SEMINAR REPORT ON:

Autacoids (Local Hormones)

BY BUTOOL FATIMA 11411S0103 M.PHARMACY( PHARMACOLOGY)

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

Some notable 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

Prostaglandins Prostacyclins Thromboxanes Leukotrienes Epoxyeicosatrienoic acids

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)

PGs and related compounds -collectively known as eicosanoids

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

Scheme for prostaglandin Biosynthesis

Stimulus Disturbance of cell membrane

Corticosteroids inhibit Lipoxygenase

Phospholipids Phospholipase A2 Arachidonic Acid X Cyclooxygenase Aspirin & NSAIDs inhibit

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.

Effects of Prostaglandins & Thromboxanes (TX)

A. Smooth Muscle
1. Vascular vasoconstrictors: TXA2 (potent), PGF2, iPF2III vasodilators: PGI2 PGE2 ( cAMP and Ca)
2. GIT ( most PGs and TXs activate) PGE2 ( via EP3) , PGF2 & PGI2 contract PGE2 ( via EP4) relax

Effects of Prostaglandins & Thromboxanes (TX).

A. Smooth Muscle 3. Airways Relaxed by: PGI2, PGE2 contracted by: PGD2 , TXA2 & PGF2 4. Reproductive system

Effects of Prostaglandins & Thromboxanes (TX).

B. Platelets
aggregation enhanced by low conc of PGE2 & TXA2 aggregation inhibited by PGD2, PGI2 & high conc of

PGE2

Role Of Aspirin

Effects of Prostaglandins & Thromboxanes (TX).

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

Effects of Prostaglandins & Thromboxanes (TX).

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

Effects of Prostaglandins & Thromboxanes (TX).

D. Reproductive organs
2. Male Reproductive Organs: PGE1 cause relaxation of smooth muscle of corpora cavernosa penile erection

Effects of Prostaglandins & Thromboxanes (TX).

E. Central & Peripheral Nervous System

1. Fever: PGE2 increases body temperature Exogenous PGF2 and PGI2 induce fever 2. Sleep: PGD2 induces natural sleep (infused into cerebral ventricles) PGE2 causes wakefulness (infused into posterior hypothalamus)

Effects of Prostaglandins & Thromboxanes (TX).

E. Central & Peripheral Nervous System

3. Neurotransmission: PGE componds inhibit the release of NE PGE2, PGD2 , PGI2 and PGF2 sensitize the peripheral nerve endings to painful stimuli

Effects of Prostaglandins & Thromboxanes (TX).

F. Inflammation & Immunity

PGE2 and PGI2 markedly enhance edema formation & leucocyte infiltration -- predominant effect on inflammation PGD2 -- a potent chemoattractant for eosinophils induces degranulation and LT biosynthesis

Effects of Prostaglandins & Thromboxanes (TX).

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)

Effects of Prostaglandins & Thromboxanes (TX).

I. Cancer
PGE2 - pro-oncogenic prostanoid (facilitates tumor initiation, progression & metastasis) TXA2 - procarcinogenic mediator

Actions of Prostaglandins (PGs)

Act as local signals PGD2 vasodilatation, relaxation of gut and

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.

Mechanism of Action of PAF

Extracellular PAF exerts its actions by stimulating a specific GPCR (Honda et al., 2002). The PAF receptor's strict recognition requirements, including a specific head group and specific atypical sn-2 residue, also are met by oxPLs.

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

Physiological and Pathological Functions of PAF

Reproduction and Parturition
A role for PAF in ovulation, implantation, and parturition

has been suggested by numerous studies.

Inflammatory and Allergic Responses The pro-inflammatory actions of PAF, and its elaboration

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

PAF generally contracts GI, uterine, and pulmonary

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