Pharmacology of Eicosanoids in Health & Disease

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Questions and Answers

Which eicosanoid agonists have been demonstrated to reduce both morbidity and mortality in patients with elevated pulmonary pressures?

Specific eicosanoid agonists recommended for the treatment of pulmonary hypertension.

What precursor is primarily involved in the biosynthesis of eicosanoids?

Arachidonic acid (correct)

EPA

DHA

Phospholipids

What are the major families of eicosanoids?

Prostaglandins, thromboxanes, leukotrienes, and epoxyeicosatrienoic acids.

What do the isoforms COX-1 and COX-2 produce?

Prostaglandins Signup and view all the answers

What is the rate limiting step in eicosanoid synthesis?

Activation of phospholipase A2 (PLA2). Signup and view all the answers

Leukotrienes are produced mainly in red blood cells.

False Signup and view all the answers

Which eicosanoid is primarily involved in vasoconstriction?

TXA2 Signup and view all the answers

What are the therapeutic uses of eicosanoids?

Induction of labor, abortion, maintenance of ductus arteriosus, treatment of peptic ulcers. Signup and view all the answers

What is one major function of prostaglandins?

Induce labor Signup and view all the answers

The main pathways of eicosanoid biosynthesis include cyclooxygenase (COX), lipoxygenase (LO), and __________.

cytochrome P450s Signup and view all the answers

What is the effect of PGE2 on gastric acid secretion?

PGE2 decreases gastric acid secretion. Signup and view all the answers

What do NSAIDs primarily inhibit?

COX enzymes Signup and view all the answers

Aspirin selectively inhibits COX-2 without affecting COX-1.

False Signup and view all the answers

What is the role of arachidonic acid in NSAID action?

It enters the active site of the COX enzyme to produce pain-causing substances. Signup and view all the answers

What side effect can NSAIDs cause?

Gastrointestinal irritation Signup and view all the answers

What is the primary benefit of low dose aspirin therapy?

It reduces the ability for blood to clot. Signup and view all the answers

Which COX enzyme is primarily expressed at sites of inflammation?

COX-2 Signup and view all the answers

Name one example of a COX-2 inhibitor that has been withdrawn from the market.

Rofecoxib Signup and view all the answers

COX-2 inhibitors have been developed to minimize GI toxicity.

True Signup and view all the answers

Match the following terms with their descriptions:

COX-1 = Constitutive form of COX COX-2 = Induced at sites of inflammation Rofecoxib = Withdrawn from the market Celebrex = Approved COX-2 inhibitor with warnings Signup and view all the answers

PG analogues are used clinically to mimic endogenous ______.

bioactivity Signup and view all the answers

Study Notes

Eicosanoids Overview

Eicosanoids are endogenous fatty acid autacoids derived from arachidonic acid, a 20-carbon fatty acid.
Short half-lives (10 seconds to 5 minutes) limit their functions to local actions.
They bind to G-protein coupled receptors, generally increasing cellular cAMP levels.

Major Families of Eicosanoids

Prostaglandins
Thromboxanes
Leukotrienes
Epoxyeicosatrienoic acids

Roles of Eicosanoids

Inflammation and fever regulation
Blood pressure modulation
Blood clotting mechanisms
Immune system response
Control of reproductive processes and tissue growth
Sleep/wake cycle regulation

Biosynthesis of Eicosanoids

Produced on-demand from phospholipid membranes via phospholipase A2 activation.
Arachidonic acid release is the rate-limiting step in eicosanoid synthesis, inhibited by glucocorticoids.
Key pathways include Cyclooxygenase (COX) and Lipoxygenase (LO).

Cyclooxygenase (COX) Pathway

COX enzymes convert arachidonic acid to prostaglandin H2 (PGH2), which is then converted to various prostaglandins, thromboxane A2 (TXA2), and prostacyclin (PGI2).
COX-1 is constitutively expressed; COX-2 is induced during inflammation.

Functions of Prostaglandins

Cardiovascular: PGI2 dilates blood vessels; TXA2 causes vasoconstriction.
Renal: Enhance urine formation and regulate renin release.
Nervous: Induces fever and sensitizes pain.
Gastrointestinal: Decrease gastric acid secretion and promote mucus production.
Reproductive: Induce labor and increase uterine contractions.

Therapeutic Uses of Eicosanoids

Abortion: Induction using PGE2 and PGF2α.
Labor Induction: Carboprost and dinoprostone infusions.
Maintenance of Ductus Arteriosus: PGE1 for pre-surgical conditions.
Peptic Ulcers: Misoprostol to reduce ulceration risk.
Erectile Dysfunction: Alprostadil injections for improved blood flow.

Adverse Effects of Eicosanoids

Local pain and irritation
Gastrointestinal disturbances: nausea, cramping, diarrhea
Bronchospasm

NSAIDs and COX Inhibition

Aspirin inhibits both COX-1 and COX-2, reducing pain and inflammation but poses gastrointestinal risks.
Other NSAIDs (e.g., ibuprofen) compete with arachidonic acid for COX binding.

COX-2 Selective Inhibitors

Developed to minimize gastrointestinal side effects while targeting inflammation.
Examples include celecoxib and etoricoxib, with some withdrawn due to safety concerns.

Leukotrienes and Their Functions

Mediators of inflammation and bronchoconstriction, particularly in asthma.
LTB4 facilitates leukocyte activation and attraction.

Lipoxins and Their Role

Derived from leukocyte action; they have anti-inflammatory properties and help resolve inflammation.

Epoxygenase Pathway

Involves cytochrome P450 enzymes, creating epoxyeicosatrienoic acids, which modulate vascular tone.

Key Mechanisms of Action

Eicosanoids mediate processes such as inflammation, pain response, fever induction, smooth muscle contraction/relaxation, and mucosal protection.

Recent Developments in Eicosanoid Therapy

Research focuses on better anti-inflammatory drugs that selectively inhibit eicosanoid pathways to minimize side effects while maximizing therapeutic impact.### Eicosanoid Biosynthesis
Initiated by phospholipase A2 activation, leading to arachidonic acid (AA) release from membrane phospholipids.
AA is converted through cyclooxygenase (COX) and lipoxygenase (LO) pathways into eicosanoids: prostaglandins, thromboxane, and leukotrienes.
Eicosanoid production significantly increases during inflammatory responses.
COX and LO pathways are highly relevant in clinical settings.

COX Pathways and Pharmacology

COX pathway is the primary target for non-steroidal anti-inflammatory drugs (NSAIDs), which are commonly used to manage pain, fever, and inflammation.
Discovery of the two COX isozymes in 1991: COX-1 and COX-2.
COX-2 is mainly expressed at inflammation sites and is responsible for producing pro-inflammatory eicosanoids.

COX-2 Selective Inhibitors (COXIBs)

Developed to minimize gastrointestinal (GI) toxicity associated with traditional NSAIDs.
COX-2 selective inhibitors have shown adverse cardiovascular effects, leading to the market withdrawal of drugs like rofecoxib and valdecoxib.
Selective COX-2 inhibition without affecting COX-1 can disrupt the balance between prostacyclin and thromboxane, increasing thrombotic risk.
This imbalance helps explain the cardiovascular risks associated with COX-2 selective inhibitors.

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Description

This quiz explores the pharmacology of eicosanoids, focusing on their roles in health, disease, and therapeutic applications. Through a case study approach, students will analyze symptoms and therapeutic implications related to eicosanoid mechanisms. Enhance your understanding of pharmacological principles that underlie clinical presentations and treatments.