Pharmacology of Prostaglandins and Eicosanoids

Introduction and Overview

Prostaglandins and related eicosanoids represent a diverse class of bioactive lipids that arise from arachidonic acid metabolism. Their involvement in physiological and pathological processes—ranging from vascular tone regulation to inflammatory responses—has rendered them central to both basic science research and clinical therapeutics. The clinical relevance of these mediators is underscored by the widespread use of prostaglandin analogues in ophthalmology, obstetrics, gastroenterology, and oncology, as well as by the pivotal role of cyclooxygenase (COX) inhibitors in the management of pain, fever, and cardiovascular disease.

Learning objectives for this monograph include:

• To describe the biochemical pathways that generate prostaglandins and eicosanoids.
• To elucidate the pharmacodynamic properties and receptor interactions of key prostaglandin analogues.
• To summarize the pharmacokinetic profiles that influence dosing strategies and therapeutic efficacy.
• To identify approved indications and off‑label uses for prostaglandin‑based therapies.
• To recognize adverse effect profiles and drug interaction potentials associated with these agents.

Classification

Chemical Classification

Prostaglandins are cyclopentanone derivatives with varying side‑chain unsaturation and oxidation states. They are conventionally grouped into five families based on the structure of the side chain: PG_A, PG_B, PG_D, PG_E, and PG_F. PG_E and PG_I are often highlighted due to their prominent physiological roles. Eicosanoids encompass a broader spectrum, including thromboxanes, leukotrienes, lipoxins, and resolvins, which share the 20‑carbon backbone derived from arachidonic acid but differ in cyclization patterns and functional groups.

Drug Classes and Categories

Pharmacologic agents targeting prostaglandin pathways can be grouped into:

• Prostaglandin analogues and synthetic derivatives—e.g., misoprostol, dinoprostone, latanoprost, bimatoprost.
• COX inhibitors—nonselective NSAIDs (ibuprofen, naproxen) and selective COX‑2 inhibitors (celecoxib, rofecoxib).
• Thromboxane receptor antagonists—e.g., terutroban (limited clinical use).
• Leukotriene receptor antagonists—montelukast, zafirlukast, used primarily in asthma.

Mechanism of Action

Pharmacodynamics of Prostaglandins

Prostaglandins exert their effects by binding to G‑protein–coupled receptors (GPCRs) distributed across numerous tissues. The five main prostaglandin receptor families—EP (E prostanoid), FP (prostaglandin F receptor), IP (prostacyclin receptor), DP (prostaglandin D2 receptor), and TP (thromboxane A2 receptor)—mediate distinct signaling cascades. For instance, activation of EP2 and EP4 receptors typically stimulates adenylate cyclase, increasing cyclic AMP (cAMP) and promoting vasodilation and anti‑platelet aggregation. Conversely, TP receptor stimulation elevates intracellular calcium, inducing platelet aggregation and vasoconstriction.

Prostaglandin analogues often exhibit selectivity for one receptor subtype. Latanoprost, for example, preferentially activates EP2/EP4 receptors in the trabecular meshwork, enhancing aqueous humor outflow and lowering intraocular pressure. Misoprostol, a PGE1 analogue, binds EP2/EP3 receptors in the gastric mucosa, stimulating mucous secretion and bicarbonate production, thereby protecting the epithelium from acid injury.

Molecular and Cellular Mechanisms

At the cellular level, prostaglandins influence numerous processes. In vascular endothelium, PGI₂ (prostacyclin) activates the IP receptor, leading to cAMP‑dependent relaxation of smooth muscle cells and inhibition of platelet aggregation. PGD₂ can induce bronchoconstriction via DP1 receptor activation and modulate immune cell trafficking through DP2 (CRTH2) receptor signaling. Leukotrienes, derived from 5‑lipoxygenase metabolism, contribute to chemotaxis of eosinophils and neutrophils, underpinning allergic inflammation.

Beyond GPCRs, prostaglandins can also interact with nuclear receptors such as peroxisome proliferator‑activated receptors (PPARs), influencing gene transcription related to lipid metabolism and inflammatory responses. The integration of these signaling pathways underscores the pleiotropic nature of prostaglandin actions.

Pharmacokinetics

Absorption

Oral absorption of prostaglandin analogues varies with formulation. Misoprostol displays a bioavailability of approximately 30%, largely due to extensive first‑pass metabolism. Topical ophthalmic preparations such as latanoprost achieve ocular bioavailability of 30–50% via corneal penetration, with the remainder excreted via the nasolacrimal duct. Intramuscular or subcutaneous routes, employed for agents like dinoprostone, yield near‑complete systemic absorption, with a rapid onset of action within 30–60 minutes.

Distribution

Prostaglandins are lipophilic molecules that readily cross cell membranes. Their distribution is influenced by plasma protein binding; for example, misoprostol is largely unbound, whereas prostacyclin analogues exhibit moderate binding to albumin and lipoproteins. Tissue penetration is enhanced by the presence of specific transporters, such as the prostaglandin transporter (PGT) in renal proximal tubules.

Metabolism

Metabolic pathways are dominated by hydrolysis and oxidative reactions. Misoprostol undergoes rapid conversion to 16‑α‑hydroxypregnan-4,6-diene-3,20-dione, an active metabolite responsible for mucosal protection. COX‑2 inhibitors are metabolized primarily by cytochrome P450 enzymes (CYP2C9, CYP3A4), leading to hydroxylated and glucuronidated metabolites. Thromboxane antagonists are typically hydrolyzed to inactive acids before excretion.

Excretion

Renal clearance constitutes the major elimination route for most prostaglandin analogues. Their renal excretion can involve both glomerular filtration and active tubular secretion mediated by PGT. Hepatic excretion is less prominent but relevant for lipophilic analogues that undergo biliary secretion. The half‑life (t_1/2) of misoprostol is approximately 1–2 hours, whereas latanoprost has a t_1/2 of 5–6 hours in ocular tissues, supporting once‑daily dosing.

Dosing Considerations

Therapeutic regimens are tailored to the pharmacokinetic profile and clinical target. For instance, misoprostol is administered orally at 200 μg four times daily for ulcer protection, whereas dinoprostone may be given intramuscularly at 0.5 mg every 4–6 hours for labor induction. Ocular prostaglandin analogues are typically dosed once daily due to sustained ocular tissue exposure. Adjustments may be necessary in populations with altered hepatic or renal function.

Therapeutic Uses and Clinical Applications

Approved Indications

Prostaglandin analogues are approved for a range of indications:

• Ophthalmology—latanoprost, bimatoprost, and travoprost are licensed for open‑angle glaucoma and ocular hypertension, reducing intraocular pressure via enhanced aqueous humor outflow.
• Gastroenterology—misoprostol is indicated for the prevention of NSAID‑induced gastric ulcers, particularly in patients requiring chronic NSAID therapy.
• Obstetrics—dinoprostone (PGE2) and 15‑oxo‑prostaglandin E1 (15‑OH-PGE1) are used for cervical ripening and induction of labor. Additionally, misoprostol is employed off‑label for cervical ripening and abortion induction in resource‑limited settings.
• Reproductive Medicine—progesterone‑like prostaglandin analogues (e.g., dinoprostone) facilitate embryo implantation in assisted reproduction protocols.

Off‑Label and Emerging Uses

Several prostaglandin derivatives are explored in clinical trials:

• Topical prostaglandin analogues for androgenic alopecia, exploiting their vasodilatory effects on scalp vasculature.
• Intravenous misoprostol for the management of postpartum hemorrhage, leveraging uterotonic activity.
• PGI₂ analogues (iloprost) for treatment of peripheral arterial disease and digital ulcers in systemic sclerosis.

Adverse Effects

Common Side Effects

Adverse events are largely receptor‑mediated and dose‑dependent. In ocular preparations, conjunctival hyperemia, burning sensation, and transient mydriasis are frequent. Misoprostol commonly causes gastrointestinal symptoms including abdominal cramping, nausea, and diarrhea, reflecting its potent stimulation of the GI tract. Dinoprostone may induce uterine hyperstimulation, leading to tachysystole and fetal distress.

Serious and Rare Reactions

Serious adverse reactions, though uncommon, include:

• Reversible visual field defects or central serous retinopathy with long‑term use of prostaglandin analogues.
• Allergic reactions to misoprostol, manifesting as urticaria or anaphylaxis.
• Severe uterine hyperstimulation culminating in fetal hypoxia or uterine rupture.

Warnings and Contraindications

Black box warnings are present for misoprostol regarding the risk of severe gastrointestinal ulcers and perforation in patients with a history of peptic ulcer disease. Caution is advised when combining COX‑2 inhibitors with anticoagulants due to heightened bleeding risk. Prostaglandin analogues should be avoided in patients with known hypersensitivity to the drug or its excipients.

Drug Interactions

Major Drug–Drug Interactions

Interactions frequently involve pathways of metabolism or plasma protein binding:

• Co‑administration of misoprostol with systemic corticosteroids may attenuate its mucosal protective effect due to altered prostaglandin synthesis.
• NSAIDs and COX‑2 inhibitors can potentiate the hypotensive effect of prostaglandin analogues via additive vasodilatory mechanisms.
• Strong inhibitors of CYP2C9 (e.g., fluconazole) can increase plasma concentrations of COX‑2 inhibitors, potentially enhancing adverse effects.

Contraindications

Contraindications include:

• Active peptic ulcer disease or significant GI bleeding for misoprostol.
• History of hypersensitivity to prostaglandin or excipients.
• Severe cardiovascular disease for COX‑2 inhibitors, given increased thrombotic risk.

Special Considerations

Use in Pregnancy and Lactation

For pregnant patients, misoprostol is category C, with limited data regarding teratogenicity but evidence of efficacy in cervical ripening. Dinoprostone is category B and frequently employed for labor induction. Latanoprost is category C but generally avoided due to insufficient safety data. During lactation, prostaglandin analogues are excreted in breast milk at negligible levels; however, caution is advised during active nursing periods.

Pediatric and Geriatric Use

Pediatric dosing of prostaglandin analogues is guided by weight and surface area calculations. Misoprostol is employed for neonatal gastric protection, but dosing must account for immature hepatic metabolism. In geriatric populations, decreased renal clearance may necessitate dose reduction, and the risk of anticholinergic side effects is heightened.

Renal and Hepatic Impairment

In patients with renal impairment, the excretion of misoprostol and its metabolites may be prolonged, increasing the risk of gastrointestinal toxicity. COX‑2 inhibitors require dose adjustment or avoidance in severe hepatic dysfunction due to reliance on hepatic metabolism. Monitoring of liver function tests is recommended during prolonged therapy.

Summary and Key Points

• Prostaglandins are derived from arachidonic acid via COX‑1 and COX‑2 enzymes, with distinct receptor subtypes mediating varied physiological effects.
• Prostaglandin analogues exhibit receptor selectivity, enabling targeted therapeutic applications such as ocular pressure reduction and gastric mucosal protection.
• Pharmacokinetic attributes—absorption route, protein binding, metabolic pathways, and elimination—dictate dosing regimens and necessitate adjustments in special populations.
• Common adverse effects are largely receptor‑mediated; serious reactions, though rare, require vigilance, especially in patients with comorbidities.
• Drug interactions are mediated through metabolic enzymes and additive pharmacodynamic effects; contraindications are defined by hypersensitivity, active disease states, and pregnancy status.
• Clinical pearls include the importance of monitoring intraocular pressure after initiating prostaglandin analogues, ensuring adequate fluid status when administering uterotonic agents, and recognizing the potential for conjunctival hyperemia as a benign sign of therapeutic efficacy.

References

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