Pharmacology of Prostaglandins and Eicosanoids

Introduction/Overview

Prostaglandins and related eicosanoids constitute a vast family of lipid-derived autacoids that function as potent local signaling molecules. These compounds are not stored within cells but are synthesized de novo from membrane phospholipid-derived arachidonic acid in response to diverse physiological and pathological stimuli. Their actions are predominantly autocrine and paracrine, influencing nearly every organ system in the human body. The pharmacology of this system is fundamentally dualistic, encompassing both the endogenous roles of these mediators and the extensive class of drugs designed to inhibit their synthesis or action.

The clinical relevance of understanding this pharmacology is profound. Dysregulation of eicosanoid pathways is implicated in a wide spectrum of diseases, including inflammation, pain, fever, thrombosis, asthma, peptic ulcer disease, and dysmenorrhea. Consequently, pharmacological modulation of these pathways represents one of the most common therapeutic interventions in clinical medicine. Drugs affecting eicosanoids, particularly nonsteroidal anti-inflammatory drugs (NSAIDs), are among the most widely used medications globally. Furthermore, synthetic analogues of specific prostaglandins have been developed for targeted therapeutic applications in obstetrics, gastroenterology, and ophthalmology.

The learning objectives for this chapter are:

• To describe the biosynthetic pathways of major eicosanoid classes from arachidonic acid.
• To explain the molecular mechanisms of action, receptor subtypes, and downstream signaling of principal prostaglandins and leukotrienes.
• To classify therapeutic agents based on their site of action within eicosanoid pathways and summarize their pharmacokinetic properties.
• To detail the approved clinical applications, major adverse effects, and significant drug interactions of both synthetic prostaglandin analogues and synthesis inhibitors.
• To apply knowledge of eicosanoid pharmacology to special patient populations, including those with renal or hepatic impairment, and during pregnancy.

Classification

Eicosanoids are classified based on their enzymatic pathway of synthesis from the 20-carbon essential fatty acid, arachidonic acid. The primary classification hinges on the initial enzyme committing arachidonate to a specific metabolic route.

Enzymatic Pathway-Based Classification

The major classes are defined by the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 epoxygenase pathways.

• Cyclooxygenase (COX) Derivatives (Prostanoids): This family includes prostaglandins (PGs), thromboxanes (TXs), and prostacyclin (PGI₂). They are characterized by a central five-membered ring. Key members are:
  • Prostaglandin D₂ (PGD₂)
  • Prostaglandin E₂ (PGE₂)
  • Prostaglandin F_2α (PGF_2α)
  • Prostaglandin I₂ (Prostacyclin, PGI₂)
  • Thromboxane A₂ (TXA₂)
• Lipoxygenase (LOX) Derivatives: This pathway, involving 5-, 12-, or 15-lipoxygenase, yields metabolites without a cyclic ring structure.
  • 5-Lipoxygenase products: Leukotrienes (LTB₄, LTC₄, LTD₄, LTE₄) and lipoxins.
  • 12- and 15-Lipoxygenase products: Hydroxyeicosatetraenoic acids (HETEs) and additional lipoxins.
• Cytochrome P450 Epoxygenase Derivatives: This pathway generates epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs), which are involved in vascular and renal physiology.

Pharmacological Agent Classification

Drugs targeting the eicosanoid system are classified by their mechanism.

1. Inhibitors of Eicosanoid Synthesis
   • Cyclooxygenase Inhibitors (NSAIDs):
     • Non-selective COX-1/COX-2 inhibitors (e.g., ibuprofen, naproxen, diclofenac).
     • Preferential COX-2 inhibitors (e.g., meloxicam, etodolac).
     • Selective COX-2 inhibitors (coxibs: celecoxib, etoricoxib).
   • Lipoxygenase Pathway Inhibitors:
     • 5-Lipoxygenase inhibitors (e.g., zileuton).
     • Leukotriene receptor antagonists (e.g., montelukast, zafirlukast).
   • Phospholipase A₂ Inhibitors: Corticosteroids (indirect, via induction of annexins).
2. Synthetic Eicosanoid Analogues (Receptor Agonists)
   • Prostaglandin E₁ analogue: Alprostadil.
   • Prostaglandin E₂ analogue: Dinoprostone.
   • Prostaglandin F_2α analogue: Carboprost, Latanoprost, Travoprost, Bimatoprost.
   • Prostacyclin analogues: Epoprostenol, Iloprost, Treprostinil, Selexipag (a prostacyclin receptor agonist).
   • Prostaglandin E₁ analogue with antisecretory activity: Misoprostol.
3. Thromboxane A₂ Receptor Antagonists (e.g., Terutroban – investigational).
4. Thromboxane Synthase Inhibitors (e.g., Picotamide – combines synthase inhibition and receptor antagonism).

Mechanism of Action

The mechanism of action of eicosanoids is complex, involving biosynthesis from membrane phospholipids, interaction with specific G-protein coupled receptors (GPCRs), and modulation of diverse intracellular signaling cascades.

Biosynthesis

The initial step is the liberation of arachidonic acid from the sn-2 position of membrane phospholipids by phospholipase A₂ (PLA₂), activated by mechanical, chemical, or inflammatory stimuli. Free arachidonate then serves as the substrate for three major enzymatic pathways.

1. Cyclooxygenase (COX) Pathway: The COX enzyme (prostaglandin-endoperoxide synthase, PGHS) possesses two distinct activities: a cyclooxygenase activity that adds two molecules of O₂ to form the cyclic endoperoxide PGG₂, and a peroxidase activity that reduces PGG₂ to PGH₂. PGH₂ is the unstable precursor for all prostanoids. Tissue-specific isomerases and synthases then convert PGH₂:
   • Prostaglandin D synthase → PGD₂
   • Prostaglandin E synthase → PGE₂
   • Prostaglandin F synthase → PGF_2α
   • Prostacyclin synthase → PGI₂
   • Thromboxane synthase → TXA₂

   Two major COX isozymes exist: COX-1 is constitutively expressed in most tissues (e.g., gastric mucosa, platelets, kidneys) and is involved in homeostatic functions. COX-2 is inducible by inflammatory stimuli (cytokines, growth factors) and is primarily responsible for prostanoid production in inflammation, pain, and fever.

2. Lipoxygenase (LOX) Pathway: 5-Lipoxygenase (5-LO), with its helper protein 5-lipoxygenase-activating protein (FLAP), converts arachidonate to 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which is then dehydrated to the unstable epoxide leukotriene A₄ (LTA₄). LTA₄ is metabolized by LTA₄ hydrolase to the chemoattractant LTB₄, or conjugated with glutathione by LTC₄ synthase to form LTC₄. Sequential cleavage of amino acids from LTC₄ yields LTD₄ and LTE₄, collectively known as the cysteinyl leukotrienes (CysLTs).

Receptor Interactions and Signaling

Prostanoids exert their effects by activating specific cell-surface GPCRs. A standardized nomenclature exists: DP (for PGD₂), EP_1-4 (for PGE₂), FP (for PGF_2α), IP (for PGI₂), and TP (for TXA₂). Leukotrienes act on BLT₁/₂ receptors (for LTB₄) and CysLT₁/₂ receptors (for CysLTs).

• EP Receptors: PGE₂ actions are highly context-dependent due to four receptor subtypes.
  • EP₁: G_q-coupled → increases intracellular Ca²⁺ → involved in pain sensitization and smooth muscle contraction.
  • EP₂ and EP₄: G_s-coupled → increase cAMP → cause smooth muscle relaxation (e.g., bronchodilation, vasodilation), inhibit immune cell function.
  • EP₃: G_i-coupled → decreases cAMP → mediates fever induction in the hypothalamus, promotes gastric acid secretion, and causes uterine contraction.
• IP Receptor: G_s-coupled. PGI₂ activation increases cAMP, leading to potent vasodilation and inhibition of platelet aggregation.
• TP Receptor: G_q-coupled. TXA₂ activation increases intracellular Ca²⁺ and activates protein kinase C, causing potent vasoconstriction and platelet aggregation.
• FP Receptor: G_q-coupled. PGF_2α increases Ca²⁺, causing smooth muscle contraction (notably in the uterus and bronchus). In the eye, it increases uveoscleral outflow.
• CysLT₁ Receptor: G_q-coupled. Activation by LTD₄ primarily causes bronchoconstriction, increased vascular permeability, and mucus secretion.

The cellular response is thus determined by the specific receptor complement on the target cell and the downstream second messenger system activated.

Pharmacokinetics

The pharmacokinetic profiles of drugs affecting eicosanoids are highly diverse, ranging from rapidly metabolized endogenous-like substances to long-acting synthetic molecules. The discussion is separated into synthesis inhibitors and synthetic analogues.

Pharmacokinetics of Synthesis Inhibitors (NSAIDs and LOX Inhibitors)

Most traditional NSAIDs are weak organic acids, which influences their distribution.

• Absorption: Generally well absorbed orally, with bioavailability often exceeding 80%. Food may delay absorption but does not typically affect overall bioavailability. Some agents (e.g., ketorolac, diclofenac) are available for parenteral administration.
• Distribution: Extensive tissue distribution occurs. Their acidic nature promotes concentration in sites of inflammation (lower pH) and in the gastric mucosa. Plasma protein binding is typically very high (>95%), primarily to albumin. Volume of distribution is usually low (0.1-0.3 L/kg).
• Metabolism: Hepatic metabolism via cytochrome P450 enzymes (primarily CYP2C9 and CYP2C8) is the principal route. Common metabolic reactions include oxidation and glucuronidation. Several NSAIDs (e.g., naproxen, ibuprofen) are administered as racemic mixtures, with enantiomeric inversion occurring in vivo for some.
• Excretion: Metabolites are excreted primarily in urine, with minor biliary excretion. Renal excretion of unchanged drug is usually low due to high protein binding. The elimination half-life (t_1/2) varies widely:
  • Short-acting (t_1/2 2-6 hours): Ibuprofen, diclofenac, ketoprofen.
  • Intermediate-acting (t_1/2 10-20 hours): Naproxen.
  • Long-acting (t_1/2 >24 hours): Piroxicam, celecoxib, meloxicam.
• Special Agents:
  • Aspirin: Rapidly deacetylated to salicylate in the gut wall and liver. Salicylate has nonlinear pharmacokinetics. Aspirin’s unique irreversible acetylation of platelet COX-1 confers a long-lasting antiplatelet effect (7-10 days) despite a short plasma t_1/2 (15-20 minutes).
  • COX-2 Selective Inhibitors (Coxibs): Celecoxib is metabolized by CYP2C9 and has a t_1/2 of about 11 hours. It is less dependent on renal excretion.
  • Leukotriene Modifiers: Zileuton (5-LO inhibitor) is metabolized hepatically. Montelukast (CysLT₁ antagonist) is extensively metabolized by CYP3A4 and 2C9.

Pharmacokinetics of Synthetic Prostaglandin Analogues

These agents are designed to resist rapid metabolic inactivation, often achieved by structural modifications.

• Misoprostol: A PGE₁ analogue administered orally. It is rapidly de-esterified to its active free acid form, misoprostol acid. Peak plasma concentrations occur within 30 minutes. It undergoes extensive first-pass metabolism, and its active metabolite has a short t_1/2 of 20-40 minutes.
• Prostaglandins for Obstetrics (Dinoprostone, Carboprost): These are typically administered via local routes (vaginal, intramyometrial) to achieve high local concentrations while minimizing systemic effects. Systemic absorption can still occur, leading to potential adverse effects.
• Ophthalmic Prostaglandins (Latanoprost, etc.): Administered topically. They are prodrugs (isopropyl esters) that are hydrolyzed to the active acid in the cornea. Systemic absorption from the eye is minimal but detectable.
• Prostacyclin Analogues (Epoprostenol, Treprostinil, Iloprost):
  • Epoprostenol has an extremely short half-life (2-3 minutes), requiring continuous intravenous infusion.
  • Treprostinil is more stable, with a t_1/2 of 4-6 hours, allowing for subcutaneous infusion.
  • Iloprost, administered by inhalation or intravenous infusion, has a t_1/2 of 20-30 minutes.
  • Selexipag is an oral prostacyclin receptor agonist with a long-acting active metabolite (t_1/2 ≈ 8 hours).

Therapeutic Uses/Clinical Applications

Therapeutic applications exploit either the inhibition of “bad” eicosanoids or the administration of “good” synthetic analogues to achieve desired physiological effects.

Therapeutic Uses of Synthesis Inhibitors

• Analgesia: NSAIDs are effective for mild to moderate pain, particularly of inflammatory origin (e.g., postoperative pain, dental pain, musculoskeletal pain). Their effect is primarily peripheral, reducing PGE₂-mediated sensitization of nociceptors.
• Anti-inflammatory Therapy: A cornerstone in managing chronic inflammatory conditions like rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. They reduce swelling, pain, and stiffness but do not alter disease progression.
• Antipyresis: Inhibition of PGE₂ synthesis in the hypothalamic thermoregulatory center resets elevated temperature. Drugs like ibuprofen and aspirin are commonly used.
• Antiplatelet Therapy:
  • Low-dose aspirin (75-100 mg/day): Irreversibly inhibits platelet COX-1, blocking TXA₂ production for the platelet’s lifespan. Used for secondary prevention of cardiovascular events (MI, stroke).
  • Other NSAIDs are reversible inhibitors and are not used for this purpose; some may interfere with aspirin’s cardioprotective effect.
• Closure of Patent Ductus Arteriosus (PDA): Indomethacin or ibuprofen (IV) is used to promote closure of PDA in preterm neonates by inhibiting local PGE₂ and PGI₂, which maintain ductal patency.
• Treatment of Gout: High-dose NSAIDs are a first-line treatment for acute gouty arthritis due to potent anti-inflammatory effects.
• Leukotriene Modifiers in Asthma and Allergy:
  • Montelukast and zafirlukast (CysLT₁ antagonists) are used as controller medications for mild persistent asthma, especially in exercise-induced or aspirin-exacerbated respiratory disease.
  • Zileuton (5-LO inhibitor) is an alternative for asthma.
  • Montelukast is also indicated for allergic rhinitis.

Therapeutic Uses of Synthetic Prostaglandin Analogues

• Gastroprotection: Misoprostol is used for the prevention of NSAID-induced gastric ulcers in high-risk patients, acting via EP receptors to inhibit acid secretion and enhance mucosal defense.
• Obstetrics and Gynecology:
  • Cervical Ripening and Labor Induction: Dinoprostone (PGE₂) vaginal insert or gel is used to ripen the cervix prior to labor induction.
  • Medical Abortion: Mifepristone (anti-progesterone) followed by misoprostol is a highly effective regimen for early medical abortion. Misoprostol alone is also used.
  • Postpartum Hemorrhage (PPH): Carboprost (15-methyl PGF_2α) is used intramyometrially to treat refractory uterine atony and PPH by causing intense uterine contraction.
• Ophthalmology – Glaucoma: Latanoprost, travoprost, bimatoprost, and tafluprost are first-line topical agents for open-angle glaucoma. They lower intraocular pressure primarily by increasing uveoscleral outflow of aqueous humor via FP receptor-mediated matrix metalloproteinase induction.
• Vascular Diseases – Pulmonary Arterial Hypertension (PAH):
  • Prostacyclin analogues (epoprostenol IV, treprostinil SC/IV/inhaled/oral, iloprost inhaled) are used to treat PAH. They induce pulmonary vasodilation, inhibit platelet aggregation, and have antiproliferative effects on vascular smooth muscle.
  • Selexipag, an oral IP receptor agonist, is also indicated for PAH.
• Erectile Dysfunction and Vascular Assessment: Alprostadil (PGE₁) can be administered via intracavernosal injection or intraurethral pellet for erectile dysfunction. It is also used as a diagnostic agent to maintain patency of the ductus arteriosus in neonates with congenital heart disease.

Adverse Effects

Adverse effects stem from the disruption of physiological roles of eicosanoids. The profile differs significantly between synthesis inhibitors and administered analogues.

Adverse Effects of Cyclooxygenase Inhibitors (NSAIDs)

• Gastrointestinal (GI) Effects: The most common adverse effects. Non-selective NSAIDs inhibit constitutive COX-1-derived PGE₂ and PGI₂ in the gastric mucosa, which normally inhibit acid secretion, stimulate mucus and bicarbonate production, and maintain mucosal blood flow. This leads to dyspepsia, erosions, ulcers, and life-threatening bleeding or perforation. Risk is dose-dependent and increased with age, concomitant corticosteroids or anticoagulants, and history of ulcer.
• Renal Effects: Renal prostaglandins (PGE₂, PGI₂) are crucial for maintaining renal blood flow, particularly in states of decreased effective circulating volume (e.g., heart failure, cirrhosis, dehydration, chronic kidney disease). NSAID inhibition can cause:
  • Fluid and electrolyte retention (edema, hypertension, hyperkalemia).
  • Acute kidney injury (due to afferent arteriolar vasoconstriction).
  • Interstitial nephritis (an idiosyncratic reaction, more common with some agents like fenoprofen).
  • Papillary necrosis with chronic, high-dose use.
• Cardiovascular Effects: A class-wide concern. Inhibition of vascular COX-2-derived PGI₂ (a vasodilator and anti-aggregatory) without concomitant inhibition of platelet COX-1-derived TXA₂ can create a prothrombotic state. This is most clearly established with selective COX-2 inhibitors (increased risk of myocardial infarction and stroke), but non-selective NSAIDs (except possibly naproxen) also carry some increased risk, particularly with prolonged high-dose use.
• Hematologic Effects: Antiplatelet effect (reversible with most NSAIDs) can increase bleeding risk, especially with concomitant anticoagulants. Agranulocytosis or aplastic anemia are rare, idiosyncratic reactions.
• Hypersensitivity Reactions: Aspirin-exacerbated respiratory disease (AERD, or Samter’s triad) involves asthma, nasal polyps, and severe reactions to COX inhibitors due to shunting of arachidonate to the leukotriene pathway. NSAIDs can also cause urticaria, angioedema, and anaphylaxis.
• Central Nervous System Effects: Headache, dizziness, tinnitus (especially with high-dose aspirin – salicylism), and aseptic meningitis (rare, associated with ibuprofen and others).
• Hepatic Effects: Transaminase elevation can occur; diclofenac carries a higher risk of significant hepatotoxicity.

Adverse Effects of Synthetic Prostaglandin Analogues

These are often extensions of their pharmacological actions.

• Misoprostol: Diarrhea and abdominal cramping are very common due to increased intestinal motility. Uterine contractions and vaginal bleeding are expected when used for obstetric/gynecologic indications but are adverse when used for GI protection. It is a potent abortifacient and is absolutely contraindicated in pregnancy when used for GI protection.
• Obstetrical Prostaglandins (Dinoprostone, Carboprost): Can cause uterine hyperstimulation, fetal distress, nausea, vomiting, diarrhea, pyrexia, and chills. Carboprost can cause significant bronchoconstriction and is contraindicated in asthmatic patients.
• Ophthalmic Prostaglandins: Local effects include conjunctival hyperemia, increased iris pigmentation (permanent, particularly with latanoprost in hazel eyes), elongation and darkening of eyelashes, and periocular skin darkening. Uveitis and cystoid macular edema are rare risks.
• Prostacyclin Analogues for PAH: Adverse effects are often dose-limiting and related to systemic vasodilation: flushing, headache, jaw pain, diarrhea, nausea, and hypotension. Epoprostenol requires a central venous catheter, with risks of line infection, sepsis, and thrombosis. Treprostinil given subcutaneously causes severe infusion site pain and reactions in most patients.

Drug Interactions

Interactions are numerous and clinically significant, primarily involving NSAIDs.

Major Drug-Drug Interactions

• Anticoagulants (Warfarin, DOACs) and Antiplatelets: NSAIDs increase bleeding risk through additive antiplatelet effects (reversible COX-1 inhibition), GI mucosal injury, and potential pharmacokinetic interactions (some NSAIDs may displace warfarin from protein binding). This combination requires extreme caution.
• Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin Receptor Blockers (ARBs), and Diuretics: NSAIDs attenuate the antihypertensive and natriuretic effects of these agents by inhibiting renal prostaglandin-mediated vasodilation and sodium excretion. Concurrent use can precipitate acute kidney injury and severe hyperkalemia, particularly in volume-depleted patients.
• Lithium: NSAIDs reduce renal clearance of lithium by up to 60%, potentially leading to lithium toxicity. Serum lithium monitoring is essential.
• Methotrexate: NSAIDs can reduce renal clearance of methotrexate, increasing the risk of myelosuppression and mucositis, particularly with high-dose methotrexate regimens.
• Corticosteroids: Concomitant use synergistically increases the risk of GI ulceration and bleeding.
• Selective Serotonin Reuptake Inhibitors (SSRIs): Increased risk of upper GI bleeding when combined with NSAIDs.
• Other NSAIDs (including Aspirin): Combining two or more NSAIDs increases toxicity without added benefit. Notably, ibuprofen can interfere with the antiplatelet action of low-dose aspirin by sterically hindering access to the COX-1 active site if taken before aspirin.
• CYP450 Interactions: NSAIDs metabolized by CYP2C9 (e.g., celecoxib, ibuprofen, diclofenac) may interact with inhibitors (e.g., fluconazole) or inducers of this enzyme. Zileuton is a moderate inhibitor of CYP1A2.

Contraindications

• NSAIDs are contraindicated in patients with:
  • Active peptic ulcer disease or recent GI bleeding.
  • History of aspirin/NSAID-induced asthma, urticaria, or other hypersensitivity reactions.
  • Severe heart failure (NYHA Class IV), unless under specialist care.
  • Severe renal impairment or hyperkalemia.
  • Third trimester of pregnancy (risk of premature closure of ductus arteriosus and delayed labor).
  • Coronary artery bypass graft (CABG) surgery peri-operative period (for selective and non-selective NSAIDs).
• Specific Contraindications:
  • Carboprost: Active cardiac, pulmonary, or hepatic disease; asthma.
  • Misoprostol: Pregnancy when used for GI protection.

Special Considerations

Pregnancy and Lactation

• Pregnancy:
  • NSAIDs: Generally avoided, especially in the third trimester. Use in the first and second trimesters may be associated with a small increased risk of miscarriage and congenital malformations (cardiac, gastroschisis). After 30 weeks’ gestation, they can cause premature closure of the fetal ductus arteriosus, leading to pulmonary hypertension, and oligohydramnios due to reduced fetal renal blood flow. Low-dose aspirin (81 mg/day) is used under specialist guidance for preeclampsia prevention in high-risk women.
  • Prostaglandin Analogues: Misoprostol is a known abortifacient and teratogen (associated with Möbius sequence and limb defects) and is absolutely contraindicated. Dinoprostone and carboprost are used intentionally for obstetric indications (induction, PPH). Latanoprost may be absorbed systemically; use in pregnancy is not recommended unless benefit outweighs risk.
• Lactation: Most NSAIDs (e.g., ibuprofen, naproxen) are considered compatible with breastfeeding as they are excreted in milk in very low amounts. Aspirin is avoided due to theoretical risk of Reye’s syndrome and potential effects on platelet function in the infant. Data on prostaglandin analogues are limited; use with caution.

Pediatric Considerations

Ibuprofen and naproxen are commonly used for analgesia and antipyresis in children. Dosing is weight-based. Aspirin is generally avoided in children and adolescents (<19 years) with febrile illnesses due to the strong association with Reye's syndrome. Indomethacin and ibuprofen are standard for pharmacological closure of PDA in preterm neonates. Leukotriene receptor antagonists like montelukast are widely used in pediatric asthma and allergic rhinitis.

Geriatric Considerations

Elderly patients are at significantly increased risk for NSAID-related complications: GI bleeding, renal impairment, hypertension, heart failure, and drug interactions due to polypharmacy. Renal function decline with age increases susceptibility to prostaglandin-dependent renal effects. The lowest effective dose for the shortest duration should be used. COX-2 selective inhibitors may be considered for patients at high GI risk but low CV risk, with concomitant proton pump inhibitor therapy.

Renal and Hepatic Impairment

• Renal Impairment: NSAIDs should be avoided or used with extreme caution. They can precipitate acute-on-chronic kidney injury. Dosing adjustments are often required, and agents with significant renal excretion of active metabolites (e.g., ketorolac) are particularly problematic. Prostaglandin analogues like misoprostol do not require renal dose adjustment, but their metabolites are renally excreted.
• Hepatic Impairment: NSAIDs metabolized hepatically should be used cautiously, starting with low doses, as impaired metabolism can lead to accumulation. Patients with advanced liver disease are at increased risk of GI bleeding and renal impairment, making NSAIDs especially hazardous. Diclofenac carries a higher hepatotoxicity risk. Dose reduction may be necessary for some agents (e.g., celecoxib in moderate hepatic impairment).

Summary/Key Points

• Prostaglandins and eicosanoids are locally acting lipid mediators derived from arachidonic acid via COX, LOX, and P450 pathways, playing critical roles in homeostasis and disease.
• Pharmacology involves two main strategies: inhibition of synthesis (NSAIDs, leukotriene modifiers) and administration of synthetic analogues (misoprostol, latanoprost, prostacyclins).
• Mechanism of action is receptor-specific: Prostanoids act on DP, EP, FP, IP, and TP GPCRs, while leukotrienes act on BLT and CysLT receptors, modulating cAMP, Ca²⁺, and other second messengers.
• NSAIDs are among the most used drugs worldwide for pain, inflammation, and fever but carry significant risks of GI, renal, and cardiovascular adverse effects, which are dose- and duration-dependent.
• Selective COX-2 inhibitors reduce GI toxicity but increase cardiovascular risk, highlighting the delicate balance between COX-1 and COX-2 derived prostanoids.
• Synthetic prostaglandins have targeted uses: misoprostol for GI protection and obstetrics, latanoprost for glaucoma, prostacyclin analogues for pulmonary hypertension, and specific agents for labor induction and postpartum hemorrhage.
• Major drug interactions occur with anticoagulants, antihypertensives, diuretics, lithium, and methotrexate, necessitating careful review of concomitant medications.
• Special caution is required in the elderly, patients with renal or hepatic impairment, and during pregnancy, where NSAIDs are generally contraindicated in the third trimester.

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References

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⚠️ Medical Disclaimer

This article is intended for educational and informational purposes only. It is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read in this article.

The information provided here is based on current scientific literature and established pharmacological principles. However, medical knowledge evolves continuously, and individual patient responses to medications may vary. Healthcare professionals should always use their clinical judgment when applying this information to patient care.

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Mentor, Pharmacology. Pharmacology of Prostaglandins and Eicosanoids. Pharmacology Mentor. Available from: https://pharmacologymentor.com/pharmacology-of-prostaglandins-and-eicosanoids-3/. Accessed on February 3, 2026 at 09:01.
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