Autocoids Flashcards
What are the Autocoids
Naturally available substances
Examples of autocoids
Eicosanoids
Angiotensin
Nrurotensin
NO
Kinins
Histamine
Serotonin
Endothelins
Features of the Eicosanoids
Oxygenation products of AA
Wide range of therapeutic usefulness
Prostaglandins
Thromboxanes
Leukotrienes
AA libearted from where
Cell membrane phospholipids
Which enzyme is responsible for the generation of AA from the cell membrane
Phospholipase A
What are the forms of PLA
Cardiac
Cytosolic— Ca dependent
Secretory— Ca dependent
Pathways of AA
1-COX Pathway
2- 5-Lipoxygenase pathways
How is the COX pathway occur
COX coverts AA to PGG2 and then Eicosanoids
Isoforms of COX
COX-1= always secreted, important for physiological situations.
COX-2=specific for pathological situations, secreted when needed
COX-3
COX-2 inhibitors
NSAIDs
Rofecoxib
Celecoxib
Nimesulide
Side effects of COX-1 inhibitors
COX is responsible for inhibition of gastric acid secretion and helps to secrete gastric mucus
Inhibiting COX-1 can result with decrease in mucus secretion and cause ulcers
COX enzymes converts AA to what?
Prostaglandin G2
Which is an unstable cyclic endoperoxide and coverts to PGH2
PGH2 also unstable and yields to PGI2,PGE2,PGF2a,PGD2, Thromboxane A2 and Thrombaxe B2.
Why corticoids are used as an anti-inflammatory drug?
They induce the formation of lipocortin that inhibts PLA
They can also inhibit COX-2 gene expression
What are the general effects of Eicosanoids
Effect on
Vascular
Airway
Reproductive
GI smooth muscles
Vasoconstrictor Eicasonids
TXA2
PGF2a
Vasodilator prostaglandins
PGI2
PGE2
GI smooth muscle contractor Eicosanoids
PGs
TXA2
Constrictor of bronchial smooth muscles
TXA2
PGE2
PGF2a
Bronchodilator Eicosanoids
PGI2
PGE2
PGE1
Inhibitors of platelet aggregation
PGE1
PGI2
Enhances the Platelet aggregation
TXA2
Role of aspirin
Aspirin inhibts TXA2 formation only in platelets
Inhibits vasodilator PGI2 formation
Antiaggregant
Kidney synthesizes which Eicasonoids
PGs— PGE1,PGE2,PGD2— for glomerular filtration due to their vasodilator effect
Effects of PGs in the reproductive system
PGE2 and PGF2a are oxytocic molecules— normal delivery
Used for the abortion and initiation of labor
PGE1 helps erection
Seminal vesicles, prostate and testes produce PGs
Eicasonoids involved in fever
PGE1
PGE2
Eicasonoid that regulates natural sleep
PGD2
Eicosanoids that decrease the intraocular pressure
PGE
PGF
Dinoprostone
Synthetic analogue of PGE2
Produces contraction of uterine muscles
Alprostadil
PGE1 analogue
Used for the treatment of erectile dysfunction in men
Epoprostenol
PGI2 analogue
Uses for pulmonary hypertension
Eicosanoids that involved in Patent Ductus Arteriousus
PGE2 and PGI2
NSAIDs are used for the duct closure
If duct should remain open Alprostadil is administered
Misoprostol
PGE1 analogue
Used for ulcer treatment
COX-1 effects are minimized where administered with NSAIDs
How is the Lipoxygenase Pathway
AA— Leukotriene A4—Leukotriene B4—Leukotriene C4—Leukotriene D4—Leukotriene E4
Which Leukotriene types are Bronchoconstrictors
LTC4
LTD4
Zileuton and Zafirkulast used in which disease
Asthma
Features of Lipoxins
Derived from AA
Gamma-6 fatty acid
2 types= LXA and LXB
Formed by platelets but platelets cannot synthesize them alone.
Inhibit chemotaxis,transmigration,superoxide generation and NF-kB activation.
Antagonize the receptors of cysteine leukotrienes so that inflammation stop.
Signal macrophages to phagocyte the remains of these cells.
LTA4 will form bc of platelets?
LTA4 converted to LXA4 and LXB4 by 12-Lipoxygenase.
LTA4 will form LTC4,LTD4,LTE4 which are synthesized in platelets.
LXA4 will form?
Cysteinyl-Lipoxins— LXC4,LXD4,LXE4
Lipoxins act on which receptors?
LXA4R and inhibit chemotaxis,transmigrationisuperoxide generation and NF-kB activation
Lipoxins antagonize which receptors?
Cysteinyl Leukotrienes receptors so that inflammation can stop
During the acute inflammatory process, the pro inflammatory cytokines such as IFN-y and IL-1beta can induce the expression of?
Anti-inflammatory mediators such as Lipoxins and IL-4, which promote the resolution phase of ingfalmmation.
How is the production of Histamine
B-imidazoleethylamine = Histamine
Histidine———— Histamine by Histidine Decarbozylase
What inhibits the conversion of Histidine to Histamine
Alpha-fluoromethyl histidine
Tritocaline
Histamine is present in
Mast cells— as a complex with heparin
Neuronal histamine
Enterokromaffine cells (APUD cells)
How is the liberation of Histamine from Mast cells
Mast cells contain IgE as receptors on their surface. As the ag interacts with IgE, histamine liberated.
Can Histamine be absorbed?
Yes but the microorganisms in the GIT metabolism histamine.
Histamine is metabolized by histamine N-methyl transferase or diamond oxidase.
End product is methyl imidazole acetic acid
Histamine receptors
H1—G protein coupled receptor — produces phosphoinositidyl hydrolysis
H2— G protein coupled receptor — inhibition of Adenylate cyclase activity.
H3— inhibits Acetyl Choline release
Agonists do H1,H2,H3
H1: 2-methyl histamine
H2: 4-methyl histamine
H3: alpha-methyl histamine
Betazole used in?
H1 analogue
Meniere’s Disease
Pharmacological effects of histamine
Decrease in blood pressure
Vasodilation (sometimes vasoconstriction)
Increase PGI2 secretion
Increase in capillary permeability
Lewis’ triple response: edema, flare and urticaria
Increases leukocyte infiltration to the tissues during inflammation. Contracts uterus smooth muscle
Increases gastric acid secretion via H2 receptor stimulation.
Role of histamine in endogenous pathological situations
Systemic or local reaction
Allergic reactions due to physical factors
Drug mediated allergic reactions
Histamine mediated headache
Mast cell or basophil tumors
Peptic ulcer
Prutitus,flare,pain sensation
Tissue proliferation and repair
H1 involved in awakefulness
Serotonin formed from
Tryptophan— tryptophan hydroxylase— 5-hydroxytryptophan— l-aromatic acid decarboxylase— serotonin
Serotonin present in
Enteric NS
Thrombocytes
Enterokromaffin cells (APUD cells)
Serotonin receptor subtypes
5-HT1a— regulation of sleep
5-HT1b
5-HTm
5-HT2a
5-HT2b
5-HT2c
5-HT3—should not used in pregnant women
5-HT4
5-HT6
5-HT7
Pharmacological effects of serotonine
Produces severe vasoconstriction
Migraine
Renal vessels are sensitive to serotonin
Decrease cardiac rate suddenly
Stimulates respiration but the bronchi are not sensitive to serotonine
Increases peristaltic movements in small intestine
Mediates pain sensation
Initiates emesis
Dumping syndrome
Kinins produced from
Prekallikrein— activated haegeman— kaliikrein
Kallikrein converts Kininogens to Kinins
Pharmacological effects of Kinins
Dilation of arterioles
Constriction of venules
Contracts intestinal muscles
Stimulate pain receptor in the tissues
B1 and B2 receptors.
Tachykinins and bradykinins
Which drug inhibits kallikrein
Aprotinin
Endothelia secreted from where and how?
Vascular endothelium
Synthesized as pre-pro-endothelin
Endothelia-1— Endothelin-2— Endothelin-3
Receptors of Endothelin
ETa
ETb
Antagonist of endothelin receptor
Bosentan— pulmonary hypertension
Pharmacological effects of endothelins
Vasoconstriction
Renal vascular bed is very sensitive endothelins
Bronchoconstriction occurs
Mito genie activity occurs
In hypertension,myocardial infraction, pulmonary hypertension, chronic renal failure— ET-1 increases
ET-1 RECEPTOR ANTAGONISTS DO NOT DECREASE THE VASCULAR TONUS
Features of Urotensin-2
Strongest vasoconstrictor
Effect on BV
May help to depression
NO synthesized from?
L-arginine by nitric oxide synthase
Forms of Nitric Oxide Synthase
NNOS
ENOS
Both constitutive
INOS is Inducible NOS
NOS inhibitor
L-NAME
How does NO causes vasodilation in vascular smooth muscles?
NO binds to Guanylate Cyclase and cGMP is formed
CGMP deactivates MLCK
MLCK cannot phosphorylated MLC
Myosin and actin cannot combine to form the contracted muscle filaments
Clinical implications of NO system
Hypertension
Atherosclerosis
Immune system
Excitotoxicity, ischemia
Neurotransmitter release
Impotence
Features of Neurotensin
Acts as a neuromodilator of neurotransmitter
Vasodilation
Increased vascular permeability
Anterior pituitary hormones
Hyperglycemia
Inhibition of gastric acid
3 types of receptors
Therapeutic potential in Parkinson’s and schizophrenia
