Pharmacology of Prostaglandin Analogues

Introduction

Prostaglandin analogues are a class of drugs that bind to a prostaglandin receptor¹. They have revolutionized the management of glaucoma, with their intraocular pressure (IOP) reducing efficacy combined with few systemic side effects and once a day dosing².

Mechanism of Action

1. In Glaucoma Treatment: Prostaglandin analogues work by enhancing uveoscleral outflow of aqueous humour. They may also have some effect to increase the trabecular meshwork outflow of aqueous humour. This action reduces intraocular pressure, which is beneficial in the treatment of glaucoma³.
2. Gastrointestinal Protection: Misoprostol, a PG analogue, acts on the stomach’s prostaglandin receptors to decrease acid secretion and increase mucous and bicarbonate production, protecting the lining.
3. Induction of Labor: PG analogues such as dinoprostone facilitate labor by ripening the cervix and stimulating uterine contractions. The side effects like uterine hyperstimulation, nausea, vomiting, and diarrhea arise from excessive stimulation of prostaglandin receptors in the uterus and gastrointestinal tract.
4. In Neonatology Patent Ductus Arteriosus (PDA) Management: Alprostadil is used to maintain the patency of the ductus arteriosus in neonates by relaxing the smooth muscle. Side effects like apnea, fever, hypotension, and flushing are due to its vasodilatory effects and action on the respiratory and cardiovascular systems.
5. Erectile Dysfunction Treatment: Alprostadil induces vasodilation and increases blood flow to the penis, leading to an erection. Adverse effects like penile pain, priapism, or fibrosis are related to its direct action on penile vasculature and local tissue reactions.
6. As an Abortifacient: Misoprostol induces uterine contractions and cervical ripening, facilitating abortion. The side effects, including heavy bleeding, cramps, and gastrointestinal symptoms, are due to its potent effect on the uterus and gastrointestinal tract.
7. In Pulmonary Hypertension: Epoprostenol, used in pulmonary arterial hypertension, acts as a potent vasodilator of the pulmonary and systemic vascular beds. Side effects like headache, jaw pain, flushing, hypotension, and nausea are associated with its systemic vasodilatory properties and direct action on vascular smooth muscle.
8. Cryopreservation: The adverse effects of PG analogues in cryopreservation are less about direct effects on individuals and more about their potential impact on the viability and integrity of the preserved cells and tissues.

Pharmacokinetics

The pharmacokinetics of prostaglandin analogues can vary depending on the specific drug. However, they are generally well absorbed and have a long duration of action, making them suitable for once-daily dosing².

Clinical Uses

Prostaglandin analogues such as misoprostol are used in the treatment of duodenal and gastric ulcers¹. In ophthalmology, they have become the drugs of first choice for IOP reduction (latanoprost)². They are particularly useful in the treatment of glaucoma, a group of progressive, age-related, and chronic optic neuropathies⁴.

1. Ophthalmological Application in Glaucoma: PG analogues, notably latanoprost, bimatoprost, and travoprost, are frequently employed in glaucoma management. Their mechanism involves augmenting aqueous humor drainage from ocular structures, resulting in diminished intraocular pressure.
2. Gastrointestinal Tract Protection: The PG analogue misoprostol is utilized for the prophylaxis of gastric ulcers in patients prescribed nonsteroidal anti-inflammatory drugs (NSAIDs). Its therapeutic action replicates the gastroprotective attributes of prostaglandins on the gastric mucosa.
3. Obstetrical Use in Labor Induction: Specific PG analogues, such as dinoprostone, are administered for labor induction. These agents facilitate cervical maturation and promote uterine contractility.
4. Neonatal Management of Patent Ductus Arteriosus (PDA): Within the realm of neonatology, PG analogues like alprostadil are instrumental in maintaining the patency of the ductus arteriosus in neonates with specific congenital cardiac anomalies, pending surgical resolution.
5. Therapeutic Role in Erectile Dysfunction: Alprostadil, a derivative of prostaglandin E1, is indicated for the management of erectile dysfunction. Its administration, either intracavernosal or intraurethral, induces vasodilation and enhances penile blood flow.
6. Application as an Abortifacient: PG analogues, including misoprostol, in conjunction with other pharmacological agents, are used for the induction of medical abortion. They induce uterine contractions, facilitating the expulsion of the gestational product.
7. Treatment of Pulmonary Hypertension: Epoprostenol, another PG analogue, is utilized in the management of pulmonary arterial hypertension. Its vasodilatory effect on pulmonary vasculature contributes to the amelioration of hemodynamic parameters.
8. Use in Cryopreservation: Certain PG analogues find application in the cryopreservation of cellular and tissue specimens, offering cytoprotection against freezing-induced damage.

Adverse Effects

1. Gastrointestinal Disturbances: Commonly causing nausea, vomiting, diarrhea, and abdominal pain.
2. Cardiovascular Changes: Including fluctuations in blood pressure and palpitations.
3. Respiratory Issues: Notably apnea in neonates treated for Patent Ductus Arteriosus (PDA).
4. Ocular Effects: Changes in eye color, eyelash growth, and irritation, particularly in glaucoma treatments.
5. Uterine Contractions: Intense contractions when used in labor induction or as abortifacients, potentially causing discomfort and complications.
6. Central Nervous System Symptoms: Such as headaches and dizziness.
7. Local Reactions: Irritation or pain at the site of application or injection.
8. Allergic Reactions: Ranging from mild skin reactions to severe anaphylaxis.
9. Increased Bleeding Risk: Especially in higher doses or vulnerable populations.

The main limiting factor in the use of prostaglandin analogues for glaucoma is severe conjunctival hyperemia, burning, irritation, and foreign body sensation after instillation². However, the prevalence of adverse events is lower for some prostaglandin analogues than for others⁴.

Conclusion

Prostaglandin analogues have significantly advanced the treatment of conditions such as glaucoma and gastric ulcers. Their ability to reduce intraocular pressure with minimal systemic side effects has made them a first-line treatment in the management of glaucoma. However, further research is needed to fully understand the pharmacokinetics and pharmacodynamics of these drugs, as well as to develop strategies to manage their adverse effects².