Pharmacology of Prostaglandins and Eicosanoids

Introduction/Overview

Prostaglandins and eicosanoids constitute a vast family of bioactive lipid mediators derived from polyunsaturated fatty acids, primarily arachidonic acid. These autacoids are not stored but are synthesized de novo in response to physiological and pathological stimuli, acting locally near their site of synthesis to exert potent, short-lived effects. The pharmacology of this system is fundamentally dualistic, encompassing both the endogenous mediators themselves, used as therapeutic agents, and the pharmacological agents designed to inhibit their synthesis or action. The clinical relevance of understanding this system is profound, as it underpins the mechanism of the most widely used class of drugs worldwide—nonsteroidal anti-inflammatory drugs (NSAIDs)—and is central to processes including inflammation, pain, fever, hemostasis, parturition, gastrointestinal mucosal integrity, and renal function. Dysregulation of eicosanoid pathways is implicated in a spectrum of diseases from asthma and allergic disorders to cardiovascular thrombosis and cancer.

Learning Objectives

• Outline the biosynthetic pathways of major eicosanoids, including prostaglandins, thromboxanes, leukotrienes, and lipoxins, from arachidonic acid.
• Describe the pharmacodynamics of eicosanoids, including receptor subtypes, signaling mechanisms, and resultant physiological and pathological effects.
• Explain the mechanisms of action, therapeutic uses, and adverse effect profiles of pharmacological agents that modulate eicosanoid pathways, such as NSAIDs, COX-2 selective inhibitors, and leukotriene receptor antagonists.
• Analyze the pharmacokinetic properties of representative eicosanoid-based drugs and inhibitors, and their implications for dosing and drug interactions.
• Apply knowledge of eicosanoid pharmacology to clinical scenarios involving special populations, including pregnant patients and those with renal or hepatic impairment.

Classification

The classification of agents related to prostaglandins and eicosanoids can be organized based on their relationship to the endogenous pathways: as exogenous replacements for endogenous mediators or as inhibitors of their synthesis or action.

Endogenous Eicosanoid Classes

Eicosanoids are classified chemically and by their biosynthetic enzyme pathways.

• Prostanoids (Cyclooxygenase Pathway Products): This class includes prostaglandins (PGs) and thromboxanes (TXs). They are characterized by a cyclopentane ring. Major members are:
  • PGE₂, PGD₂, PGF_2α, PGI₂ (prostacyclin).
  • Thromboxane A₂ (TXA₂).
• Leukotrienes and Lipoxins (Lipoxygenase Pathway Products): These are linear molecules synthesized via 5-, 12-, or 15-lipoxygenase enzymes.
  • Leukotrienes: LTB₄, LTC₄, LTD₄, LTE₄ (collectively known as cysteinyl leukotrienes).
  • Lipoxins: LXA₄, LXB₄.
• Epoxyeicosatrienoic Acids (EETs) and Hydroxyeicosatetraenoic Acids (HETEs): Derived via the cytochrome P450 epoxygenase and ω-hydroxylase pathways.

Pharmacological Agent Classes

Drugs are classified by their primary target within the eicosanoid system.

1. Eicosanoid Receptor Agonists (Therapeutic Prostaglandins):
   • PGE₁ analog: Alprostadil.
   • PGE₂ analog: Dinoprostone.
   • PGI₂ analogs: Epoprostenol, Iloprost, Treprostinil.
   • PGF_2α analog: Latanoprost, Travoprost, Bimatoprost.
   • Analog of PGD₂ metabolite: Latanoprostene bunod.
2. Cyclooxygenase Inhibitors:
   • Non-selective COX-1/COX-2 inhibitors (traditional NSAIDs): Ibuprofen, Naproxen, Diclofenac, Indomethacin.
   • Preferential COX-2 inhibitors: Meloxicam, Etodolac.
   • Selective COX-2 inhibitors (Coxibs): Celecoxib, Etoricoxib.
   • Irreversible COX-1 inhibitor: Aspirin (acetylsalicylic acid).
3. 5-Lipoxygenase Pathway Inhibitors:
   • 5-Lipoxygenase inhibitor: Zileuton.
   • Cysteinyl leukotriene receptor antagonists: Montelukast, Zafirlukast.
   • LTB₄ receptor antagonist: Not widely used clinically.
4. Prostanoid Receptor Antagonists:
   • TP (thromboxane) receptor antagonist: Terutroban (investigational).
   • EP₁ receptor antagonist: Used in combination analgesics in some markets.

Mechanism of Action

The mechanism of action involves the biosynthesis of endogenous eicosanoids and the subsequent interaction with specific G-protein coupled receptors (GPCRs) to elicit cellular responses. Pharmacological agents either mimic these actions or inhibit the synthesis or receptor binding of these mediators.

Biosynthesis

The substrate for classic eicosanoid synthesis is arachidonic acid (5,8,11,14-eicosatetraenoic acid), a 20-carbon polyunsaturated fatty acid esterified in membrane phospholipids. Upon cellular activation (e.g., by mechanical trauma, cytokines, growth factors), phospholipase A₂ (PLA₂) is activated, cleaving arachidonic acid from the membrane. This free acid is then metabolized via three major enzymatic pathways.

1. Cyclooxygenase (COX) Pathway: The COX enzyme (prostaglandin-endoperoxide synthase) has two catalytic activities: a cyclooxygenase activity that adds two molecules of O₂ to form the cyclic endoperoxide PGG₂, and a peroxidase activity that reduces it to PGH₂. PGH₂ is the unstable precursor for all prostanoids. Tissue-specific isomerases and synthases then convert PGH₂ to the active prostanoids:
   • PGD synthase → PGD₂
   • PGE synthase → PGE₂
   • PGF synthase → PGF_2α
   • PGI synthase → PGI₂ (prostacyclin)
   • Thromboxane synthase → TXA₂

   Two major COX isoforms exist: COX-1 is constitutively expressed in most tissues and is involved in homeostatic functions. COX-2 is inducible by inflammatory stimuli and is the primary source of prostanoids in inflammation, though it also has constitutive roles in the kidney, brain, and reproductive tract.

2. Lipoxygenase (LOX) Pathway: 5-Lipoxygenase (5-LOX), in concert with the 5-lipoxygenase-activating protein (FLAP), converts arachidonic acid to 5-HPETE and then to the unstable epoxide LTA₄. LTA₄ is metabolized by LTA₄ hydrolase to LTB₄, a potent chemotactic agent, or by LTC₄ synthase to LTC₄. LTC₄ is exported and sequentially converted to LTD₄ and LTE₄, the cysteinyl leukotrienes responsible for bronchoconstriction and vascular permeability. 12-LOX and 15-LOX pathways lead to the formation of other HETEs and lipoxins, which often have anti-inflammatory or pro-resolving actions.
3. Cytochrome P450 (CYP) Monooxygenase Pathway: CYP epoxygenases generate epoxyeicosatrienoic acids (EETs), which have vasodilatory and anti-inflammatory effects, while CYP ω-hydroxylases produce 20-HETE, a vasoconstrictor.

Receptor Interactions and Signaling

Prostanoids act on specific cell surface receptors, designated DP, EP, FP, IP, and TP for PGD₂, PGE₂, PGF_2α, PGI₂, and TXA₂, respectively. The EP receptor has four subtypes (EP_1-4). These are all GPCRs, coupling to different intracellular signaling pathways:

• IP, DP₁, EP₂, EP₄: Typically couple to G_s, stimulating adenylate cyclase and increasing intracellular cAMP, leading to smooth muscle relaxation and inhibition of platelet aggregation.
• TP, FP, EP₁: Typically couple to G_q, activating phospholipase C (PLC), increasing IP₃ and DAG, leading to calcium mobilization and smooth muscle contraction.
• EP₃: Generally couples to G_i, inhibiting adenylate cyclase and decreasing cAMP.

Leukotrienes act on BLT receptors (for LTB₄) and CysLT receptors (CysLT₁ and CysLT₂ for cysteinyl leukotrienes). CysLT₁ receptors primarily mediate bronchoconstriction, edema, and mucus secretion via G_q coupling.

Molecular and Cellular Effects

The physiological and pathological effects of eicosanoids are a direct consequence of receptor activation in specific tissues.

• Vascular System: PGI₂ (IP receptor) causes vasodilation and inhibits platelet aggregation. TXA₂ (TP receptor) causes vasoconstriction and promotes platelet aggregation. PGE₂ has complex vascular effects depending on the EP receptor subtype involved.
• Inflammation and Pain: PGE₂ and PGI₂ are key mediators of inflammation, causing vasodilation (redness, heat) and potentiating the edema caused by histamine and bradykinin. PGE₂ sensitizes peripheral nociceptors to pain stimuli (hyperalgesia) and acts centrally in the hypothalamus to produce fever. Leukotrienes, particularly LTB₄, are potent chemoattractants for neutrophils, while cysteinyl leukotrienes increase vascular permeability.
• Gastrointestinal Tract: PGE₂ and PGI₂ maintain mucosal integrity by stimulating bicarbonate and mucus secretion, inhibiting gastric acid secretion, and promoting mucosal blood flow.
• Kidney: In the renal vasculature, vasodilator PGs (PGE₂, PGI₂) help maintain renal blood flow, particularly under conditions of decreased effective circulating volume. They also promote natriuresis.
• Reproductive System: PGE₂ and PGF_2α are critical in ovulation, luteolysis, and uterine contraction during labor.
• Respiratory System: PGE₂ causes bronchodilation, while PGF_2α and TXA₂ cause bronchoconstriction. Cysteinyl leukotrienes are extremely potent bronchoconstrictors and promote airway remodeling.

Pharmacokinetics

The pharmacokinetic profiles of eicosanoid-related drugs vary immensely, from labile endogenous mediators administered by continuous infusion to stable synthetic analogs and enzyme inhibitors given orally.

Therapeutic Prostaglandins and Analogs

Most natural prostaglandins are chemically unstable and rapidly metabolized, necessitating specialized routes of administration.

• Alprostadil (PGE₁): Administered by intravenous infusion or intracavernosal injection. It has a very short half-life (minutes) due to rapid pulmonary metabolism (≈80% in one pass) and systemic degradation. Continuous IV infusion is required for sustained effect.
• Dinoprostone (PGE₂): Used locally in the vagina as a gel, tablet, or pessary for cervical ripening. Systemic absorption occurs but is limited by extensive first-pass hepatic metabolism (15-hydroxyprostaglandin dehydrogenase, PG dehydrogenase), resulting in a short systemic half-life and localized action.
• Epoprostenol (PGI₂): Extremely labile, with a plasma half-life of approximately 3 minutes. It requires continuous intravenous infusion via a central venous catheter. It is hydrolyzed non-enzymatically in blood to inactive metabolites.
• Iloprost/Treprostinil: More stable analogs of PGI₂. Iloprost has a longer half-life (20-30 minutes) and can be administered by intravenous infusion or via inhalation. Treprostinil can be administered subcutaneously, intravenously, orally, or by inhalation, with a half-life of 4-6 hours.
• Latanoprost/Travoprost/Bimatoprost: Prodrug esters of PGF_2α analogs designed for topical ophthalmic use. They are well-absorbed through the cornea, where esterases hydrolyze them to the active acid. Systemic absorption is minimal, but measurable plasma concentrations can occur. Systemic half-life is short (minutes) for the active acid.

Cyclooxygenase Inhibitors (NSAIDs and Coxibs)

These are generally well-absorbed orally, highly protein-bound, and metabolized hepatically.

• Absorption: Most are weak organic acids, which facilitates absorption in the acidic stomach but also promotes concentration in inflammatory sites (which have a lower pH) and renal tubular fluid. Absorption is generally rapid and complete.
• Distribution: High degree of plasma protein binding (>90-99%), primarily to albumin. This contributes to a low volume of distribution (V_d ≈ 0.1-0.2 L/kg). This high protein binding is the basis for significant drug interactions with other highly protein-bound drugs like warfarin.
• Metabolism: Primarily hepatic via cytochrome P450 enzymes (e.g., CYP2C9 for ibuprofen, celecoxib, diclofenac; CYP2C8 for ibuprofen) and glucuronidation. Many NSAIDs (e.g., naproxen, ketorolac) are administered as racemic mixtures, with enantiomers having different activities and metabolic rates.
• Excretion: Metabolites are excreted renally. Minimal unchanged drug is excreted, except for some agents like ketorolac. Renal excretion of active metabolites can be significant for some drugs (e.g., sulindac sulfide).
• Half-life and Dosing: Half-lives vary widely, influencing dosing frequency.
  • Short t_1/2 (2-4 hours): Ibuprofen, diclofenac.
  • Intermediate t_1/2 (12-17 hours): Naproxen.
  • Long t_1/2 (>24 hours): Piroxicam, celecoxib (11 hours, but once-daily dosing is often sufficient).
• Aspirin: Unique pharmacokinetics. It is rapidly deacetylated to salicylate in the gut wall, liver, and plasma. Salicylate has dose-dependent kinetics (first-order at low doses, zero-order at high anti-inflammatory doses). Its antiplatelet effect is irreversible, lasting for the lifespan of the platelet (7-10 days), despite a short plasma half-life of 15-20 minutes for the parent drug.

Leukotriene Pathway Modifiers

• Montelukast/Zafirlukast: Orally active, well-absorbed leukotriene receptor antagonists. Montelukast is extensively metabolized by CYP3A4 and 2C9. Zafirlukast is metabolized by CYP2C9. Both are highly protein-bound (>99%). Food can reduce the bioavailability of zafirlukast. Montelukast has a half-life of 3-6 hours, zafirlukast 10 hours.
• Zileuton: An oral 5-LOX inhibitor. It is rapidly absorbed and metabolized by glucuronidation and oxidation via CYP1A2, 2C9, and 3A4. It has a short half-life (2-3 hours), requiring multiple daily dosing, and is a moderate inhibitor of CYP1A2.

Therapeutic Uses/Clinical Applications

The clinical applications of eicosanoid pharmacology are diverse, ranging from the inhibition of prostanoid synthesis for analgesia to the replacement or augmentation of specific prostanoid actions for targeted therapy.

Therapeutic Uses of Prostaglandin Analogs

1. Ophthalmology – Glaucoma: PGF_2α analogs (latanoprost, travoprost, bimatoprost, tafluprost) are first-line agents for reducing intraocular pressure (IOP). They increase uveoscleral outflow of aqueous humor. Latanoprostene bunod provides additional nitric oxide-mediated effects.
2. Obstetrics and Gynecology:
   • Cervical Ripening and Labor Induction: Dinoprostone (PGE₂) vaginal inserts, gels, or tablets are used to soften and dilate the cervix. Misoprostol (a PGE₁ analog) is used off-label for cervical ripening, labor induction, and medical management of miscarriage or postpartum hemorrhage.
   • Postpartum Hemorrhage: Carboprost tromethamine (15-methyl PGF_2α) is used intramyometrially to induce uterine contraction in refractory hemorrhage.
3. Cardiovascular and Pulmonary Vascular Disease:
   • Patent Ductus Arteriosus (PDA): Alprostadil (PGE₁) is infused to maintain ductal patency in neonates with ductal-dependent congenital heart disease until surgical correction.
   • Pulmonary Arterial Hypertension (PAH): Prostacyclin analogs (epoprostenol, iloprost, treprostinil) are cornerstone therapies for PAH. They induce pulmonary vasodilation, inhibit platelet aggregation, and have antiproliferative effects on vascular smooth muscle.
4. Erectile Dysfunction: Alprostadil can be administered via intracavernosal injection or intraurethral pellet for the treatment of erectile dysfunction, causing direct vasodilation of cavernosal arteries.
5. Gastroprotection: Misoprostol (PGE₁ analog) is indicated for the prevention of NSAID-induced gastric ulcers in high-risk patients, mimicking the gastroprotective effects of endogenous PGs.

Therapeutic Uses of Cyclooxygenase Inhibitors

1. Analgesia: Widely used for mild to moderate pain (e.g., headache, dental pain, dysmenorrhea, musculoskeletal pain). Ketorolac is a potent NSAID available for short-term management of moderate to severe acute pain, often as an opioid-sparing agent.
2. Anti-inflammatory Therapy: A primary use in chronic inflammatory conditions such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and acute gout.
3. Antipyretic Therapy: Effective in reducing fever by resetting the hypothalamic thermostat, an effect mediated by inhibition of central PGE₂ synthesis.
4. Antiplatelet Therapy:
   • Aspirin: Low-dose (75-325 mg/day) irreversibly inhibits platelet COX-1, blocking TXA₂ production for the platelet’s lifespan. This is fundamental for secondary prevention of myocardial infarction, stroke, and other atherothrombotic events.
   • Non-aspirin NSAIDs provide reversible platelet inhibition, which is transient and dependent on plasma drug concentration.
5. Colorectal Cancer Prevention: Long-term use of aspirin and possibly other NSAIDs is associated with a reduced risk of colorectal adenomas and carcinoma, likely through COX-2 inhibition and other mechanisms. This use is generally considered chemopreventive in high-risk individuals rather than a standard indication.

Therapeutic Uses of Leukotriene Modifiers

1. Asthma:
   • Leukotriene Receptor Antagonists (LTRAs): Montelukast and zafirlukast are used as controller medications for mild persistent asthma, often as an alternative to inhaled corticosteroids. They are particularly useful in asthma with an allergic component and in exercise-induced bronchoconstriction.
   • 5-LOX Inhibitor: Zileuton is used for chronic asthma therapy.
2. Allergic Rhinitis: Montelukast is approved for the relief of symptoms of seasonal and perennial allergic rhinitis.

Adverse Effects

Adverse effects arise from the non-selective inhibition of physiologically beneficial prostanoids or from the exaggerated pharmacological effects of administered analogs.

Adverse Effects of Cyclooxygenase Inhibitors (NSAIDs)

The adverse effect profile is largely a consequence of inhibiting constitutive, homeostatic COX-1 activity, though COX-2 inhibition also contributes to certain toxicities.

• Gastrointestinal: The most common adverse effects. Inhibition of gastroprotective PGs (PGE₂, PGI₂) leads to:
  • Dyspepsia, nausea, abdominal pain.
  • Gastric and duodenal erosions and ulcers, with risk of perforation and bleeding. Risk factors include advanced age, high dose, prolonged use, concomitant corticosteroids or anticoagulants, and history of ulcer.
• Renal: Inhibition of vasodilator PGs in the kidney can impair renal function, especially in states of decreased renal perfusion (e.g., heart failure, cirrhosis, volume depletion, chronic kidney disease). Effects include:
  • Fluid and electrolyte retention (edema, hypertension).
  • Acute kidney injury (due to reduced glomerular filtration rate).
  • Interstitial nephritis (an idiosyncratic reaction, more common with some NSAIDs like fenoprofen).
  • Papillary necrosis with chronic, high-dose use.
• Cardiovascular: A class effect for most NSAIDs, particularly concerning for selective COX-2 inhibitors and some traditional NSAIDs. Inhibition of vascular PGI₂ (an antithrombotic vasodilator) without concomitant inhibition of platelet TXA₂ (by COX-1) may create a prothrombotic state. Risks include:
  • Increased incidence of myocardial infarction, stroke, and heart failure.
  • Exacerbation of hypertension.
• Hematological: Reversible inhibition of platelet COX-1 impairs thromboxane-dependent platelet aggregation, prolonging bleeding time (except with aspirin, which causes irreversible inhibition). This can increase bleeding risk, particularly with concomitant anticoagulants.
• Hepatic: Elevations in liver transaminases can occur; rare cases of severe hepatotoxicity have been reported with drugs like diclofenac.
• Hypersensitivity: NSAID-exacerbated respiratory disease (NERD) occurs in some asthmatics, where COX inhibition shunts arachidonate to the leukotriene pathway, provoking bronchospasm. NSAID-exacerbated cutaneous disease and true immunoglobulin E-mediated anaphylaxis are less common.

Adverse Effects of Therapeutic Prostaglandin Analogs

• Systemic Prostaglandins (Epoprostenol, Alprostadil): Adverse effects are often direct extensions of their pharmacological actions and can be dose-limiting.
  • Flushing, headache, hypotension, jaw pain, diarrhea, nausea, vomiting.
  • For epoprostenol, complications of the continuous IV infusion system (e.g., line infections, sepsis, pump failure) are significant risks.
  • For alprostadil in PDA, apnea is a serious risk, requiring ventilatory support readiness.
• Ophthalmic Prostaglandin Analogs:
  • Local: Conjunctival hyperemia, foreign body sensation, iris pigmentation (increased brown pigment), eyelash growth (hypertrichosis), periocular skin darkening, cystoid macular edema (in aphakic patients or those with ruptured posterior capsule).
  • Systemic effects are rare but may include exacerbation of asthma or headaches.
• Obstetrical Prostaglandins:
  • Uterine hyperstimulation, which can lead to fetal distress.
  • Nausea, vomiting, diarrhea, fever.

Adverse Effects of Leukotriene Modifiers

• Generally well-tolerated. Most common: headache, dyspepsia.
• Neuropsychiatric Events: Post-marketing reports for montelukast have included agitation, aggression, depression, suicidal ideation, and behavior changes, leading to a Boxed Warning from regulatory agencies. Patients should be monitored for such changes.
• Churg-Strauss Syndrome: A rare eosinophilic vasculitis has been reported in association with leukotriene modifier use, often in the context of steroid tapering in asthmatic patients; a causal relationship is not firmly established.
• Zileuton-specific: Elevation of liver transaminases (requires monitoring), and potential for drug interactions via CYP1A2 inhibition.

Drug Interactions

Significant drug interactions occur due to pharmacokinetic and pharmacodynamic mechanisms.

Major Pharmacokinetic Interactions

• Protein Binding Displacement: NSAIDs are highly protein-bound and can displace other highly bound drugs (e.g., warfarin, sulfonylureas, phenytoin, methotrexate) from albumin, potentially increasing their free, active concentration and toxicity. This effect is usually transient as increased free drug leads to increased metabolism or excretion, but the pharmacodynamic interaction with warfarin (increased bleeding risk) is particularly dangerous.
• Cytochrome P450 Interactions:
  • NSAIDs metabolized by CYP2C9 (e.g., celecoxib, ibuprofen, diclofenac) may interact with inhibitors (e.g., fluconazole, amiodarone) or inducers of this enzyme.
  • Zileuton inhibits CYP1A2, potentially increasing levels of drugs like theophylline, caffeine, and clozapine.
• Renal Excretion Interactions: NSAIDs can reduce renal clearance of lithium and methotrexate by inhibiting renal prostaglandin-mediated vasodilation, leading to increased plasma levels and toxicity. Close monitoring and dose adjustment are required.

Major Pharmacodynamic Interactions

• Anticoagulants and Antiplatelets: NSAIDs increase the risk of bleeding when combined with warfarin (via protein displacement and antiplatelet effects), heparin, direct oral anticoagulants (DOACs), and other antiplatelet agents (e.g., clopidogrel). Aspirin combined with other NSAIDs may competitively block aspirin’s access to the platelet COX-1 active site, potentially attenuating its cardioprotective effect.
• Antihypertensives: NSAIDs can antagonize the effects of diuretics, ACE inhibitors, angiotensin receptor blockers (ARBs), and beta-blockers by promoting sodium retention and reducing renal blood flow, leading to increased blood pressure or worsening of heart failure.
• Corticosteroids: Concomitant use significantly increases the risk of GI ulceration and bleeding.
• Other Nephrotoxic Agents: Concurrent use with aminoglycosides, cyclosporine, or other NSAIDs increases the risk of acute kidney injury.

Contraindications

• NSAIDs: Contraindicated in patients with a history of hypersensitivity to aspirin or any NSAID, especially those with NSAID-induced asthma, urticaria, or other allergic reactions. They are also contraindicated in the setting of active peptic ulcer disease or GI bleeding, severe heart failure, severe renal impairment, and in the third trimester of pregnancy (risk of premature closure of the ductus arteriosus and prolonged labor).
• Prostaglandin Analogs: Specific contraindications exist, such as the use of dinoprostone when there is a history of cesarean delivery or major uterine surgery, or in cases of unexplained vaginal bleeding. Alprostadil is contraindicated in conditions predisposing to priapism.

Special Considerations

Pregnancy and Lactation

• Pregnancy:
  • NSAIDs: Generally avoided, especially in the first and third trimesters. Use in the first trimester may be associated with a small increased risk of miscarriage and congenital malformations. Use after 30 weeks gestation is contraindicated due to the risk of premature closure of the fetal ductus arteriosus, which can lead to persistent pulmonary hypertension of the newborn, and the risk of oligohydramnios and prolonged labor.
  • Therapeutic Prostaglandins: Dinoprostone and misoprostol are used intentionally for obstetric indications. Misoprostol is a potent teratogen in the first trimester and its use is absolutely contraindicated in pregnancy except for intended obstetric procedures.
  • Leukotriene Modifiers: Montelukast is classified as Pregnancy Category B; data are limited but no major teratogenic risk has been identified. Use should be based on a risk-benefit assessment.
• Lactation: Most NSAIDs are considered compatible with breastfeeding as they are excreted in milk in very low concentrations. Ibuprofen and indomethacin are often preferred choices. Aspirin is generally avoided due to theoretical risks of Reye’s syndrome and potential effects on platelet function in the infant. Data on leukotriene modifiers are limited but montelukast is considered likely safe.

Pediatric Considerations

• Ibuprofen and naproxen are commonly used in children for analgesia and antipyresis. Dosing is based on weight.
• Aspirin is generally avoided in children and adolescents (<19 years) with febrile illnesses due to the association with Reye's syndrome, a rare but severe condition characterized by hepatic encephalopathy.
• Montelukast is approved for asthma and allergic rhinitis in children as young as 6 months (asthma) or 2 years (allergic rhinitis).
• Alprostadil is used in neonates for PDA.

Geriatric Considerations

Older adults are at significantly increased risk for adverse effects from NSAIDs due to age-related pharmacokinetic changes (reduced renal clearance, altered volume of distribution) and increased prevalence of comorbidities (hypertension, heart failure, renal impairment, peptic ulcer disease). They should be prescribed at the lowest effective dose for the shortest possible duration. COX-2 selective inhibitors may offer a lower GI risk but do not mitigate cardiovascular or renal risks.

Renal and Hepatic Impairment

• Renal Impairment: NSAIDs should be used with extreme caution or avoided in patients with moderate to severe renal impairment (eGFR <30 mL/min/
  

  References

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  4. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
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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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  Mentor, Pharmacology. Pharmacology of Prostaglandins and Eicosanoids. Pharmacology Mentor. Available from: https://pharmacologymentor.com/pharmacology-of-prostaglandins-and-eicosanoids-2/. Accessed on February 3, 2026 at 07:35.
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