PG Classroom - Seminar - Prostaglandins(PG)

HISTORY

 The name Prostaglandins (PG) is derived from the prostate gland from where when PG was 1st isolated from seminal fluid in 1936.

The biochemists       -    Sune K. Bergstrom

-         Bengt I. Samuelsson

-         John R. Vane

Jointly received the 1982 Nobel Prize in physiology or medicine for their research in PGs in Sweden.

They were honoured for their isolation, identifications and analysis of numerous PGs, a family of natural compounds that can influence blood pressure, body temperature, allergic reaction and other physiological phenomena. 

Bergstrom:

He has purified several PGs & determine their chemical structure.

He showed that PG is formed from unsaturated fatty acid. 

Bengt Samuelsson :

He has given a detailed picture of arachidonic acid & PG metabolism. And also clarified the chemical process involved in formation & breakdown of the various compounds in the system.

He also presented understanding of biological significance of this system by discovering endoperoxides, thromboxanes & leucotrines.  

John Vane :

Discovered prostacyclin & carried out detailed analyses of its biological effects & function.

Anti inflammatory compounds such as aspirin act by blocking the formation of PGs & thromboxanes.
 

BIOCHEMISTRY

 Prostaglandins are C-20 carboxylic acids containing cyclopentane ring and are derivatives of prostanic acid.

In 1970 14 natural prostaglandins were known, with the help of efficient and sensitive analytical techniques, hundreds of these compounds have been described.

The nomenclature of PGs is based on :

-         The letter component (PGA, PGB, PGC) which identities the functional groups of the cyclopentane ring.

-         PG Es contain a keto oxygen at C-9 and a hydroxyl group at C-17, where as PG Fs have hydroxyl group at both positions in the cyclopentane ring.

-         Numerical subscript (PGE1, PGE2) denotes number of double bond in carbon chain this number depends on the precursor Fatty acid.

 

 

Prostaglandins E and F series are synthesized from arachidonic acid [C20 Fatty acid]. Free archidonic acid is required for PG synthesis. Liberation of arachidonate from phospholipids by phospholipases is the rate limiting step in cascade of synthesis.


 

 

 

 

This endoperoxide synthetase catalyzes the sequential formation of PGG2 & PGH2 (endoperoxides) by addition of molecular oxygen at the C9, C11 & C15 position.

 

 

PGH2 is enzymatically (endoperoxide isomerase, endoperoxide reductase) & nonenzymatically converted in several molecules, which are biologically active & also are precursors of other active molecule.

These PGs are PGD2 which is principal cyclo oxygenase product of mast cells & nervous system, PGE2 produced nearly in all cells, PGF2, PGI2, TXA, 12 HHT (12- hydroxyheptadeca -5,8,10 – trienoic acid).


 

 

 

 

Prostaglandin of A & B series produced from PG E series & TXB2 (stable but biologically inactive) formed from TXA2.

Ø           Dietary Sources of Prostaglandins
 

·         Rich Sources

Sunflower Seed

Sesame

Cotton Seed oil

 

·         Good Sources

Mustard

Ground Nut Oil

Egg Yolk

 

·         Poor Source

Butter

Coconut Oil

 

  

PHARMACOLOGY OF PROSTAGLANDINS

 

-         Chemically, prostaglandins may be considered to be derivatives of prostanoic acid (a cyclopentane / pentene ring with two side chains).

-         PGs are broadly classified as PGA – PGH based on their cyclopentane / pentene ring substitution patterns.

-         Each general PG class has members with subscript 1, 2, and 3 indicating the number of double bonds in the side chain.

-         Leukotrienes are so named because they were first obtained from leucocytes and have 3 conjugated double bonds (Triene). They have also been similarly designated A, B, C……F and given subscripts 1, 2, 3, 4.

-         In the body prostaglandins, thromboxanes and leukotrienes are all derived from eicosa (referring to 20 carbon atoms) tri/tetra/pentaenoic acids. Therefore they can be collectively called eicosanoids.

-         The key precursor in eicosanoid biosynthetic pathways is arachidonic acid. Cells store arachidonic acid as a component of membrane phospholipids such as phosphoinositol. In response to appropriate stimulus, arachidonic acid is liberated from the storage lipid by an enzymatic reaction catalyzed by phospholipase A2. The conversion of free arachidonic acid to prostaglandins and other eicosanoids is initiated by oxidative enzymes of the cyclooxygenase and lipooxygenase families.


 

 

 

INHIBITION OF SYNTHESIS

-         Glucocorticoids inhibit the release of arachidonic acid from membrane lipids by stimulating production of proteins called lipocortins which inhibit phospholipase A2.

-         Moreover they inhibit the induction of COX-2 by cytokines at the site of inflammation.

-         Cyclooxygenase enzyme exists in two isoforms COX-1 and COX-2, cox-1 is constitutive while cox-2 can be detected is significant amounts only during an inflammatory response.

-         Synthesis of cyclooxygenase products can be inhibited by NSAIDs.

-         Aspirin causes irreversible inhibition while other NSAIDs are competitive and reversible inhibitors.

-         Most NSAIDs are nonselective cox-I and cox-2 inhibitors but some newer ones like celecoxib, rofecoxib are selective for COX-2.

-         NSAIDs do not inhibit the production of leucotrienes; this may even be increased since all the arachidonic acid becomes available to the lipooxygenase pathway.

 

DEGRADATION

-         Degradation of arachidonates occurs rapidly in most tissues but fastest in the lungs.

-         Most PGs, TXA2 and prostacyclin have plasma t½ of few seconds to few minutes.

-         Metabolites are excreted in urine.

-         PGI2 is catabolized mainly in the kidney.

PHYSIOLOGIC ACTIONS OF ELCOSANOIDS

-         The PGs are important mediators of normal physiologic events and have been implicated in a variety of pathologies.

-         They have been implicated in inflammation, pain, pyrexia, cardiovascular disease, renal disease, cancer, glaucoma allergic rhinitis, asthma, preterm labour, male sexual dysfunction and osteoporosis.

-         Prostaglandin effects are usually manifested locally around the site of prostaglandin synthesis (paracrine) and their actions are multiple and variable (stimulatory or inhibitory) depending upon the tissue type and the nature of the receptors with which they interact.

1)    Cardiovascular System

PGI2                     - Vasodilatory action

                              - Hypotension

TXA2                    - Vasoconstriction

Leucotrienes       - ­ capillary permeability

LTB4                    - Chemotactic for neutrophils and macrocytes

Role: PGE2 and PGI2 are continuously produced locally in the ductus arterious during fetal life – to keep it patent. At birth their synthesis is inhibited and closure occurs. Aspirin and Indomethacin has been found to induce closure when it fails to occur spontaneously.

Leukotrienes – are important mediators of inflammation LTC4 & D4 – exudation of plasma.

LTB4 – attracts inflammatory cells which reinforce the reaction.

 

2)    Platelets

TXA2 – (+) Platelet aggregation

PGI2 – (-) platelet aggregation

 

Role: TXA2 and PGI2 constitute a mutually antagonistic system; preventing aggregation of platelets while in circulation and inducing aggregation on injury when plugging and thrombosis are needed.

In low doses, aspirin selectively inhibits TXA2 production and has antithrombotic effect lasting >3 days.

 

3)    Bronchial Muscle

PGF2a, PGD2 AND TXA2 – bronchoconstrictors

PGE2 – bronchodilator

LTC4 and D4 – most important mediators of human allergic asthma

4)    Uterus

PGE2 and PGF2a contract human uterus.

Sensitivity ­ during pregnancy and there is a further modest ­ with the progress of pregnancy.

PG’s increase tone as well as amplitude of uterine contractions at term. PGs at low doses soften the cervix and make it more compliant.

Role: (1) Fetal tissues produce PGs at term and it has been postulated that PGs mediate initiation and progression of labour Aspirin has been found to delay the initiation of labour and also prolongs its duration.

Dysmenorrhoea in many women is associated with increased PG synthesis by the endometrium.

­ PG’s

¯

incoordinated uterine contractions

¯

compression of blood vessels

¯

uterine ischemia

¯

pain

 

Aspirin group of drugs are highly effective in relieving dysmenorrhoea in most women.

5)    GIT

-         ­ propulsive activity by PGE2 à colic and watery diarrhea

-         PGs appear to play a role in the growth of colonic polyps and cancer

\ Regular intake of aspirin à ¯ incidence of colon cancer

-         PGE2 à reduces acid secretion in the stomach. Secretion of mucus in stomach and mucosal blood flow are increased – antiulcerogenic.

-         Ulcerogenic action of NSAIDs may be due to loss of this protective influence.

-         PGs are involved in mediating toxin induced increased fluid movement in secretory diarrheas.

 

USE OF PROSTAGLANDINS IN OBSTETRICS

  

2ND TRIMESTER MTP WITH MEDICAL METHODS

 

Introduction

Termination of pregnancy beyond 12 weeks of gestation to 20 weeks

Indication:   - IUFD

                           -  Missed abortion evacuation

                           -  Hydatidiform mole evacuation

                           - Congenital anomaly

MEDICAL ABORTION TEACHNIQUE

 

Agent used :          Misoprostol

Intramuscular Prostaglandin E2 PGF2 a (Carboprost)

 

Misoprostol:            Methyl – 11x, 16 dihydroxy -16 methyl 9.0 x O Prost

13 E-on-loate

§         Prostaglandin E1 analogues binds with myometrial cells cause strong myometrial contraction.

§         Cause cervical ripening and softening and dilatation of cervix.


 

Ø           Molecular formula

C22H38O5

 

 

Ø           Characteristics :

·               It limits extent of gastrointestinal damage induced by ulcerogenic agents.

·               It has uterotonic and cervical ripening actions.

·               After oral administration, misoprostol is rapidly absorbed and converted to its pharmacologically active metabolite misoprostol acid.

·               After oral administration of misoprostol, plasma level of misoprostol acid reaches to peak in 30 minutes and declines rapidly thereafter.

·               When misoprostol tablets are placed in the posterior fornix of the vagina, plasma concentration of misoprostol acid reaches to peak in one or two hours and then decline slowly.

·               The bio-availability of misoprostol is decreased by concomitant ingestion of food or antacids.

 

·               Half life of misoprostol is 20-40 minutes.

·               Duration of action, 3-6 hours.

·               Metabolism.

Misoprostol is primarily metabolized in the liver and less than

1% of its active metabolite is excreted in urine.

·               Uterine contractility is initially increased and then plateaued one hour after oral administration where as uterine contractility is increased continuously for four hours after vaginal administration.

 

Thus, the effects of misoprostol on the reproductive tract are increased and gastrointestinal adverse effects are decreased, if the oral preparation of misoprostol is administered vaginally.

 

Ø           Supply

It is available as Misoprost and cytotec tab, with the strength of 100/200 microgram misoprostol.

Regime @ mifepristone rooms F16 misoprostol

 

 

Route             :    Orally, vaginally 

Mechanism

of action   :  Uterine muscle contractility ­es and has uterotonic & cervical ripening action.

Doses             :   200 mcg kept in posterior fornix every 6 hourly.

Regime          :  - Misoprostol 400 mcg 6 hourly.

   -  Mifepristone 200 mcg follow by misoprostol 400   

       mcg per vaginally

Indications:

1)               Treatment of gastric, duodenal ulcer, NSAID induced ulcers.

2)               Prophylactic for NSAID induced ulcers.

3)               For induction and augmentation of abortion.

4)               For induction and augmentation of labour.

5)               For prevention & treatment of post-partum hemorrhage.

6)               For induction & augmentation of 1st and 2nd trimester termination of pregnancy.

 

Contraindications:

1)          Previous cesarean section

2)          Past hysterotomy or surgery

3)          Classical upper segment cesarean section.

 

CARBO PROST PGF2a

Intramuscularly given (200-300 ug) 2 to 4 hourly.

Mechanism of action:

 

1)          Stimulate uterus ­es uterine contractility ­es smooth muscle contraction.

2)          ­es tubal motility

3)          ­es systemic arterial and venous pressure ¯es regional arterial flow.

Route of Administration          - intra muscular

                                                            - vaginal administration

Contraindication

-              Hypersensitivity to any of component

-              Acute PID

-              Cardiac diseases

-              Pulmonary diseases

-              Renal disease

-              Liver diseases

-              Glaucoma

 

DOSES: Carboprost 200-300 ug 2 to 4 hourly.

DISADVANTAGE OF PROSTAGLANDINS

-              Costlier drug

-              Fetus may be aborted alive

-              Abortion quicker hemorrhage and cervical laceration may occur.

 

ADVANTAGE OF MEDICAL METHOD

-              Usually avoid invasive procedure

-              High 54 case rate (95%)

-              Avoids anesthesia

-              Available during early pregnancy

-              Can be done where surgical methods are contraindicated.

 

Disadvantage

-              Require follow up to ensure complete procedure

-              Patient participation through a multiple step process

-              Require two or more visits


 

MEDICAL ABORTION

 

PROCEDURE:

Early pregnancy termination usually b/w 42 to 63 days performed without primary surgical intervention and resulting from the use of abortion inducing medications.

 

Mechanism of action

 

=>        Mifepristone (RU 486) used orally,

Mechanism of action: Mifepristone has affinity for progesterone receptor 5 times higher than progesterone thus causes choriodecidual separation by initiating breakdown of endometrium & detachment of embryo (leads to decline of  b-HCG & atrophy of corpus luteum and also decline S. progesterone level à initiate myometrial contraction.

¯

Expulsion of embryo.

 

Mifepristone alone is not effective should be followed by prostaglandin analogue.

Mifepristone also ­es uterine sensitivity to PGs thus ­es its release.

=>        Misoprostol PGE1 => Synthetic analogue of naturally occurring PGs.

            Adv. Safe, well tolerated, can be kept at room temperature etc.

Can be used Orally à GI side effects more

                                                Vaginally à GI side effects less

¯

slower ­es & low peak plasma concentration then oral

 

But uterine contractility ­es and then plateau one hour after oral administration, whereas contractility continues for four hour after vaginal route.

 

PROTOCOL FOR MEDICAL ABORTION

1)          History

2)          Exclude contraindication

3)          Clinical Examination to exclude cervicovaginal pathology.

4)          Accurate dating including TVS

5)          Hb & BG estimation

6)          Back up surgical facility should be available.

 

Currently available drugs for medical abortion:

1)          Mifepristone (RU 486) => Antiprogestin

2)          Methotrexate => Antimetabolite

3)          Tamoxifen : All above drugs to be followed by intravaginal misoprostol

4)          Misoprostol alone (Most commonly used prostaglandin analogue)

 

REGIMENS:

1)          Commonly used: Mifepristone orally 200-600 mcg on day 1.

¯Followed by

400 to 800 ug misoprostol intravaginally on 3rd day.

¯

Observation for 1 to 3 hr.

 

Follow up after 2 wks by P/v examination and TVS SOS and again after 6 wks or after 1st post abortal period. Effectiveness 94%

In oral misoprostol.  Effectiveness 87%

 

2)          Methotrexate => 50 mcg/m2 IM on day 1

¯ Followed by

400-800 ug misoprostol intravaginally.  Effectiveness 89 to 98%

3)          Tamoxifen : 20 mg 1 OD x 4 days

Followed by     

400-800 ug misoprostol intravaginally

4)          Misoprostol alone:       400 ug intravaginally every 6 hourly. OR

200 ug intravaginally every 4 hourly. Effectiveness 30%

 

Contraindications

-              Allergy

-              Asthma

-              Anticoagulant therapy

-              Hemorrhagic disorder

-              Smoker, > 35 yrs.

Advantages over surgical procedure:

1)          ¯es risk of cervical & intrauterine injury

2)          Infection chances less

3)          More natural do not require operating room.

Disadvantages:

1)          Takes longer times to abort

2)          Longer duration of bleeding

3)          Cost

4)          Compliance of patient

5)          Repeated follow up

6)          Teratogenic effects on fetus in c/o failure of medical abortion e.g. Mobius syndrome - congenital facial paralysis with or without limb defect, cranial nerve defect.

Other Regimes

If amenorrhea 7 – 14 days on day 1st mifepristone 200 mcg orally

                        ¯ followed by 48 hr later

                        5 mg PGE2 vaginal gel (metenoprost)

                        Effectiveness 94.5%

If amenorrhorea < 6 wks Tab mifepristone 600 mcg

                        ¯ followed by after 48 hrs

                        Intravaginally 100 ug of misoprostol

                        Effectiveness 97.37%

 

-              Majority of cases bleeding occurs with in 4 hr. & bleeding continues for median 10 days.

-              Total blood loss similar to / related to gestational age.

-              Heavy bleeding can occur in less than 1% cases.

 

 

PROSTAGLANDINS FOR CERVICAL RIPENING & INDUCTION

 

INTRODUCTION

In pregnancy, the uterine cervix serves 2 major functions. First, it maintains its firmness during pregnancy as the uterus dramatically enlarges. This physical integrity is critical so that the developing fetus can remain in the uterus until the appropriate time for delivery. Second in preparation for labour and delivery, the cervix softens and becomes more distensible, a process called cervical ripening.

 

 

 

CERVICAL CHARACTERISTICS

-         The human cervix consists mainly of extracellular connective tissue. The predominant molecules of this extracellular matrix are type I and type 3 collagen, with a small amount of type 4 collagen at the basement membrane.

-         Intercalated among the collagen molecules are glycosaminoglycans and proteoglycans, predominantly dermatan sulfate, hyaluronic acid and heparin sulfate. Fibronectin and elastin also run among the collagen fibers. The highest ratio of elastin to collagen is at the internal os. Both elastin and smooth muscles decrease from the internal to the external os of the cervix.

-         Cervical ripening usually begins prior to the onset of labour contractions and is necessary for cervical dilatation and passage of the fetus.

-         Cervical ripening is the result of a series of complex biochemical processes that ends with rearrangement and realignment of the collagen molecules, degradation of collagen cross-linking due to proteolytic enzymes and dilatation resulting from these processes plus uterine contractions.

-         In late pregnancy, hyaluronic acid content increases in the cervix. This leads to an increase in water molecules that intercalate among the collagen fibers. The amount of dermatan sulfate decreases which leads to reduced bridging among the collagen fibers and thus a decrease in cervical firmness. ­ activity of metalloproteinases 2 & 9 degrade extra-cellular matrix protein with leads to ¯ collagen content in the Cervix.

-         Cervical ripening is associated with decreased collagen fiber alignment, decreased collagen fiber strength and diminished tensile strength of the extra-cellular cervical matrix.

-         All of these changes cause cervical softening. With uterine, contractions, the ripened cervix dilates and is pulled over the presenting fetal part. Elastin component of cervix behaves in a ratchet like manner so that dilatation is maintained following the contraction.

 

 

ROLE OF VARIOUS HORMONES IN THE PROCESS OF CERVICAL RIPENING

-         A complex series of interactions occurs whereby various hormones stimulate the chemical reactions critical for cervical ripening.

-         Associated with cervical ripening is an increase in enzyme cyclooxygenase – 2 which leads to a local ­ of PGE2 in the cervix. The increase in local PGE2 leads to the following changes associated with cervical ripening

o       Dilatation of small vessels in the cervix

o       Increase in collagen degradation

o       Increase in hyaluronic acid

o       Increase in chemotaxis for leucocytes, which causes increased collagen degradation.

o       Increase in stimulation of IL-8 release.

 

-         PGF2a is also involved in the process via its ability to stimulate an increase in glycosaminoglycans.

-         The role of inflammatory agents in cervical ripening has also been studied IL-I, TNF & IL-8 can lead to neutrophil chemotaxis which is associated with collagenase activity and cervical ripening. These inflammatory agents may be particularly important as mediators of cervical ripening associated with preterm labour.

-         Nitric acid appears to play a role in this process by leading to an increase in metalloproteinase activity, cellular apoptosis in the cervix and glycosaminoglycan synthesis in the cervix. All of these changes are associated with the cervical ripening process. Nitric oxide could also play a role in premature cervical ripening associated with preterm labour, particularly in preterm labour triggered by infection.

 

 

 

EVALUATION OF CERVICAL RIPENING

1)    BISHOP SCORE :
 

a) Dilatation                     0 cm                                     - 0 points

                                          1-2 cm                                 - 1 point

                                          3-4 cm                                 - 2 points

                                          5-6 cm                                 - 3 points

b) Effacement                  0-30 %                                 - 0 points

                                          40-50%                               - 1 point

                                          60-70%                               - 2 points

                                          80 %                                    - 3 points

c) Station                         -3 station                             - 0 points

                                          -2 station                             - 1 points

1 & 0 station                          - 2 points

+1 to +2 station                     - 3 points

d) Consistency

Firm                                  - 0 points

Medium                            - 1 point

Soft                                   - 2 points

Posterior position           - 0 points

Mid position                     - 1 point

Anterior position             - 2 points
 

 

2)    ULTRASOUND ASSESSMENT

-       Helps to determine the length of cervix

-       Helps to determine the presence or absence of cervical funneling.

-       Prior to 20 weeks of pregnancy, a cervical length of less than 21 mm is highly predictive of preterm labour and delivery.

 

3)    DETECTION OF FETAL FIBRONECTIN IN CERVICOVAGINAL

-       Fetal fibronectin is a glycoprotein found in amniotic fluid and at the chorionic decidual interface. The presence of this protein in cervicovaginal secretions predicts preterm labour while its absence predicts prolongation of pregnancy.

-       Fetal fibronectin is also predictive of response to prostaglandin application to the cervix at term in order to induce cervical ripening and labour.


 

PROSTAGLANDINS FOR INDUCTION OF CERVICAL RIPENING

PGE2 (Dinoprostone)

a)          Prepidil 0.5 mg gel (for intracervical use)

b)          Cervidil – 10 mg dinoprostone embedded in a mesh to be placed in posterior fornix of the vagina. This allows for controlled release of dinoprostone over 12 hrs.

 

Advantage of cervidil vaginal insert is that it can be removed if hyperstimualtion occurs.

The intracervical route offers the advantages of prompting less uterine activity and greater efficacy in a woman with very unripe cervix.

Patient selection: Bishop score of 4 or less.

 

Administration:

The woman remains recumbent for atleast 30 minutes following application. The woman and fetus must be monitored for contractions, fetal well being and changes in cervical Bishop score

 

Side Effects:

1)          Uterine hyperstimulation – 6 or more contractions in 10 minutes for a total of 20 minutes.

2)          Should not be used in patients with glaucoma, severe hepatic or renal impairment and asthma.

 

PROSTAGLANDIN E1 (MISOPROSTOL)

Vaginal misoprostol

-              25 ug misoprostol to be kept in posterior fornix every 3 to 6 hourly.Such usage decreases the need for oxytocin, achieve higher rates of vaginal delivery within 24 hours of induction and significantly reduce induction – delivery intervals.

-              50 ug Misoprostol        -  ­ Tachysystole

-  Meconium passage

-  Meconium aspiration

-  ­ rate of cesarean delivery

-     25 ug misoprostol is associated with fewer side effects than the 50 ug dose.

 

ORAL MISOPROSTOL

Oral and Vaginal applications of misoprostol have similar efficacy for cervical ripening and labour induction but an oral dosage of 200 ug was associated with more frequent abnormal uterine contractility.

PROSTAGLANDINS FOR INDUCTION OF LABOUR IN SPECIAL SITUATIONS

1)     Pregnancy with Heart disease

Cardiac disease it self is not an indication for labour induction. But induction should not be withheld if it is necessary for obstetric reasons.

Induction at labour may also be suitable, for patient with prosthetic valves, who have transferred from warfarin to heparin as this will minimize the period without warfarin.

PGE2 can be used for induction: PGE2 is potent vasodilator & causes a marked rise in cardiac output. In high doses when used, has caused cardiac arrest even in normal patients.

Minimum dose should be used & prolonged treatment should not be attempted. A study was conducted by Rush RW Mabin 7, in which 4 mg of PGE2 tablet was used per vaginally for heart disease patient for induction at labour when indicated. 84% patient went into labour & delivered within 24 hrs. 90% at them delivered vaginally. None of them developed deterioration in cardiac status.

2)     Women with cesarean section scar :

There is an increasing incidence of multipara presenting in pregnancy with a history of delivery by lower segment cesarean section. In consequence there is greater need to consider how best to manage subsequent confinements.

A major concern of women attempting VBAC is uterine rupture, the frequency of which varies with the type of cesarean section.

Type of incision

Incidence of rupture (%)

Low transverse

Low vertical

Classical vertical

0.2 – 1.5%

1 – 7%

4 – 9%

 

There is a dearth of evidence from which to assess the risks and benefits of using prostaglandins to induce labour in women with a scar from previous LSCS.

While it is difficult for clinicians to find and assimilate the evidence it is important to remember that the woman is also participant in the decision making process. For some women the shorter recovery time & feeling satisfaction if a vaginal delivery is achieved would be important factor in favour of inducing labour. For others, the convenience & feeling of being in control, apprehension of the possibility of failed trial of labour f/b an emergency section may make an elective cesarean section preferable to induction. A summary of 10 studies found that there is no statistical difference in scar disruption rate between PG E2 group (1.60%) & spontaneous labour group (1.23%).

In one large prospective study (Mackenzie et al) of 143 patients with previous LSCS whose labour was induced using vaginal PGE2: 68% patients with an unfavourable cervix delivered vaginally & it increase to 89% with favourable cervix. In none did the lower segment scar rupture. But misoprostol does not appear to be safe for induction in patients with scared uterus. Different studies had shown high frequency of disruption of prior uterine incision (3.5 – 5.6%) scar.


 

Study

Uterine rupture per study group Induction with misoprostol

Spontaneous delivery

Plant et al (1999)

Cunha et al (1999)

Butt et al (1999)

5/89

2/57

3/37

0/364

0/57

13/560

TOTAL

10/285 (3.5%)

13/1069 (1.1%)

 

It women with previous lower segment scar are induced with prostaglandins using preparation & regimen suggested by Mackenzie risk of symptomatic scar rupture seems to be no greater than the rate quoted for spontaneous labour in women with a cesarean scar. At present, faced with the lack of comparative evidence, clinicians can only provide women with the best estimate of risk based on uncontrolled observational data.

3)     IUFD

An Intrauterine fetal death is a catastrophic incident. The diagnosis itself heralds the fact that it is too late to intervene. What is left to obstetrician often falls under the domain of damage limitation.

A spontaneous labour usually ensues within few weeks of a failed pregnancy. However due to the psychological effect on mother, to prevent complication and to overcome the uncertainty of spontaneous labour, induction of labour is usually done in a case of IUFD.

Prostaglandins E & F and their various analogues have been used via different routes for induction of labour in case of IUFD.

PGE2: Dinoprostone (oral tablets, vaginal gel) may be used. 15 methyl PGF2a can be administered by I/M, extraamniotic or extra amniotic route Gemeprost (PGE1) 1 gm pessaries can be used vaginally at 3 hourly interval for a maximum of 5 doses course may be repeated after an interval of 24 hrs. But they are expensive, thermolabile & require refrigeration”. Sulprostone : synthetic derivative of PGE2 may be used 1/M or I/V. Anaphylactic reaction & severe hypotension can occur.

Misoprostol: Synthetic PGE1 analogue tablets are inexpensive, can be stored at room temperature can be used orally or vaginally. Randomized study from Thailand compared effectiveness & side effects of oral & vaginal misoprostol for termination of pregnancy with IUFD. They concluded that oral misoprostol 400 ug every 4 hourly was more effective than vaginal misoprostol 200 ug/ 12 hourly. A quicker uterine response is found in mothers with advanced gestation (> 34 wk) & higher Bishop score (>5).

4)     PROM :

I.e. rupture of membrane before the onset of labour Incidence is 6-19%.  When the fetal membranes rupture spontaneously around term, labour generally establishes within few hours. (86% go into labour within 24 hrs.) when there is delay in onset of labour, there are concerns of intrauterine infection developing and many obstetricians favour stimulating contractions with an Oxytocics. Prostaglandins have been used for this purpose in variety of ways.

Many trials have compared the obstetric outcome that follows stimulation of labour with prostaglandin as opposed to oxytocin in PROM at term. Metaanalysis of such trials shows a tendency for reduced cesarean section rate with use of prostaglandins, decrease rate of maternal infection & neonatal intensive care unit admission. Prostaglandins appear to be safe in stimulating labour when membranes have ruptured & appear to be safe whichever administration route is used.

One randomized control study compared expectant management, oxytocin & PGE2 vaginal tablet for cervical ripening & induction in patients with PROM with unfavourable cervix. The results of this study have shown that PG induction is the method of choice in such patients. PGE2, E1 can be used either vaginally or orally with varying doses without any significant difference in outcome. Misoprostol is used with dose ranging from 25-200 ug. Increasing the dose of misoprostol to more than 25-50 ug may lead to faster deliveries but also to more unpredictable or uncontrollable uterine stimulation.

 

 

Post term Pregnancy

Pregnancy beyond 294 days from 1st day of last menstrual period. Incidence varies from 3-10%. Women with uncomplicated pregnancy beyond 41 wks should be offered induction.

Recent metaanalysis of 13 controlled trials, where induction of labour for prolonged pregnancy was compared with intention to await spontaneous labour, showed small but a statistically significant reduction in the likelihood of delivery by caesarean section when labour was induced at 41 wk 3 day. The risk of perinatal death was reduced in the induction group. Either PGE2 or E1 can be used for induction.

Rate of C.S. for failed induction depends upon parity & cervical score.

C.S. rate for failed induction according to parity & cervical score :

Cervical Score

Para O

Para 1 <

n

%

n

%

0-3

4-6

10

27/59

30/292

3/208

45.8

10.3

1.4

2/26

10/257

2/215

7.7

3.9

09

 

The incidence of cesarean section for failed induction in nullipara with poor cervical score was low with PGs.

Indication for C.S. in nulliparae with a poor cervical score :

Treatment regimen Indication

Oxytocin & Amniotomy

Prostaglandins

N=230

%

N=152

%

Fetal distress

CPD or molposition

Failed induction

Others

27

10

55

8

11.4

4.4

23.9

3.5

13

8

14

1

8.6

5.3

9.2

0.7

TOTAL

100

43.5

36

23.7

P< 0.001


 

PGs CAUSING PIH

 

Prostaglandin H Synthetase (PGHS) is a rate liming enzyme in the production of PGs and thromboxane which are important regulator of vascular function.

Under normal physiological condition PGHS dependant vasodilators such as prostacyclin modulate the vascular tone, while PGHS dependent vasoconstriction which is mediated by thromboxane A2 & PGH2, predominant in some vascular pathology like HT, DM, cerebral ischemia.

 

Prostaglandin H synthetase pathway

 

Superoxide anions are released by activity of PGHS

(1)        These anions can initiate the membrane lipid peroxidation which leads to ­ed production of TXA2 à vasoconstriction.

(2)        Superoxide anions also react with Nitric oxide to form, Peroxi nitrite thus reduce nitric oxide bioavailability ®¯ vasodilation

(3)        Superoxide anions also produced isoprostants which further ­es the PGHS activity.

(4)        Due to extensive lipid peroxidation, peroxi nitrite ®¯ production of PGI2 ®¯ vaso relaxation.

            All these pathways collectively may represent the mechanism for balance b/w relaxing & contracting factor there by contributing to vascular dysfunction.

PGHS :  -     It is a 69 KDA protein

               -     Present in endothelium and smooth muscle cells

               -     Concentration of PGHS is 20 times more in endothelium than smooth muscle cells

               -     Mainly present in luminal surface of endoplasmic reticulum.

               -     Mainly ­es in oxidative stress, dyslipidemia, heart diseases, obesity

               -     Also derived from platelet.

 

In pre-eclampsia ® PGHS activity increases

¯

­ TXA2 activity than PGI2

In pre eclampsia patient there is ­ activity of PGHS in placental trophoblast.

¯

Which alter fetoplacental function and also ­es thromboxane receptor in vasculature which also leads to IUGR

Low dose of aspirin used to inhibit platelet derived PGHS in pregnant women to prevent pre eclampsia.

 

ANTIPROSTAGLANDINS FOR TREATMENT OF PIH

 

-         Preeclampsia is associated with vasoconstriction and microthrombosis in the mother and can lead to IUGR and fetal death.

-         The evidence of activation of the clotting system and the imbalance of the prastanoids ratio in pre-eclampsia and IUGR with early platelet involvement suggested the use of antiplatelet agents (usually low dose aspirin) to prevent or relieve the condition.

-         The pharmacological basis for preventing pre-eclampsia with aspirin is that aspirin in low doses selectively inhibits cyclo oxygenase activity in platelets but not in the endothelium thereby suppressing the synthesis of platelet TXA2, without effecting the production of vascular prostacyclin.

-         The reason for this selective inhibition lies in the fact that platelets being anucleated cells have a limited life span (8-11 days) and cannot synthesise new cyclooxygenase. Therefore once platelet cyclooxygenase is inhibited, its activity will be suppressed for the platelet’s life span and recovery will occur only when unaffected platelets are produced. On the other hand, endothelial cells do have a nucleus so they can resynthesise cyclo oxygenase after inhibition by ASA.

-         The biochemical selectivity of low dose aspirin may be related to its unusual kinetics. Aspirin is quickly absorbed in the small intestine and is rapidly metabolized by the liver (first pass effect), allowing unrecordably low plasma concentrations in the post systemic circulation.

Aspirin in such doses acetylates the cyclooxygenase in platelets in the prehepatic circulation whereas very little drug reaches the systemic vascular endothelium and uteroplacental circulation and thus has a little influence on the production of prostacyclin. This significantly improves prostacyclin / TXA2 ratio.

-         Low dose aspirin selectively and significantly reduces TXA2 production by total platelet and placenta of women with pre-eclampsia without affecting PGI2 production by human placental arteries. This selective inhibition could be possible because fetal platelet cycloxygenase was 4.44 times more sensitive to aspirin than umbilical artery cyclooxygenase.

-         Pre-eclampsia is associated with increased levels of lipid peroxides because cyclooxygenase activity generates not only TAX2 but also oxygen radicals. When oxygen radicals interact with polyunsaturated fatty acids they form lipid peroxides, low dose aspirin, by inhibiting cyclooxygenase can reduce both TXAs and lipid peroxides.

 

ADVERSE EFFECTS OF LOW DOSE ASPIRIN

Potential major clinical adverse effects are relatively rare with low dose aspirin

MATERNAL

FETAL

NEONATAL

-         Anemia

-         APH

-         PPH

-         Prolonged bleeding time

-         Prolonged gestations and labour

-         Congenital defects (mainly cardiac)

-         Oligohydroamnios

-         Premature closure of ductus arteriosus.

-         Bleeding disorders

-         Intraventricular hemorrhage in preterm infants.

-         Persistent pulmonary hypertension.

 

PROSTGLANDINS IN PPH

 

INTRODUCTION Active management of third stage of labour is recommended to avoid PPH by:

1)                 Administration of a prophylactic oxytocin during & immediately after the delivery.

2)                 Early cord cutting

3)                 Delivery of the placenta by control cord traction.

Inspite of this three measures if PPH occurs

¯

h’age is severe à leads to shock

¯                                                                                                      ¯        

   Needs blood transfusion

Hypofibrinogenemia            ­es morbidity + mortality & further bleeding                                ¯

                                                Use of prostaglandin

                                                            ¯

Reduced risk for our patient to expose to major Sx.

Why PGS : Cessation of uterine bleeding after delivery occurs due to vessel wall constrictions & thrombosis.

Concentration of PGs & its metabolite. ­es in amniotic fluid& maternal circulation   during labour.

¯

Peak level of PGF2 a in maternal circulation reached after birth

¯ &

Rapid surge with in few minutes after placental separation.

¯

Thus exogenous PGs used when endogenous production is insufficient to prevent hypotonia.

 

 

 

Carbopost – 15 methyl PG F22 à intra muscular             

Misoprostol à PGE1

PGs use

 

 

 

¯

                                                            per rectally

                                                            Orally

                                                            Sublingually

For Prevention of PPH:

      In Active Management third stage of labour.

In high risk patients like eclampsia, major degree placenta previa, and severe anemia

                  ¯

      125 ug of carboprost intra muscularly

ADR : diarrhoea, vomiting

 

Management of PPH : Initial Management

                                    à BGCM, fresh frozen plasma

                                    à Check uterine contractility

                                    à Recheck entity of placenta & memb.

                                    à Genital tract injury

If uterine atony         

à  Uterine massage

à Methergin 0.5 mg IV after 10 min if no response then 100 unit of syntocin +0.5 mg of methergin in 1pint NS at 90° /min

                                    ¯

if no response in 10 min

­es oxytocin 300 units + 0.5 mg of methergin in 10 RL 90° /min

                        ¯

                        No response to 10 min

Intramusculur / intra myometrial

Inj. carboprost 0.25 mg every 15-30 min.

Max : 2 mg can be given. Onset of action with in 5 minutes.

 

Sulprostone 1000 ug in 10 NS 60-80°/min

¯ if fail

Sulprostone 500 ug diluted in 10 ml of NS given trans-abdominally in four uterine quadrant.

Along with pulse, BP, cardiac monitoring of patient.

PGE1 vaginal suppository used but due to continuous bleeding it can be washed out.

¯

Continuous irrigation of uterine cavity with low concentration of PGE2 is effective in severe PPH.

Misoprostol 800 ug/ 1000 ug per rectally.

¯

Adv. over oral

Slow uptake but prolong duration of action

All this fails then Sx intervention like internal iliac artery ligation

Internal iliac artery embolisation

Obstetric hysterectomy

Contraindication

-              Asthma

 

 

-              Cardiac

 

 

-              Renal

 

diseases

-              Hepatic

 

 

 

Conclusion :

Administration of PGs is effective in treatment of severe PPH with few side effects.

¯

It is a life saving medical therapy for PPH.

¯

Also its use avoids the need for major surgery

¯

Thus reduce morbidity & mortality

 

Adv. : Awareness in the staff related to labour room & maintain a readily accessible supply of injectable PG or its analogue in any locality where deliveries are regularly under taken.

 

USE OF PROSTAGLANDINS IN GYNAECOLOGY

 

ENDOMETRIOSIS

 

-              Endometriosis is defined as the presence of endometrial tissue (glands and stroma) outside the uterus.

-              The most frequent sites of implantation are the pelvic viscera and the peritoneum.

-              There are 2 groups of prostaglandins which are most relevant to endometriosis – good/bad.

-              Good – take part in (N) functions of the body without contributing to the processes which cause negative effects of endometriosis.

-              Bad – Take part in the functions of the body which contribute to the signs and symptoms of endometriosis i.e. pain, inflammation, digestive disturbance, connective tissue damage.

-              Women with endometriosis can alter the balance of PG production to reduce their symptoms by reducing the bad PGs and aim to increase the good PGs through their diet and with supplements.

-              This can be done by including vegetable, nut and seed oils in the diet and decreasing the amount of saturated fat, junk food and dairy products in the diet.

-              High stress, too much sugar or refined flours also tend to ­ the levels of bad PGs in the body.

 

IMMUNOLOGIC FACTORS AND INFLAMMATION IN THE AETIOLOGY OF ENDOMETRIOSIS

-              Apoptosis is the physiologic process of programmed cell death that contributes to endometrial breakdown and turnover during the late secretory and menstrual phases of the cycle. Ectopic endometrium is resistant to, apoptosis which improves the survival of endometrial cells entering the peritoneal cavity and also explains why ectopic endometrium is resistant to macrophage- mediated immune surveillance and clearance.

-              Matrix metalloproteinases are enzymes that degrade the extracellular matrix and help to mediate normal endometrial breakdown and new estrogen stimulated growth. Expression of matrix metalloproteinases is increased early in the cycle and usually suppressed by progesterone during the secretory phase.

-              In women with endometriosis, secretory endometrial matrix metalloproteinase expression is unusually resistant to progesterone suppression.

-              Persistent matrix metalloproteinase expression in shed endometrial cells can confer an invasive potential to refluxed endometrium that facilitates invasion of the peritoneal surface and subsequent cell proliferation.

-              The development and growth of endometriosis are estrogen dependent and there is now substantial evidence that aromatase, the enzyme that converts androgens to estrogen is over expressed in women with endometriosis.

-              Transcription factors which stimulate the aromatase enzyme activity (notably steroidogenic factor-1, sf-1) are over expressed in endometriotic tissue and those that inhibit the enzyme are under-expressed, resulting in abnormal aromatase activity and estrogen synthesis.

-              Estrogen stimulates local cyclooxygenase type 2 (cox2) activity that generates PGE2, a potent stimulator of aromatase in endometriosis- derived stromal cells thereby creating a positive feedback for continuous local estrogen production

-              Endometriosis is associated with a state of sub-clinical peritoneal inflammation marked by ­ peritoneal fluid volume, ­ peritoneal fluid WBC concentration and ­ inflammatory cytokines, growth factors and angiogenesis promoting substances.

-              Administration of NSAIDs are used to relieve pain Ibuprofen 800 – 1200 mg / day or Mefenamic acid 150-600 mg/day in quite effective.

 

 

PROSTAGLANDIN IN MENORRHAGIA

INTRODUCTION

Cyclical bleeding at normal interval. The bleeding is either excessive in amount or duration or both.

CAUSES

·               ­es in size of endometrial cavity & bleeding surface.

·               ­ed vascularity of uterus

·               Endometrial hyperplasia

·               Hyper estrogenic state.

 

PROSTAGLANDIN IN MENORRHAGIA

·         Produce Strong uterine contraction

·         ­es vasoconstriction ischemia of myometrium

                                                              i.      Produce ­es pain

                                                            ii.      ­es blood loos

·         ­amount of Estrogen& progesterone.

¯

­ed release of prostaglandins

­ed pains, blood loss

 

ANTI PROSTAGLANDINS ARE USED

-         Inhibition of cyclooxygenase II enzyme & reduce prostaglandins

-         ¯es pain & blood loss, ¯es uterine contraction

-        Vasodilatation & produce inhibition of platelet aggregation ®¯es amount of clots.¯ es pain & blood loss.

PROSTAGLANDIN IN DYSMENORRHOEA

 

Introduction

Ø      Definition : Painful menstruation in sufficient magnitude so as to incapacitate the day to day activities. 

Ø      Two- types

(1)   Primary : Painful menstruation with out pelvic pathology

(2)   Secondary : Painful menstruation with pelvic pathology.

 

Role of Prostaglandin in dysmenorrhoea

In ovulatory cycle

¯

Progesterone, prostaglandins synthesised by secretory endometrium

¯

Fall in estrogen, progesterone prior to menstruation

¯

Prostaglandin release with maximum production during shedding of endometrium

¯

PG F2a à     Strong Uterine contraction

              à      Increase vaso constriction

                                    ¯

Cause ischemia of myometrium

                                    ¯

§               ­es Pain and blood loss

§               ­es sensitivity of nerve endings to pain


 

 

CLINICAL FEATURES

- Pain

- Weakness, easy fatiguability

 

Ø      Treatment :       1) Prostaglandin synthesis inhibitors

                                    2) Hormonal therapy

 

Ø           Prostaglandin synthesis inhibitors :

-              Inhibit cyclo oxygenase II enzyme & reduce prostaglandin production.

-              No binding with COX-1 enzyme.

-              Selective cyclo oxygenase II inhibitor

-              Location GI tract mucosa, platelet, kidney

 

Drugs :     1)      Rofecoxib

                  2)      Non steroidal anti influmatory agent

                           -  Brufen

                           - Mefenamic acid

                           - Naproxen sodium

Dose :

            T. Brufen (400 mg) 1 tds

            Naproxen sodium (250 mg) 1 tds

            Mefenamic acid 250 to 500 mg  bd or tds

 

Hormonal Therapy

 

Prolong suppression of estrogen& progesterone

¯

Low prostaglandin content

¯

Atrophic, decidualized endometrium


 

 

PROSTAGLANDINS IN OVARIAN CANCER

 

Ovulation

Arachidonic acid à PGs

                                    COX-1

                                    COX-2     Enzyme activity mainly induced by (TNFa)

 

TNFa also induced proteolytic enzymes like urokinase type plasminogen activator

Matrix metalloproteinase (2-9)

These entire factors are associated with removal, remodeling of basement membrane of ovary.

During ovulation à Gonadotropins stimulate dissolution of basement memb. mediated by COX-2

COX-2 Plays a role in ovarian surface epithelial morphological remodeling

¯

May also promote & select the transformation of cells with oncogenic mutation & neoplastic potential.

COX-1: May be reductant & compensatory for COX-2 and also contribute to ovarian tumorigenicity.

TNFa induced COX-2 expression is lost in ovarian cancer cell.

¯

Contribute to early step of ovarian epithelial neoplastic transformation.

COX-2 expression in morphologically pre-neoplastic epithelium is stimulated by TNFa.

TNFa, urokirase plasminogen activator, MPNP-2, MMP-9 play imp. role in ovulation & epithelial transformation & provide, molecular linking of ovulation & ovarian cancer risk.

 

CONCLUSION :

Inflammatory activities mediated by TNFa induced COX-2, uPA, MMP-2

¯

Inducing incessant ovulation

¯

Degradation & remodeling of basement membrane

Select & promotes the transformation of epithelial cells with oncogenic potential.

Thus TNFa, COX-2, MMP-2 à Induces epithelial neoplastic transformation.

Use of COX-2 inhibitors to other chemo preventive agent

¯

Can reduce risk of ovarian cancer in high risk women.

Role of prostaglandins in ovulation & luteolysis

In addition to other steroid hormones granulosa cells also contains specific receptor sites for prostaglandins, clearly indicating it’s role in normal menstrual cycle.

The LH surge appears responsible for stimulating the local synthesis of prostaglandins concentration of PGs increases markedly in preovulatory follicle & is highest at ovaluation thereby suggesting a role in ovulatory process. Inhibition of PG synthesis may block follicle rupture without affecting process of luteinization of granulosa cells & oocyte maturation. (Luteinized unruptured follicle)

PGI2 brings about vasodilatation ­ed vascular permeability within the wall of preovulatory follicle.

Suggested Mechanism through which PG2 induces follicle rupture :

a)     Release of proteolytic enzymes to digest the follicular wall.

b)     Smooth muscle fibers have been identified in the cortical stroma & in the the externa of ovarian follicle. Prostaglandins may also contract these smooth muscles thereby aiding the extrusion of oocyte cumulus cell mass.

This role of PGs is so well demonstrated that infertility patients should be advised to avoid prostaglandin synthesis inhibiting drugs.

Luteolysis :

In (N) cycle the time period from the LH midcycle to menses is consistently close to 14 days. For practical purposes luteal phases lasting between 11-17 days can be considered as normal.

The luteal phase cannot be extended indefinitely even with progressively increasing LH exposure, indicating that demise of corpus luteum is due to an active luteolytic mechanism.

The decline in progesterone production occurs as estradiol again rises to plateau at the midluteal phase suggesting that estrogen may initiate luteolysis. Estrogen induced luteolysis can be blocked by inhibiting PG synthesis. PGE2 stimulates progesterone production whereas PGF2 inhibits progesterone production. It appears to operate through modulation of LH dependent CAMP accumulation.

In proliferative phase equal amount of PGF2 & PGE2 are synthesized but in luteal phase level of PGF2 progressively increases.

Exprimental evidence indicates that the luteolytic effect of PGF2 is mediated by endothelin -1. PGF2 stimulates synthesis of endothelin -1 which inhibits luteal steroidogenesis. In addition endothelin -1 stimulates the release of TNF-a, a growth factor known to induce apoptosis.

ROLE OF PROSTAGLANDINS IN OVULATION & LUTEOLYSIS

 

In addition to other steroid hormones granulosa cells also contains specific receptor sites for prostaglandins, clearly indicating it’s role in normal menstrual cycle.

The LH surge appears responsible for stimulating the local synthesis of prostaglandins. Concentration of PGs increases markedly in preovulatory follicle & is highest at ovulation, thereby suggesting a role in ovulatory process. Inhibition of PG synthesis may block follicle rupture without affecting process of luteinization of granulosa cells & oocyte maturation. (Luteinized unruptured follicle)

PGI2 brings about vasodilatations ­ed vascular permeability within the wall of preovulatory follicle.

Suggested Mechanism through which PGs induces follicle rupture :

c)      Release of proteolytic enzymes to digest the follicular wall.

d)     Smooth muscle fibers have been identified in the cortical stroma & in the theca externa of ovarian follicle. Prostaglandins may also contract these smooth muscles thereby aiding the extrusion of oocyte cumulus cell mass.

This role of PGs is so well demonstrated that infertility patients should be advised to avoid prostaglandin synthesis inhibiting drugs.

Luteolysis:

In normal cycle the time period from the LH midcycle to menses is consistently close to 14 days. For practical purposes luteal phase lasting between 11-17 days can be considered as normal.

The luteal phase cannot be extended indefinitely even with progressively increasing LH exposure, indicating that demise of corpus luteum is due to an active luteolytic mechanism.

The decline in progesterone production occurs as estradiol again rise to plateau at the midluteal phase suggesting that estrogen may inttiate luteolysis. Estrogen induced luteolysis can be blocked by inhibiting PG synthesis. PGE2 stimualtes progesterone production whereas PGF2 inhibits progesterone production. Both appears to operate through modulation of LH dependent cAMP accumulation.

In proliferative phase equal amount of PGF2-a & PGE2-a are synthesized but in luteal phase level of PGF2-a progressively increases.

Experimental evidence indicate that the luteolytic effect of PGF2-a is mediated by endothelin -1. PGF2-a stimulates synthesis of endothelin -1 which inhibits luteal steroidogenisis. In addition endothelin -1 stimulates the release of TNF-a, a growth factor known to induce apoptosis.

PGS IN BIRTH CONTROL MEASURE

Introduction :

Prostaglandins are produced in most tissues of the body & have varying physiological action.

On endometrium :

Prostaglandins acts in similar manner to that of hormones à by stimulating target cell but they are differ from hormones à as they act locally near their site of synthesis & metabolized very rapidly thus they cause

¯

Vasoconstriction & smooth muscles contraction

Leads to sloughing of endometrium during menstruation

XPL7:  Vaginal suppository

              Contains some fatty acid which  convert into PGS

¯

Produces effects on cell levels in endometrium

              Herbal formulation

              Comes in applicator

              Used with in 72 hrs. after an unprotected sexual exposure to prevent pregnancy.

 

 

IUD: Causes ­es local secretion of PGs with fibrinolytic mechanism needed for hemostasis is affected.

¯

PGs causing à aseptic inflammatory reactions in endometetrium

¯ So

makes endometrium  hostile for implantation of blastocyst.

 

PGS à also cause asynchronous development of endometrium

¯

Also cause smooth muscle contraction

& ­ uterine activity

¯

So it is responsible for contraceptive effects of IUD

¯

So when it inserted postcoitally with in 5 day of unprotected intercourse. It can prevent implantation of fertilized ovum

In abnormal uterine bleeding

à IUD makes uterus to more sensitive to PGs.

¯

So even (N) level of PG can cause a strong reaction in smooth muscle.

¯

So PG suppressants will be significant in treating abnormal uterine bleeding

 

Mifepristone :

Can prevent ovulation if given in proliferative phase & hinder development of the endometrium when given so on after ovulation.

Dose  à         10 mg up to 5 days of unprotected inter course effectiveness 18%

                        High dose can be used 600 mg effectiveness 38%

Dis adv à      Period may be delayed up to 7 days.

 

PROSTAGLANDIN IN SURGICAL PROCEDURE

 

Non steroidal antiflammatory agent

(Anti prostaglandin)             -  Aspirin

                                                -  Carboten

                                                -  Deracoxib

M/A : Inhibition of cyclo oxygenase pathway

            Inhibit conversion of Arachidonic acid into prostaglandin

 

USE :  Post operative pain relief

 

I)            Prostaglandins in hysteroscopic myomectomy

M/A :      

1)           After resection of protruding portion of myoma, injection prostaglandin (Frog)

¯

Allows complete removal

2)           Uterine Neoplasm surgery

3)           Intraoperative use of prostaglandin F2a

¯

Allow one step hystero resectoscopy of asessile submucous leiomyoma.


 

 

II)         Prostaglandin after cesarean delivery or uterine surgery

·         Induce uterine contraction

¯

Prevention of blood loss

I)            Prostaglandins  in pre operative cervical ripening

·         ­es uterine contraction

·         Promote cervical ripening

Dose :

T. Misoprost (400 microgram)

Vaginaly 3-4 hr. prior surgery

·         Allow complete evacuation

·         Less cervical dilatation require so less chances of injury.

 

II)         Prostaglandin in atonic PPH

·         Intramyometrial inj. prostaglandin given in C/o intra-operative Atonic PPH

·         T. Misoprost per rectal can be used in treatment of PPH.

 

 
     

 
         
     

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