The eicosanoids are oxygenation products of polyunsaturated long-chain fatty acids. They are ubiquitous in the animal kingdom and are also found—together with their precursors—in a variety of plants. They constitute a very large family of compounds that are highly potent and display an extraordinarily wide spectrum of biologic activity. Because of their biologic activity, the eicosanoids, their specific receptor antagonists and enzyme inhibitors, and their plant and fish oil precursors have great therapeutic potential.

1. EICOSANOIDS
Reza Heidari
Pharm D, Toxicology PhD

4. EICOSANOIDSEICOSANOIDS
((Prostaglandins,,
Thromboxanes,, Leukotrienes))

5. EicosanoidsEicosanoids

6. EicosaniodsEicosaniods
• Derived from 20-crabon polyunsaturated fatty
acids (AA)
• Paracrine or autocrine messengers molecules
• Short half-lives (10 secs – 5 mins) so that functions
are usually limited to actions on nearby cells
• Bind to specific cell surface G-protein coupled
receptors, and generally increase cAMP levels May
also bind to nuclear receptors and alter gene
transcription
• Wide variety of functions

7. Major Classes of EicosanoidsMajor Classes of Eicosanoids
• Prostaglandins
• Thromboxanes
• Prostacyclins
• Leukotrienes

8. • Induction of inflammation
• Mediation of pain signals
• Induction of fever
• Smooth muscle contraction (including
uterus)
• Smooth muscle relaxation
• Protection of stomach lining
• Simulation of platelet aggregation
• Inhibition of platelet aggregation
• Sodium and water retention
Effects of EicosanoidsEffects of Eicosanoids

9. Precursors of EicosanoidsPrecursors of Eicosanoids

10. Dietary Linoleic Acid (C18: ∆9,12
) (from plant oils)
Elongase
Desaturase
Arachidonic Acid (C20: ∆5, 8, 11, 14
)
Membrane Phospholipids

13. Phosphatidyl choline
Arachidonic acid
Phospholipase A2
Ca++
Phosphatidylinositol bisphosphate
Phospholipase C
1,2 Diacylglycerol
Arachidonic acid Monoacylglycerol
DAG
lipase
Arachidonic acid
MAG
lipase
Arachidonic acid release from membraneArachidonic acid release from membrane
lipidslipids
Stimulus

14. Pathways for Arachidonic Acid MetabolismPathways for Arachidonic Acid Metabolism
Arachidonic acid
Cyclo-oxygenase
Pathway
PGG2
Prostaglandins
Thromboxanes
lipoxygenase
Pathway
HPETE
Leukotrienes
HETE
Lipoxins

15. Prostaglandins – Structural FeaturesProstaglandins – Structural Features
PGA, PGD, PGE, PGF, PGG, PGH, PGI
Depending on the functional groups present at X
and Y
PGF 1, 2 or 3
Depending on the number of double bonds present
in the linear hydrocarbon chain

16. PGF 1, 2 or 3

17. Thromboxane AThromboxane A22 (TXA(TXA22) - structure) - structure

18. CYCLO-OXYGENASECYCLO-OXYGENASE
PATHWAYPATHWAY
PG and TX synthesisPG and TX synthesis
2GSH
2GSSG
PGD2
PGD synthase
PGF2a
PGE 9-keto
reductase
PGE2
PGE synthase
PGI2
PGI synthase
TXA2
TXA synthase

19. Some Functions of ProstaglandinsSome Functions of Prostaglandins
PGI2, PGE2, PGD2
• ↑ Vasodilation
• ↓ Platelet and leukocyte aggregation, IL1 and
IL2, T-cell proliferation, lymphocyte migration
PGF2α
• ↑ Vasoconstriction, Bronchoconstriction,
smooth muscle contraction
TXA2
• ↑ Vasoconstriction, Platelet aggregation,
lymphocyte proliferation, bronchoconstriction

20. LipoxygenaseLipoxygenase pathwaypathway

22. Some Functions of LeukotrienesSome Functions of Leukotrienes
LTB4
• ↑ Vascular permeability, T-cell proliferation,
leukocyte aggregation, IL -1, IL-2, IFN-γ
LTC4 and LTD4
• ↑ Bronchoconstriction, Vascular permeability,
IFN-γ

23. •Leukotrienes are a hundred
times more potent than
histamine
•Histamine provided a rapid
response to an allergen
•In the later stages
leukotrienes are principally
responsible for
inflammation, smooth muscle
constriction, constriction of
the airways and mucous
secretion form mucosal
Leukotrienes and allergiesLeukotrienes and allergies

24. Anti inflammatory Drugs inhibitAnti inflammatory Drugs inhibit
Eicosanoids SynthesisEicosanoids Synthesis
LeukotrienesProstaglandins,
thromboxanes
NSAIDs
Cyclo-oxygenase Lipoxygenase
Membrane lipids
Arachidonic Acid
Steroids
Phospholipase A2

25. Mechanism of Aspirin ActionMechanism of Aspirin Action

26. • COX-1 is constitutively expressed in nearly all
tissues responsible for normal physiological
functions
• Little or no COX-2 is present in normal resting cells.
COX-2 is induced by inflammatory stimuli
(cytokines, bacterial lipopolysaccharides).
• 20% of patients on long term NSAID treatment
develop gastric ulcers
• It was postulated that inhibitors selective for COX-
2 should relieve pain and inflammation without
gastric complications

28. • Low dose aspirin has an anti
-thromobogenic effect and lowers the
risk of heart attacks and strokes.
• It inhibits the formation of TXA2 in
platelets, by inhibition of COX-1 which
cannot be overcome because platelets
have no nucleus.
• Endothelial cells have a nucleus and
synthesis more COX-1 enzyme needed
for the normal prostaglandin functions
Aspirin and cardiovascular diseaseAspirin and cardiovascular disease

29. Omega-6/omega-3 fatty acid balanceOmega-6/omega-3 fatty acid balance
• ω6 and ω3 are not interconvertible in
humans (mammals).
• Diets rich in ω3 fatty acids result in high
content of these fatty acids in membrane
phospholipids

30. A diet rich in omega-6 FAs shifts the
physiological state to one that is
proinflammatory, prothrombotic and
proaggregatory… leading to heart disease
in susceptible individuals
Omega-6/omega-3 fatty acid balanceOmega-6/omega-3 fatty acid balance

37. Effects of Prostaglandins &
Thromboxanes
• Smooth Muscle
• Platelets
• Kidney
• Reproductive Organs
• Central and Peripheral Nervous Systems
• Inflammation and Immunity
• Bone Metabolism
• Eye
• Cancer

38. Thank you!Thank you!

39. Clinical Pharmacology of
Eicosanoids
Reza Heidari
Pharm D, Toxicology PhD

40. NSAIDs
Non Steroidal Anti Inflammatory Drugs

42. INFLAMMATION
• Inflammation (Latin, inflamatio, to set on fire) is
the complex biological response of vascular tissues
to harmful stimuli, such as pathogens, damaged
cells, or irritants.
• It is a protective attempt by the organism to
remove the injurious stimuli as well as initiate the
healing process for the tissue.

43. • Burns
• Chemical irritants
• Toxins
• Infection by pathogens
• Physical injury
• Immune reactions due to hypersensitivity
• Radiation
• Foreign bodies
CAUSES

44. Process of Inflammation
• Inflammation can be classified as either acute or chronic.
• The initial phase of cell injury is known as the acute
phase and is mediated by several autacoids like :
– Histamine
– 5-HT
– Bradykinin
– Prostaglandins
• When a tissue is injured, from any cause, prostaglandin
synthesis in that tissue increases.

45. Synthesis of Prostaglandins
Cyclo-oxygenase (COX) pathway
Membrane Phospholipids
Phospholipase A2
Arachidonic Acid
Prostaglandins
Thromboxanes
Prostacyclin
COX

47. Preferential COX-2 inhibitors:
Nimesulide, Meloxicam, Nabumatone
Selective COX-2 inhibitors
Celecoxib, Rofecoxib, Valdecoxib
Analgesic –Antipyretics with poor Anti inflammatory action
Para amino phenol derivatives Paracetamol (Acetaminophen)
Pyrazolone derivatives Metamizol (Dypirone),
Propifenazone
Benzoxazocine derivative Nefopam
Classification cont..

48. Non selective COX inhibitors:
Salicylates Aspirin, Diflunisal
Pyrazolone derivatives Phenylbutazone,
Oxyphenbutazone
Indole derivatives Indomethacin, Sulindac
Propianic acid derivatives Ibuprofen, Naproxen,
Ketoprofen, Flurbiprofen
Anthranilic acid derivatives Mephenamic acid
Aryl-acetic acid derivatives Dicofenac
Pyrrolo-pyrrolo derivative ketorolac

49. Mechanism of action
• When a tissue is injured, from any cause, prostaglandin
synthesis in that tissue increases.
• PGs have TWO major actions:
• They are mediators of inflammation
• They also sensitize pain receptors at the nerve endings,
lowering their threshold of response to stimuli

50. • Naturally, a drug that prevents the synthesis of PGs is likely to
be effective in relieving pain due to inflammation of any kind
• In 1971 Vane and coworkers made the landmark observation
that aspirin and some NSAIDs blocked PG generation.
• This is they do by inhibiting cyclo –oxygenase (COX) enzyme in
the pathway for PGs synthesis
Mechanism of action Cont..

51. COX
• Exists in two isoforms:
1. COX-1 (constitutive)
2. COX-2 (inducible)
– Oxidative stress
– Injury
– Ischemia
– Neurodegenerative diseases

52. Beneficial actions due to PG synthesis
inhibition
• Analgesia
• Anti-pyresis
• Anti-inflammatory
• Antithrombotic

53. Shared toxicities due to PG synthesis
inhibition
• Gastric mucosal damage
• Bleeding
• Limitation of renal blood flow/Na+
& water
retention
• Asthma and anaphylactic reactions in
susceptible individuals

54. Salicylates - Aspirin
• Acetylsalicylic acid
• It was obtained from ‘willow bark’ (Salicaceae) but is
now synthesized
• Methyl salicylate is a volatile liquid derivate.(Counter irritant)
• Irreversible inhibitor of COX
• Nonselective inhibitor of COX

56. Aspirin – Pharmacological actions
Anti-inflammatory action:
 Potent
 Signs of inflammation are suppressed
 Acts mainly by inhibiting PG synthesis

57. Aspirin – Pharmacological actions
Analgesic action:
• Mild analgesic effect ≤
codeine
• Effective in non -visceral
pain
• Inhibition of peripheral PG
synthesis

58. Effect on platelets/coagulation
•TXA2 enhances platelet aggregation
•PGs
•Low doses(80-100mg/day)
•Prolong effect
Aspirin – Pharmacological actions

59. Gastrointestinal:
•Most common
•Epigastric distress, Nausea, Vomiting
•Increased occult blood loss in stools
•Gastric mucosal damage and peptic ulcer
Rey’s syndrome
•Occurs in infants and children
•Occurs when aspirin given during viral infections
•Characterized by liver damage and encephalopathy
•Replaced by acetaminophen in such condition to reduce
fever
Aspirin – Adverse effects

60. Salicylism
•High doses(at anti-inflammatory doses) or chronic use of
aspirin may induce a syndrome characterized by tinnitus,
hearing defects, blurring of vision, dizziness, headache and
mental confusion
•Effects are reversible
Aspirin – Adverse effects

61. contraindications
• Peptic ulcer
• Ulcerative colitis
• Renal failure
• Patients hypersensitive to salicylates
• Hemophilias
Aspirin – Contraindications

62. Uses
1. As analgesic
2. As antipyretic
3. Anti-inflammatory
4. Cardio protective
Aspirin – Uses

63. • As analgesic and antipyretic:
 300-600 mg, 6-8 hourly
• Cardio protective:
 80-100mg/day
Aspirin – Doses(oral)

64. Methylsalicylate (Topical):
•Used topically as a counterirritant in muscle and joint pain
•Systemic absorption can lead to toxicity
Salicylic acid (Topical):
•Used as keratolytic and corn remover
•Combined with benzoic acid (Whitefield ointment) for local
use in epidermophytosis
Other clinically used Salicylates

68. These are:
Nimesulide, Meloxicam, Nabumatone
Prefer. COX-2 inhibitors

69. • Selectively block COX-2 activity more than COX-1
activity
• Less action on stomach, blood vessels and kidneys
This group includes:
Celecoxib, Rofecoxib and Valdecoxib
• Given orally, absorption is complete
• Established analgesic- anti-inflammatory NSAIDs
• They have to be shown effective in treatment of
osteoarthritis and rheumatoid arthritis
• Their major advantage is that they cause fewer gastric
ulcers and do not inhibit platelet aggregation
• Stomach friendly
Selective COX-2 Inhibitors

70.  Recently, the use of rofecoxib and valdecoxib has
been reported to be associated with increased incidence
of MI and stroke
 Hence, they have been withdrawn by the original
manufacturers
 Currently all the selective COX -2 inhibitors are under
suspicion regarding their long term toxicity
 They have been described as drugs with “marginal
efficacy, heighted risk and excessive cost compared with
traditional NSAIDs”
Selective COX-2 Inhibitors Cont..

71. Misoprostol
• Start labor
• Cause
an abortion
• Prevent and
treat stomach
ulcers
• Treat postpartum
bleeding due to
poor contraction
of the uterus
It is a prostaglandin analogue
(a synthetic prostaglandin
E1; PGE1)

72. Latanoprost
 Latanoprost is an analog of
prostaglandin F2α that acts as a
selective agonist at the
prostaglandin F receptor
 Increases outflow of aqueous fluid
thus lowering intraocular pressure

73. Alprostadil
(PGE1)

74. Montelukast
Prevention and long-term
treatment of asthma. It is also
used in certain patients to
relieve allergy symptoms (eg,
itchy, runny, or stuffy nose;
sneezing) and to prevent asthma
attacks caused by exercise

76. Thank you!Thank you!