Eicosanoids: Prostaglandins, Thromboxanes,
Leukotrienes, & Related Compounds

Eicosanoids: Prostaglandins, Thromboxanes,
 SYNTHESIS OF EICOSANOIDS
 Products of Prostaglandin Endoperoxide
Synthases (Cyclooxygenases)
 Two unique COX isozymes convert arachidonic acid into prostaglandin endoperoxide.
 PGH synthase-1 (COX-1) is expressed constitutively in most cells.

Eicosanoids: Prostaglandins, Thromboxanes,
 In contrast, PGH synthase-2 (COX-2) is inducible
 its expression varies markedly depending on the stimulus.
 COX-2 is an immediate early-response gene product that is
 markedly up-regulated by shear stress, growth factors, tumor promoters, and cytokines

Eicosanoids: Prostaglandins, Thromboxanes,
Physiological role
 COX-1 generates prostanoids
 such as gastric epithelial cytoprotection
 whereas COX-2 is the major source of prostanoids in inflammation and cancer.
 For example, endothelial COX-2 is the primary source of vascular prostacyclin
 whereas renal COX-2-derived prostanoids are important for normal renal development and maintenance of function. (maintain blood flow)

Eicosanoids: Prostaglandins, Thromboxanes,
Physiological role

 Mainly centrally FEVER AND PAIN and can be inhibited by
 PARACETAMOL

PHARMACOLOGY OF EICOSANOIDS
 Effects of Prostaglandins & Thromboxanes
 The prostaglandins and thromboxanes have major effects on four types of smooth muscle:
1- vascular
2- gastrointestinal
3- airway
4- eye ( smooth muscle)
5- reproductive

PHARMACOLOGY OF EICOSANOIDS
 Effects of Prostaglandins & Thromboxanes
1- platelets and monocytes
2- kidneys
3- the central nervous system, autonomic presynaptic nerve terminals
4- sensory nerve endings
5- endocrine organs

PHARMACOLOGY OF EICOSANOIDS
 A. SMOOTH MUSCLE
 1. Vascular TXA2 is a potent vasoconstrictor
 TXA2 is a smooth muscle cell mitogen
 The mitogenic effect is potentiated by exposure of smooth muscle cells to testosterone

PHARMACOLOGY OF EICOSANOIDS
 INTESTINE
 Lubiprostone: Amitiza
®
USES
 Lubiprostone is a PGE1 derivative used for the
 Tretament of chronic idiopathic constipation and irritable bowel syndrome with constipation.

PHARMACOLOGY OF EICOSANOIDS
 INTESTINE
 Lubiprostone: Amitiza
®
 Mechanism of action:
 Lubiprostone stimulates chloride channels
 (ClC-2) in the luminal cells of the intestinal epithelium, thereby
 increasing intestinal fluid secretion.
 The increased chloride concentration within the intestinal lumen softens the stool and increases intestinal motility.

PHARMACOLOGY OF EICOSANOIDS
 INTESTINE
 Lubiprostone: Amitiza
®
 b. Side eff ects:
 Nausea is the most common side eff ect of lubiprostone which can be decreased if taken with food.
 diarrhea is the second most reported adverse
 reaction, followed by headache and abdominal pain.

PHARMACOLOGY OF EICOSANOIDS
 INTESTINE
 Lubiprostone: Amitiza
®
 Pharmacokinetics
 Absorption: Minimal absorption, action is primarily in GI tract.
 Distribution: Minimal systemic distribution.
 Contraindicated :
 Mechanical gastrointestinal obstruction

PHARMACOLOGY OF EICOSANOIDS
 INTESTINE
 Lubiprostone: Amitiza
®
 Pharmacokinetics
 Absorption: Minimal absorption, action is primarily in GI tract.
 Distribution: Minimal systemic distribution.
 Contraindicated :
 Mechanical gastrointestinal obstruction

PHARMACOLOGY OF EICOSANOIDS
 A. SMOOTH MUSCLE
 2. PGF2a is also a vasoconstrictor but is not a mitogen for smooth muscle cells.
 the isoprostane 8iso -PGF2a (iPF2aIII) which is also a vasoconstrictor may act via the TP receptor.
 In patients with cirrhosis
 8-iso-PGF2a is produced in large amounts in the liver
 and is thought to play a pathophysiologic role as an important vasoconstrictor substance in the hepatorenal syndrome.

PHARMACOLOGY OF EICOSANOIDS
Vasodilator prostaglandins
1- PGI2 and PGE2, promote vasodilation by increasing cAMP and decreasing smooth muscle intracellular calcium
2- Vascular prostacyclin is synthesized by both smooth muscle and endothelial cells,
3- In the microcirculation, PGE2 is a vasodilator produced by endothelial cells.

PHARMACOLOGY OF EICOSANOIDS
Vasodilator prostaglandins

 ILOPROST (VENTAVIS)
 ILOPROST , a synthetic analog of prostacyclin
(PGI
2
), is a vasodilating agent and a plateletaggregation inhibitor.
 Indications
 Pulmonary arterial hypertension leading to
Improved exercise capacity
 USE BY INHALATION

PHARMACOLOGY OF EICOSANOIDS
Vasodilator prostaglandins
 ILOPROST (VENTAVIS)

 MECHANISM OG ACTION
 Dilates pulmonary and arterial vasculature.
 These actions are mediated through activation of the IP receptors (prostacyclin receptors)
 Leading to an increase in the production of intracellular cyclic adenosine monophosphate
(cAMP).

PHARMACOLOGY OF EICOSANOIDS
Vasodilator prostaglandins
 ILOPROST (VENTAVIS)
 TXA2 production is also inhibited

 Contraindicated in:
 Hypersensitivity
 Systolic BP <85 mm Hg
 Lactation: Lactation.
 Use Cautiously in:
 •


PHARMACOLOGY OF EICOSANOIDS
Vasodilator prostaglandins



ILOPROST (VENTAVIS)
 Contraindicated in:
 Systolic BP <85 mm Hg
 lactation

PHARMACOLOGY OF EICOSANOIDS
Vasodilator prostaglandins
 ILOPROST (VENTAVIS)

 Concurrent use of drugs or coexisting medical conditions that may risk of syncope
 COPD, asthma, or acute pulmonary infection (may risk of bronchospasm)
 Hepatic impairment (may need to dosing interval)
 OB: Use only if maternal benefit outweighs fetal risk.

PHARMACOLOGY OF EICOSANOIDS
Vasodilator prostaglandins
 ILOPROST (VENTAVIS) •.

 Cough
 headache
 vasodilation (flushing)
 Hypotension, syncope and palpitations
 hemoptysis due to thrombaxe-A2 inhibition

PHARMACOLOGY OF EICOSANOIDS
Vasodilator prostaglandins
 ILOPROST (VENTAVIS) •..

 risk of hypotension with other vasodilators or diuretics

 Risk of bleeding may be by anticoagulant

PHARMACOLOGY OF EICOSANOIDS
2. . Airways Respiratory smooth muscle
The cysteinyl leukotrienes are bronchoconstrictors.
They act principally on smooth muscle in peripheral airways and are a thousand times more potent than histamine both in vitro and in vivo.
They also stimulate bronchial mucus secretion and cause mucosal edema.
Bronchospasm occurs in about 10% of people taking
NSAIDs, probably because of a shift in arachidonate metabolism from COX-1 metabolism

PHARMACOLOGY OF EICOSANOIDS
 Both PGD2 and PGI2 inhibit aggregation.
 TXA2 is the major product of platelet COX-1 , is a platelet aggregator
 and amplifies the effects of other more potent platelet agonists such as thrombin.
 The platelet actions of TXA2 are restrained in vivo by PGI2
 which inhibits platelet aggregation by all recognized agonists.

PHARMACOLOGY OF EICOSANOIDS
Platelets release TXA2 during activation and aggregation.
 Urinary metabolites of TXA2 increase in patients experiencing a myocardial infarction
 this Platelet COX-1-derived thromboxane synthesis is irreversibly inhibited by chronic dosing with aspirin in low doses.
 Macrophage COX-2 appears to contribute roughly 10% of the increment in TX biosynthesis observed in smokers , while the rest is derived from platelets.

PHARMACOLOGY OF EICOSANOIDS

 Both the medulla and the cortex of the kidney synthesize prostaglandins
 the medulla substantially more than the cortex.
 The kidney also synthesizes several hydroxyeicosatetraenoic acids, leukotrienes, cytochrome
P450 products, and epoxides.
 These compounds play important autoregulatory roles in renal function

PHARMACOLOGY OF EICOSANOIDS
 KIDNEY by modifying renal hemodynamics and glomerular and tubular function.
 This regulatory role is especially important in marginally functioning kidneys, as shown by the decline in kidney function caused by COX inhibitors
 in elderly patients and those with renal disease.
 The major eicosanoid products of the renal cortex are
and

PHARMACOLOGY OF EICOSANOIDS
 KIDNEY



PHARMACOLOGY OF EICOSANOIDS
Loop diuretics, eg, furosemide, produce some of their effect by stimulating COX activity.
 In the normal kidney, this increases the synthesis of the vasodilator prostaglandins.


PHARMACOLOGY OF EICOSANOIDS
KIDNEY
The normal kidney synthesizes only small amounts of
TXA2.
 However, in renal conditions involving inflammatory cell infiltration (such as glomerulonephritis and renal transplant rejection)


PHARMACOLOGY OF EICOSANOIDS
 REPRODUCTIVE ORGANS
 1. Female reproductive organs
 PGF2-alpha, together with oxytocin, is essential for the onset of parturition
- Uterine muscle is contracted by PGF2a, TXA2

PHARMACOLOGY OF EICOSANOIDS
 CENTRAL AND PERIPHERAL NERVOUS SYSTEMS
 1. Fever
 PGE2 increases body temperature
 Exogenous PGF2a and PGI2 induce fever
 pyrogens release interleukin-1, which in turn promotes the synthesis and release of PGE2 . This synthesis is blocked by paracetamol and other antipyretic compounds

PHARMACOLOGY OF EICOSANOIDS
 PGE and PGF derivatives lower intraocular pressure. (eye drops in glaucoma)
 The mechanism of this action is unclear but probably involves increased outflow of aqueous humor from the anterior chamber via the uveoscleral pathway

PHARMACOLOGY OF EICOSANOIDS
Glaucoma
bimatoprost, travaprost , and unoprostone
1- a stable long-acting PGF2a derivatives
2- first prostanoid used for glaucoma
4- administered as drops into the conjunctival sac once or twice daily.
5- Adverse effects include irreversible brown pigmentation of the iris and eyelashes, drying of the eyes, and conjunctivitis

PHARMACOLOGY OF EICOSANOIDS
AGENTS THAT ENHANCE MUCOSAL DEFENSE
Misoprostol
Misoprostol (15-deoxy-16-hydroxy-16-methyl-PGE1; CYTOTEC ) is a synthetic analog of prostaglandin E1.
The degree of inhibition of gastric acid secretion by misoprostol is directly related to dose; oral doses of 100 to 200 mg significantly inhibit basal acid secretion (up to 85% to 95% inhibition) or foodstimulated acid secretion (up to 75% to 85% inhibition).
The usual recommended dose for ulcer prophylaxis is 200 mg four times a day.

PHARMACOLOGY OF EICOSANOIDS
AGENTS THAT ENHANCE gastric MUCOSAL
DEFENSE
Mechanism of Action; Pharmacology.
Prostaglandin E2
(PGE2) and prostacyclin (PGI2) are the major prostaglandins synthesized by the gastric mucosa.
- PGE2 also can prevent gastric injury by cytoprotective effects that include stimulation of mucin and bicarbonate secretion and increased mucosal blood flow.
Since NSAIDs diminish prostaglandin formation by inhibiting cyclooxygenase, synthetic prostaglandin analogs offer a logical approach to reducing NSAID-induced mucosal damage

PHARMACOLOGY OF EICOSANOIDS
AGENTS THAT ENHANCE GASTRIC MUCOSAL DEFENSE
Analog of prostaglandin E1
Misoprostol
Misoprostol (15-deoxy-16-hydroxy-16-methyl-PGE1; CYTOTEC) is a synthetic analog of prostaglandin E1.
The degree of inhibition of gastric acid secretion by misoprostol is directly related to dose; oral doses of 100 to 200 mg significantly inhibit basal acid secretion (up to 85% to 95% inhibition) or foodstimulated acid secretion (up to 75% to 85% inhibition).
The usual recommended dose for ulcer prophylaxis is 200 mg four times a day.

1-
 is administered vaginally for oxytocic use.
 it is approved for inducing abortion in the second trimester of pregnancy
 for missed abortion,
 and for ripening of the cervix for induction of labor in patients at or near term

CLINICAL OF EICOSANOIDS analogues
 Dinoprostone also directly affects the collagenase of the cervix, resulting in softening
For abortifacient purposes, the recommended dosage is a 20-mg dinoprostone vaginal suppository repeated at 3- to 5-hour intervals depending on the response of the uterus.
 For softening of the cervix at term, the preparations used are either a single vaginal insert containing 10 mg PGE2
 or a vaginal gel containing 0.5 mg PGE2 administered every 6 hours. The softening of the cervix for induction of labor substantially shortens the time to onset of labor and the delivery time.

CLINICAL OF EICOSANOIDS analogues
PGF2alpha
1- This drug, carboprost tromethamine
(15-methyl-PGF2a; the 15-methyl group prolongs the duration of action)
2-used to induce second-trimester abortions and to control postpartum hemorrhage that is not responding to conventional methods of management.
3Vomiting and diarrhea occur commonly, probably because of gastrointestinal smooth muscle stimulation.
Transient elevations in temperature are seen in approximately one eighth of patients .

 NSAID’s and
Corticosteroids (COX
Inhibitors)
 Lipoxygenase Inhibitors (Zileuton )
 TXA
2
Synthase Inhibitors
 LTD
4
Receptor Antagonist ( Montelukast-
SINGULAIR )

2. Platelets
ARACHIDONIC ACID
COX -1 _
Platelet
TXA
2
ASPIRIN
_ COX -2
Endothelial
PGI
2
Vasoconstriction
Platelet Aggregation
Vasodilation
Anti-Platelet Aggregation

 NSAID’s
 Corticosteroids: anti-inflammatory
 analgesic, antipyretic.
 Montelukast (LTD4 BLOCKER) in asthma

Mean % of Days 19%
33% 32%
Placebo Montelukast Beclometh.
Montelukast in
Asthma
Mean % days patients experienced sustained asthma control
% of patients without asthma attacks
Beclomethasone
NS
Montelukast
Placebo
Time after randomization (days)
Time to first asthma attack

BIOGENIC PEPTIDES
ANGIOTENSIN
Synthesis & metabolism
 Angiotensinogen (plasma substrate) to angiotensin I, by renin that is released during renal ischemia.
 Angiotensin I to II by angiotensin converting enzyme (ACE, Kinase II) in the pulmonary endothelium.
 Renin inhibited by propranolol
 Angiotensin II metabolized by angiotensinases in plasma and tissues.

BIOGENIC PEPTIDES
ANGIOTENSIN




Effects
 Causes profound vasoconstriction
 Increases peripheral vascular resistance
Increases blood pressure
Directly stimulates heart
Facilitates epinephrine and aldosterone release
Increases Na reabsorption in kidney tubules
 Releases ADH (vasopressin) to restore blood volume
 Losartan and valsartan blocks angiotensin (AT
1
) receptors
 Captopril & enalapril inhibit ACE (congest. heart fail.).

BIOGENIC PEPTIDES
BRADYKININ
Actions
 Comes under the group “kinins”
 This mediates nociception (pain)
 Regulates BP (vasodilator)
 Increases capillary permeability
 Balances electrolytes and fluid,
 Contracts gut slowly and stimulates prostaglandin synthesis
 Produced by tissue damage, viral infection, allergic reaction & inflammation
 Contracts various other smooth muscles

BIOGENIC PEPTIDE
BRADYKININ
Synthesis
Prekallikrein Kallikrein
(Plasma) Hagman factor
(activated by collagen)
(plasma & tissues)
1.
Kininogen Bradykinin, Kallidin
(alpha-2 globulins Kallikrein (nonapeptide)(decapeptide)
High and low m.w. (Activated by peptidases)
Kallidin, a decapeptide, with same actions is also produced along with bradykinin. Both are metabolized to inactive agents by kinases II and ACE

BIOGENIC PEPTIDES
BRADYKININ & KALLIDIN
Receptors
 B
1 mediates vasoconstriction, sensitive to metabolites.
 B
2 mediates vasodilatation, permeability, smooth muscle contraction, pain
 B
3 mediates guinea pig tracheal contraction, not antagonized by B
1 or B
2 antagonists.

SMALL PROTEINS
CYTOKINES (TNFa, IL-1,IL-6)
1. TNF

(Tumor Necrosis Factor

)
 A mediator of endotoxic shock
 Released by macrophages when exposed to endotoxin
 Triggers wide endotoxemic symptoms
 Elicits production of other cytokines, eicosanoids & humoral factors
 Stimulates degradation and adherence of neutrophils to endothelium


Symptoms of septicemia at high concentration
Can be neutralized by TNF
 antiserum
 Chronic exposure leads to cachexia (TNF formerly known as cachectin ) was

SMALL PROTEINS
CYTOKINES
2. Interleukin-1 (IL-1)
 Known as lymphocyte activating factor (

T-cell responses)



Activates endogenous pyrogen (induces fever)
Interacts synergestically with TNF

 synthesis & release of IL-2 by interacting with antigen stimulated T-cells




Activates B-cells and antibody synthesis
 arachidonic acid metabolism,
 inflammatory proteins
 neutrophil chemoattraction & fibroblast proliferation

PGI
2 synthesis in endothelial cells

SMALL PROTEINS
CYTOKINES






3. Interleukin-6 (IL-6)
A phosphoglycoprotein
Produced and secreted by macrophates, monocytes, fibroblasts
Inflammatory stimuli causes production by endothelium, T lymphocytes, mast cells
IL-6 induces production of hepatic fibrinogen for protection against microorganisms
Endotoxin, TNF alpha and IL-1 increase the levels of IL-6
Does not cause tissue injury or vascular thrombosis

Platelet Activating Factor (PAF)
General Information
•
Hanson (1971) identified a platelet aggregating agent
•
Same substance (

BP) was found in adrenal medulla
•
Phospholipase A
2 releases AA
from membrane
•
LysoPAF is acetylated by acetyl coenzyme A to PAF
(catalyzed by acetyl transferase)
•
Antigen-antibody reaction, chemotactic peptides, thrombin, collagen and other autacoids
 synthesis.
•
Platelets, neutrophils, monocytes, mast cells, eosinophils, renal medullary cells and endothelium synthesize
PAF

Physiological functions
•
PAF in amniotic fluid derived from fetal lung.
•
It is a potent bronchoconstrictor (long lasting) & causes pulmonary edema
•
Simulates G proteins that are on the cell surface
•
This activates phospholipase C & A
2
•
Forms inositol phosphate, diacylglycerol and arachidonates
•
Thus,
PAF leads to the formation of PGs, LT and TXA

Pharmacological actions
•
Increases platelet aggregation
•
Potent vasodilator ,

PVR and

BP
•
Constricts pulmonary vessels
•
Microvascular permeability

•
Releases eicosanoids, generates superoxides
•
Contracts nonvascular smooth muscles ,
•
Increases respiratory secretions, forms pulmonary edema
•
Decreases renal flow

Known as endothelium derived relaxing factor
(EDRF)
•
Organic nitrates (amyl nitrate, nitroglycerin, nitroprusside) release NO
•
Nitric Oxide Synthase (NOS) antagonists counteracts vascular relaxation

EFFECTS OF NO
•
Physiological vasodilator
• eNOS blockers increase BP by vasoconstriction
•
Macrophages kill microorganisms by NO
It causes: involved in penile erection

PHARMACOLOGIC MANIPULATION OF
NITRIC OXIDE
Inhibitors of Nitric Oxide Synthesis
•
In many disorders, such as inflammation and sepsis
• inhibition of the iNOS isoform is NEEDED
SEPTIC SHOCK increased urinary excretion of nitrate, the oxidative product of NO, is a feature of gramnegative bacterial infection.
•
Lipopolysaccharide components from the bacterial wall induce synthesis of iNOS, resulting in exaggerated hypotension, shock, and, in some cases, death.
•
This hypotension is reversed by NOS inhibitors such as L-NMMA in humans
•
A similar reversal of hypotension is produced by compounds that prevent the action of
NO (such as methylene blue
)
• as well as by scavengers of NO (such as hemoglobin
).

Nitric Oxide Donors
1. Organic nitrates Nitroglycerin
• metabolized to NO by mitochondrial aldehyde reductase, an enzyme enriched in venous smooth muscle,
.
2. Sodium nitroprusside generates NO in response to light as well as chemical or enzymatic mechanisms in cell membranes.
3. Hybrid NO donors
A new strategy involves the incorporation of NO-donating moieties onto currently available cardiovascular drugs. captopril. SNOCap, which incorporates a nitrosothiol moiety on captopril, is currently being examined for its efficacy in cardiovascular disorders

•
Nitric Oxide Donors
6. Alternate strategies
Sildenafil (VIAGRA)
- inhibitor of type 5 phosphodiesterase
- results in prolongation of the duration of NOinduced cGMP elevations in a variety of tissues

potent vasoconstrictor peptides that were first isolated from aortic endothelial cells.
Receptors:
ET
B causes transient drop in BP
ET
A causes prolonged increases in BP
Bosentan is a nonselective antagonist

is currently approved for use in pulmonary hypertension
1-Bosentan has been associated with fatal hepatotoxicity patients taking this drug must have monthly liver function tests.
2- Negative pregnancy test results are required for women of childbearing age to take this drug