eicosanoids: prostaglandins, thromboxanes, leukotrienes, & related compounds stings and venom,...

Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds

Eicosanoids: Prostaglandins, Thromboxanes,

SYNTHESIS OF EICOSANOIDSProducts 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

COX-3

Mainly centrally FEVER AND PAIN and can be inhibited by

PARACETAMOL

prostaglandins and prostaglandins and

prostaglandin analogsprostaglandin analogs

currently in clinical use. currently in clinical use.

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 & Thromboxanes1- 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 MUSCLE1. 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 INTESTINELubiprostone: Amitiza®

USESLubiprostone is a PGE1 derivative used for theTretament of chronic idiopathic constipation and

irritable bowel syndrome with constipation.

PHARMACOLOGY OF EICOSANOIDS INTESTINELubiprostone: Amitiza®

 Mechanism of action: Lubiprostone stimulates chloride channels(ClC-2) in the luminal cells of the intestinal

epithelium, therebyincreasing intestinal fluid secretion. The increased chloride concentration within the

intestinal lumen softens the stool and increases intestinal motility.

PHARMACOLOGY OF EICOSANOIDS INTESTINELubiprostone: 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 INTESTINELubiprostone: Amitiza®

Pharmacokinetics Absorption: Minimal absorption, action is

primarily in GI tract.Distribution: Minimal systemic distribution.

Contraindicated : Mechanical gastrointestinal obstruction

PHARMACOLOGY OF EICOSANOIDS INTESTINELubiprostone: 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 8-iso-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 (PGI2), is a vasodilating agent and a platelet-aggregation inhibitor.

Indications  Pulmonary arterial hypertension leading to

Improved exercise capacityUSE 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: HypersensitivitySystolic BP <85 mm HgLactation: Lactation.Use Cautiously in: • 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)• Pedi: Safety not established• OB: Use only if maternal benefit outweighs fetal risk.Adv. Reactions/Side Effects CNS: dizziness, fainting, headache, insomnia.EENT: epistaxis.Resp: cough, bronchospasm, dyspnea, hemoptysis, wheezing.CV: HF, vasodilation, chest pain, hypotension, peripheral edema, supraventricular tachycardia.GI: diarrhea, gingival bleeding, nausea, vomiting.GU: renal failure.Derm: facial flushing.MS: back pain, jaw-muscle spasm, muscle cramps.Interactions Drug-Drug: • risk of hypotension with other vasodilators or diuretics.• Risk of bleeding may be by anticoagulants. 

3- In the microcirculation, PGE2 is a vasodilator produced by endothelial cells.

PHARMACOLOGY OF EICOSANOIDS Vasodilator prostaglandins ILOPROST (VENTAVIS)   

Contraindicated in: Systolic BP <85 mm Hglactation

PHARMACOLOGY OF EICOSANOIDS Vasodilator prostaglandins ILOPROST (VENTAVIS) Use Cautiously in: 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) •.Common Adverse Effects Cough headachevasodilation (flushing)Hypotension, syncope and palpitations hemoptysis due to thrombaxe-A2 inhibition

PHARMACOLOGY OF EICOSANOIDS Vasodilator prostaglandins ILOPROST (VENTAVIS) •..Interactions 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 to leukotriene formation

PHARMACOLOGY OF EICOSANOIDS

PLATELETS 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

PLATELETSPlatelets 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 KIDNEY

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

PGE2 and PGI2

PHARMACOLOGY OF EICOSANOIDS KIDNEY

PGE2 and PGI2 increase glomerular filtration through their vasodilating effects.

These prostaglandins also increase water and sodium excretion.

PHARMACOLOGY OF EICOSANOIDS

KIDNEYLoop diuretics, eg, furosemide, produce some of their

effect by stimulating COX activity.

In the normal kidney, this increases the synthesis of the vasodilator prostaglandins.

Therefore, patient response to a loop diuretic is diminished if a COX inhibitor is administered concurrently

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)

the inflammatory cells (monocyte-macrophages) release substantial amounts of TXA2

PHARMACOLOGY OF EICOSANOIDS REPRODUCTIVE ORGANS1. Female reproductive organsPGF2-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

EYE

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

Latanoprostbimatoprost, 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 food-stimulated 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 food-stimulated acid secretion (up to 75% to 85% inhibition).

The usual recommended dose for ulcer prophylaxis is 200 mg four times a day.

CLINICAL OF EICOSANOIDS analogues

1- Dinoprostone, a synthetic preparation of PGE2

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.

3- Vomiting and diarrhea occur commonly,

probably because of gastrointestinal smooth muscle stimulation. Transient elevations in temperature are seen in approximately one eighth of patients.

Modulators of the pathwaysModulators of the pathwaysNSAID’s and Corticosteroids (COX

Inhibitors)Lipoxygenase Inhibitors (Zileuton)

TXA2 Synthase Inhibitors LTD4 Receptor Antagonist (Montelukast-

SINGULAIR)

ARACHIDONIC ACID

Platelet TXA2

EndothelialPGI2

VasoconstrictionPlatelet Aggregation

VasodilationAnti-Platelet Aggregation

COX -1 COX -2

ASPIRIN

_ _

Pharmacological/Physiological Pharmacological/Physiological EffectsEffects

2. Platelets2. Platelets

NSAID’s

Corticosteroids: anti-inflammatory

analgesic, antipyretic.

Montelukast (LTD4 BLOCKER) in asthma

Therapeutic Uses of Therapeutic Uses of ModulatorsModulators

Placebo Montelukast Beclometh.

Mean %of Days 19%

33% 32%

Mean % days patients experiencedsustained asthma control

% of patientswithoutasthma attacks

Time after randomization (days)

Placebo

Montelukast

Beclomethasone

NS

Time to firstasthma attack

Montelukast inAsthma

BIOGENIC PEPTIDESBIOGENIC PEPTIDESANGIOTENSINANGIOTENSIN

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 PEPTIDESBIOGENIC PEPTIDESANGIOTENSINANGIOTENSIN

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 (AT1)

receptors Captopril & enalapril inhibit ACE (congest. heart fail.).

BIOGENIC PEPTIDESBIOGENIC PEPTIDESBRADYKININBRADYKININ

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 PEPTIDEBIOGENIC PEPTIDEBRADYKININBRADYKININ

SynthesisPrekallikrein Kallikrein(Plasma) Hagman factor (plasma & tissues)

(activated by collagen)

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 PEPTIDESBIOGENIC PEPTIDESBRADYKININ & KALLIDINBRADYKININ & KALLIDIN

Receptors B1 mediates vasoconstriction, sensitive to

metabolites. B2 mediates vasodilatation, permeability,

smooth muscle contraction, pain B3 mediates guinea pig tracheal contraction,

not antagonized by B1 or B2 antagonists.

SMALL PROTEINSSMALL PROTEINSCYTOKINES (TNFa, IL-1,IL-6)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 was

formerly known as cachectin)

SMALL PROTEINSSMALL PROTEINSCYTOKINESCYTOKINES

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 PGI2 synthesis in endothelial cells

SMALL PROTEINSSMALL PROTEINSCYTOKINESCYTOKINES

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)Platelet Activating Factor (PAF)General Information• Hanson (1971) identified a platelet aggregating agent• Same substance (BP) was found in adrenal medulla • Phospholipase A2 releases AA & lysoPAF 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

PLATELET ACTIVATING FACTORPLATELET ACTIVATING FACTORPhysiological 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 & A2

• Forms inositol phosphate, diacylglycerol and arachidonates

• Thus, PAF leads to the formation of PGs, LT and TXA

PAFPAFPharmacological 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

Nitric Oxide (NO)Nitric Oxide (NO)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 NOEFFECTS 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 OXIDEInhibitors of Nitric Oxide Synthesis

In many disorders, such as inflammation and sepsis • inhibition of the iNOS isoform is NEEDED•

SEPTIC SHOCKincreased urinary excretion of nitrate, the oxidative product of NO, is a feature of gram-negative 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 strategiesSildenafil (VIAGRA)

- inhibitor of type 5 phosphodiesterase

- results in prolongation of the duration of NO-induced cGMP elevations in a variety of tissues

EndothelinEndothelin

potent vasoconstrictor peptides that were first isolated from aortic endothelial cells.

Receptors:

ETB causes transient drop in BPETA causes prolonged increases in BP

endothelin receptor antagonists

Bosentan is a nonselective antagonist

Endothelin ANTAGONISTEndothelin ANTAGONIST

Bosentan

is currently approved for use in pulmonary hypertension

ADVERSE EFFECTS OF Bosentan

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 child-bearing age to take this drug