LIPID DERIVED AUTOCOIDS
❑Derived from membrane PhospholipidsEicosanoids & Platelet Activating Factor
❑Mediators and modulator of inflammation
❑Physiological & Pathological process
▪ Inflammation
▪ Haemostasis
▪ Thrombosis
▪ Smooth muscle tone
▪ Parturition
▪ Fever
▪ Gastrointestinal secretion
Eicosanoids
– Eicosanoids include:
1. Prostaglandins
2. Thromboxanes
3. Leukotrienes
❑ Prostanoids : Prostaglandins & Thromboxanes
CHEMISTRY
• Membrane phospholipids
• Polyunsaturated 20 carbon essential fatty acids
- Arachdonic acid
• Greek word : eicosi- twenty, tetraenoic- four
double bonds
• 5,8,11,14 – eicosa teraenoic acid
• 3 double bond – 8,11,14- eicosatrienoic acid
• 4 double bond – 5,8,11,14- eicosatetraenoic acid
• 5 double bond – 5,8,11,14, 17 eicosapentaenoic acid
PROSTAGLANDINS
• Seminal fluid (Prostglandin) secretion
• Derivatives of prostanoic acid- 20 carbon
carboxylic acid with cyclopentane ring
• Prostaglandins designated as
• Prostaglandins A, B, C, D, E, F, G, H & I
• Numeric script 1,2 & 3 – Number of double
bonds
• PGE1 : C13- 14
• PGE2 : C5-6 & C13 – 14
• PGE3 : C5-6, C13 – 14 & C17-18
THROMBAXANES
• Anologues of unsaturated Thrombanoic acid
• Synthesised in thrombocytes
• Contain six membered oxane ring
BIOSYNTHESIS
•
•
•
•
Cyclooxygenase pathway
Lipoxygenase pathway
Cyclooxygenase pathway :
Prostaglandin endoperoxide synthetase – Fatty
acid cyclooxygenases – COX
• Two isoforms- COX-1 & COX-2
• COX-1 : Most cells and normal homeostasis
• COX-2 : induced by the cytokines and Growth
factors- inflammatory reaction
LEUKOTRINES
• Leucocytes
• 3 conjugated double bonds
• Neutrophils, monocytes, macrophages, mast cells
and keratinocytes & Lungs.
• Leucotrienes- A,B,C,D ,E & F
• Subscripts : 1,2,3 & 4
• LTB4, LTC4 & LTBD4
• LTB4 – Potent chemotactic agent
• LTC4, LTBD4 & LTE4 – Cysteinyl Leukotrienesconstitute the Slow Reacting substances of
anaphylaxis (SRS- A)
• Unstable HPETES- converted in to hydroxy fatty acidshydroxyeicosatetraenoic acid (HETE)
• 12 - HETE leads to epoxyhydroxyeicosatrienoic acid –
Hepoxilins
• 15- HETE forms Trihydroxylated metabollites- Lipoxines
• Arachdonic acid by cytochrome P- 450 – 19 & 20 –
HETES and epoxyeicosatrienoic acids
• Free radicals : Arachdonic
Isoprotenes
• Steroids and NSAIDs- donot block production.
DISTRUBUTION
• Widely distrubuted in the body
• Every cell and tissue capable of synthesising
eicosanoids
• Not localised or stored in tissue pools
• Synthesised de novo at rates governed by the
release of Arachdonic acid from membrane
phospholopids in response stimuli
• Have short half life (Few seconds)
• Produced biological activities and are rapidly
inactivated
METABOLISM
• Degrading enzymes located in lungs (PGE2 &
PGF2ά), kidney, spleen , adipose tissues and
intestine.
• PGI2
6-Keto PGI ά (Biologically
Inactive)
• Leukotrienes:
LT B4
20 –Hydroxy LTB4
20- Carboxy LTB4
MECHANISM OF ACTION
▪ Prostaglandins, thrombaxanes and leukotrienes
mediate their actions by acting on their own
specific receptors located on cell membranes
▪ Prostanoid Receptor :
✓DP receptor – PGD2
✓EP receptor - PGE
✓FP receptor – PGF2ά
✓IP receptor - PGE1
✓TP receptor - TXA2
LEUKOTRIENE RECEPTORS
• bLT – LTB4
• cLT – LTC4
• dLT – LTD4/ E4
❑ Activate through the IP3/ DAG transducer
mechanisms.
PHYSIOLOGICAL AND PHARMACOLOGICAL
EFFECTS SYSTEM
CARDIO VASCULAR
• In most vascular beds, PGE2 elicits vasodilatation and a drop
in blood pressure, although vasoconstrictor effects have been
reported, depending on which PGE2 receptor is activated
• Infusion of PGD2 results in flushing, nasal stuffiness, and
hypotension; subsequent formation of F-ring metabolites may
result in hypertension.
• PGF2ά vary with vascular bed - Potent constrictor of both
pulmonary arteries and veins but does not alter blood
pressure.
• PGI2 - Relaxes vascular smooth muscle, causing
prominent hypotension and reflex tachycardia on
intravenous administration. It is about five times
more potent than PGE2.
• TxA2 - Potent vasoconstrictor.
• PGG2 & PGH2- Potent vasoconstriction
• PGI2- Vasodilation in vascular endothelium.
DIGESTIVE SYSTEM
• Complex
• PGE2 & PGF2ά - Contraction of longitudinal
muscles
• PGI2
& PGF2ά
-
Contraction of Circular
muscle
• PGI2 - Relaxation of smooth muscle
- Inhibition of Gastric acid Secretion
RESPIRATORY SYSTEM
• TXA2 & PGF2ά - Contraction
• PGE1,PGE2 & PGI2 - Relaxation
• PGI2 - Inhibition of histamine release
• Asthamtics are more sensitive to constrictor as
well as dilator effect of prostanoids.
REPRODUCTIVE SYSTEM
• PGE2 & PGF2ά – contract uterine smooth
muscle in gravid uterus near term.
• PGF2ά - Luteolytic effect
• Semen from fertile men contains about 400 g/mL
of PGE and PGF and their 19-hydroxy
metabolites.
• There is about 20 times more PGE than PGF in
fertile semen.
• Testosterone does promote prostaglandin
production.
• Thromboxane and leukotrienes have not been found
in seminal plasma.
• Men with a low seminal fluid concentration of
prostaglandins are relatively infertile.
• Large doses of aspirin reduce the prostaglandin
content of seminal plasma.
• PGE1 - Smooth muscle–relaxing prostaglandins
enhance penile erection by relaxing the smooth
muscle of the corpora cavernosa.
PLATELETS AND BLOOD CELLS
• Platelet aggregation is markedly affected by eicosanoids.
• PGE1, PGD2 and PGI2 - Inhibit aggregation,
• TXA2, PGG2 & PGH2 - Potent platelet aggregator.
• Platelets
release
TXA2
during
activation
and
aggregation.
• Aspirin -
thromboxane synthesis is significantly
inhibited only in platelets.
• Other cells may contribute to the increase in TXA2
• Monocytes,
• Neutrophils and lymphocytes synthesize prostaglandins,
• Eosinophils - Prostaglandin and Thromboxane synthesis.
• Damage to the endothelial cell causes the formation of
the haemostatic plug – decrease in the PGI2 synthesis in
the vascular endothelium and Increase in TXA2 synthesis
by platelets.
KIDNEY AND URINE FORMATION
• PGs influence renal salt and water excretion by alterations
in renal blood flow and by direct effects on renal tubules.
• PGE2 and PGI2 infused directly into the renal arteries of
dogs increase renal blood flow and provoke diuresis,
natriuresis, and kaliuresis with little change in glomerular
filtration rate.
• TxA2 decreases renal blood flow, decreases the rate of
glomerular filtration.
• PGEs inhibit water reabsorption induced by vasopressin
(antidiuretic hormone).
• PGE2 -
inhibits Chloride reabsorption in the thick
ascending limb of the loop of Henle in the rabbit.
• PGI2, PGE2, and PGD2 stimulate renin secretion direct
effect on the granular juxtaglomerular cells
• TXA2 - Intrarenal vasoconstriction - decline in renal
function.
EYE
• PGE & PGF2ά induces constriction of the iris
sphincter muscle - Decrease intraocular pressure
by increasing the aqueous humor outflow of the
eye via the uveoscleral and trabecular meshwork
pathway.
• A variety of F prostaglandin-receptor agonists
have proven effective in the treatment glaucoma.
CENTRAL AND PERIPHERAL NERVOUS SYSTEMS
FEVER
• PGE1 and PGE2 increase body temperature,
probably via EP3 receptors
• Pyrogens release interleukin-1, which in turn
promotes the synthesis and release of PGE2.
• PGD2 and TxA2 - do not induce fever.
• This synthesis is blocked by aspirin and other
antipyretic compounds.
SLEEP
• Infused into the cerebral ventricles, PGD2 induces
natural
sleep
(as
determined
by
electroencephalographic analysis).
• PGD2 - act on arachnoid trabecular cells in the
basal forebrain to mediate an increase in
extracellular adenosine facilitates induction of
sleep.
• PGE2 and PGI2 - Sensitize the peripheral nerve
endings to painful stimuli by lowering the
threshold of nociceptors.
• Centrally, PGE2 can increase excitability in pain
transmission neuronal pathways in the spinal cord.
• Hyperalgesia also is produced by LTB4.
• The release of these eicosanoids during the
inflammatory
process
thus
serves
as
an
NEUROTRANSMISSION
• PGE - Inhibit the release of norepinephrine from
postganglionic sympathetic nerve endings.
• NSAIDs increase norepinephrine release in vivo.
ENDOCRINE SYSTEM
• Systemic administration of PGE2 increases
circulating concentrations of adrenocorticotropic
hormone (ACTH), Growth hormone, Prolactin,
and Gonadotropins.
• Stimulation of steroid production by the
adrenals, stimulation of insulin release, and
thyrotropin like effects on the thyroid.
• PGF2ά - Parturition
• PGE2 - induce oocyte maturation required for
fertilization during and after ovulation.
BONE
• PGs - strong modulators of bone metabolism.
• PGE2 stimulates bone formation and resorption
through osteoblastic and osteoclastic activities affecting
bone strength and composition.
LEUKOTRIENES
•
•
•
•
•
CARDIOVASCULAR SYSTEM
LTC4 and LTD4 - Hypotension - reduction in
coronary blood flow.
LTC4 and LTD4 - little effect large arteries or
veins
Coronary arteries and distal segments of the
pulmonary artery are contracted
The renal vasculature is resistant to this constrictor
action, but the mesenteric vasculature is not.
CysLTs
prominent
effects
on
the
microvasculature.
• LTC4 and LTD4 - act on the endothelial lining of
postcapillary venules to cause exudation of
plasma, 1000-fold more potent than histamine.
• At higher concentrations - LTC4 and LTD4
constrict arterioles and reduce exudation of
plasma.
• Isoprostanes – vasoconstrictors
• LTC4 and LTD4 reduce myocardial contractility
and coronary blood flow, leading to cardiac
depression
• Lipoxin A and lipoxin B - Coronary
vasoconstrictor effects.
BLOOD CELLS AND INFLAMMATION
• LTB4 - Potent Chemotactic agent for
polymorphonuclear leukocytes, eosinophils, and
monocytes.
• In higher concentrations, LTB4 stimulates the
aggregation of polymorphonuclear leukocytes and
promotes degranulation and the generation of
superoxide.
• LTB4 promotes adhesion of neutrophils to
vascular endothelial cells and their transendothelial
migration
and
stimulates
synthesis
of
proinflammatory cytokines from macrophages and
lymphocytes.
• LTC4 and LTD4 - Potent chemoattractants for
eosinophils.
• Leukotrienes - promote eosinophil adherence,
degranulation, and oxygen radical formation.
• LTB4
-
Lymphocyte
proliferation
and
differentiation
• Lipoxin A and lipoxin B inhibit natural killer cell
cytotoxicity.
GASTROINTESTINAL TRACT
• Inflammatory bowel disease - increased amounts
of LTB4.
AIRWAYS
• LTC4 and LTD4 - Potent bronchoconstrictors and
cause
increased
microvascular
permeability,
plasma exudation, and mucus secretion in the
airways.
SMOOTH MUSCLES
• Cysteinyl
leukotrienes
(LTC4
&
LTD4)
-
Contraction of smooth muscles- bronchial, GIT
• Stimulate bronchial mucus secretion and cause
mucosal oedema.
NERVOUS SYSTEM
• LTB4
–
Sensitisation
of
nociceptors
to
mediaators of pain.
• Inflammation – release of LTB4 – amplification
system for pain mechanism.
PHYSIOLOGICAL AND PATHOLOGICAL ROLES
1.
•
•
•
Cardiovascular system :
PGE2 &PGI2 modulate vascular tone
Maintanace of patent ductus arterious
Maintenance of placental blood flow during
foetal life
2. Inflammatory and Pain response :
• Prostaglandins and Leukotrienes (LTB4) –
serves as algesic agents during the
inflammation
• Sensitise nociceptors to mediators of pain
• PGE2- mediates the pyrogen induced fever
3. Brochoconstriction and Asthma:
• PGs & LTs
• Bronchoconstrictor eicosanoids (PGF2, PGD2, TXA2,
LTC4 & LTD4 ) and bronchodilator mediators (PGE2
AND PGI2)
4. Platelets and Thrombosis:
• PGG2 ,PGH2 & TXA2 – Platelet aggregation and
development of thrombosis
• PGI2 – prevents
5. Reproduction and Parturition :
• PGF2ά – Luteolysis and contraction of uterine smooth
muscles
• Mediates the intiation and inductionof parturition
• Males – erection, ejaculation, sperm motility &
steriodogenesis.
6. Kidneys:
• Modulates the renal blood flow
• Regulate the urine formation
• Regulates the secretion of Renin
7. Gastrointestinal tract :
• PGE2 – secretion of the mucus in the stomach
• PGI2 – regulation of the gastric mucosal blood flow
• Reduce the gastric acid secretion and serve as natural
ulcer protective agents
8. Endocrine system :
• PGE2 – facilitates the release of several hypothalamic
and anterior pituitary hormones and Insulin.
PHARMACOLOGY OF EICOSANOIDS
ALPROSTADIL
• PGE1
• Congenital
Heart
Defect
:
Increase
the
pulmonory blood flow in infants
• Not
used
for
closure
of
patent
Ductus
Arteriousus – vasodilatory effects of PGE1
• Intracavernosal injection or urethral suppository
therapy - treatment of erectile dysfunction,
especially in spinal cord injury.
• Alprostadil may be used as monotherapy or in
combination Papaverine or Phentolamine
• Doses : 2.5–25 g
• Penile injection (Caverject, Edex): 5, 10, 20, 40 g sterile
powder for reconstitution
• Parenteral (Prostin VR Pediatric): 500 g/mL ampules
DINOPROSTONE
• Synthetic PGE2
• Humanbeings
• Induction and augmentation of labour - Second
trimester of pregnancy
• Midterm abortion
• Applied locally in vagina promotes repining and
dilation of relax - increasing proteoglycan
content and changing the biophysical properties
of collagen.
• Oxytocic use.
• Dinoprostone stimulates the contraction of the
uterus throughout pregnancy.
• As the pregnancy progresses, the uterus increases
its contractile response, and the contractile effect
of oxytocin is potentiated as well.
• Dinoprostone is metabolized in local tissues and
lungs (about 95%).
• The metabolites are mainly excreted in the urine.
• The plasma half-life - 2.5–5 minutes.
• For the induction of labor
• Dinoprostone - Gel (0.5 mg PGE2) or as a
controlled-release formulation (10 mg PGE2)
that releases PGE2 in vivo at a rate of about 0.3
mg/h over 12 hours.
• Advantages
• Controlled-release formulation is a lower
incidence of gastrointestinal side effects (< 1%).
• Delivery system is that the medication is
contained within a vaginal insert that can be
retrieved at any time.
• Dinoprostone [prostaglandin E2] (Prostin E2,
Prepidil, Cervidil)
• Vaginal: 20 mg suppositories, 0.5 mg gel, 10
mg controlled release system
MISOPROSTOL
• Synthetic analogue of PGE1
• 15- deoxy – 16- hydroxy- 16 methyl PGE1
• Yellow viscous liquid – musty odour
• Ulcer healing agent- human & Veterinary field
• ENPROSTIL - Cytoprotective at low doses and
inhibit gastric acid secretion at higher doses.
PHARMACOLOGICAL EFFECTS
• Cytoprotective and antiulcer effect on gastric
mucosa
• Inhibits the basal, noctoral and food induced
gastric acid secretion by the direct action on
gastric parietal cells
• Increases the production of gastric mucus ,
bicorbonate and enhance blood supply to gastric
mucosal cells
• H2- receptor antagonist – nor provide relief
from the ulcerogenic pain.
PHARMACOKONETICS
• PO – rapidly and effectively absorbed from the GIT
• Misoprostol
Misoprostol acid
Inactive metabollite
• Urine
SIDE EFFECTS
• Diarrhoea, Nausea, abdominal cramps & flatulence
• Bitches – Uterine contraction and vaginal bleeding
• Bone pain and hyperostosis
• PGE-induced, EP4- mediated acceleration of osteoclast
and osteoblast activity.
CONTRAINDICATION AND PRECAUTION
▪ Pregnancy – uterine stimulant activity
▪ Cerebral or coronary vascular diseases
DRUG INTERACTION
• Antacids – reduce absorption and Bioavailabality
• Magnesium antacids - aggrevate misoprostol induced
diarrhoea
CLINICAL USES
• Prevention and treatment of gastric ulceration
• Less effective in duodenal ulceration and reflux
oesophagitis – increase the colonic propulsive
activity
❑ Dose:
Dogs
– 2-5 μg/kg PO 3 times daily
Horses
– 0.5 μg/kg PO 4 times daily
Humans - 200 g four times daily
✓Rioprostil
✓Enprostil
✓Abraprostil
✓Trioprostil – PGE2
• Misoprostol (Cytotec)
• Oral: 100 and 200 g tablets
PROSTAGLANDIN F AND ANALOGUE
DINOPROST
• PGF2ά
• Dinoprost tromethamine
• Dinoprost trometamol
• White hygroscopic crystalline powder
• Vet – Luteolytic and Ecbolic action.
•
•
•
•
•
•
PHARMACOLOGICAL EFFECTS
Female reproductive system
Stimulation of uterus, relaxation of the cervix
and regression of corpus luteum
Luteolytic effect - depend on dose, frequency
of administration and stage of the cycle.
Cows, mare & ewe – refractory period : 5 days
of ovulation
Sow – 11 days
Queens and Bitches : Corpus luteum is
generally unresponsive at any time after
ovulation subjected to repeated doses.
PHARMACOKINETICS
• Injection – distributed throught the body
• Half life : few minutes
SIDE EFFECTS
• Horses : Transient sweating, decreased body
temperature,tachycardia,
tachypnoea,abdominal
pain and ataxia
• Cattle: Transient salivation, Increased body
temperature, restlessness, tremor and mild
diarrhoea
• Pigs: Transient salivation, Increased body
temperature, diarrhoea and urination
• Dog : Abdominal pain, nausea, vomition, diarrhoea,
hypersalivation, tachypnoea & panting
•
▪
▪
▪
▪
TREATMENT
Supportive therapy
CONTRAINDICATION AND
PRECAUTION
Pregnancy
Bronchoconstriction
Vascular disorders
Handled carefully – absorbed through the skin
DRUG INTERACTION
• Oxytocic
agents
:
enhancement
of
pharmacological effects
• Progestin – reduce the efficasy of the dinoprost
CLINICAL USES
• Luteolytic agent : induce the onset of oestrus /
syncronisation of the oestrus
• Termination of the pregnancy
• Induction of parturition+ corticosteroids
• Pathological condition- Pyometra, mummufied
foetus and luteal cysts
• Dog & cat : after fasting – decrease the incident
of vomiting
DOSE
• For Oestrus synchronisation
Cattle : 25mg (total dose) IM once or twice at 1012 day interval
Sheep & Goat : 8mg (total dose) IM on day 4-5 of
oestrus cycle and repeat in 11 days
• Termination of pregnancy
Cattle : 25- 30mg(total dose) IM between 5150days
of
gestation
Swine : 5-10mg (Total),IM
Sheep : 10-15mg (Total), IM First two months of
• INDUCTION OF PARTURITION
Cattle : 25mg (total dose) IM Parturition occurs in about
72 hous of injection
Sheep & Goat : 2.5-5 mg (total dose) IM 2-6 days before
the expected forrowing.
Farrowing usually occurs within 24-36 hours of injection
PYOMETRA
Cattle : 25mg (total dose) IM uterus begins evacuating
within 24 hours once daily for 5 days
Dogs & cats : 0.25 mg/kg, SC Once daily for 5 days
CLOPROSTENOL
• Synthetic analogue of PGF2ά
• More potent than PGF2ά – rapid regression of the
corpus luteum
• Not recommended in case of dog & cat.
DOSE
• INDUCTION OF PARTURITION
Cattle
: 0.5 mg (total dose) IM
Sheep & Goat : 0.0625-0.125 mg (total dose) IM 144 days
of gestation
Swine : 0.175mg (Total) IM
• TERMINATION OF PREGNANCY
Cattle : 0.5mg(total dose) IM (From 7th day of
pregnancy 150days of gestation)
Horses : 0.25- 0.5 mg (Total),IM (Prior to 12th day
of gestation)
PYOMETRA / CHRONIC ENDOMETRITIS
Cattle : 0.5mg (Total ), IM
• Alfaprostol
• Etiproston
• Fluprostenol – Smooth muscle stimulant activity
Mare : Induction of parturition
• Luprostiol
• Tiaprost
•
•
•
•
•
•
•
•
•
Latanoprost,
Bimatoprost
Travaprost
Unoprostone
LATANOPROST
Stable long-acting PGF2 derivative, was the first
prostanoid used for glaucoma
Ocular hypotensive effects
These drugs act at the FP receptor and are
administered as drops into the conjunctival sac once
or twice daily.
Adverse effects include irreversible brown
pigmentation of the iris and eyelashes, drying of the
eyes, and conjunctivitis.
Latanoprost (Xalatan), Topical: 50 g/mL ophthalmic
3.PROSTAGLANDIN I & ANALOGUES
•
•
•
•
•
•
•
•
EPOPROSTENOL
Short acting Prostacycline (PGI2) preparation
Human medicine – Inhibit the platelet aggregation
during the haemo- dialysis
Used for Storage and harvest of blood platelets for
therapeutic transfusion.
Other Drugs :
Iloprost
Carbacyclin
Epoprostenol [prostacyclin] (Flolan)
Intravenous: powder to make 3, 5, 10, 15 g/mL
INHIBITORS OF EICOSANOIDS
1. Inhibitors of Eicosanoid synthesis:
GLUCOCORTICOIDS
▪ Stimulation of synthesis of a peptide – Lipocortin
▪ Blocks the Phospholipase A2 enzyme
▪ Inhibits the release of the arachdonic acid from the
membrane phospholipids
▪ Inhibit the synthesis of all Eicosanoids (PGs, Txs &
LTs)
Ex: Dexamethasone, Prednisolone Etc
NON STEROIDAL ANTIINFLAMMATORY
DRUGS
• Inhibit the cyclooxygenase enzymes and
prevent the synthesis of Prostanoids (PGs &
Txs)
• Increase the production of leukotrienes by
promoting
the
avialabality
of
substrates
(Arachdonic acid) to the lipoygenase pathway.
LEUKOTRIENE SYNTHESIS INHIBITOR
• Inhibits the 5 – Lipoxygenase enzyme and
prevent the synthesis of Leukotrienes
• Treatment of asthma & other inflammatory
conditions
• Human medicine
• Zileuton - piriprost
THROMBAXANE SYNTHESIS INHIBITOR
• Inhibits the thrombaxane synthetase enzyme
• Inhibit the biosynthesis of thrombaxanes
• Dazoxiben
• Ridogrel - Thrombaxane receptors
• Sulotroban -
Thromboembolism,
Pulmonary hypertension
Preeclampsia-eclampsia.
2. INHIBITION OF EICOSANOIDS RECEPTORS
• Not available for the clinical use
• TP receptor antagonists
• Sulotroban
• Vapiprost
LTD4 receptor antagonists
❑ Asthma
▪ Accolate
▪ Zafirlukast
▪ Montelukast
• Monteleukast (Singulair)
• Oral: 5 mg chewable, 10 mg tablets