Prostaglandin analogues

Prostaglandin analogue

• Prostaglandins and thromboxanes are synthesized from arachidonic acid with the help of enzyme cyclooxygenase (COX).
• Phospholipase A2 is rate limiting enzyme in synthesis of prostaglandins.

Actions

1. CNS
2. PGE1 and PGE2 are pyrogenic and cause fever. NSAIDs act as antipyretic agents by inhibiting these PGs.

• Peripheral Nerve Endings
• PGE2 and PGI2 sensitize pain receptors to various mediators. NSAIDs act as analgesics by decreasing the synthesis of PGs.

• CVS
• PGE2 and PGI2 are vasodilators whereas PGF2α and TXA2 are vasoconstrictor agents. Epoprostenol (PGI2) and treprostinil (longer acting PGI2 analogue) à for the treatment of pulmonary hypertension.
• PGE2 increases capillary permeability.
• PGE2 and PGI2 keeps ductus arteriosus patent. In some congenital heart diseases (like transposition of great vessels), it becomes essential to keep ductus arteriosus patent before surgery. For this indication, alprostadil (PGE1) and epoprostenol (PGI2) can be given intravenously. If ductus arteriosus fails to close (patent ductus arteriosus) at birth, NSAIDs like aspirin and indomethacin are given to close it.

• Platelets
• PGI2 inhibits platelet aggregation whereas TXA2 is a potent aggregator of platelets.
• Nonselective COX inhibitors inhibit the generation of both of these compounds.
• TXA2 is synthesized in platelets and its synthesis cannot be resumed, once it is inhibited by NSAIDs (because platelets lack nuclei) whereas synthesis of PGI2 resumes after sometime (endothelial cells can synthesize new COX).
• Low dose aspirin can be used as an antiplatelet drug for the prophylaxis of MI and stroke.
• Epoprostenol (PGI2) can be used as an anti-aggregatory drug in dialysis and cardiopulmo-nary bypass. It can also be used for storage of platelets for transfusion.

• Uterus
• PGE2 and PGF2α are powerful uterine stimulants (contractor).
• Dinoprostone (PGE2) intravaginally and carboprost (PGF2α) intraamniotic injection can be used for inducing mid trimester abortion.
• Misoprostol (PGE1) along with methotrexate or mifepristone is used for induction of abortion in first few weeks of pregnancy.
• PGE2 causes softening of cervix (cervical ripening) during labour.
• Dinoprostone or misoprostol intravaginally are employed for cervical ripening during labour.
• Carboprost (PGF2α) can be used to control post-partum hemorrhage (contraction of uterus leads to compression of blood vessels resulting in decreased bleeding).
• PGs are responsible for pain during menstruation (dysmenorrhoea) and NSAIDs like mefenamic acid are useful for relieving this pain.
• Use of misoprostol in pregnancy is associated with moebius synrome (abnormal development of cranial nerves; most commonly VI and VII).

• Bronchus
• PGI2 and PGE2 are bronchodilators and TXA2 and PGF2α are bronchoconstrictor agents.
• Aerosolized PGE2 has been used effectively to abort acute attacks of asthma.
• COX inhibitors like aspirin cause more production of LTs (because due to enzyme inhibition arachidonic acid now produces only LTs). Aspirin can result in precipitation of asthma attacks because LTs are the main bronchoconstricting mediators in human asthma.

• GIT
• PGE2 and PGI2 decrease acid secretion and increase mucus production and mucosal blood flow. All these factors decrease the chances of peptic ulcer.
• NSAIDs on long term use can precipitate PUD due to inhibition of PG synthesis.
• Misoprostol is the most specific drug for the treatment of peptic ulcer due to chronic NSAID use. [drug of choice is proton pump inhibitors]
• PGE2 and PGF2α cause diarrhea and colicky pain in the abdomen. These symptoms are important side effects of these drugs.
• PG seems to play some role in colonic cancer. Regular use of aspirin or celecoxib decreases the risk of colonic polyps and cancers.

• Kidney
• PGE2 and PGI2 cause renal vasodilation, natriuresis and increased water clearance due to inhibition of the action of ADH. These agents also facilitate renin release.
• Loop diuretics act partly by increasing the stimulation of COX; therefore NSAIDs attenuate the diuretic action of these drugs.
• Bartter syndrome is characterized by excess PGs leading to hyperreninemia, excess aldosterone and the resultant hypokalemia and alkalosis. Indomethacin is used for treatment of this syndrome.

• Male reproductive system
• PGE2 and PGI2 increases sperm motility and enhances penile erection.
• Alprostadil can be used to treat erectile dysfunction.

1. Eye
2. PGF2α decreases intraocular pressure by increasing the uveoscleral outflow.
3. Latanoprost (PGF2α) is being used as eye drops for glaucoma.
4. Bimatoprost, travaprost and unoprostone are new prostaglandin analogues for this indication.

USES à Clinical application of PGs and their analogues

1. Abortion
   1. During the first trimester, termination of pregnancy by transcervical suction is the procedure of choice. Intravaginal PGE2 pessary inserted 3 hours before attempting dilatation can minimise trauma to the cervix by reducing resistance to dilatation.
   1. Medical termination of pregnancy of upto 7 weeks has been achieved with high success rate by administering mifepristone (antiprogestin) 600 mg orally 2 days before a single oral dose of misoprostol 400 μg.
   1. Uterine contractions are provoked and the conceptus is expelled within the next few hours.
   1. Ectopic pregnancy should be ruled out beforehand and complete expulsion should be confirmed afterwards.
   1. Uterine cramps, vaginal bleeding, nausea, vomiting and diarrhoea are the common side effects
   1. Methotrexate administered along with misoprostol is also highly successful for inducing abortion in the first few weeks of pregnancy
   1. PGs have a place in midterm abortion, missed abortion and molar gestation, though delayed and erratic action and incomplete abortion are a problem.
   1. PGs convert the oxytocin resistant midterm uterus to oxytocin responsive one: a single extraamniotic injection (PGE2) followed by i.v. infusion of oxytocin or intraamniotic (PGF2α) with hypertonic solution produces 2nd trimester abortion in a high percentage

• Induction/augmentation of labour
  • PGs do not offer any advantage over oxytocin for induction of labour at term.
  • They are less reliable and show wider individual variation in action.
  • PGE2 and PGF2α (rarely) have been used in place of oxytocin in toxaemic and renal failure patients, because PGs do not cause fluid retention that is possible with oxytocin.

• Cervical priming (ripening)
  • Applied intravaginally or in the cervical canal, low doses of PGE2 which do not affect uterine motility make the cervix soft and compliant.
  • If needed labour may be induced 12 hours later with oxytocin: chances of failure are reduced.

4. Postpartum haemorrhage (PPH)

• Carboprost (15-methyl PGF2α) injected i.m. is an alternative drug for control of PPH due to uterine atony, especially in patients unresponsive to ergometrine and oxytocin.
• PGE2 (Dinoprostone) à for induction/augmentation of labour, midterm abortion.

• Peptic ulcer
  • Stable analogue of PGE1 (misoprostol) isà peptic ulcer, especially in patients who need continued NSAID therapy

• Glaucoma à Topical PGF2α analogues like latanoprost, travoprost, bimatoprost that are FP receptor agonists are the first choice drugs in wide angle glaucoma

• To maintain patency of ductus arteriosus à PGE1 (Alprostadil)

• To avoid platelet damage PGI2 (Epoprostenol) à prevent platelet aggregation and damage during haemodialysis or cardiopulmonary bypass.

• Peripheral vascular diseases PGI2 (or PGE1) infused i.v. à relieve rest pain and promote healing of ischaemic ulcers in severe cases of intermittent claudication and in Raynaud’s disease.

• Impotence à Alprostadil (PGE1) injected into the penis causes erection lasting 1–2 hours. However, oral sildenafil/tadalafil is now preferred for erectile dysfunction.

SIDE EFFECTS

nausea, vomiting, watery diarrhoea, uterine cramps, unduly forceful uterine contractions, vaginal bleeding, flushing, shivering, fever, malaise, fall in BP, tachycardia, chest pain.