pharmacology of drugs for pph
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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.
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