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Prostaglandins
General information
Eicosanoids are the oxygenated metabolites of 20-carbon unsaturated fatty acids found in the phospholipids of cell membranes (Greek eikosi = 20). The eicosanoids include the prostaglandins, thromboxanes, and leukotrienes. Precursor fatty acids include arachidonic acid C20:4n − 6 (for 2-series prostaglandins and thromboxane and 4-series leukotrienes), dihomogammalinolenic acid C20:3n − 6 (for PGE 1 ), and eicosapentaenoic acid C20:5n − 3 (for 3-series prostaglandins and 5-series leukotrienes). Naturally occurring eicosanoids are predominantly metabolites of arachidonic acid, reflecting the dominance of n − 6 fatty acids in the terrestrial food chain.
Nomenclature
The names of prostaglandins are generally abbreviated to a three-letter abbreviation with a subscripted number. The first two letters are always PG; the third is E, F, or I. The recommended International Non-proprietary Names (rINNs) of various prostaglandins are given in Table 1 . The convention is that, for example, PGE 1 is the name given to the endogenous prostaglandin and alprostadil is the name given to the same compound available for exogenous administration.
Table 1
Recommended International Non-proprietary Names (rINNs) and chemical names of the major prostaglandins
| Prostaglandin | rINN | Chemical name (omitting stereochemical information) |
|---|---|---|
| PGE 1 | Alprostadil | 11,15-Dihydroxy-9-oxoprosta-13-en-1-oic acid |
| PGE 2 | Dinoprostone | 11,15-Dihydroxy-9-oxoprosta-5,13-dien-1-oic acid |
| PGF 2α | Dinoprost | 9,11,15-Trihydroxyprosta-5,13-dien-1-oic acid |
| PGI 2 (PGX, prostacyclin) | Epoprostenol | 6,9-Epoxy-11,15-dihydroxyprosta-5,13-dien-1-oic acid |
Types of prostaglandins
The principal biologically active, naturally occurring prostaglandins are prostaglandin E 1 (PGE 1 ), prostaglandin E 2 (PGE 2 ), prostaglandin F 2α (PGF 2α ), prostacyclin (PGI 2 ), and thromboxane (TXA 2 ). These agents have various, sometimes opposing, biological actions [ ]. Their half-lives are short, owing to their rapid breakdown (a few minutes for PGE 2 and PGF 2α , a few seconds for PGI 2 ) [ ]. Prostaglandins thus have principally local biological actions. Analogues (mostly methyl derivatives) have been synthesized and are more slowly inactivated. The adverse reactions encountered when prostaglandins are used therapeutically will depend on the indications (see Table 2 ), since these will determine the dose and route of administration and hence the type of reaction likely to occur. Many of the problems experienced are attributable to their main pharmacological effects ( Table 3 ).
Table 2
Indications for prostaglandin therapy
| In obstetrics |
| First- and second-trimester abortion |
| Cervical reopening |
| Induction of labor |
| Augmentation of labor |
| Postpartum hemorrhage |
| Ectopic pregnancy |
| Lactation suppression |
| In gastrointestinal disease |
| Peptic ulceration |
| Liver transplantation |
| Chemotherapy-induced mucosal lesions |
| In cardiovascular disease |
| Congenital cardiac malformations |
| Raynaud’s syndrome |
| Chronic obstructive pulmonary disease |
| Adult respiratory distress syndrome |
| Pulmonary hypertension |
| Arterial occlusive disease |
| Extracorporeal circulation |
| In urology |
| Erectile dysfunction |
| Cystitis after radiation or chemotherapy |
| In ophthalmology |
| Glaucoma |
Table 3
Actions of prostaglandins
| Prostaglandin E series |
| Increased hormone secretion |
| Growth hormone, corticotropin, thyrotropin, luteinizing hormone, thyroid hormone, insulin, glucocorticoids, progesterone, erythropoietin, renin |
| Increased body temperature |
| Sensitization of pain-mediating nerve fibers |
| Increased force of myocardial contraction |
| Increased blood flow in gastric mucosa, liver, kidney, and placenta |
| Increased renal secretion of sodium, potassium, and water |
| Antagonistic action against antidiuretic hormone |
| Increased intraocular pressure |
| Increased permeability of blood capillaries |
| Increased gastrointestinal motility |
| Reduced gastrointestinal secretions |
| Reduced blood pressure |
| Bronchodilatation |
| Inhibition of bronchial secretions |
| Sedation |
| Contraction of the non-pregnant uterus |
| Induction of abortion and labor |
| Prostaglandin F series |
| Bronchial constriction, especially in patients with asthma |
| Reduced pulmonary blood flow and increased pulmonary blood pressure |
| Increased erythropoietin secretion |
| Increased neurotransmission at sympathetic nerve endings |
| Increased gastrointestinal motility |
| Reduced blood pressure |
| Sedation (effects on the central nervous system) |
| Luteolytic effects in mammalian species (except man) |
| Induction of abortion and labor |
| Prostaglandin I series |
| Reduced platelet aggregation |
| Reduced mean arterial pressure |
| Reduced total peripheral and pulmonary resistances |
| Increased heart rate |
| Increased renal secretion of sodium (tubular effect) |
Synthetic analogues of PGE 1 , PGE 2 , PGF 1 , PGF 2α , and PGI 2
Synthetic analogues of prostaglandins are listed in Table 4 . Their use allows reduction of dosages and adverse reactions. In general, they cause fewer adverse reactions than their naturally occurring counterparts, although this depends on the method of administration. Newer analogues [ ] and oral forms [ ] are in development.
Table 4
Synthetic analogues of prostaglandins
| PGE 1 analogues | PGF 2α analogues |
| Enisoprost | Alfaprostol |
| Limaprost | Bimatoprost |
| Mexiprostil | Carboprost |
| Misoprostol | Cloprostenol |
| Ornoprostil | Fenprostalene |
| Rioprostil | Fluprostenol |
| Rosaprostol | Latanoprost |
| PGE 2 analogues | Luprostiol |
| Arbaprostil | Tafluprost |
| Enprostil | Tiaprost |
| Gemeprost | Travoprost |
| Meteneprost | Unoprostone |
| Nocloprost | PGI 2 analogues |
| Sulprostone | Beraprost |
| Trimoprostol | Cicaprost |
| Viprostol | Ciprostene |
| PGF 1 analogues | Iloprost |
| Prostalene |
General adverse effects and adverse reactions
The most prominent and frequent adverse reactions to prostaglandins are those in the gastrointestinal tract. However, the most dangerous are likely to be the cardiovascular reactions, which in predisposed patients can sometimes cause life-threatening collapse and heart failure. Hyperthermia and headache are frequent nervous system reactions. Epileptiform convulsions occur rarely. When used for termination of pregnancy, uterine hyperstimulation and, less often, uterine rupture can occur [ ]. Hypersensitivity to prostaglandins can cause skin reactions, bronchospasm (also seen as a direct pharmacological effect), and occasionally anaphylaxis. There have been a few reports of infants with limb deformities with and without Möbius sequence after exposure to misoprostol (a PGE 1 analogue) in the first trimester.
Prostaglandins in cardiovascular disease
Maintaining the patency of the ductus arteriosus
PGE 1 and PGE 2 are effective in maintaining the patency of the ductus arteriosus in the initial management of congenital cardiac malformations [ , ]. The most frequent adverse reactions during prolonged treatment are diarrhea, necrotizing enterocolitis, cortical hyperostosis [ ], fever, respiratory depression and apnea, and seizure-like activity [ ]. The frequency of adverse reactions is not necessarily reduced with low-dose intravenous or oral administration [ ]. Maternal/fetal hyperglycemia due to reduced insulin secretion is rare, except in the infants of diabetic mothers [ ]. Less common adverse reactions include gastric outlet obstruction due to antral hyperplasia [ ].
Raynaud’s phenomenon and digital ischemia
Studies of PGE 1 infusion for treatment of Raynaud’s syndrome have shown variable changes in frequency of attacks and of healing ischemic digital ulcers [ ]. Infusion of prostacyclin (using PGI 2 or its synthetic analogue iloprost) appears to have beneficial effects, both in reducing the severity and frequency of attacks and in healing ischemic digital ulcers. Adverse reactions are common and include headache, flushing, jaw pain, nausea, vomiting, diarrhea, and inflammation and pain at the injection site [ , ]. Iloprost has also been used effectively in the treatment of local gangrene secondary to chemotherapy [ ]. Application of a PGE 2 analogue to the skin produced both subjective and objective improvement in patients with Raynaud’s syndrome and produced only minor self-limiting adverse reactions (headache, flushing, and diarrhea) [ ].
Peripheral vascular disease
Synthetic PGI 2 has been used in arterial occlusive disease as an anti-aggregatory drug [ ]. Adverse reactions are common (85%). Headache, fever, nausea, anorexia, diarrhea, pain at the infusion site, and arthralgia are the most prominent. A single study has suggested an increased risk of thromboembolism after the use of iloprost in peripheral vascular disease [ ].
Beraprost, an epoprostenol (PGI 2 ) analogue, has been studied in intermittent claudication. Adverse events included gastrointestinal disorders, headaches, skin disorders, and fever [ ].
Primary pulmonary hypertension
Initial studies of continuous intravenous prostacyclin infusion in patients with primary pulmonary hypertension have shown sustained improvement in pulmonary artery pressure, exercise capacity, and survival compared with historical controls [ , ]. Minor complications (diarrhea, jaw pain, flushing, photosensitivity, and headache) were dose-related. Serious complications were related to problems with the drug delivery system, including catheter thrombosis, sepsis, and temporary interruption of the infusion, resulting in abrupt deterioration [ ].
Regulation of pulmonary vascular perfusion in advanced respiratory disease
PGE 1 significantly reduces right ventricular pulmonary after-load in patients with pulmonary hypertension due to chronic obstructive airways disease [ ]. PGE 1 can also be useful in the treatment of adult respiratory distress syndrome [ ]. Preliminary studies using aerosolized prostacyclin showed a reduction in pulmonary artery pressure and improved arterial oxygenation with reduction in intrapulmonary shunt in ventilated patients with adult respiratory distress syndrome [ ] and severe community-acquired pneumonia [ ]. However, ventilated patients with severe community-acquired pneumonia and pre-existing fibrosis required much higher doses, with a reduction in systemic vascular resistance and an increase in intrapulmonary shunting [ ]. A single report described improved oxygenation, mainly due to reduction of intrapulmonary shunting, in two neonates with pulmonary hypertension treated with aerosolized prostacyclin [ ].
Other uses
PGI 2 has been used to reduce the re-stenosis rate during transluminal coronary angioplasty [ ].
Prostacyclin infusion (using PGI 2 or its synthetic analogue, iloprost) has been used during extracorporeal circulation to prevent blood clotting in the dialyser coil [ ]. The risk of severe hypotension can be avoided by carefully controlling the infusion rate.
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