📖 Step 2 — Learning Material

🔹 1️⃣ Introduction

Eicosanoids are powerful biochemical mediators derived from fatty acids that regulate inflammation, pain, fever, allergy, platelet function, and smooth muscle activity. They are produced in almost all tissues of the body, especially at sites of injury and inflammation. Although synthesized in very small amounts, they have potent local effects.

The major eicosanoids include prostaglandins, thromboxanes, leukotrienes, and prostacyclin. These mediators are formed mainly from arachidonic acid released from membrane phospholipids. Their synthesis occurs through cyclo-oxygenase (COX) and lipoxygenase pathways.

Clinically, eicosanoids are extremely important because many commonly used drugs such as aspirin, NSAIDs, corticosteroids, montelukast, and zileuton act by modifying their synthesis or action. Excess or deficiency of eicosanoid activity contributes to diseases like asthma, gastric ulcer, thrombosis, allergy, and chronic inflammation.

Understanding eicosanoid metabolism helps explain:

• Mechanism of inflammation
• Drug action of NSAIDs and steroids
• Bronchial asthma pathogenesis
• Fever and pain mechanisms
• Platelet aggregation and thrombosis

🔹 2️⃣ Foundation Concepts

Key Definitions

• Eicosanoids: Biologically active lipid mediators derived from 20-carbon polyunsaturated fatty acids mainly arachidonic acid.
• Arachidonic acid: A 20-carbon omega-6 fatty acid stored in membrane phospholipids.
• Cyclo-oxygenase (COX): Enzyme pathway producing prostaglandins and thromboxanes.
• Lipoxygenase (LOX): Enzyme pathway producing leukotrienes.
• Prostaglandins (PGs): Mediators involved in inflammation, pain, fever, and smooth muscle regulation.
• Thromboxane (TXA₂): Promotes platelet aggregation and vasoconstriction.
• Prostacyclin (PGI₂): Inhibits platelet aggregation and causes vasodilation.
• Leukotrienes: Mediators important in bronchoconstriction and allergic inflammation.
• NSAIDs: Non-steroidal anti-inflammatory drugs that inhibit COX enzymes.

Essential Terminology

• Local hormones
• Autocrine action
• Paracrine action
• Inflammatory mediators
• Platelet aggregation
• Bronchoconstriction
• Vasodilation
• Chemotaxis

Basic Overview

• Cell membrane phospholipids contain arachidonic acid.
• Injury or inflammation activates phospholipase A₂.
• Arachidonic acid is released.
• It enters:
  1. COX pathway → prostaglandins + thromboxanes
  2. LOX pathway → leukotrienes
• Drugs modify these pathways to reduce inflammation.

🔹 3️⃣ Core Learning — Curriculum Coverage

2️⃣ Cyclo-Oxygenase (COX) Pathway

🧠 CORE

• Cyclo-oxygenase (COX) pathway converts arachidonic acid into prostaglandins and thromboxanes.
• It is the major inflammatory pathway of eicosanoid metabolism.
• COX enzymes act on arachidonic acid released from membrane phospholipids.
• Two major COX isomers:
  • COX-1
  • COX-2
• COX-1 is constitutive and protective.
• COX-2 is inducible and inflammatory.
• NSAIDs and aspirin inhibit COX enzymes.
• Prostaglandins mediate:
  • Pain
  • Fever
  • Inflammation
• Thromboxane A₂ promotes platelet aggregation.

🔬 CONCEPT EXPLAINED

Cell membrane phospholipids contain arachidonic acid. During tissue injury or inflammation, phospholipase A₂ releases arachidonic acid from the membrane.

The released arachidonic acid enters the cyclo-oxygenase pathway.

Main Steps of COX Pathway

1. Arachidonic acid enters COX enzyme.
2. COX converts arachidonic acid into:
   • PGG₂
   • PGH₂
3. PGH₂ is converted into different prostanoids depending on tissue type.

Important Prostanoids Produced

The body uses this pathway because inflammation requires rapid local chemical signaling to protect tissues and recruit immune responses.

COX-1 vs COX-2

🧠 CORE

COX-1

• Physiological enzyme
• Present normally in tissues
• Protects gastric mucosa
• Maintains renal blood flow
• Produces platelet thromboxane

COX-2

• Inducible enzyme
• Activated during inflammation
• Produces inflammatory prostaglandins
• Responsible for pain and swelling

🔬 CONCEPT EXPLAINED

COX-1 — “Protective Housekeeping Enzyme”

COX-1 functions continuously in normal tissues.

Major functions:

• Gastric mucosal protection
• Platelet aggregation
• Maintenance of renal perfusion

In the stomach:

• Stimulates mucus secretion
• Stimulates bicarbonate secretion
• Reduces acid injury

In platelets:

• Produces TXA₂
• Helps hemostasis

COX-2 — “Inflammatory Enzyme”

COX-2 is induced by:

• Cytokines
• Trauma
• Infection
• Inflammation

Produces prostaglandins causing:

• Pain
• Fever
• Vasodilation
• Edema

This separation allows the body to preserve normal physiological protection while still mounting inflammatory responses when needed.

⚠️ IF DAMAGED

Excess COX-2 Activity

Cause:

• Increased inflammatory prostaglandins

Effect:

• Pain
• Fever
• Chronic inflammation

COX-1 Inhibition

Cause:

• Loss of protective prostaglandins

Effect:

• Gastric ulcer
• GI bleeding
• Reduced platelet function

COX Inhibition

🧠 CORE

• NSAIDs inhibit cyclo-oxygenase enzymes.
• This decreases prostaglandin synthesis.
• Reduces inflammation, pain, and fever.
• Most NSAIDs reversibly inhibit COX.
• Aspirin irreversibly inhibits COX.
• COX inhibition is the basis of anti-inflammatory drug therapy.

🔬 CONCEPT EXPLAINED

Inflammation produces prostaglandins that sensitize pain receptors and increase vascular permeability.

NSAIDs block conversion of arachidonic acid into prostaglandins.

Effects of COX Inhibition

This mechanism explains why NSAIDs are widely used in:

• Fever
• Headache
• Arthritis
• Musculoskeletal pain

⚠️ IF DAMAGED

Excessive COX Inhibition

Cause:

• Reduced protective prostaglandins

Effect:

• Gastric mucosal injury
• Peptic ulcer
• Renal ischemia
• Bleeding tendency

Aspirin Mechanism

🧠 CORE

• Aspirin irreversibly inhibits COX enzyme.
• Acetylates COX active site.
• Prevents thromboxane synthesis.
• Reduces platelet aggregation.
• Used in cardiovascular disease prevention.
• Has analgesic, antipyretic, and anti-inflammatory actions.

🔬 CONCEPT EXPLAINED

Aspirin transfers an acetyl group to the COX enzyme, permanently inactivating it.

In Platelets

Platelets lack nuclei and cannot synthesize new COX enzyme.

Result:

• Persistent reduction in TXA₂
• Reduced platelet aggregation
• Reduced thrombosis risk

In Endothelial Cells

Endothelial cells can synthesize new COX enzyme.

Therefore:

• PGI₂ production recovers
• Vasodilatory protection continues

This selective balance explains why low-dose aspirin is used for prevention of:

• Myocardial infarction
• Stroke

⚠️ IF DAMAGED

Excess Aspirin Use

Cause:

• Excessive COX inhibition

Effect:

• Gastric bleeding
• Peptic ulceration
• Hemorrhage
• Tinnitus
• Salicylate toxicity

Aspirin in Children

Cause:

• Viral illness + aspirin use

Effect:

• Reye syndrome
• Hepatic dysfunction
• Encephalopathy

3️⃣ Clinical Pharmacology of COX Inhibition

NSAIDs Adverse Effects

🧠 CORE

Major adverse effects:

• Gastritis
• Peptic ulcer
• GI bleeding
• Renal impairment
• Sodium retention
• Hypersensitivity
• Bronchospasm

🔬 CONCEPT EXPLAINED

NSAIDs inhibit protective prostaglandins produced by COX-1.

In Stomach

Normally prostaglandins:

• Increase mucus
• Increase bicarbonate
• Maintain blood flow

NSAID inhibition causes:

• Acid injury
• Mucosal erosion
• Ulcer formation

In Kidney

Prostaglandins maintain renal perfusion.

NSAID inhibition causes:

• Renal vasoconstriction
• Reduced GFR
• Fluid retention

In Airways

COX inhibition shifts arachidonic acid metabolism toward leukotriene pathway.

Result:

• Bronchospasm in susceptible patients

⚠️ IF DAMAGED

Cause → Effect

• Loss of gastric protection → ulcer
• Reduced renal blood flow → renal injury
• Increased leukotrienes → asthma exacerbation

Steroid Adverse Effects

🧠 CORE

• Steroids inhibit phospholipase A₂.
• Block both COX and LOX pathways.
• Powerful anti-inflammatory drugs.
• Cause immunosuppression.

Major adverse effects:

• Hyperglycemia
• Hypertension
• Osteoporosis
• Infection risk
• Muscle wasting

🔬 CONCEPT EXPLAINED

Steroids act earlier than NSAIDs in the inflammatory pathway.

They prevent release of arachidonic acid from membrane phospholipids.

Therefore:

• Prostaglandin synthesis decreases
• Leukotriene synthesis decreases

This produces strong anti-inflammatory action.

However, long-term suppression of inflammatory and immune pathways causes systemic adverse effects.

⚠️ IF DAMAGED

Long-term steroid therapy may cause:

• Diabetes mellitus
• Osteoporosis
• Cushingoid appearance
• Delayed wound healing
• Increased infection susceptibility

Prostanoid Catabolism

🧠 CORE

• Prostanoids have very short half-life.
• Rapidly metabolized in lungs, liver, and kidneys.
• Inactivated by enzymatic oxidation.
• Prevents excessive inflammation.

🔬 CONCEPT EXPLAINED

Prostaglandins and thromboxanes act locally near their site of synthesis.

Rapid degradation is necessary because prolonged prostanoid action could cause:

• Excess vasodilation
• Persistent pain
• Chronic inflammation
• Hemodynamic instability

This allows tight regulation of inflammatory responses.

⚠️ IF DAMAGED

Reduced prostanoid breakdown may cause:

• Persistent inflammatory response
• Chronic pain
• Excess vascular effects

4️⃣ Lipoxygenase (LOX) Pathway and Leukotrienes

🧠 CORE

• Lipoxygenase pathway converts arachidonic acid into leukotrienes.
• Mediated mainly by 5-lipoxygenase enzyme.
• Leukotrienes are important inflammatory mediators.
• Major role in asthma and allergy.
• Cause bronchoconstriction and chemotaxis.
• Leukotriene inhibitors are used in asthma therapy.

🔬 CONCEPT EXPLAINED

When arachidonic acid enters the lipoxygenase pathway, it is converted into leukotrienes.

Leukotriene Synthesis

1. Arachidonic acid released from membrane
2. 5-lipoxygenase activated
3. Formation of LTA₄
4. LTA₄ converted into:
   • LTB₄
   • LTC₄
   • LTD₄
   • LTE₄

Functions of Leukotrienes

Leukotrienes exist because inflammatory cells require chemical mediators to recruit immune cells and regulate airway responses.

Leukotriene Inhibitors

🧠 CORE

• Zileuton inhibits 5-lipoxygenase.
• Prevents leukotriene synthesis.
• Reduces bronchoconstriction.
• Used in bronchial asthma.

🔬 CONCEPT EXPLAINED

Zileuton blocks conversion of arachidonic acid into leukotrienes.

Result:

• Reduced airway inflammation
• Reduced edema
• Reduced bronchospasm

This improves airflow in asthmatic patients.

⚠️ IF DAMAGED

Adverse effect:

• Hepatotoxicity
• Elevated liver enzymes

Leukotriene Receptor Antagonists

🧠 CORE

Examples:

• Montelukast
• Zafirlukast

Functions:

• Block leukotriene receptors
• Reduce bronchoconstriction
• Improve asthma symptoms

🔬 CONCEPT EXPLAINED

These drugs do not stop leukotriene formation.

Instead, they block leukotriene receptors on bronchial smooth muscle and inflammatory cells.

Effects:

• Bronchodilation
• Reduced mucus secretion
• Reduced airway edema

Especially useful in:

• Allergic asthma
• Exercise-induced asthma

⚠️ IF DAMAGED

Failure of therapy may cause:

• Persistent wheezing
• Airway inflammation
• Recurrent asthma attacks

Rare adverse effects:

• Headache
• Neuropsychiatric symptoms

⚙️ 4️⃣ Functional Flow

Eicosanoid Metabolism Flow

1. Cell membrane phospholipids contain arachidonic acid
2. Phospholipase A₂ releases arachidonic acid
3. Arachidonic acid enters two pathways:

COX Pathway

4. COX converts arachidonic acid → prostaglandins + thromboxanes
5. Prostaglandins produce:

• Pain
• Fever
• Vasodilation

6. TXA₂ promotes platelet aggregation

LOX Pathway

7. 5-lipoxygenase converts arachidonic acid → leukotrienes
8. Leukotrienes cause:

• Bronchoconstriction
• Chemotaxis
• Allergy

Drug Actions

9. Steroids inhibit phospholipase A₂
10. NSAIDs inhibit COX enzymes
11. Aspirin irreversibly inhibits COX
12. Zileuton inhibits 5-LOX
13. Montelukast blocks leukotriene receptors

🩺 5️⃣ Clinical Correlation

Bronchial Asthma

• Leukotrienes are major mediators of bronchospasm.
• Montelukast and zileuton are used therapeutically.

Peptic Ulcer Disease

• NSAIDs reduce protective gastric prostaglandins.
• Causes gastric erosion and bleeding.

Cardiovascular Disease Prevention

• Low-dose aspirin reduces platelet aggregation.
• Prevents thrombosis and myocardial infarction.

Aspirin-Induced Asthma

• COX inhibition increases leukotriene pathway activity.
• Produces bronchospasm.

Long-Term Steroid Therapy

May cause:

• Hyperglycemia
• Osteoporosis
• Infection susceptibility

📌 6️⃣ Summary Points

• Eicosanoids are derived from arachidonic acid.
• COX pathway forms prostaglandins and thromboxanes.
• LOX pathway forms leukotrienes.
• COX-1 is protective; COX-2 is inflammatory.
• Aspirin irreversibly inhibits COX.
• NSAIDs commonly cause gastric ulceration.
• Steroids inhibit phospholipase A₂.
• Leukotrienes are major mediators in asthma.
• Montelukast blocks leukotriene receptors.
• Zileuton inhibits 5-lipoxygenase.
• TXA₂ promotes platelet aggregation.
• PGI₂ inhibits platelet aggregation.

🎥 7️⃣ Video Explanation