eicosanoids

abortifacient

a drug that induces abortion or miscarriage

• example: prostaglandin F_2α

cyclooxygenase

converts arachidonic acid to PGG & PHG (precursors of the prostaglandins PGE, PGF, prostacyclin, thromboxane)

• exists in at least 2 forms - 1 & 2

dysmenorrhea

painful uterine cramping caused by prostaglandins released during menstruations

great vessel transposition

congenital anomaly in which the pulmonary artery exits from the left ventricle & the aorta from the right ventricle

• baby after birth unless a large patent ductus or ventricular septal defect is present

lipoxygenase

converts arachidonic acid to leukotriene precursors

nonsteroidal anti-inflammatory drug (NSAID)

drugs that non-selectively inhibit both COX-1 & COX-2 and the production of thromboxane, prostaglandins, & prostacyclin

• examples: aspirin, ibuprofen, indomethacin, naproxen celecoxib

ibuprofen, indomethacin

NSAIDs that can accelerate closure of a patent ductus arteriosus in an otherwise normal infant

celecoxib

most selective COX-2 inhibitor available in the US

oxytocic

a substance that causes uterine contraction

patent ductus arteriosus

abnormal persistence after birth of the shunt between the pulmonary artery and aorta

• normal in the fetus

phospholipase A₂ (PLA₂)

enzyme in the cell membrane that generates arachidonic acid from cell membrane lipids

slow-reacting substance of anaphylaxis (SRS-A)

material originally identified by bioassay from tissues of animals in anaphylactic shock, now rec

eicosanoids

group of fatty acid autacoids metabolites of arachidonic acid (20-C fatty acid lipid in cell membranes)

potent, endogenous, regulatory substances which are synthesized & released for immediate, local (autacoid) action

prostaglandins, prostacyclin, thromboxane (cyclic derivatives), leukotrienes (straight-chain derivatives)

autacoid

biological factors (molecules) which act like local hormones, have a brief duration, and act near their site of synthesis

eicosanoid synthesis enzymes

• phospholipase A₂ (PLA₂)

• cyclooxygenase 1 & 2 (COX1 & 2)

• lipoxygenase (LOX)

eicosanoids synthesis

stimuli activate phospholipases in cell membrane or cytoplasm → release of arachidonic acid (a tetraenoic compound)

• cyclooxygenase 1 & 2 (COX1 & 2) - cyclization to prostaglandins, prostacyclin, thromboxane

• lipoxygenase (LOX) - form straight-chain leukotrienes

PGE₁ infusion

used to maintain patency of the ductus arteriosus in infants with transposition of the great vessels until surgical correction can be undertaken

PGE₁ (alprostadil)

used in treatment of impotence by injection into the cavernosa or as a urethral suppository

misoprostol

orally active PGE₁ analog

used with progesterone antagonist mifepristone (RU486) in an abortifacient combination

used in combination with methotrexate as abortifacient

approved for the prevention of peptic ulcers in patient taking high doses of NSAIDs for arthritis & who have a history of ulcer associated with NSAID use

PGE₂

cause contraction of the uterus; used at abortifacients in the second trimester of pregnancy

adverse effects in labor at term (nausea, vomiting, diarrhea)

mechanism of action & pharmacologic effects:

• major receptor: EP_1-4

• receptor coupling protein: Gs + Gq

• vascular tone: ↓

• bronchial tone: ↓↓

• uterine tone: ↑ , ↓

• platelet aggregation: ↑ or ↓

• leukocyte chemotaxis:

PGE₂ (dinoprostone)

approved for softening the cervix at term before induction of labor with oxytocin

PGF_2α

cause contraction of the uterus; used at abortifacients in the second trimester of pregnancy

adverse effects in labor at term (nausea, vomiting, diarrhea)

mechanism of action & pharmacologic effects:

• major receptor: FP_A,B

• receptor coupling protein: Gq

• vascular tone: ↑ or ↓

• bronchial tone: ↑↑

• uterine tone: ↑↑↑

• platelet aggregation:

• leukocyte chemotaxis:

PGF_2α derivatives

used extensively for the tropical treatment of glaucoma

latanoprost, bimatoprost, travoprost, unoprostone

PGF_2α derivatives used to reduce intraocular pressure by increasing the outflow of aqueous humor

PGI₂

prostacyclin

mechanism of action & pharmacologic effects:

• major receptor: IP

• receptor coupling protein: Gs

• vascular tone: ↓↓

• bronchial tone: ↓

• uterine tone: ↓

• platelet aggregation: ↓↓↓

• leukocyte chemotaxis:

PGI₂ (epoprostenol)

used in severe pulmonary hypertension and to prevent platelet aggregation in dialysis machines

LTB₄

leukotriene involved in inflammation

mechanism of action & pharmacologic effects:

• major receptor: BLT_{1, 2}

• receptor coupling protein: Gq

• vascular tone:

• bronchial tone:

• uterine tone:

• platelet aggregation:

• leukocyte chemotaxis: ↑↑↑↑

LTC₄

leukotriene that increase in vascular permeability & contraction of bronchial smooth muscle associated with an anaphylactic reaction or an acute asthma attack; one of the constituents of slow-reacting substance of anaphylaxis (SRS-A)

mechanism of action & pharmacologic effects:

• major receptor: CysLT₂

• receptor coupling protein: Gq, Gi

• vascular tone: ↑ or ↓

• bronchial tone: ↑↑↑↑

• uterine tone:

• platelet aggregation:

• leukocyte chemotaxis: ↑↑

LTD₄

leukotriene whose main function in the body is to induce the contraction of smooth muscle → bronchoconstriction & vasoconstriction

mechanism of action & pharmacologic effects:

• major receptor: CysLT₁

• receptor coupling protein: Gq

• vascular tone: ↑ or ↓

• bronchial tone: ↑↑↑↑

• uterine tone:

• platelet aggregation:

• leukocyte chemotaxis: ↑↑

COX-1

constitutive cyclooxygenase found in many tissues

• prostaglandins produced appear to be important for a variety of normal physiologic processes

COX-2

inducible cyclooxygenase found primarily in inflammatory cells

eicosanoid antagonists

drugs useful for modulating inflammatory responses in a variety of conditions such as asthma, allergy, & chronic inflammatory conditions (e.g. rheumatoid arthritis)

zileuton

selective inhibitor of lipoxygenase (LOX) for prophylaxis & chronic treatment of asthma

montelukast, zafirlukast

oral inhibitors of CysLT₁ (LTD₄ receptor)

uses for the treatment of asthma

corticosteroids

dexamethasone, prednisone, hydrocortisone

inhibit release of arachidonic acid by phospholipases → increase expression of specific protein that inhibit phospholipases (lipoxin A4)

inhibit synthesis of COX-2

• important anti-inflammatory actions

prostaglandin signaling

coupled to downstream signaling through G-proteins (Gs, Gq, Gi)

TXA₂

thromboxane; increases platelet aggregation

mechanism of action & pharmacologic effects:

• major receptor: TP_{α, β}

• receptor coupling protein: Gq

• vascular tone: ↑↑↑

• bronchial tone: ↑↑↑

• uterine tone: ↑↑

• platelet aggregation: ↑↑↑

• leukocyte chemotaxis: