celecoxib, sulfonamides, or other NSAIDS.

2. Cardiovascular Conditions

• History of heart attack, stroke, or severe heart failure.

3. Gastrointestinal Disorders

• Active peptic ulcers or gastrointestinal bleeding.

4. Severe Liver or Renal Impairment

• Liver failure or severe renal dysfunction.

5. Pregnancy

• Third trimester (due to risk of premature ductus arteriosus closure).

6. CABG Surgery

• Contraindicated for perioperative pain in coronary artery bypass graft

surgery.

7. Uncontrolled Hypertension

• Risk of cardiovascular complications.

Meloxicam

MOA

Meloxicam is a non-selective NSAID that works by inhibiting

cyclooxygenase (COX) enzymes:

1. Inhibition of COX-1 and COX-2

• Primarily inhibits COX-2 more selectively than COX-1, which helps

reduce inflammation, pain, and fever.

• COX-1 inhibition is less pronounced, leading to a lower risk of

gastrointestinal side effects compared to non-selective NSAIDs.

2. Reduction of Prostaglandin Synthesis

• By blocking COX enzymes, meloxicam reduces the synthesis of

prostaglandins, which are mediators of inflammation, pain, and fever.

Pharmacokinetics

1. Absorption

• Well absorbed from the gastrointestinal tract.

• Peak plasma concentration occurs within 5-

6 hours after oral administration.

2. Distribution

• Highly protein-bound (~99%) to plasma proteins.

• Widely distributed in tissues, including synovial fluid.

3. Metabolism

• Metabolized in the liver via CYP450

enzymes (mainly CYP2C9).

• Converted to inactive metabolites.

4. Excretion

• Excreted primarily in the feces (~60%) and urine (~16%) as

metabolites.

5. Half-Life

15-20 hours, a' ng for once-daily dosing.

Clinical use

1. Osteoarthritis

• Pain and inflammation management.

2. Rheumatoid Arthritis

• Treatment of pain, swelling, and stiffness.

3. Ankylosing Spondylitis

• Reduces inflammation and pain.

4. Acute Pain

• Used for moderate pain relief, such as postoperative or

musculoskeletal pain.

5. Other Uses
• Short-term treatment of acute flare-ups of gout and other inflammatory
conditions.

Adverse effects

1. Gastrointestinal

• Abdominal pain, nausea

• Dyspepsia

• Risk of gastrointestinal bleeding, ulcers, or perforation

2. Cardiovascular

• Increased risk of heart attack, stroke, and hypertension (especially with

long-term use)

3. Renal

• Kidney dysfunction or acute renal failure

• Fluid retention, edema

4. Hematological

• Anemia (rare)

• Prolonged bleeding time

5. Hypersensitivity

• Rash, itching

• Severe allergic reactions (rare)

6. Liver

• Elevated liver enzymes (rarely leading to liver injury)

7. Central Nervous Svstem

• Headache

Drug drug / food drug interactions

1. Drug-Drug Interactions

​ •​ Anticoagulants (e.g., warfarin)

​ •​ Increased risk of bleeding.

​ •​ Other NSAIDs or Corticosteroids

​ •​ Increased risk of gastrointestinal side effects (e.g., ulcers,

bleeding).

​ •​ Antihypertensives (e.g., ACE inhibitors, diuretics)

​ •​ Reduced antihypertensive efficacy due to fluid retention.

​ •​ Lithium

​ •​ Increased lithium levels, potentially leading to toxicity.

​ •​ Methotrexate

​ •​ Increased risk of methotrexate toxicity (e.g., bone marrow

suppression).

​ •​ Cyclosporine

​ •​ Increased risk of kidney damage.

2. Drug-Food Interactions

.Alcohol

​ • Increased risk of gastrointestinal irritation and bleeding.

​ • Food

​ • Food may delay absorption but does not significantly affect

overall bioavailability.

Contraindication

1. Allergy or Hypersensitivity

• Known hypersensitivity to meloxicam, other NSAIDs, or sulfonamides.