THE PHARMACOLOGY OF THE PHARMACOLOGY OF DRUGS USED IN THE DRUGS USED IN THE

MANAGEMENT OF POSTPARTUM MANAGEMENT OF POSTPARTUM HEMORRHAGE: the evidenceHEMORRHAGE: the evidence

Ma. Stephanie Fay S. Cagayan, MD, FPOGS, FPSECP,FPSSTDMa. Stephanie Fay S. Cagayan, MD, FPOGS, FPSECP,FPSSTDAssociate ProfessorAssociate Professor

Department of Pharmacology and Toxicology andDepartment of Pharmacology and Toxicology andDepartment of Obstetrics and GynecologyDepartment of Obstetrics and Gynecology

UP College of MedicineUP College of Medicine

Session Objectives

By end of the session, participants will be able to:

Identify Uterotonic Drugs Describe pharmacologic aspects

related to •Selection•Storage•Use and dosage

Review the evidence on selection of specific agents

‘‘‘‘She died in She died in childbirth’’childbirth’’

An estimated150,000 maternal deaths

worldwide result from obstetric

hemorrhage each year

More women have probably been killed by

Hemorrhage than any other complication of

pregnancy in the history of mankind.

90% of deaths frompostpartum

hemorrhage are preventable.

Those caring for pregnant women must be

prepared to aggressively treat

this complication when it occurs.

WE HAVE THE

TOOLS

GOOD NEWS

What What can be can be done?done?

Preparation for Postpartum Hemorrhage

THE STEPS TO MANAGING PPH:

POSTPARTUM HEMORRHAGE:

PREDICT

HANDLE

PREPARE

Identify patients at risk

Use a multi-disciplinary approach

Optimize clinical/medical management

80% OF CASES OF POSTPARTUM HEMORRHAGE

ARE DUE TO UTERINE ATONY

What about DIC?

Coagulopathy is a relatively uncommon cause of primary PPH

Coagulopathy most commonly occurs when another cause of PPH already has produced significant blood loss.

“Perhaps the most important aspect in the management of PPH

is the attitude of the attendant in charge. It is

critical to maintain equanimity in what can be a chaotic and

stressful environment”.

Yinka Oyelese, MD, Obstet Gynecol Clin N Am 34 (2007) 421–441

Medical Treatment of Medical Treatment of Postpartum HemorrhagePostpartum Hemorrhage

Medications that cause

uterine contractions

Medications that

promote coagulation

TONE

Uterotonic drugs used for AMTSL

• Oxytocin- posterior pituitary extract– Carbetocin

• Ergot alkaloidsMehtylergonovine maleate

• Prostaglandins– Carboprost- prostaglandin F2 nalogue– Misoprostol- prostaglandin E1 analogue

• Syntometrine- combination of oxytocin and ergometrine

May be given IV, IM, orally, vaginally, rectally or bucally

METHERGINE

“Speedy”

OXYTOCIN“The Champ”

CytotecInexpensive (?) Effective

Medications for Uterine AtonyMedications for Uterine Atony

Factors in the Selection of Appropriate Agent

• Efficacy– Response time, stability, adverse effects,

contraindications

• Cost – acquisition, administration, storage

• Requirements for drug administration

Oxytocin• From posterior pituitary lobe• Available as 1 ml ampoule• Advantages

– Acts within 2.5 minutes when given IM– Generally does not cause side effects– Does not have any contraindications for

postpartum use• Disadvantages

– More expensive than ergometrine– IM or IV preparations only– Not heat stable

• Dosage for AMTSL– 10 IU IM or 5 IU IV slow push

Dose, route, and precautions for oxytocin use for PPH treatment

Uniject device• Oxytocin 10 IU

– a prefilled, easy-to-use, non-reusable syringe

– is an advance in the method of delivering oxytocin and is currently being used in pilot studies

– ensures the correct dose is given with little preparation and medical waste.

Ergometrine or Methylergonovine maleate

• Oral: 125mcg tablet • Inj: 200mcg/mL, 1mL ampule• Advantages

– Low price, Effect lasts 2–4 hours • Disadvantages

– Takes 6–7 minutes to become effective when given IM; oral form insufficiently effective

– Increased risk of hypertension, vomiting, headache– Contraindicated in women with hypertension or

heart disease• Dosage for AMTSL

– 0.2 mg IM

Misoprostol

• Prostaglandin E1 analogue• directions on its use for AMTSL is

included in the International Federation of Gynaecology and Obstetrics (FIGO)/International Confederation of Midwives (ICM) statement, Prevention and Treatment of Postpartum Haemorrhage: New Advances for Low Resource Settings

Misoprostol• 100 and 200 mcg tablets• Advantages

• Effect lasts 75 minutes • Does not require injection skill or infection

prevention measures • Can be distributed at the community level

• Disadvantages• Acts within 6 minutes.• Common side effects: shivering and elevated

temperature• Dosage for AMTSL

• 600 mcg po

Dose, route, and precautions for misoprostol use for PPH treatment

Other Uterotonics

• Fixed dose combination oxytocin and ergometrine

• Carbetocin• Carboprost

Oxytocin Evidence• In six trials involving 3200 women, oxytocin use

was found to halve the risk of PPH with blood loss ≥ 500 ml [Relative Risk (RR) 0.50; 95% confidence interval (CI) 0.43–0.59]

• In four trials (involving 2243 women), compared with placebo or no uterotonics, oxytocin decreased the risk of severe PPH with blood loss ≥ 1000 ml (RR 0.61; 95% CI 0.44–0.87).

• A significant reduction in the use of additional uterotonics was also found in five trials involving 2327 women (RR 0.50; 95% CI 0.39–0.64).

Oxytocin vs. Ergometrine

• There was little evidence of differential effects for oxytocin versus ergot alkaloids (six trials, ~2800 women, RR 0.90; 95% CI 0.70–1.16).

• However, oxytocin was associated with fewer manual removals of the placenta (RR 0.57; 95% CI 0.41–0.79).

• One small trial suggested that there was less raised blood pressure with oxytocin compared with ergot alkaloids.

• Five trials (~2800 women) had compared oxytocin plus ergometrine versus ergometrine alone. These trials showed little evidence of a synergistic effect of oxytocin plus ergometrine (RR 1.29; 95%CI 0.90–1.84).

Oxytocin vs Ergometrine

• Results of trials do not show a difference in outcomes related to blood loss and transfusion between lower doses of oxytocin and the recommended dose of ergometrine

• A lower rate of manual removal of placenta was seen in women treated with oxytocin

• Ergometrine is associated with more adverse effects, especially with regard to causing high blood pressure

Recommendation: Oxytocin vs Ergometrine

• In the context of active management of the third stage of labor, if all injectable uterotonic drugs are available:– Skilled attendants should offer oxytocin

to all women for prevention of PPH in preference to ergometrine/methylergometrine to women without hypertension or heart disease for prevention of PPH.

Oxytocin vs. Syntometrine: Results

• Syntometrine was associated with a small reduction in risk of PPH < 1000 mL (OR 0.74, 95% CI 0.65-0.85)

• Adverse effects of vomiting and hypertension were associated with the use of syntometrine

• There were no differences in other maternal or neonatal outcomes

Conclusion• Need to weigh benefit of reduction in risk of PPH

with risk of other adverse effects associated with syntometrine

Recommendation: Oxytocin vs Syntometrine

• In the context of active management of the third stage of labor, if all injectable uterotonic drugs are available:

• Skilled attendants should offer oxytocin to all women for prevention of PPH in preference to the fixed drug combination of oxytocin and ergometrine to women without hypertension or heart disease for prevention of PPH.

Carbetocin evidence

• Carbetocin, an oxytocin agonist, was compared with placebo (one trial) or oxytocin (three trials) for preventing postpartum haemorrhage in recently published systematic review (2007)– Su LL, Chong YS, Samuel M. Oxytocin agonists for preventing

postpartum haemorrhage. Cochrane Database of Systematic Reviews 2007;Issue 3. Art. No.: CD005457; DOI: 10.1002/14651858.CD005457.pub2.

• Limited evidence suggests that there is little difference in the effectiveness between carbetocin and oxytocin, and adverse effects like headache, nausea and vomiting were also similar.

• Three of the included trials were known to be have been supported by grants from a pharmaceutical company.

Prostaglandins in the treatment of PPH

• Prostaglandins included misoprostol administered via buccal, sublingual, oral, and rectal routes and intramuscular prostaglandins (PGF2alpha [carboprost] and PGE2 [misoprostol])

• Results of studies comparing buccal, sublingual, oral, or rectal misoprostol with no uterotonic/placebo are equivocal and come from small trials showing effects in different directions.

• Across the trials, side-effects were more common and consistent in those receiving misoprostol.

• The rate of severe PPH (RR 1.36; 95% CI 1.17–1.58) and the use of additional uterotonics were statistically significantly higher with 600 µg of oral misoprostol compared with conventional injectable uterotonics.

• These results are dominated by the large WHO trial (Gülmezoglu AM, Villar J, Ngoc NN, Piaggio G, Carroli G, Adetoro L, et al., 2001) but other trials showed the same trend.

• There were no significant differences between the 600 µg dose and lower doses (i.e. 500 µg or 400 µg) in terms of the rate of severe PPH, although trials using the lower doses had smaller sample sizes compared with the trials with the 600 µg dose.

• The use of additional uterotonics was also significantly higher with the 400 µg dose of misoprostol compared with conventional injectable uterotonics.

• When compared with conventional uterotonics, intramuscular prostaglandins resulted in less blood loss [one trial, 46 women, weighted mean difference (WMD) –224.00 ml; 95% CI -420.35 ml –27.65 ml) and shorter duration of the third stage (WMD –3.60 minutes; 95%CI –7.65 minutes –0.45 minutes).

• Other outcomes occurred infrequently for any reliable conclusions to be drawn.

• The concerns related to safety, costs and side-effects are important limitations of intramuscular prostaglandins.

• Prostaglandin-related side-effects – especially shivering, pyrexia, nausea, vomiting and diarrhoea – were more frequent and consistent across trials.

• Oral misoprostol is not as effective as oxytocin when used for prevention of PPH

HOWEVER • Oral misoprostol:

– is easy to administer– has no known contraindications for use in the

postpartum– can be stored easily at room temperature (it is

thermostable and light stable)– does not require specific conditions for transfer – has a shelf life of several years

Oxytocin vs. Misoprostol: Conclusion

• In the context of active management of the third stage of labor:

• Skilled attendants should offer oxytocin for prevention of PPH in preference to oral misoprostol (600 mcg).

• In situations where oxytocin is not available or birth attendants’ skills are limited:

• administer misoprostol 600 mcg by mouth soon after the birth of the baby to reduce the occurrence of hemorrhage

• In the absence of active management of the third stage of labor, a uterotonic drug (oxytocin or misoprostol) should be offered by a health worker trained in its use for prevention of PPH.

Oxytocin vs. Misoprostol: Recommendations

Response Time

Adverse Effects

• Overall, ergometrine alone or in combination with oxytocin is associated with more adverse effects, especially with regard to causing high blood pressure.

• Misoprostol is associated with an increase in shivering, diarrhea, and temperature higher than 38°C.

Stability of Injectable Uterotonics in Tropical Climates

Simulation condition

Ergometrine/

methylergometrine

Oxytocin

Refrigeration for 12 months

Lost 4-5% active ingredient

No loss

30oC, dark Lost 25% Lost 14%

21–25oC, light Lost 21–27% in one month

>90% in 12 months

Lost 5%

40oC dark Lost > 50% Lost 80%

Stability of Injectable uterotonics in Tropical Climates

• Stability of oxytocin is better than ergometrine/ methylergometrine, especially regarding light

• Carefully read the manufacturer’s recommendations for storage of injectable uterotonics – where possible, store uterotonics in refrigerator (2–8ºC) and away from light

• Remove injectable uterotonics from box only for immediate use

• Short periods unrefrigerated are fine (1 month at 30°C)

Storage of uterotonic drugs - In the Pharmacy

• adequate stocks of uterotonic drugs, syringes, and injection safety materials

• Follow the rule of first expired – first out (or first in – first out) to reduce wastage of uterotonic drugs

• If possible, keep injectable uterotonics refrigerated at 2–8°C

• Protect ergometrine and syntometrine from freezing and light.

Storage of uterotonic drugsIn Delivery Rooms

• Periodically remove ample amount of injectable uterotonics needed for expected client load from refrigerator

• Avoid storage of injectable uterotonics in open kidney dishes, trays, or coat pockets

• Store oxytocin outside the refrigerator at a maximum of 30°C for up to three months

• Store ergometrine and syntometrine vials outside the refrigerator in closed boxes and protected from the light for up to one month at 30°C

Cost

• Acquisition cost– Oxytocin and ergometrine almost same– Misoprostol

• Administration cost– Higher for injectables

• Storage cost– Ergometrine slightly higher

Requirements for Administration

• Administering any uterotonic will require – a health worker authorized and trained

to provide the drug;– a health worker who understands the

timing and dose of the drug;– a health worked trained to recognize and

manage side effects of the drugs;– application of manufacturer-specific

storage recommendations.

Requirements for Administration

• Administering injectable uterotonic will require – a health worker authorized and trained to

perform injections;– a health worked trained to recognize

contraindications to ergometrine;– consumables and supplies to ensure

adequate infection prevention measures;– consumables and supplies to ensure

injection safety, including disposable needles and syringes;

Summary

BMJ Clinical Evidence

WHO Recommendations Concerning Selection of Uterotonic for AMTSL

• Oxytocin is the uterotonic of choice for AMTSL

• If oxytocin is not available, use syntometrine or ergometrine

• If injectable uterotonic drugs are not available, use misoprostol 600 mcg by mouth

Remember: Do not use ergometrine or syntometrine in women with hypertension or

heart disease

WHO guidelines for the management of postpartum haemorrhage and retained placenta. Geneva, Switzerland, 2009

Abalos E. Choice of uterotonic agents in the active management of the third stage of labour: RHL commentary (last revised: 2 March 2009). The WHO Reproductive Health Library; Geneva: World Health Organization.

POPPHI. Selection of uterotonic drugs in tropical climates. Seattle:PATH; 2008.

International Confederation of Midwives (ICM), International Federation of Gynaecology and Obstetrics (FIGO). Prevention and Treatment of Post-partum Haemorrhage: New Advances for Low Resource Settings Joint Statement. The Hague: ICM; London: FIGO; 2006. Available at: www.figo.org/docs/PPH%20Joint%20Statement%202%20English.pdf. Accessed Nov. 5, 2011.

References

Cotter A, Ness A, Tolosa J. Prophylactic oxytocin for the third stage of labour. Cochrane Database of Systematic Reviews 2001;Issue 4. Art. No.: CD001808; DOI: 10.1002/14651858.CD001808.

McDonald SJ, Abbott JM, Higgins SP. Prophylactic ergometrine-oxytocin versus oxytocin for the third stage of labour. Cochrane Database of Systematic Reviews 2004;Issue 1. Art. No.: CD000201; DOI: 10.1002/14651858.CD000201.pub2.

Gülmezoglu AM, Forna F, Villar J, Hofmeyr GJ. Prostaglandins for preventing postpartum haemorrhage. Cochrane Database of Systematic Reviews 2007;Issue 4. Art. No.: CD000494; DOI: 10.1002/14651858.CD000494.pub3.

Su LL, Chong YS, Samuel M. Oxytocin agonists for preventing postpartum haemorrhage. Cochrane Database of Systematic Reviews 2007;Issue 3. Art. No.: CD005457; DOI: 10.1002/14651858.CD005457.pub2.

Sackett DL, Haynes RB. Summarising the effects of therapy: a new table and some more terms. Evidence Based Medicine 1997;2:103-104.

Gülmezoglu AM, Villar J, Ngoc NN, Piaggio G, Carroli G, Adetoro L, et al. for the WHO Collaborative Group to Evaluate Misoprostol in the Management of the Third Stage of Labour. WHO multicentre double-blind randomized controlled trial to evaluate the use of misoprostol in the management of the third stage of labour. The Lancet 2001;358:689-695.

The 4 “Ts” Recalled

“THROMBIN” Check labs if suspicious.