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Choice of antihypertensive
Peter von DadelszenBMedSc, MBChB, DipObst, DPhil, FRANZCOG, FRCSC, FRCOG
Associate Professor of Obstetrics & Gynaecology, UBCConsultant in Maternal-Fetal Medicine, BC Women’s
Co-Director, CFRI Reproduction & Healthy Pregnancy Cluster
Dr Peter von DadelszenBMedSc, MBChB, DipObst, DPhil, FRANZCOG, FRCSC, FRCOG
Principal Investigator
Department of Obstetrics & Gynaecology, UBCReproduction & Healthy Pregnancy Cluster, CFRI Consultant in Maternal-Fetal Medicine, BC Women’s
2H30-4500 Oak Street, Vancouver, BC V6H 3N1, Canada
PRE-eclampsiaEclampsiaMonitoring,Prevention &Treatment
Phone: +1-604-875-3054 | Fax: +1-604-875-2725 | e-mail: [email protected]
PRE-EMPT(PRE-eclampsia-Eclampsia Monitoring, Prevention &
Treatment)
• Five objective, LMIC community intervention-focussed, pre-eclampsia project
• Funding:– Bill & Melinda Gates Foundation
Why use antihypertensives?
• Maternal stroke risk associated with both severe systolic and/or diastolic hypertension– sBP >160mmHg– dBP >110mmHg CEMACH 2007
• Severe hypertension associated with placental abruption and attendant maternal and perinatal risks
• Severe hypertension is included in most definitions of ‘severe’ pre-eclampsia, although such classification systems are flawed
Menzies et al. Hypertens Pregnancy 2007
Why use antihypertensives?
• In non-severe pregnancy hypertension – No clear evidence of benefit other than to reduce
the frequency of episodes of severe hypertension– May adversely effect fetal growth velocity
von Dadelszen et al. Lancet 2000
• Therefore, my focus will be on the pharmacological management of severe hypertension
The ‘ideal’ agent in rural & remote settings
• Oral administration• Reliable reduction in BP• Smooth reduction in BP• Rapid onset of action• Minimal overshoot
– BP in target range• sBP 130-160mmHg• dBP 80-110mmHg
From what can we choose?
• Hydralazine• Beta-blockers (& alpha-/beta-blockers)
– Atenolol– Labetalol
• Calcium channel blockers– Nifedipine
• Alpha-methyldopa• Angiotensin converting enzyme inhibitors• Angiotensin-II receptor blockers
From what can we choose?
• Hydralazine• Beta-blockers (& alpha-/beta-blockers)
– Atenolol– Labetalol
• Calcium channel blockers– Nifedipine
• Alpha-methyldopa• Angiotensin converting enzyme inhibitors• Angiotensin-II receptor blockers
– Risks of fetal renal toxicity and IUFD
The ‘ideal’ agent in rural & remote settings
• Oral administration• Reliable reduction in BP• Smooth reduction in BP• Rapid onset of action• Minimal overshoot
– BP in target range• sBP 130-160mmHg• dBP 80-110mmHg
Oral administration
• Atenolol– No adverse effects on fetal growth when used acutely
• Labetalol• Methyldopa• Nifedipine capsules• Nifedipine intermediate acting
– PA/Retard• Hydralazine
Modified from: Magee & Abdullah. Expert Opin Drug Saf 2004
The ‘ideal’ agent in rural & remote settings
• Oral administration• Reliable reduction in BP• Smooth reduction in BP• Rapid onset of action• Minimal overshoot
– BP in target range• sBP 130-160mmHg• dBP 80-110mmHg
Reliable reduction in BPsevere hypertension
• CCBs are more reliable than hydralazine in lowering BP in pregnant women with severe hypertension
Magee et al. BMJ 2004Duley et al. CDSR 2006
• Hydralazine appears more reliable than labetalolMagee et al. BMJ 2004
• Methyldopa may be an agent of choice for severe hypertension
Reliable reduction in BPsevere hypertension
• CCBs are more reliable than hydralazine in lowering BP in pregnant women with severe hypertension
Magee et al. BMJ 2004Duley et al. CDSR 2006
• Hydralazine appears more reliable than labetalolMagee et al. BMJ 2004
• Methyldopa may be an agent of choice for severe hypertension
Reliable reduction in BPsevere hypertension
• CCBs are more reliable than hydralazine in lowering BP in pregnant women with severe hypertension
Magee et al. BMJ 2004Duley et al. CDSR 2006
• Hydralazine appears more reliable than labetalolMagee et al. BMJ 2004
• Methyldopa may be an agent of choice for severe hypertension– Widely used – routinely on EMLs
The ‘ideal’ agent in rural & remote settings
• Oral administration• Reliable reduction in BP• Smooth reduction in BP• Rapid onset of action• Minimal overshoot
– BP in target range• sBP 130-160mmHg• dBP 80-110mmHg
Smooth reduction in BP
• The ideal agent will reduce BP effectively and over a relatively short period of time– <60min– Stabilise and reduce MAP by 10% per hour
• BP fall will not be precipitous– Adverse maternal CNS effects– Adverse fetal effects
The ‘ideal’ agent in rural & remote settings
• Oral administration• Reliable reduction in BP• Smooth reduction in BP• Rapid onset of action• Minimal overshoot
– BP in target range• sBP 130-160mmHg• dBP 80-110mmHg
‘Rapid’ onset of action
Modified from: Magee & Abdullah. Expert Opin Drug Saf 2004
Drug Dosage Onset Peak Duration
Atenolol 25 – 50 mg 1hr 2-4hr 24hr
(dose dependent)
Labetalol 200 mg 20min – 2hr 1-4 hr 8-12hr
(dose dependent)
Methyldopa 500 mg – 2 g 40 min 3-6hr 12-24hr
Nifedipine PA (or retard) 10 mg 30min 4hr 12hr
Nifedipine capsule 5 – 10 mg 5-10min 30min 6.5hr
The ‘ideal’ agent in rural & remote settings
• Oral administration• Reliable reduction in BP• Smooth reduction in BP• Rapid onset of action• Minimal overshoot
– BP in target range• sBP 130-160mmHg• dBP 80-110mmHg
Minimal overshoot
• CCBs less likely to cause overshoot than hydralazine Magee et al. BMJ 2004
• Beta-blockers less likely to cause overshoot than hydralazine Magee et al. BMJ 2004
• Nifedipine PA/Retard less likely to cause overshoot than capsules? Brown et al. AJOG 2002
– Small RCT– End-point (‘in range BP’) measured at time PA
approaching maximal effect
On balance• An intervention package should include 1 - 3 oral
antihypertensive agent(s)• The choice for a single antihypertensive lies between
methyldopa, nifedipine, and another beta-blocker, probably atenolol – labetalol is not on EMLs
• Theoretical and practical reasons to have all available– Combined CNS control, beta-blockade and vasodilatation– Second effective agent for women whose BP is resistant to
another agent • Reserve i.v. hydralazine for obtunded/comatose
women
PRE-EMPTObjective 3
• CLIP (Community-Level Interventions for Pre-eclampsia)
– Cluster randomised controlled trial of community level interventions for women with pre-eclampsia
– Aims• Can
– identification, – early risk stratification, and – initiation of life-saving treatment at the community level
• decrease pre-eclampsia-related maternal and perinatal mortality in LMIC?
CLIP• Intervention
– CLIP package of care• Case recognition & triage• Treatment of severe hypertension (sBP ≥160mmHg)
– Oral antihypertensive ? Atenolol; ? Nifedipine, ? Methyldopa– Intramuscular MgSO4 (5g each buttock)
• Treatment of eclampsia– Intramuscular MgSO4 (5g each buttock)
• Transfer into facilities offering evidence-based care – Setting
• Community – community health workers• Primary health units (not repeated)