Pharmacology
Lipid-derived Autacoids
Anju Bajracharya, PharmD
LA College
anjubajra@[Link]
Objectives – I
At the end of today’s lecture, the students should be able to
1. Define lipid-derived autacoids.
2. Classify lipid-derived autacoids.
3. Define eicosanoids.
4. Classify eicosanoids.
5. List the physiological roles of prostaglandins.
6. List the physiological roles of thromboxanes
7. List the physiological roles of leukotrienes.
8. List the therapeutic eicosanoids with their formulations, indications,
adverse effects, and contraindications
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What are lipid-derived autacoids?
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Lipid-derived autacoids
• Autacoids
• Derived from membrane phospholipids
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How are lipid-derived autacoids
classified?
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Classification of lipid-derived autacoids
• Based on the derrivation
1. Eicosanoids
• Prostaglandins
• Thromboxanes
• Leukotrines
2. Non-eicosanoids
• Platelet-activating factor (PAF)
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What are eicosanoids?
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Eicosanoids
• Etymology
• eicosa, from Greek eikosi meaning twenty
• -noic, suffix used in names of fatty acids
• -oid, suffix meaning “resembling,” “like”
• Definition
• Large group of autacoids
• Derived from metabolism of eicosaonic acids (20-carbon,
unsaturated fatty acids)
• Possessing potent effects on virtually every tissue in the body
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Eicosanoic acids
• Saturated
• Arachidic acid
• Unsaturated
• Arachidonic acid
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What are the different types of
eicosanoids?
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Types of eicosanoids
• Prostaglandins
• Thromboxanes
• Leukotrienes
• Hydroperoxyeicosatetraenoic acids (HPETEs)
• Hydroxyeicosatetraenoic acids (HETEs)
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Eicosanoids
• compounds derived from oxygenation of fatty acids
• the precursor fatty acids are
• eicosa = 20-carbon
• polyunsaturated
• the primary precursor fatty acids is arachidonic acid
• local-acting autocrine and paracrine hormones stimulate cells
adjacent to their site of synthesis
• short half-life, usually minutes
• not stored in cells
• released as soon as synthesized
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Classes of eicosanoids
• Prostanoids - have a ring structure
• Prostaglandins (PGs)
• Prostacyclins (PGIs)
• Thromboxanes (TXs)
• Linear eicosanoids - no ring structure
• Leukotrienes (LTs)
• Lipoxins (LXs)
• Hydroxyeicosatetraenoic acids (HETEs)
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Prostaglandins
• secreted by many tissues
• not just prostate gland
• modulate many physiological functions
• blood pressure (vasodilation)
• uterine contraction
• bronchodilation
• pain
• fever
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Prostaglandins
• classes (based on the functional groups on the cyclopentane
ring)
• PGA
• PGD
• PGE
• PGF
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Prostaglandins
• examples
• PGE2
• the linear chain consists of two double bonds
• the ring contains 9-keto and an 11-hydroxy group
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Prostaglandins
• examples
• PGF2a
• the linear chain consists of two double bonds
• the ring contains two hydroxyl groups
• a designates the stereochemistry of the C9 hydroxyl group
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Prostacyclins
• additional oxygen-containing ring between C6-C9
• example
• PGI2
• inhibits platelet aggregation
• promotes vasodilation
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Thromboxanes
• six-membered oxygen-containing ring
• example
• TXA2
• promotes platelet aggregation
• promotes vasoconstriction
• promotes bronchoconstriction
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Leukotrienes
• name is derived from
• their cells of origin - leukocytes leuko
• number of double bonds in conjugation - three triene
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Leukotrienes
• types
• LTA4, LTB4
• Cysteinyl derivates of LTA4 and LTB4 LTC4, LTD4, LTE4
• Slow-reacting substance of anaphylaxis (SRS-A)
• promotes bronchoconstriction
• increases capillary permeability edema
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Lipoxins
• contain
• three hydroxyl groups
• a conjugated tetraene system
• Example
• LXA4
• many physiological functions
• antiangiogenic
• enhanced clearance of exudates, produced from pulmonary edema
• protection from reperfusion injury
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Hydroxyeicosatetraenoic acids
• resemble noncysteinyl leukotrienes ( LTA4, LTB4)
• but lack the conjugated series of three double bonds
• example
• 5-HETE
• regulates neutrophil and eosinophil function
• mediates chemotaxis
• promotes degranulation
• promotes release of lysosomal enzymes
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Sites of synthesis of selected
eicosanoids – I
• GIT
• PGE2
• synthesized by epithelial and smooth muscle cells in the stomach
• reduces gastric acid secretion
• stimulates production of mucus
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Sites of synthesis of selected
eicosanoids – II
• CVS
• TXA2
• produced by platelets
• promotes platelet aggregation
• promotes vasoconstriction
• PGF2a
• produced by vascular smooth muscle
• promotes vasoconstriction
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Sites of synthesis of selected
eicosanoids – III
• CVS
• PGI2
• produced by vascular endothelial cells
• inhibits platelet aggregation
• promotes vasodilation
• PGE2
• produced by vascular smooth muscle
• promotes vasodilation
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Sites of synthesis of selected
eicosanoids – IV
• Respiratory
• LTs
• produced by monocytes and neutrophils in the lungs
• promote bronchoconstriction
• LTC4 is more potent than histamine in contraction of bronchiolar smooth
muscle cells
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Sites of synthesis of selected
eicosanoids – V
• Female reproduction tract
• PGE2
• produced by ovarian follicle and uterine smooth muscle
• role in ovulation
• cervical softening and ripening during parturition
• stimulate uterine contractions to expel the fetus
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Conditions in which eicosanoids
production is up-regulated
• Inflammation
• PGE2
• mediator of edema, erythema, fever, and pain associated with inflammation
• pyrogens ( endotoxin) possibly induce production of PGE2 in hypothalamus
fever
• Allergy
• 5-HETE
• binding of IgE antibodies to mast cell membrane stimulates the cells to release 5-
HETE
• 5-HETE stimulates other immune cells
• LTB4
• produced by activated leukocytes
• causes degranulation of neutrophil and eosinophil
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Effects of Prostaglandins and
thromboxane
• Smooth muscle
• Vascular
• TXA2, PGF2a - Vascular smooth muscle contraction
• PGI2 and PGE2 – endothelial vasodialator
• Gastrointestinal tract
• PGE2 and PGF2a– contract longitudinal muscle
• PGI2 and PGF2a – contract circular muscle
• PGE2 – relax circular muscle
• Airway
• PGE1, PGE2 and PGI2 – relax respiratory smooth muscle
• TXA2 and PGF2a– contracts respiratory smooth muscle
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Effects of Prostaglandins and
thromboxane
• Platelets and Blood cells
• PGE1 and PGI2 – inhibit platelet aggregation
• TXA2– aggregates platelets
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Effects of Prostaglandins and
thromboxane
• Kidney ( medulla and cortex synthesize prostaglandins)
• PGE2 and PGI2 – increase renin release
• PGE1, PGE2 and PGI2 – Vasodialatory effects increase
glomerular filtration increase water and sodium excretion
• Loop diuretics produce some of their effects by stimulating
cyclooxygenage activityincrease synthesis of vasodialator
prostaglandins
• Patient taking cyclooxygenase inhibitor has decrease response to
loop diuretics
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Effects of Prostaglandins and
thromboxane
• Reproductive organs
• Female
• PGE2
• Cervical softening and ripening during parturition
• Stimulate uterine contractions to expel the fetus
• Male – PGE1relaxes smooth muscle of corpora cavernosa penile
erection
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Effects of Prostaglandins and
thromboxane
• CNS
• Fever – PGE1 and PGE2 increase body temperature
• Sleep – PGD2 induce natural sleep
• Neurotransmission – PGE inhibit release of norepinephrine from
postganglionic sympathetic nerve endings
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Effects of Prostaglandins and
thromboxane
• Neuroendocrine organs
• PGE – promote release of GH, prolactin, TSH,ACTH, FSH and LH
• Bone metabolism
• Prostaglandin stimulate bone resorption and formation
• Eye
• PGE and PGF derivatives lower the intraocular pressure – increase
outflow of aqueous humor
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Effects of leukotrienes
• CVS
• LTC4 and LTD4 reduce myocardial contractility and coronary blood
flow
• Lipoxin A and Lipoxin B – coronary vasoconstrictor
• Airways
• LTC4 and LTD4
• Bronchoconstriction
• Increase vascular permeability
• Increase mucus secretion
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Clinical Pharmacology of Eicosanoids
• Female reproductive system
• Abortion- PGE2 and PGF2a have oxytocic effect
• Used to terminate pregnancy
• Used for cervical ripening
• Drug used – Dinoprostone
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Clinical Pharmacology of Eicosanoids
• Dinoprostone
• Synthetic PGE2
• Administered vaginally for oxytocic use
• Indications
• Induction of abortion
• For missed abortion
• For benign hydatiform mole
• For ripening of cervix for induction of labor in patients at or near term
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Clinical Pharmacology of Eicosanoids
• Dinoprostone
• Pharmacokinetics
• Metabolized in local tissues
• Also through first pass metabolism through the lungs ( about 95%)
• Metabolites are excreted in the urine
• Plasma half life is 2.5 to 5 minutes
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Clinical Pharmacology of Eicosanoids
• Dinorprostone
• Dosage forms
• Induction of labor
• Gel – 0.5mg PGE2 administered every 6 hours
• Controlled release formulation ( vaginal insert)– 10mg PGE2 that release PGE2 in
vivo at a rate of about 0.3mg/h over 12 hours
• Advantage – vaginal insert can be retrieved at any time
• Abortifacient
• Vaginal suppository – 20mg given repeatedly at 3 to 5 hour interval
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Clinical Pharmacology of Eicosanoids
• Dysmenorrhea
• Due to increase endometrial synthesis of PGE2 and PGF2a during
menstruationcontraction of uterus
• NSAIDs – inhibit formation of these prostaglandins relieves
dysmenorrhea
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Clinical Pharmacology of Eicosanoids
• Male reproductive organs
• Alprostadil(PGE1)
• Used in erectile dysfunction
• Dose – 0.2 – 140 microgram
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Clinical Pharmacology of Eicosanoids
• Cardiovascular system
• Pulmonery hypertension – Prostacycline lowers peripheral
resistance, pulmonary resistance and coronary resistance
• Epoprostenol – commercial preparation of prostacyclin
• Used for pulmonary hypertension
• Given as continuous intravenous infusion through central line
• Short half life
• Adverse effects – Nausea, vomiting, headache, hypotension and flushing
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Clinical Pharmacology of Eicosanoids
• Cardiovascular system
• Patent Ductus Arteriosus
• PGI2 and PGE2 are important for patency of ductus arteriosus
• Patency of ductus arteriosus is important for certain congenital heart disease
before surgery
• Drug used is Alprostadil
• Drug used to close the ductus arteriosus – Indomethacin
• Indomethacin – NSAIDs
• Inhibit cycloxygenase
• Used in Premature infant who develop respiratory distress symptoms
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Clinical Pharmacology of Eicosanoids
• Blood
• TXA2– Promote platelet aggregation
• PGI2 – Inhibit platelet aggregation
• Aspirin inhibit platelet cyclooxygenase inhibit platelet aggregation
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Clinical Pharmacology of Eicosanoids
• Respiratory system
• PGE2 – bronchodialator
• PGF2a– bronchoconstrictor
• TXA2– bronchoconstrictor
• LTC4 , LTD4, LTE4 – mediators in asthma
• Lipoxygenase inhibitors – Zileuton
• Leukotriene receptor inhibitors – Zafirlukast and Montelukast
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Clinical Pharmacology of Eicosanoids
• GI
• Misoprostol
• PGE1 analogue
• Orally active
• Cytoprotective(lower doses) and inhibit gastric acid secretion( higher doses)
• Used for NSAIDs induced ulcer
• Dose 200microgram four times daily
• Adverse effects
• Abdominal discomfort and occasional diarrhea
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Clinical Pharmacology of Eicosanoids
• Glaucoma( Open angle)
• Latanoprost (0.005% w/v solution)
• Long acting PGF2a derivative
• Administered as drops into conjunctival sac once or twice daily
• Side effects
• Blurring of vision
• Increased iris pigmentation ( brownish pigmentation)
• Ocular irritation and pain
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