Pharmacology of Prostaglandins and Eicosanoids

1. Introduction/Overview

Prostaglandins and eicosanoids constitute a vast family of lipid-derived autacoids and paracrine hormones that exert profound and diverse physiological and pathophysiological effects. These compounds are not stored within cells but are synthesized de novo from membrane phospholipid-derived arachidonic acid in response to various mechanical, chemical, and hormonal stimuli. Their actions are typically local, acting on cells in the immediate vicinity of their synthesis, which classifies them as local hormones. The clinical relevance of this system is immense, as it is integral to processes including inflammation, pain, fever, hemostasis, parturition, gastrointestinal mucosal integrity, and renal function. Pharmacological manipulation of eicosanoid pathways, primarily through inhibition of their synthesis, represents one of the most common therapeutic interventions in medicine, exemplified by the widespread use of nonsteroidal anti-inflammatory drugs (NSAIDs). Conversely, several synthetic prostaglandin analogs are used therapeutically to mimic or augment their natural effects in specific clinical contexts.

Learning Objectives

• Outline the biosynthetic pathways of major eicosanoids from arachidonic acid, including the cyclooxygenase, lipoxygenase, and cytochrome P450 epoxygenase pathways.
• Describe the pharmacodynamics of eicosanoids, including receptor subtypes, signaling mechanisms, and resultant physiological actions in major organ systems.
• Explain the mechanisms of action, therapeutic uses, and adverse effect profiles of pharmacological agents that inhibit eicosanoid synthesis (e.g., NSAIDs, COX-2 selective inhibitors) or antagonize their receptors (e.g., leukotriene receptor antagonists).
• Identify the clinical indications, pharmacokinetics, and major adverse effects of therapeutic prostaglandin analogs such as misoprostol, alprostadil, and epoprostenol.
• Apply knowledge of eicosanoid pharmacology to predict drug interactions, contraindications, and necessary considerations for special populations including pregnant patients and those with renal or hepatic impairment.

2. Classification

Eicosanoids are classified primarily based on their enzymatic pathway of synthesis from arachidonic acid, a 20-carbon polyunsaturated fatty acid (eicosatetraenoic acid). This classification correlates with distinct chemical structures and biological activity profiles.

2.1. Chemical and Biosynthetic Classification

The primary biosynthetic pathways are the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 epoxygenase pathways.

• Cyclooxygenase (COX) Pathway Products (Prostanoids): This pathway yields prostaglandins and thromboxanes. The initial step involves the conversion of arachidonic acid to the unstable intermediate PGG₂ and then PGH₂ by the COX enzyme, which possesses both cyclooxygenase and peroxidase activity. PGH₂ is then isomerized by specific synthases into active prostanoids:
  • Prostaglandin D₂ (PGD₂): Synthesized by hematopoietic PGD synthase or lipocalin-type PGD synthase.
  • Prostaglandin E₂ (PGE₂): Synthesized by microsomal or cytosolic PGE synthase.
  • Prostaglandin F_2α (PGF_2α): Synthesized by PGF synthase or via reduction of PGH₂.
  • Prostaglandin I₂ (PGI₂, Prostacyclin): Synthesized by prostacyclin synthase.
  • Thromboxane A₂ (TXA₂): Synthesized by thromboxane synthase.
• Lipoxygenase (LOX) Pathway Products: This pathway involves the insertion of molecular oxygen into arachidonic acid by various lipoxygenase enzymes (5-LOX, 12-LOX, 15-LOX).
  • 5-Lipoxygenase Products: The most clinically significant pathway, leading to the synthesis of leukotrienes (LTs) and lipoxins. 5-LOX converts arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which is then converted to the unstable LTA₄. LTA₄ is metabolized to LTB₄ (by LTA₄ hydrolase) or conjugated with glutathione to form LTC₄, which is sequentially metabolized to LTD₄ and LTE₄ (the cysteinyl leukotrienes).
  • Lipoxins: Generated via transcellular metabolism involving interactions between 5-LOX and 12-LOX or 15-LOX pathways, possessing anti-inflammatory and pro-resolving actions.
• Cytochrome P450 Epoxygenase Pathway Products: These enzymes convert arachidonic acid to epoxyeicosatrienoic acids (EETs), which have vasodilatory, anti-inflammatory, and protective effects, and hydroxyeicosatetraenoic acids (HETEs).

2.2. Pharmacological Classification

Drugs targeting the eicosanoid system are classified based on their primary mechanism.

• Inhibitors of Eicosanoid Synthesis:
  • Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Inhibit cyclooxygenase enzymes. This class includes non-selective COX-1/COX-2 inhibitors (e.g., ibuprofen, naproxen, indomethacin, diclofenac) and COX-2 selective inhibitors (coxibs, e.g., celecoxib, etoricoxib).
  • Glucocorticoids: Induce the synthesis of annexin-1 (lipocortin), which inhibits phospholipase A₂, thereby reducing the release of arachidonic acid from membrane phospholipids and suppressing the synthesis of all downstream eicosanoids.
  • 5-Lipoxygenase Inhibitors: e.g., zileuton.
  • Thromboxane Synthase Inhibitors: e.g., picotamide (also has thromboxane receptor antagonist activity).
• Receptor Agonists (Prostaglandin Analogs):
  • PGE₁ Analog: Alprostadil.
  • PGE₂ Analog: Dinoprostone.
  • PGF_2α Analog: Carboprost, latanoprost, travoprost, bimatoprost.
  • PGI₂ (Prostacyclin) Analogs: Epoprostenol, iloprost, treprostinil, selexipag (a prostacyclin receptor agonist).
  • Prostaglandin E Analog with Cytoprotective Action: Misoprostol.
• Receptor Antagonists:
  • Cysteinyl Leukotriene Receptor Antagonists (LTRAs): Montelukast, zafirlukast.
  • Thromboxane Receptor Antagonists: Terutroban.

3. Mechanism of Action

The pharmacodynamic actions of eicosanoids are mediated through binding to specific G-protein-coupled receptors (GPCRs) on the surface of target cells. The diversity of effects stems from the multiplicity of receptor subtypes, their differential tissue distribution, and the specific G-protein coupling, which activates distinct intracellular signaling cascades.

3.1. Prostanoid Receptors and Signaling

Prostanoid receptors are classified based on the primary endogenous ligand: DP (for PGD₂), EP (for PGE₂), FP (for PGF_2α), IP (for PGI₂), and TP (for TXA₂). Furthermore, several subtypes exist, particularly for the EP receptor (EP₁, EP₂, EP₃, EP₄), each with unique signaling profiles.

• EP Receptors: PGE₂ actions are highly context-dependent due to multiple receptor subtypes.
  • EP₁: Couples to G_q, increasing intracellular calcium (Ca²⁺). Mediates pain sensitization and smooth muscle contraction in certain tissues.
  • EP₂ and EP₄: Couple to G_s, stimulating adenylate cyclase and increasing intracellular cyclic AMP (cAMP). This generally leads to smooth muscle relaxation (e.g., bronchodilation, vasodilation), inhibition of immune cell function, and cytoprotection in the gastric mucosa.
  • EP₃: Couples to G_i, inhibiting adenylate cyclase and decreasing cAMP. Mediates contraction of uterine and gastrointestinal smooth muscle, and may contribute to fever generation in the hypothalamus.
• IP Receptor: Couples to G_s, increasing cAMP. This mediates potent vasodilation, inhibition of platelet aggregation, and cytoprotective effects in vascular endothelium.
• TP Receptor: Couples to G_q and G_12/13, activating phospholipase C (increasing IP₃ and DAG) and Rho kinase pathways. This mediates potent vasoconstriction, platelet aggregation, and smooth muscle proliferation.
• FP Receptor: Primarily couples to G_q, increasing intracellular Ca²⁺. Mediates contraction of uterine and bronchial smooth muscle, and is critically involved in the ocular hypotensive effect via remodeling of the uveoscleral outflow pathway.
• DP₁ Receptor: Couples to G_s, increasing cAMP, leading to vasodilation and inhibition of platelet aggregation. DP₂ (CRTH2) couples to G_i and is involved in chemotaxis of Th2 cells, eosinophils, and basophils, playing a role in allergic inflammation.

3.2. Leukotriene Receptors and Signaling

• Cysteinyl Leukotriene Receptors (CysLT₁ and CysLT₂): Primarily activated by LTC₄, LTD₄, and LTE₄. CysLT₁ is the main therapeutic target and couples to G_q, leading to increased intracellular Ca²⁺. Activation results in potent bronchoconstriction, increased vascular permeability, enhanced mucus secretion, and recruitment of inflammatory cells.
• BLT₁ Receptor: High-affinity receptor for LTB₄, coupling to G_i and G_q. It is a potent chemoattractant receptor for neutrophils, monocytes, and T-cells, promoting adhesion and degranulation.

3.3. Molecular and Cellular Effects

The cellular consequences of eicosanoid receptor activation are tissue-specific and form the basis of their physiological and pharmacological effects. In vascular smooth muscle, increased cAMP (via IP, EP₂, EP₄) causes relaxation and vasodilation, while increased Ca²⁺ (via TP, FP, EP₁) causes contraction and vasoconstriction. In platelets, increased cAMP inhibits aggregation, whereas TP activation promotes it. In the stomach, PGE₂ via EP receptors increases mucus and bicarbonate secretion while decreasing gastric acid secretion, thereby maintaining mucosal integrity. In the kidney, vasodilator prostaglandins (PGE₂, PGI₂) help maintain renal blood flow and glomerular filtration rate, particularly in states of decreased effective circulating volume. In the central nervous system, PGE₂ acts on EP₃ receptors in the hypothalamus to raise the body’s temperature set-point, causing fever.

4. Pharmacokinetics

The pharmacokinetic profiles of drugs acting on the eicosanoid system vary widely between the synthetic enzyme inhibitors (like NSAIDs) and the exogenous prostaglandin analogs.

4.1. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

• Absorption: Most traditional NSAIDs are weak organic acids with pK_a values between 3-5. They are generally well absorbed orally, with food potentially delaying but not reducing overall absorption. Some are available in topical, rectal, and parenteral formulations.
• Distribution: They are highly protein-bound (>95%), primarily to albumin. This high protein binding is a source of significant drug interactions with other highly protein-bound drugs like warfarin. Their volume of distribution is typically low (≈0.1-0.2 L/kg). They distribute well into synovial fluid and sites of inflammation.
• Metabolism: Metabolism occurs primarily in the liver via cytochrome P450 enzymes (notably CYP2C9) and phase II conjugation reactions (glucuronidation). Several NSAIDs (e.g., naproxen, celecoxib) are administered as prodrugs or are metabolized to active compounds.
• Excretion: Metabolites are excreted mainly in the urine, with a small fraction excreted in bile. Renal excretion of the parent drug is usually minimal due to high protein binding.
• Half-life and Dosing: NSAIDs exhibit a wide range of elimination half-lives (t_1/2), which dictates dosing frequency. Short-acting agents (t_1/2 2-6 hours; e.g., ibuprofen, diclofenac) require dosing 3-4 times daily. Long-acting agents (t_1/2 >10 hours; e.g., piroxicam, celecoxib, naproxen) can be dosed once or twice daily.

4.2. Therapeutic Prostaglandin Analogs

These agents are generally administered via routes that bypass extensive first-pass metabolism or are designed for local/targeted delivery due to their rapid systemic inactivation.

• Misoprostol: A synthetic PGE₁ analog. It is rapidly absorbed orally but undergoes extensive and rapid de-esterification to its active free acid metabolite, misoprostol acid. The onset of action is 30 minutes, with a peak effect at 60-90 minutes. The plasma half-life of the active metabolite is short (20-40 minutes), but its pharmacological effects on gastric secretion last 3-6 hours. It is metabolized in the liver and excreted in urine.
• Alprostadil (PGE₁): Used for ductus arteriosus patency or erectile dysfunction. When used for ductal patency, it is administered as a continuous intravenous infusion due to rapid pulmonary metabolism (single pass clearance >80%), resulting in a very short half-life of 3-5 minutes. For erectile dysfunction, it is administered via intracavernosal injection or intraurethral pellet to achieve local effect with minimal systemic exposure.
• Dinoprostone (PGE₂): Used for cervical ripening and labor induction. It is administered vaginally as a gel, tablet, or controlled-release pessary to provide local action, minimizing systemic effects. It is rapidly metabolized in local tissues and the lungs.
• Latanoprost, Travoprost, Bimatoprost: Prostaglandin F_2α analogs for glaucoma. They are administered as topical ophthalmic solutions. Systemic absorption from the eye is minimal, but enough can be absorbed to cause systemic side effects (e.g., darkening of iris and periorbital skin, exacerbation of asthma).
• Epoprostenol (PGI₂): Has an extremely short half-life (2-3 minutes) and is unstable at neutral pH. It requires continuous intravenous infusion via a central venous catheter, typically for pulmonary arterial hypertension. Its analogs (treprostinil, iloprost) have longer half-lives and offer alternative routes (subcutaneous, inhaled, oral).

5. Therapeutic Uses/Clinical Applications

5.1. Inhibition of Eicosanoid Synthesis (NSAIDs and COXIBs)

• Analgesia: Effective for mild to moderate pain of somatic origin (e.g., postoperative pain, musculoskeletal pain, headache, dysmenorrhea). Their effect on visceral pain is more variable.
• Anti-inflammatory: A cornerstone in the management of inflammatory arthropathies such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and acute gout.
• Antipyretic: Used to reduce fever by resetting the hypothalamic temperature set-point.
• Anti-thrombotic (Aspirin-specific): Low-dose aspirin (75-325 mg daily) irreversibly acetylates platelet COX-1, inhibiting TXA₂ synthesis for the lifespan of the platelet, providing cardioprotective and stroke-preventive effects.
• Closure of Patent Ductus Arteriosus: Indomethacin or ibuprofen (IV) is used to promote ductal closure in preterm neonates by inhibiting local PGE₂ synthesis, which maintains ductal patency.

5.2. Therapeutic Prostaglandin Analogs

• Gastroprotection: Misoprostol is used for the prevention of NSAID-induced gastric ulcers in high-risk patients.
• Obstetrics and Gynecology:
  • Cervical Ripening and Labor Induction: Dinoprostone (PGE₂) is used to prepare the cervix and induce labor.
  • Medical Abortion: Misoprostol, often combined with mifepristone (a progesterone receptor antagonist), is highly effective for medical termination of pregnancy in the first and second trimesters.
  • Postpartum Hemorrhage: Carboprost (15-methyl PGF_2α) is used as a second-line agent for refractory uterine atony due to its potent uterotonic effect.
• Ophthalmology: Prostaglandin F_2α analogs (latanoprost, travoprost, bimatoprost, tafluprost) are first-line agents for the reduction of intraocular pressure in open-angle glaucoma and ocular hypertension by increasing uveoscleral outflow.
• Vascular Disorders:
  • Pulmonary Arterial Hypertension (PAH): Prostacyclin analogs (epoprostenol, treprostinil, iloprost) and the IP receptor agonist selexipag are used to induce pulmonary vasodilation, inhibit platelet aggregation, and exert anti-proliferative effects on vascular smooth muscle.
  • Peripheral Vascular Disease: Alprostadil (PGE₁) and iloprost are used to improve symptoms of critical limb ischemia, primarily via vasodilation and inhibition of platelet aggregation.
• Erectile Dysfunction: Alprostadil can be administered intracavernosally or intraurethrally to induce penile erection by relaxing corporal smooth muscle.
• Maintenance of Ductal Patency: Alprostadil is infused intravenously in neonates with ductal-dependent congenital heart lesions (e.g., pulmonary atresia) to maintain patency of the ductus arteriosus until surgical correction can be performed.

5.3. Leukotriene Modifiers

• Asthma and Allergic Rhinitis: Cysteinyl leukotriene receptor antagonists (montelukast, zafirlukast) are used as controller medications for mild persistent asthma, particularly in patients with an aspirin-exacerbated respiratory disease (AERD) phenotype or concomitant allergic rhinitis. Zileuton, a 5-LOX inhibitor, is also used in asthma.
• Exercise-Induced Bronchoconstriction: Montelukast is used for prophylaxis.

6. Adverse Effects

6.1. Adverse Effects of NSAIDs and COX-2 Selective Inhibitors

The adverse effects of NSAIDs are largely attributable to the suppression of physiologically important prostaglandins.

• Gastrointestinal: The most common adverse effects. Inhibition of COX-1-derived PGE₂ and PGI₂ in the gastric mucosa reduces mucosal blood flow, mucus/bicarbonate secretion, and epithelial cell turnover, leading to dyspepsia, erosions, ulcers, and potentially life-threatening bleeding or perforation. COX-2 selective inhibitors (coxibs) have a significantly lower incidence of serious GI complications compared to non-selective NSAIDs, though risk is not absent.
• Renal: Inhibition of vasodilatory prostaglandins (PGE₂, PGI₂) can impair renal autoregulation, leading to fluid retention, edema, hypertension, and in susceptible individuals (e.g., those with heart failure, cirrhosis, chronic kidney disease, volume depletion), acute kidney injury. Chronic use may contribute to analgesic nephropathy (papillary necrosis, chronic interstitial nephritis).
• Cardiovascular: All NSAIDs, including coxibs, are associated with an increased risk of major adverse cardiovascular events (MACE), including myocardial infarction and stroke. The mechanism is believed to involve an imbalance between platelet-derived TXA₂ (pro-thrombotic) and endothelial-derived PGI₂ (anti-thrombotic). The risk appears to be dose-dependent and duration-dependent, and is highest with diclofenac and some coxibs. This risk has led to black box warnings for all NSAIDs (except aspirin) regarding cardiovascular thrombotic events.
• Hematological: Antiplatelet effect (reversible with most NSAIDs, irreversible with aspirin) can increase bleeding risk, particularly when combined with anticoagulants.
• Hypersensitivity: Can range from urticaria/angioedema to bronchospasm. A distinct syndrome, Aspirin-Exacerbated Respiratory Disease (AERD) or Samter’s triad, involves asthma, chronic rhinosinusitis with nasal polyps, and respiratory reactions to COX-1 inhibitors due to shunting of arachidonic acid toward leukotriene production.
• Hepatic: Idiosyncratic hepatotoxicity can occur, most notably with diclofenac.

6.2. Adverse Effects of Therapeutic Prostaglandin Analogs

These are often extensions of their pharmacological actions and are route-dependent.

• Misoprostol: Diarrhea and abdominal cramping are very common due to increased intestinal motility. Uterine contractions and vaginal bleeding can occur, making it contraindicated in pregnancy unless for intended abortion. Nausea and vomiting may also occur.
• Dinoprostone/Carboprost: Can cause excessive uterine activity (tachysystole, hypertonus), potentially leading to fetal distress. Nausea, vomiting, diarrhea, and fever are also common.
• Ophthalmic Prostaglandins: Local effects include conjunctival hyperemia, iris pigmentation (increased brown pigment), elongation and darkening of eyelashes, and periocular skin darkening. Cystoid macular edema is a rare but serious risk, particularly in aphakic or pseudophakic patients with a ruptured posterior capsule.
• Prostacyclin Analogs (Epoprostenol, Treprostinil, Iloprost): Adverse effects are often dose-limiting and include flushing, headache, jaw pain (characteristic), diarrhea, nausea, and hypotension. With epoprostenol infusion, catheter-related complications (sepsis, thrombosis) are significant risks. Iloprost inhalation can cause cough and bronchospasm.
• Alprostadil (for erectile dysfunction): Intracavernosal injection can cause penile pain, priapism (prolonged erection), and fibrosis with chronic use. Intraurethral administration can cause urethral burning, pain, and dizziness.

7. Drug Interactions

7.1. Major Drug-Drug Interactions

• Anticoagulants (Warfarin, DOACs) and Antiplatelets: NSAIDs increase bleeding risk through additive antiplatelet effects (inhibition of TXA₂), gastroduodenal ulcerogenic effects, and displacement of warfarin from plasma protein binding sites (increasing free warfarin concentration). This combination requires extreme caution.
• Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin II Receptor Blockers (ARBs): NSAIDs can attenuate the antihypertensive effect of these drugs and, by inhibiting renal prostaglandins, increase the risk of hyperkalemia and acute kidney injury, particularly in volume-depleted patients.
• Diuretics: NSAIDs reduce the natriuretic and antihypertensive efficacy of loop and thiazide diuretics by inhibiting prostaglandin-mediated renal vasodilation and may increase the risk of nephrotoxicity.
• Lithium: NSAIDs can reduce renal lithium clearance by up to 60%, potentially leading to lithium toxicity. This interaction is particularly prominent with indomethacin and naproxen.
• Methotrexate: NSAIDs may reduce renal clearance of methotrexate, increasing the risk of myelosuppression and mucositis, especially with high-dose methotrexate regimens.
• Corticosteroids: Concomitant use with NSAIDs significantly increases the risk of peptic ulcer disease and GI bleeding.
• Cyclosporine/Tacrolimus: NSAIDs may potentiate the nephrotoxicity of calcineurin inhibitors.
• Zafirlukast: Metabolism is inhibited by erythromycin and ketoconazole, and induced by rifampin. Zafirlukast itself can inhibit CYP2C9 and increase warfarin levels.
• Zileuton: Inhibits CYP1A2 and can increase levels of theophylline, propranolol, and warfarin.

7.2. Contraindications

• NSAIDs/COXIBs: Absolute contraindications include active peptic ulcer disease or GI bleeding, history of hypersensitivity reactions (including AERD) to any NSAID, severe heart failure (NYHA Class IV), third trimester of pregnancy (risk of premature ductus arteriosus closure), and severe renal impairment. COX-2 selective inhibitors are contraindicated in patients with ischemic heart disease, cerebrovascular disease, or peripheral arterial disease.
• Misoprostol: Contraindicated in pregnancy when the intent is to maintain the pregnancy, due to its abortifacient properties.
• Dinoprostone/Carboprost: Contraindicated in patients with a history of cesarean section or major uterine surgery (risk of uterine rupture), unexplained vaginal bleeding, fetal malpresentation, or evidence of fetal distress.
• Leukotriene Receptor Antagonists: Montelukast is contraindicated in patients with a history of neuropsychiatric events (e.g., depression, suicidal ideation) linked to its use, though this is a precautionary label warning.

8. Special Considerations

8.1. Pregnancy and Lactation

• 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). Third-trimester use can cause premature closure of the ductus arteriosus, oligohydramnios, and delayed labor. Most NSAIDs are considered compatible with breastfeeding in low doses for short durations, though ibuprofen is preferred.
• Misoprostol: Pregnancy Category X. It is a potent abortifacient and teratogen (associated with Möbius sequence and terminal transverse limb defects) and must be avoided in pregnancy unless for intended termination.
• Dinoprostone/Carboprost: Used specifically for obstetric indications (cervical ripening, labor induction, postpartum hemorrhage). Not used outside of pregnancy.
• Prostaglandin Analogs for Glaucoma: Latanoprost is classified as Pregnancy Category C; use only if benefit justifies potential fetal risk. It is excreted in breast milk in small amounts; caution is advised during lactation.

8.2. Pediatric and Geriatric Considerations

• Pediatrics: Ibuprofen and naproxen are commonly used for analgesia and antipyresis. Aspirin is generally avoided in children and adolescents (<19 years) with viral illnesses due to the risk of Reye's syndrome. Dosing is typically weight-based. Alprostadil is used in neonates for ductal patency.
• Geriatrics: Older adults are at significantly increased risk for all major NSAID toxicities (GI bleeding, renal impairment, hypertension, heart failure, cardiovascular events) due to comorbidities, polypharmacy, and altered pharmacokinetics. The lowest effective dose for the shortest duration is imperative. COX-2 inhibitors may be considered for those at high GI risk but low CV risk, with caution.

8.3. Renal and Hepatic Impairment

• Renal Impairment: NSAIDs should be avoided or used with extreme caution. Inhibition of renal prostaglandins can precipitate acute kidney injury. Dosing adjustment is often required, and monitoring of serum creatinine, electrolytes, and volume status is essential. Prostaglandin analogs like misoprostol do not require renal dose adjustment, but active metabolites of some NSAIDs may accumulate.
• Hepatic Impairment: NSAIDs that are extensively metabolized by the liver (e.g., diclofenac, naproxen, celecoxib) should be used with caution, starting at low doses. Patients with advanced liver disease are at increased risk of GI bleeding and renal impairment. Monitoring of liver function tests is recommended with chronic use.

9. Summary/Key Points

9.1. Bullet Point Summary

• Eicosanoids, including prostaglandins, thromboxanes, and leukotrienes, are potent lipid mediators synthesized from arachidonic acid via COX, LOX, and P450 pathways, acting locally on specific GPCRs.
• NSAIDs exert their therapeutic effects (analgesia, anti-inflammatory, antipyretic) by inhibiting COX enzymes, but this also underlies their major adverse effects on the GI tract, kidneys, and cardiovascular system.
• COX-2 selective inhibitors (coxibs) offer improved GI safety but carry a class-associated increased risk of cardiovascular thrombotic events.
• Therapeutic prostaglandin analogs are used to mimic beneficial eicosanoid actions in specific settings: misoprostol (GI protection, abortion), dinoprostone (labor induction), PGF_2α analogs (glaucoma), and prostacyclin analogs (pulmonary hypertension).
• Leukotriene modifiers (receptor antagonists like montelukast and the 5-LOX inhibitor zileuton) are important in the management of asthma, particularly the AERD phenotype.
• Major drug interactions for NSAIDs involve anticoagulants, antihypertensives, diuretics, and lithium, primarily due to effects on renal function, protein binding, and hemostasis.
• Special caution is required in pregnant patients, the elderly, and those with renal or hepatic impairment due to heightened risks of toxicity.

9.2. Clinical Pearls

• When prescribing NSAIDs, always assess the patient’s cardiovascular, gastrointestinal, and renal risk factors. Use the lowest effective dose for the shortest necessary duration.
• For patients at high GI risk requiring NSAID therapy, concomitant use of a proton pump inhibitor (PPI) or misoprostol, or use of a COX-2 selective inhibitor, is recommended.
• Aspirin’s irreversible platelet inhibition is unique and underpins its role in secondary cardiovascular prevention. Other NSAIDs cause reversible inhibition and may interfere with aspirin’s cardioprotective effect if dosed concomitately.
• In a patient with asthma, chronic rhinosinusitis
  

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  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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