AUTACOIDSMr.ManikantaTMC

Autacoids- Local hormones

Means self remedies

Localized in tissue

Don't normally circulate

Has physio- pathological activities

Differ from hormones & N.T

Short duration of action

Involved in response to injury

Site of action is restricted to the

synthesis area.

Sever as neuromodulators/ transmitters.

TYPES OF Autacoids

• Amines

-Histamine,

-Serotonin (5-HT)

• Lipid derived

- PG’s, TXA2, LT’s & PAF.

• Peptides

-Angiotensin &Bradykinin

- Cytokine, Gastrin, somatostatin & VIP etc.,

Lipid derived Autacoids

Prostaglandins, Thromboxanes,

Leukotrienes, Platelet Activating

Factor

History

Prostaglandins were 1st discovered in human semen

by Ulf Von Euler.

Bergstrom, Samuelsson & Vane- Noble prize.

Prostaglandins derived from Prostanoic acid.

Leukotrienes - obtained from leukocytes.

P.G’s, LTs ,TXA2 & PAF - Eicosanoids.

Eicosanoids are derived from Arachidonic acid.

P.G’s & TXA2- Prostanoids.

Arachidonic acid

Membrane Phospholipids

Phospholipase A2

PG’S

TXA2

LT’S

COX

LOX

Cyt.P450

Epoxygenase pathway

Isoprostane pathway

Isoprotanes

19 & 20 HPETE’s

Cardiac

Cytosolic

Secretory

Physical, Chemical

Neurological or Hormonal,

Bradykinin

Synthesis:-

Synthesis of eicosanoids depend upon the release of arachidonic acid

from membrane lipids in response to stimuli.

Ca2+

Membrane Phospholipid

Arachidonic acid

5-HPETE

Leukotrienes

PGD2

PGE2

PGF2α

PGI2

TXA2 ---B2

Phospholipase A2Stimulus

Ring structure compounds

Open structure compounds

5,8,11,14-eicostetraenoic acid

Non selective &

Selective COX2

inhibitors

Non-Selective

COX inhibitor

COX2- Bacteria, Lipopolysaccharides, IL, TNF,

Epidermal / Platelet derived growth factors

Constitutive Inducible

COX-1 COX-2 COX-3

Constitutive

enzymes

(always present in

cells)

Constitutive in brain

endothelium & kidney

Recently isolated

from cerebral cortex

Serves as house

keeping function-

e.g.-

gastro protective,

Inducible-synthesis is

stimulated by endotoxins &

other inflammatory

mediators

Involved in pain

perception & fever

Haemostasis

Reno protective

Participates in inflammation Not involved in

inflammation

Pro-carcinogenic due to

inhibition of cell apoptosis,

stimulation of cell migration

angiogenesis,& invasiveness

Paracetamol targets

COX-3

Membrane

PhospholipidArachidonic acid

cyclooxygenase

PGG2

PGH2

TXA2 PGE2 PGF2αPGI2PGD2

PGI SynthaseTXA Synthase

PGH Synthase

PG Synthase

Vascular

endotheliumPlatelets GIT, LUNGs,

Uterus, B.V’sMast

cells

PLA2

PG’s & TXA2 Metabolism-

PG’s are rapidly inactivated.

Inactivation occurs through specific enzymes & oxidation.

PGI & TXA2 are metabolised by non enzymatically.

Short t ½ life.

Prostanoid receptors

All are G-protein coupled receptors.

IP3/DAG or CAMP transducer mechanism.

PGD2 PGF2α PGI2 TXA2 PGE2

TP EP1-4IPFPDP

PG Receptor Functions

PGD2, DP X P. aggregation, Vasodilatation, Relaxation of GIT

& uterus, regulates Sleep-wake cycle.

PGF2 FP Contractions Uterus & Bronchi.

PGI2 IP X platelet aggregation, Vasodilatation, Renin

release & Natriuresis

TXA2 TP P. aggregation, Vasoconstriction,

Bronchoconstriction.

PGE2

EP1

PEF2

Bronchonstrction, GIT motility, increases colon

cancer.

EP2 Br.dilation, Vasodilatation, GIT relaxation,

Intestinal fluid secretion, Ovulation & Fertilization

EP3 X gastric acid secretion, Cytoprotective action,

contraction of pregnant uterus & GIT muscle, X

lipolysis & ANS neurotransmitter release.

-Maintains patency of ductus arteriosus.EP4

Drugs inhibiting P.G & LT synthesis-

Membrane phospholipids

Arachidonic acid

PGG2/H2 LTA4

PGE2

PGF2α

PGD2

PGI2TXA2

LTB4LTC4

LTD4

LTE4

Act on Cys-LT receptors

Bronchoconstriction

NSAIDS

COX1,2 5-LOX Zileuton

Montelukast

zafirlukast

PLPA2Steroids

Pharmacological actions-

1.CVS:-

PGE2/PGI2

-Vasodilation- B.P, weak +ve inotropic, C.O slightly .

- Capillary permeability

- Maintains patent ducts arteriosus (D.A).

- NSAIDs - during labour & child with D.A ?

PGF2α- Vasoconstrictor.

- Mild effect on H.R/B.P/F.O.C/Capillary permeability.

TXA2- Vasoconstrictor, Smooth muscle mitogen-Testosterone.

PGF2αPGE2/I2

2.Platelets-

PGI2/ PGD2- X Platelet aggregation.

TXA2 - Platelet aggregation (P.A)

-both maintains integrity of vascular endothelium

-Prevents P.A & stick to arteriolar wall.

Platelets- No nuclei(DNA), No COX-1 synthesis.

-limited amount of COX-1 & TXA2 persist.

-L.Dose Aspirin-prevention of coronary thrombosis.

-H.Dose NASID’s -X PGI2 & TXA2.

Vascular endothelium-

-Has nuclei & continuous synthesis of COX-1—PGI2.

PG

I

COXB

loo

d v

essel

COX

PGI2

TXA2

P.Aggregation

Vascular endothelium

Platelet

L.D-ASPIRIN

Aspirin antiplatelet effect persists till the life span of platelet 7 to 10days.

Aspirin- administered O.D/ alternative days.

Nuclei

3.Uterus- (In vivo)

PGE2 & PGF2α -contracts Pregnant/Non-pregnant uterus

In Vitro- PGE2 relax non.preg & contracts preg.uterus.

PGF2α - contracts both.

PG’s At term - soften cervix.

Foetus- involves initiation & progression of labour.

Dysmenorrhoea- PGE2 & PGF2α during menstruation.

-Uterine contractions- ischaemic pain.

Aspirin-effective in Rx dysmenorrhoea & to delay the labour.

P.G’s analogues – Rx uterine inertia.

4.Bronchial muscles

PGE2 & PGI2 – Dilation.

PGF2α , TXA2 & LTs - Contraction.

Asthma-due to imbalance.

Aspirin induced asthma due to shift to LOX pathway.

LTs are powerful Br.constrictors.

6.GIT - Anti-ulcerogenic.

PGE2 & PGI2 - gastric acid & pepsin secretion.

- Mucous production & Blood flow.

Aspirin- Cytoprotective action is lost.

PGE2 & PGF2α - Contracts longitudinal muscle.

- H20 & Electrolyte secretions- Colic & diarrhoea as S/E.

PGI2 - opposes propulsive movements.

P.G’s - imp role in colonic cancer.

Aspirin- risk of colon cancer & PGE2 induced diarrhoea.

6.kidney-

PGE2 & PGI2 – Natriuresis, Renal vasodilation & Cl-ion.

- X ADH action to promote H20 clearance.

- β1+ R- Renin release.

Bartter’s syndrome - Rx Indomethacin.

TXA2 - Renal vasoconstriction (ADH like action)

Furosemide - + COX activity to produce vasodilators PG’s.

Indomethacin - X Furosemide diuretic action.

7.CNS-

PGE1,2 -pyrogenic. PGD2 & TXA2- n’t pyrogenic.

Aspirin blocks P.G actions i.e. antipyretic

PGD2- sleep.

P.G’s X NE release.

P’G’s – headache due to vasodilation.

8.Males-

PGE1,2 - fertile semen , sperm motility, penile erection.

Fertilization by coordinating uterine contractions.

Testosterone promotes P.G synthesis.

Aspirin the P.G content in semen.

9.Pheripheral nerve endings-

PGE2 & PGI2- sensitize the receptors to pain &

inflammatory mediators -amplify algesia.

10. Endocrine-

PGE2 promotes the release of GH/ACTH/FSH/LH &

Prolactin.

11.Bone metabolism-

PGE2- Osteoporosis due + of bone resorption.

12.Eye- PGE2 , PGF2α - IOP by uveoscleral out flow

13.Cancer- PGE2 is a pro-carcinogen-colon cancer.

Uses of Prostaglandin analogues-

1.Abortion-

Dinoprostone - PGE2.

Induction of mid-term abortion

Cervical ripening & induction of labour at full term.

Not used for menstrual regulation/early abortion.

Carboprost - PGF2α

Used for mid-term abortion.

Misoprostol -PGE1

used for abortion-200μg.BD/orally.

along with mifepristone to induce abortion in 1st

few wks of

pregnancy.

2.Facilitation of labour, cervical priming & PPH-

1.Dinoprostone - PGE2.

Orally - to augmenting labour & to check PPH.

Vaginally- softens the cervix before labour induction.

Preferred over oxytocin for labour induction in pre-

eclampsia, eclampsia, cardiac & renal disease.

Intrauterine foetal deaths / along with oxytocin.

2. Carboprost - PGF2α - RX PPH-intra-amniotic inj.

3.Ulcer healing-

Misoprostol -PGE1

Ulcer protective agent-200μg orally QID

Enprostil - PGE2.

Used in NSAID’s induced P.U & Chronic smokers.

4) To prevent platelet aggregation-

Epoprostenol-

PGI2- Haemodialysis & Cardiopulmonary bypass.

PGE2 & PGI2- used to store platelets for transfusion.

5.To treat pulmonary HTN-

Epoprostenol (PGI2)-I.V - pulmonary & coronary resistance.

Treprostinil -longer acting.

6.Patency of Ductus arteriosus-

Epoprostenol (PGI2) or Alprostadil (PGE1)- I.V infusion.

7.P.V.D-

Beraprost (PGI2)-orally ,T.I.D.

8.Glaucoma-

Latanoprost (PGF2α) - Reduces I.O.P.

9.Male impotence- Alprostadil to RX E.D.

-2.5-25mcg intracavernosal inj.

10.To reduce infract size- iloprost- in post-MI. Period.

11.Asthma- areosolised PGE2- Rx A/C attacks.

A patient come to you complaining that when ever he takes

aspirin for headache, he develops sever shortness of breath.

What might be the reason?

A lady with 2 children and history of amenorrhea for 35

days went to a doctor for termination of pregnancy. The

obstetrician advised her Misoprostol 400μg stat

1. Comment on prescription?

2. Which analogue is used for midterm abortion?

3. Name one non-obstetric use of Misoprostol?

MCQ’s

A new born baby was diagnosed as having a congenital

abnormality that result in transportation of great vessels. While

preparing for the surgery, the medical team needed to keep the

ducts arteriosus open. They did this by infusion ?

A ) Corticsol b) Indomethacin

c) Alprostadil d) Tacrolimus

S/E-

Hypotension, Syncope & Flushing

Carboprost-mid term abortion- Anaphylactic shock & CVS

collapse.

Alprostadil- Ductus fragility & rupture.

PGF2-GIT toxicity & Bronchoconstriction.

Misoprostol/Enprostil-Diarrhoea.

Long term use-PGE2-EP4 R mediated increase in osteoclast

& osteoblast activity.

Renal Ca2+ oxalate stone- hypercalciuria.

LEUKOTRIENES

ZileutonArachidonic acid

5HPETE

LTA4

LTC4

LTD4

LTE4

LTB4

5-Lipooxygenase

5-Lipooxygenase

LTB4 Synthase LTC4 Synthase

Glutanyl Transpetidase,

Glutanyl Leucotrienase

Dipeptidase

SRS-A

FLAP

Zafirlukast

Blood-

LTB4 – Neutrophil chemotaxis, lymphocyte proliferation.

LTC4 & LTD4 -Eosinophils chemotaxis , Degranulation &

O2 radical formation.

Heart & B.V-

LTC4 & LTD4 - contractility & coronary blood flow.

Play imp role in myointimal proliferation-angioplasty.

GIT smooth muscles-

LTB4- causes neutrophil chemotaxis - IBD’s.

Bronchial smooth muscle-

LTC4, LTD4 & LTE4

Bronchoconstriction

Increased permeability

Increased mucus secretion.

Inflammation –LTB4

- Imp mediator of all types of inflammations like R.A,

Psoriasis & Ulcerative colitis.

LT receptors- (LT.R)

LTB4- BLT receptors

LTC4/LTD4/LTE4- cyst LT receptors.

LT R are G-protein coupled & function through IP3/DAG

transduction mechanism.

LT inhibitor-

Zileuton LOX inhibitor, X LT induced responses.

LT receptor antagonists-

Zafirlukast, Montelukast & Iralukast.

Antiasthmatic & Anti-inflammatory agent.

Platelet Activating Factor (PAF)

Membrane Acyl-Glycero phosphocholine

Lyso PAF

PAF

PAF-Acetyl transferase

PL A2Fatty acid

Acetyl CoA

Acetyl hydroxylase

Lyso PAF

Acyl-Glycero phosphocholine

Acetate

Fatty acid

Synthesis

Degradation

Pharmacological actions-

Vasodilation, vascular permeability

Chemotactic to neutrophil & eosinophils.

Activation of leucocytes

Promotes platelet aggregation

Involved in inflammation & bronchial hyper-responsiveness

Foetus- involved in progression labour at term

Potent peptic ulcerogen.

M.O.A- G-ptn R - IP3/DAG---Ca2+ pathway.

Some of it actions are mediated through the release of P/G’s,

TXA2 & LT’s.

PAF antagonist-

Ginkgolide -B & structural analogues of PAF.

Alprazolam & Triazolam antagonize PAF actions.

Used in Rx of shock, M.I, P.U, intermittent claudication,

asthma, sepsis & contraceptives.

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