Autacoids ผศ. พญ. มาลียา มโนรถ

Autacoids n Autos = self n Akos = medicinal agent [are circulating or locally acting hormone- like substances which originate from diffuse tissues]

Two main function 1. Moderate local circulation 2. Influence the process of inflammation

Major classes 1. Endogenous amines : – histamine, serotonin 2. Polypeptides : – angiotensin, kinins 3. Lipid-derived autacoids : – prostaglandins, leukotrienes, thromboxane

Lipid-derived autacoid 1. Eicosanoids Polyunsaturated fatty acid (Arachidonic acid) – Prostaglandins (PG) – Prostacycline (PGI) – Thromboxane (TXA) – Leukotrienes (LT)

Lipid-derived autacoid 2. Modified phospholipids – Platelet-activating factor (PAF) – Potent vasodilator – Potent stimulator of platelet aggregation n Circulating leukocyte n Platelets n Endothelial cells

Origin and synthesis PGs Cell membrane phospholipid Phospholipase Arachidonic acid Lipoxygenase pathway Cyclooxygenase pathway

Lipoxygenase pathway Phospholipids Arachidonic acid 12-lipoxygenase 5-lipoxygenase 5-HETE Leukotrienes (LT) LTA 4, LTB 4, LTC 4, LTD 4 12-HETE Leukostatic agent

HETE = Hydroxyeicosatetraenoic acid Leukotriene พบที่ leukocyte conjugate with triene SRS-A is a mixture of peptide leukotriene (LTC 4, LTD 4, LTE 4 )

Leukotrienes n Biosynthesis take place chiefly in leukocytes n Pharmacologic effects – LTC 4, LTD 4, LTE 4 (SRS-A) Potent vasoconstrictor Potent bronchoconstrictor – ญ  permeability of postcapillary venules – ญ  mucus secretion

Leukotrienes n LTB 4 – Chemotactic & chemokinetic – Leukocytes adhere the vascular endothelium & to extravasate

Cyclooxygenase pathway Phospholipids Arachidonic acid Cyclooxygenase (COX-1; COX- 2) PGG PGH PGI (Prostacycline) TXA (Thromboxane) PGDPGEPGF (Prostaglandins)

Prostaglandins n Kurzrok & Lieb 1930 semen : uterus n Goldblatt 1933 and Von Euler 1934 – semen : vascular smooth muscle contraction ฌ  Prostaglandin n Bergstorm & Sjovall : PGE 1, PGF 1 n Karim 1986 : Oxytocic properties PGE 2, PGF 2

Pharmacological Properties OrganPGE 2 PGF 2  TXA 2 1.Smooth muscle VascularRCC GI longCC- circularRC- RespiratoryRCC Uterus non-pregnancyRC- pregnancyCC-

Pharmacological Properties OrganPGE 2 PGF 2  TXA 2 2. Platelet aggregation ฏ - ญ 3. Body temperature ญ GI tract Gastric secretion ฏ -- Mucous ญญ - Water & electrolytes ญญ - 5. Afferent nerve & painSen.-- Sen. = sensitization

Inactive end product Metabolism n Lung, kidney, liver n PGI 2 : 6 keto-PGF 1 n TXA 2 : TXB 2 n PGF : ,14-dihydro PGF 2

Clinical Uses n 1. CVS : dilate – PGI : 1 o, 2 o pulmonary hypertension – PGE1 : maintain patency of ductus arteriosus n 2. GI : inhibit – PGE : cytoprotection (prevention of NSAIDs induced gastric ulcer )

Clinical Uses n 3. Uterus : contract – PGE, PGF : abortion, postpartum hemorrhage, facilitation of labor n 4. Platelets : inhibit – PGI & analog : in place of heparin during dialysis – PGI & PGE : improving storage of blood platelets for therapeutic transfusion