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AUTACOIDS
AUTACOIDS
Autacoids
The word autacoids comes from the Greek "Autos"
(self) and "Acos" (relief, i.e. drug) Biological factors which act like local hormones (sometimes called also Local hormones or Autopharmacological agents) Low molecular weight compounds, have a brief duration, act near the site of synthesis (paracrine manner), and are not blood borne Have varied pharmacological activities
Autacoids
Eicosanoids, Angiotensin, Neurotensin, NO (Nitric Oxide), Kinins, Histamine, Serotonin, Endothelins, etc. In many tissues and cell types, any of the above agents may indirectly or directly be involved in the activities of cytokines and growth factors
Eicosanoids
EICOSANOIDS are autacoids that are produced from arachidonic acid, a 20-carbon polyunsaturated fatty acid (5,8,11,14-eicosatetraenoic acid) eicosa=20 carbon enoic=containing double bonds
Eicosanoids
The eicosanoids are considered "local hormones."
They have specific effects on target cells close to their site of formation.
They are rapidly degraded, so they are not transported to distal sites within the body.
But in addition to participating in intercellular signaling, there is evidence for involvement of eicosanoids in intracellular signal cascades
Eicosanoids
Examples
Eicosanoids
Roles of Eicosanoids
Inflammation Fever Regulation of blood pressure Blood clotting Immune system modulation Control of reproductive processes & tissue growth Regulation of sleep/wake cycle
Prostaglandins
(PGs)
Prostaglandins
Prostaglandins were originally shown to be
synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. Now found in all tissues Involved in a variety of biological processes
Prostaglandins
Prostaglandins are not hormones, but autocrine or
paracrine, which are locally acting messenger molecules They differ from hormones in that they are not produced at a discrete site but in many places throughout the human body Also, their target cells are present in the immediate vicinity of the site of their excretion
PGs - Biosynthesis
Prostaglandins (PGs) are products of polyunsaturated acid
metabolism, particularly arachidonic acid (AA) released from membrane phospholipids by the action of phospholipase A2 in response to a variety of physical, chemical, and neurohormonal factors AA is rapidly metabolized to oxygenated products by two distinct enzymatic pathways: cyclooxygenase and lipoxygenase The intermediate cyclooxygenase products are converted to primary PGs, while the lipoxygenase products are converted to leukotrienes.
Mechanism of action
Cosrticosteroids Membrane phospholipids Phospholipase Arachidonic acid Lipoxygenase COX NSAIDS
Leukotienes
Prostaglandins
Thromboxane
Prostacyclin
Prostanoids
Hydroperxides
PGG2
Endoperoxides
PGH2
Leukotrienes
PGE2
PGF2
PGD2
TXA2
Prostacycline
Prostaglandins - structure
All PGs have the basic structure
prostanoic acid, which consists of a cyclopentone ring with 2 aliphatic side chains Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring.
Prostaglandins structure
Prostaglandin receptors
Prostaglandins & related compounds are transported out of the cells that synthesize them Currently ten known PG receptors on various cell types
Prostaglandin receptors
Most affect other cells by interacting with plasma membrane G-protein coupled receptors
Depending on the cell type, the activated G-protein may stimulate or inhibit formation of cAMP, or may activate a phosphatidylinositol signal pathway leading to intracellular Ca++ release
Another prostaglandin receptor, designated PPARg, is related to a family of nuclear receptors with transcription factor activity
Prostaglandin receptors
Prostaglandin receptors are specified by the same letter
code. E.g., receptors for E-class prostaglandins are EP. Thromboxane receptors are designated TP. Multiple receptors for a prostaglandin are specified by subscripts (E.g., EP1, EP2, EP3, etc.). Different receptors for a particular prostaglandin may activate different signal cascades Effects of a particular prostaglandin may vary in different tissues, depending on which receptors are expressed. E.g., in different cells PGE2 may activate either stimulatory or inhibitory or G-proteins, leading to either increase or decrease in cAMP formation.
A. Smooth Muscle 3. Airways Relaxed by: PGI2, PGE2 contracted by: PGD2 , TXA2 & PGF2 4. Reproductive system
B. Platelets
aggregation enhanced by low conc of PGE2 & TXA2 aggregation inhibited by PGD2, PGI2 & high conc of
PGE2
Role Of Aspirin
C. Kidney PGE2 & PGI2 maintain renal BF and GFR through local vasodilating effects, also modulate BP through regulation of Na & water excretion PGE2 promote renin release enhanced GFR and Na absorption rise in BP TXA2 causes intrarenal vasoconstriction decline in renal functions
D. Reproductive organs
1. Female Reproductive Organs: PGE2 & PGF2 role in early reproductive processes such as ovulation, luteolysis & fertilization PGF2 TXA2 & low conc of PGE2 cause contraction of uterine smooth muscle PGI2 and high conc of PGE2 cause relaxation of uterine smooth muscle
D. Reproductive organs
2. Male Reproductive Organs: PGE1 cause relaxation of smooth muscle of corpora cavernosa penile erection
G. Bone metabolism
PGE2 increase bone turnover, i.e. stimulation of bone resorption and formation
H. Eye
PGE and PGF lower IOP (increases outflow of aq. humor)
I. Cancer
PGE2 - pro-oncogenic prostanoid (facilitates tumor initiation, progression & metastasis) TXA2 - procarcinogenic mediator
uterine smooth muscle PGF2 uterine contractions TXA2 platelet aggregation, bronchoconstriction PGE2 increased gastric mucous secretion, constriction of bronchial and uterine smooth muscle, stimulates hypothalamus to cause fever PGE2, D2, F2 vasodilatation and synergize with histamine and bradykinin.
Clinical uses
To induce childbirth (parturition) or abortion (PGE2 or
PGF2, with or without mifepristone, a progesterone antagonist) To prevent closure of patent ductus arteriosus in newborns with particular cyanotic heart defects (PGE1) To prevent and treat peptic ulcers (PGE) As a vasodilator in severe Raynaud's phenomenon or ischemia of a limb
Clinical uses
In pulmonary hypertension In treatment of glaucoma (as in bimatoprost ophthalmic
solution, a synthetic prostamide analog with ocular hypotensive activity) To treat erectile dysfunction or in penile rehabilitation following surgery (PGE1 as alprostadil). Synthetic prostaglandins are used:
Adverse Effects of Prostaglandins Common but varies with PG N, V, D Uterine cramps, unduely forceful uterine contractions Vaginal bleeding Flushing Shivering, fever, malaise Fall in BP, tachycardia & chest pain
Platelet-Activating Factor
Chemistry and Biosynthesis
PAF is 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine. PAF contains a long-chain alkyl group joined to the
glycerol backbone in an ether linkage at position 1 and an acetyl group at position 2. PAF actually represents a family of phospholipids because the alkyl group at position 1 can vary in length from 12-18 carbon atoms. In human neutrophils, PAF consists predominantly of a mixture of the 16- and 18-carbon ethers, but its composition may change when cells are stimulated.
The PAF receptor couples to activation of the PLC-IP3Ca2+ pathway and to inhibition of adenylyl cyclase, via Gq and Gi respectively. Activation of phospholipases A2, C, and D give rise to second messengers. These include AA-derived PGs, TxA2, or
LTs, which may function as extracellular mediators of the effects of PAF.
SYNTHESIS OF PAF
by endothelial cells, leukocytes, and mast cells under inflammatory conditions, are well characterized. The plasma concentration of PAF is increased in experimental anaphylactic shock, and the administration of PAF reproduces many of its signs and symptoms, suggesting a role for the autacoid in anaphylactic shock.
Cardiovascular System PAF is a potent vasodilator in most vascular beds; when administered intravenously, it causes hypotension in all species studied. PAF may, alternatively, induce vasoconstriction depending on the concentration, vascular bed, and involvement of platelets or leukocytes.
Platelets
The PAF receptor is constitutively expressed on the surface of
platelets. PAF potently stimulates platelet aggregation in vitro and in vivo. Although this is accompanied by the release of TxA2 and the granular contents of the platelet, PAF does not require the presence of TxA2 or other aggregating agents to produce this effect. The intravenous injection of PAF causes formation of intravascular platelet aggregates and thrombocytopenia.
Smooth Muscle
smooth muscle. Stomach In addition to contracting the fundus of the stomach, PAF is the most potent known ulcerogen. Kidney When infused intrarenally in animals, PAF decreases renal blood flow, glomerular filtration rate, urine volume, and excretion of Na+ without changes in systemic hemodynamics .These effects are the result of a direct action on the renal circulation. PAF exerts a receptormediated biphasic effect on afferent arterioles, dilating them at low concentrations and constricting them at higher concentrations. The vasoconstrictor effect appears to be mediated, at least in part, by COX products, whereas vasodilation is a consequence of the stimulation of NO production by endothelium.
REFERENCES
1. www.wikipedia.org
2. www.googlescholar.com 3. Goodman & Gilmans- The Pharmacological
basis of therapeutics 4. K.D. Tripathi Essentials of pharmacology 5. http://jem.rupress.org/content/168/4/1293.full.p df 6. Sharma & sharma- pharmacology