Prostaglandins By Ashwin Mascarenhas

Ergot alkaloids Fungus which grows on rye, millet and some other grains Had been used by midwives to quicken labour since the middle ages Received medical sanction, but due to its danger , its use advocated only after delivery Ergometrine was isolated in 1935

Natural ergot alkaloids a. Amine alkaloid: Ergometrine (Ergonovine) → Oxytocic b. Amino acid alkaloids: Ergotamine, Ergotoxine (mixture of ergocristine + ergocornine + ergocryptine) → Vasoconstrictor and α agrenergic blocker/partial agonist. Other semisynthetic derivatives Dihydroergotamine (DHE), Dihydroergotoxine (Codergocrine): Antiadrenergic, cerebroactive 2-Bromo-α-ergocryptine (Bromocryptine): Dopaminergic D2 agonist Methysergide: Mainly anti 5-HT

Actions Ergotamine Partial agonist and antagonist at α adrenergic and subtypes of 5-HT1 and 5-HT2 Produces sustained vasoconstriction, visceral smooth muscles contraction, vasomotor centre depression Antagonizes action of NA and 5-HT on smooth muscles Potent emetic and moderately potent oxytocic Chronic exposure → thrombosis, vascular stasis and gangrene

Bromocriptine Relatively selective D2 agonist On pituitary lactotropes → inhibit prolactine release In striatum → antiparkinsonian action In CTZ → Emesis Weak anti 5-HT or α blocker and not oxytocic Ergometrine Weak agonist to α adrenergic receptors → vasoconstriction not significant Partial agonistic action on 5-HT in uterus, placental blood vessels and certain areas of brain

Low emetic potential Most prominent action – contraction of myometrium; used exclusively in obstetrics Pharmacokinetic: Slow and incomplete absorption, high first pass metabolism Crosses BBB Excreted primarily in bile Adverse effects Nausea, vomiting, abdominal pain, muscle cramps, weakness, chest pain

Containdications Sepsis, IHD, PVD, hypertension, pregnancy, liver and kidney disease Preparation and dose Ergotamine: Migraine 1-3 mg oral/SL repeat as required (max 6 mg in aday) Dhydroergotamine: Migraine 2-6 mg (max 10 mg/day), 0.5-1 mg IM, SC repeat hrly (max 3 mg) Also used for postural hypotension, herpes zoster, mumps Dihydroergotoxin: for dementia 1-1.5 mg oral/SL, 0.15-0.6 mg IM

Prostaglandins and Leucotrienes Prostaglandins (PGs) and Leucotrienes (LTs): Biologically active derivative of 20 carbon atom polyunsaturated essential fatty acid Released from cell membrane phospholipids. Eicosa = Twenty (indicates 20-carbon atoms) Enoic = double bond The eicosanoids are derived from arachidonic acid (AA) which has 20 carbon atoms & certain double bonds.

Chemistry, biosynthesis & Degradation Leucotriens are so named because they were first obtained from leucocytes (leuco) and have 3 conjugated double bonds (triene).

Biosynthesis - Eicosonoids develop from the phopholipid of cell membrane - Enzyme phospholipase A2 is activated when the cell membrane is subjected to a stimulus (physical, chemical, neurological or humoral).

- Practically every cells & tissue caable of synthesizing one or more types of PGs and LTs - PGs and LTs are synthesized at the rate governed by the release of arachidonic acid from membrane phospholipid in response to stimulus

Lung & spleen can synthesize the whole range of COX products Platelets practically synthesize TXA2, chemically unstable spontaneously change to TXB2 Vessel wall mainly generates prostacyclines (PGI2) → 6 keto PGF1α

COX exists in 2 isoforms COX-1 & COX-2 Eicosanoids produced by COX-1 participates in physiological function - Secretion of mucus and protection of gastric mucosa, haemostasis & maintenance of renal functions Eicosanoids produced by COX-2 → inflammatory & other pathological changes

Lipoxygenase pathway operate in lungs, WBCs & platelets - Most important products are leucotriens particularly LTB4 → potent chemotactic and - LTC4 and LTD4 →together constitute the slow reacting substances of anaphylaxis (SRS-A)

INHIBITION OF PG SYNTHESIS Glucocorticoids Inhibit the release of A.A. from membrane lipids. Indirectly reduce production of all eicosanoids i.e. PGs, TXs & LTs. Moreover they inhibit induction of COX-2 b cytokines at the site of inflammation. NSAIDs: Inhibit synthesis of COX products Aspirin → irreversible inhibition while other NSAIDs are competitive & reversible inhibitors

Most NSAIDs are nonselective COX-1 & COX-2 inhibitors but later ones (Celecoxibs, etoricoxib) are selective for COX-2 Thus NSAIDs inhibit PG as well as TXs synthesis NSAIDs do not inhibit the production of LTs: This may even increased since all A.A. become available to the LOX pathway for LTs production.

Actions and pathophysiological roles Zeleuton inhibit LOX and decrease production of LTs, but withdrawn due to hepatotoxicity Degradation: Occurs in most tissues, excreted in urine Actions and pathophysiological roles Prostaglandins, thromboxanes and prostacycline 1. CVS: PGE2 and PGF2α → Vasodilatation in most, but not all vascular beds PGI2 → Vasodilatation TXA2 → Vasoconstriction

PGG2 & PGH2 → Inherently vasoconstrictor but often produces vasodilatation/biphasic response due to rapid conversion to other PGs especially PGI2 Role: PGI2 continuosly produced locally in the ductus arteriosus by COX-2 during foetal life → keeps it patent: At birth its synthesis stops and closure occurs Aspirin and indomethacin induce closure when it fails to occur spontaneously

2. Platelets: TXA2 → induce platelet aggregation. PGI2 → Inhibit platelet aggregation Role: TXA2 produced by platelets and PGI2 produced by vascular endothelium constitute a mutually antagonistic system Prevent aggregation of platelets while in circulation Induce aggregation on injury (when plugging and thrombosis are needed) Platelets → unable to regenerate fresh COX-1, while vessel wall is able to do so. Thus in low doses, aspirin selectively inhibits TXA2 production and has antithrombotic effects lasting for > 3 days

3. Uterus: PGE2 and PGF2α → contracts pregnant as well as non-pregnant human uterus Sensitivity higher during pregnancy At term PGs softens the cervix at low doses → more compliant Role: PGs → mediates initiation and progression of labour Aspirin → delay initiation of labour and prolongs its duration ii. PGs present in semen → helps in transport of sperm and facilitate fertilization

iii. ↑ PG synthesis in women by endometrium → dysmenorrhoea Aspirin group of drugs effective in relieving dysmenorrhoea 4. Bronchial muscles: PGF2α, PGD2 & TXA2 → Bronchoconstrictor PGE2 & PGI2 → Bronchodilator Role: Asthma occurs due to imbalance between constrictor PGs and LTs and dilator. Aspirin like drugs, induce asthma by diverting AA → excess LTC4 and LTD4. This sensitivity is not shared by selective COX-2 inhibitors

5. GIT: PGE2 → ↑ water, electrolyte and mucuc secretion → colic and watery diarrhoea Role: i. PGs → may cause colonic polyps and cancers NSAIDs affords relief in familial colonic polyposis ii. PGE2 → ↓ acid secretion in stomach, ↓ volume of juice and pepsin content. PGs are anti-ulcerogenic iii. PGI2 → ↑gastric mucus & HCO3- production, improves mucosal circulation → act as natural ulcer protective NSAIDs → cause ulcer, due to loss of this protective influence

6. Kidney: PGE2 and PGI2 → ↑ Na+ and K+ excretion → diuretic effect. PGE2 → antagonize ADH action, adds to diuretic effect PGE2, PGI2 and PGD2 → ↑ renin release Role: PGE2 and PGI2 produced by COX-2 regulates blood flow and tubular absorption in kidney NSAIDs including selective COX-2 inhibitors → retain salt and water

7. CNS: PGE2 → Pyrogen induced fever and malaise Aspirin and other inhibitors of PG synthesis are antipyretic 8. Peripheral nerves: Dull pain Role: PGs → Algesic agents during inflammation, cause tenderness Inhibition of PG synthesis → major anti-inflammatory mechanism 9. Eye: PGF2α → Ocular inflammation, ↑ uveoscleral and trabecular outflow → ↓ IOT Latanoprost → first line drug in wide angle glaucoma

10. Endocrine system: PGE2 → release of GH, Prolactin, ACTH, FSH, LH, insulin and adrenal steroids 11. PGs exert insulin like effect on carbohydrate metabolism and mobilize Ca2+ from bone LEUCOTRIENES Products of LOX pathway Named because first obtained from leucocytes (leuco) having 3 conjugated double bonds (triene)

Leucotriene receptors: Termed as LT-receptor BLT receptor for LTB4: expressed in leucocytes and spleen Cys-LT receptor for LTC4, LTD4 and LTE4: Expressed in bronchial and intestinal muscles Actions 1. CVS and blood: LTC4 & LTD4 on IV LTB4 Role: LTs → important Cystenyl leucotrienes mediators of inflammation

2. Smooth muscles: bronchoconstriction, spastic contracton of GIT Role: Cystenyl LTs (C4 and D4) → important mediators of human allergic asthma USES 1. Abortion: During first trimester, termination of pregnancy by transcervical suction → procedure of choice Intravaginal PGE2 pessary inserted 3 hrs before attempting dilatation → ↓ resistance and minimize trauma

Medical termination of pregnancy of upto 7 weeks Mifepristone (antiprogestine) 600 mg orally 2 days before a single oral dose of misoprostol 400µg → valuable alternative to suction-evacuation. Methotrexate administered along with misoprostol → highly successful for inducing abortion in the first few weeks of pregnancy PGs have place in midterm, missed abortion and molar gestation PGs convert oxytocin resistant midterm uterus → oxytocin responsive one

2. Induction/augmentation of labour PGE2 and PGF2α (rarely) used in place of oxytocin in toxaemic and renal failure patients (PGs do not cause fluid retention PGE2 → used to augment labour 3. Cervical priming (ripening) Low doses of PGE2 applied intravaginally → cervix soft and compliant 4. Postpartum haemorrhage (PPH) Carboprost (15-methyl PGF2α) IM → alternative drug for PPH due to uterine atony, especially in patients unresponsive to ergotamine and oxytocin

5. Peptic ulcer Misoprostol (stable analogue of PGE1) → Healing peptic ulcer, especially in patients who need continued NSAID therapy or who continue to smoke 6. Glaucoma Latonoprost, travoprost, bimatoprost (topical PGF2α) → first choice drugs in wide angle glaucoma 7. To maintain patency of ductus arteriosus Alprostadil (PGE1), in neonates with congenital heart defects, till surgery is undertaken

8. To avoid platelet damage Epoprostenol (PGE2) →used to prevent platelet agreggation and damage during haemodialysis/cardiopulmonary bypass Other suggested use 1. Peripheral vascular disease 2. Impotance, but now there are other drugs available