18 Prostaglandins

Eicosanoids
 Eicosanoids are produced

from arachidonic acid, a 20-
carbon polyunsaturated fatty
acid (5,8,11,14-
eicosatetraenoic acid)
 The eicosanoids are
considered “autacoids"
o They act on cells close to
their site of production
o They are rapidly degraded
 They have both intercellular
signaling, & intracellular signal
cascades
The Cyclooxygenase Pathway
Prostanoids
 Prostaglandin H2 Synthase COOH
production of PGs, PGI2 & TXA2

arachidonic acid
 PGH2 synthase & Cyclooxygenase 2 O2 Cyclooxygenase
(COX) are used as synonyms O

COOH
 PG endoperoxides (PGG2 & PGH2) O

PGG2
are more potent & long-acting than OOH
2 e Peroxidase
the PGs to which they decompose
O
COOH
 TXA2 formed mainly in platelets by TX
O
synthase mediating vasoconstriction PGH2
OH
& platelet aggregation

 PGI2, formed mainly in endothelium
by PGI synthase opposes TXA2
The Cyclooxygenase Pathway
 Two isoforms of COX exists: COX-1 (constitutive form) &
COX-2 (inducible form)
 COX-1 is constitutively expressed at low levels in
many cell types
 COX-2 is constitutively expressed in kidney & CNS
 COX-2 gene transcription is stimulated by growth
factors, cytokines, & endotoxins
 A COX-1 variant, named COX-3, plays a significant
role in pain sensation in paracetamol-sensitive way
Prostanoids Receptors
 Prostanoid receptors are AC/PLC G-protein
coupled Rs
 Five main classes; DP (PGD2), FP (PGF2α),IP
(PGI2),TP (TXA2),& EP (PGE2)
 Eicosanoid synthesis is activated by:
 Pathological stimulus: tissue injury/disease
 Transmitter release like BK, AngII, NE
Prostanoids Biologic Effects
Cardiovascular System
 PGI2/D2/E2 →dilation of arterioles, pre-capillary sphincters &
post-capillary veins → increased blood flow & cardiac
output
 TXA2 is a potent vasoconstrictor
 TXA2 & PGI2 are potent platelet aggregation inducer &
inhibitor respectively (blood fluidity)
 PGI2 de-aggregate platelets clumps & reduces myocardial
infarct size & ischemic organ damage
 PGI2, PGE2, & NO are simultaneously released from
endothelium
 PGE2 inhibits B- & T-lymphocyte activation & proliferation,
inhibiting antibodies & lymphokines production
 Smooth muscle:
 Bronchial muscle relaxation by PGE2 & PGI2, but
constriction by TXA2, LTC4 & LTD4
 Human pregnant uterus is contracted by PGE 1/2,
and PGF2α
 GIT: PGEs & PGI2 inhibit gastric acid secretion &
reduce pepsin content
 They increase bicarbonate, mucus & blood flow
 Increased electrolyte/water movement into
intestinal lumen (diarrhea)
 TXA2 is pro-ulcerogenic
Renal System Nervous system
 PGs enhance urine  Hypertehermia by PGE2,
formation, natriuresis, & related pyrogen-induced fever
kaliuresis via action on  Aِntipyretic action of ASA &
renal blood flow & tubules NSAIDs is via inhibition of
 PGD2, PGE2, PGI2 COX-1, -2 & -3
stimulate renin release  ِAlgesia induction & pain
 PGs inhibit water re- sensitization to histamine, BK
absorption under ADH or mechanical stimuli
effect  Analgesic action of ASA &
NSAIDs is via inhibition of
COXs
The Lipoxygenase Pathway
 Lipoxygenase, catalze the
addition of O2 to double bond(s) of Catalyzed by 5-Lipoxygenase:
COOH
arachidonic acid forming
hydroperoxy-eicosatetraenoic acid
(HPETE) O2 arachidonate
OOH
 5-, 12- & 15- lipoxygenases → 5-, COOH
12- & 15-HPETEs respectively
5-HPETE
 5-HPETE is converted to
H2O
leukotriene-A4 (LTA4) , which in O
COOH
turn may be converted to various
other leukotrienes leukotriene-A 4
The Lipoxygenase Pathway
 LTA4 is converted into LTB4 in PMNLs & to
LTC4 in mast cells
 12-HPETE is converted to the hydroperoxide;
hepoxilins A & B
 15-HPETE is converted to the lipoxins; LXA &
LXB, having three hydroxyl groups
Leukotriens (Slow-Reacting
Substance of Anaphylaxis, SRS-A)
 Cysteinyl LTs (LTC4/D4/E4/F4) cause potent
vasoconstriction & small airway constriction
 They increase tracheal mucus secretion
 They may be of role in immediate hypersensitivity
& asthma, where corticosteroids are effective
antiallergic via LTs inhibition (but NOT ASA)
 LTB4 produced from PMNLs has a potent
chemotactic activity (Inflammation/damage)
 LTB4 induce aggregation of PMNLs in joint
diseases (gout, arthritis) & skin diseases
(psoriasis)
The Epoxygenase Pathway
 A cytochrome P450 epoxides double bonds of the
precursor FA (arachidonate) into mono-epoxide
FA; epoxy eicosatetraenoic acids (EPETEs)
 EPETEs are involved in vascular tone modulation,
ion transport, hemostasis &hematopoiesis
Prostanoids Therapeutic Uses
Uterine Stimulation
 Dinoprostone (PGE2): Prostin E2 vaginal
suppositories used to induce abortion between
12th -20th gestational weeks
 Prostin E2 oral tablets for elective induction of
labbour/obliged induction because of HTN,
toxemia, intrauterine death
• Treatment of duration ≤ 18 hrs
 Prostin E2 vaginal gel used for induction of
labour at term or near term (I-2 mg intravaginal,
repeated Q 6hrs according to response)
Uterine Stimulation
 Carboprost (15-methyl PGF2α)
 Used by IM route for induction of abortion between
12th -20th gestational weeks
 Used at a dose of 250 μg every 1-3 hrs
 Dinoprost (PGF2α)
 Injection form for intra-amniotic administration
 Used to induce labour or abortion
GIT
 Misoprostol is a synthetic methyl ester analogue
of PGE1
 Used to prevent drug-induced gastric ulceration
during NSAIDs, corticosteroid or anticoagulant
therapy
 It can be used alone or in combination with
antacids for duodenal ulcer treatment
 Not used for pregnant women or whom are
planning pregnancy
Platelet Aggregation
 Epoprostenol (PGI2):
 It is used as a heparin replacement in some
hemodialysis patients
 Used to prevent platelet aggregation in
extracorporal circulation systems
Impotence
 Alprostadil (PGE1) was used by in jection into
corpora cavernosa to maintain erection
 Replaced by PDE-V inhibitors
Leukotriens Therapeutic
Importance
 LTs have no therapeutic uses, but LTs
antagonists have
 Anti-asthma medications:
 5-Lipoxygenase Inhibitors, e.g.,
zileutin
 Leukotriene-receptor antagonists;
montelukast, & zafirlukast
Platelet-Activating factor (PAF)
 PAF, another lipid-derived autacoid
 Released from inflammatory cells & platelets by
PLA2, upon activation
 It has a role in many types of inflammation,
bronchial hyper-responsiveness, and delayed
phase of asthma
 PAF antagonists (receptor/production inhibition)
are potential antiinflammatory & antiasthmatic
drugs
 Corticosteroids anti-inflammatory effect comprise
PAF production inhibition

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Eicosanoids

 Eicosanoids are produced

production of PGs, PGI2 & TXA2

(COX) are used as synonyms O

 PG endoperoxides (PGG2 & PGH2) O

& platelet aggregation

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