Anti-Hypertensive Drugs in
Pregnancy
Present Scenario
PRE TEXT…..
Hypertension complicates almost
10% of pregnancies.
Progression from mild to severe forms of hypertension duri...
Further, treatment of PIH often
involves adjustment between
competing concerns for maternal
health, gestational age of the...
During pregnancy, the priority
regarding hypertension is in

making the correct diagnosis,

with the emphasis on distingui...
Role of Antihypertensive in
Pregnancy
Antihypertensive agents are mainly used to
prevent and treat severe hypertension; to...
Some Basic
Considerations...
Definition

Hypertension in pregnancy is

Sustained diastolic BP (DBP)
≥90mm Hg;
(most accepted)
Systolic BP ≥140mm Hg
(le...
In general, mild to moderate
hypertension in pregnancy reflects a
DBP between 90 and 109mm Hg;
severe hypertension is usua...
Chronic hypertension
diagnosed before pregnancy
or within the first 20 weeks' gestation,
Gestational hypertension
diagnose...
Classification of Hypertensive disorders in
pregnancy
Chronic hypertension
Gestational hypertension
Develops in 2nd half...
Pre Eclampsia-Eclampsia
• Preeclampsia-eclampsia is a syndrome that manifests
clinically as new-onset hypertension in late...
Preeclampsia/eclampsia definitions
Preeclampsia: Hypertension >140/90 with proteinuria
of at least 0.3g/24h
Severe preecla...
Symptoms other than hypertension and
proteinuria in severe preeclampsia
Oliguria (<400 ml/24h)
Cerebral signs (headache, b...
Hypertension in Pregnancy:
When to treat?

CONTROVERSIES ARE….
At what level of BP treatment should be
initiated?
What i...
When to treat
Controversy in mild to moderate
hypertension
B’COZ
Most Anti-hypertensives are in

Category C
of FDA safety...
When to treat…
consensus that
severe hypertension
There is

in pregnancy,

defined as >160/110 mm Hg, requires

treatment,...
When to treat…
consensus that
severe hypertension
There is

in pregnancy,

defined as >160/110 mm Hg, requires

treatment,...
Choice of drugs

The choice of antihypertensive
drugs in pregnancy is often
limited due to fetal safety
concerns.
Factors affecting choice of
anti-hypertensive Drugs


Efficacy



Familiarity and experience with the drug



Knowledge...
Drugs administered during gestational days
0 to 17 (during fertilisation and implantation)
or days 18 to 55 (when organoge...
General Principles for Anti Hypertensive
drugs in Pregnancy
When possible, drugs should be avoided in the first
trimester
...
By What To Treat
•
•
•
•
•
•

Sympatholytics:
Adrenergic receptor Blocker
Vasodilators
Ca Channel blockers
ACE Inhibitors
...
MANAGEMENT
Of
MILD TO MODERATE
HYPERTENSION
BP <160-170 Systolic
< 100-110 Diastolic
There is

no clear consensus on the management
of mild to moderate hypertension

Methyldopa,
Labetalol
Nifedipine
Are acce...
Patients with mild Hypertension who
may be candidate for Therapy
History of severe HTN in Previous pregnancy
History of abruptio Placenta
History of still birth or unexplained neonatal de...
Classes Of Drugs Useful in Treatment
DIURETICS
Furosemide
Thiazides

CENTRALLY
ACTING
DRUGS
Methyl Dopa

DRUGS that Decrea...
Methyldopa
METHYL DOPA
0.5 to 3.0 g/d in 2 divided doses

Safety after first trimester well
documented, including 7 years followup of...
Drug of first choice
r control of mild to moderate'
fo
ypertension in Pregnancy
h
Most commonly Prescribed
st documented s...
Alpha methyl Dopa
• When to start
BP > 110 mm of Hg diastolic
Initial Dose:
250 mg 3-4 times /day
Maximum dose 2gm/day
BP ...
Alpha Methyl Dopa
• Side Effects:
Postural Hypertension(dose reduction)
Depression
Headache
Fatigue
Depression
Drowsiness
...
2 Line Drugs
nd
Calcium channel Blockers
Useful In late pregnancy,
Good control of maternal BP
Including those with pre-eclampsia,
No adve...
Nifedipine/Calcium channel Blockers
30 to 120 mg/d of a slow-release preparation

..May inhibit labor
..Has synergistic ac...
Labetalol


Combined alpha & beta adrenergic blocker



Is a peripheral vascular dilator



As effective as Methyldopa ...
Labetlol
• Non selective B blocker
• Mechanism of action
Blocks –alpha 1 , Beta 1 & 2 receptors
Decreases peripheral Vascu...
Labetalol
200 to 1200 mg/d in 2 to 3 divided
doses

May be associated with fetal
growth restriction
Labetalol
• Side Effects:
Tremors
Headache
Asthma
CCF
Fetal hypoglycemia

• Contrindications:
Hepatic disorders
Asthma
CCF
Choice Between
Alpha Methyl Dopa
Labetalol
Nifedipine
Labetalol was more effective than
methyldopa and nifedipine in
controlling blood pressure in patients
with pregnancy-induc...
Severe Hypertension
There is consensus that severe
hypertension in pregnancy, defined as
>160/110 mm Hg, requires treatmen...
Which Drug Is to be used ?
Do We Have any Choice
Preferrence ?
A recent meta-analysis of 24 trials
(2949 women) in which different
antihypertensive drugs were
compared for the treatment...
Management of severe hypertension


Hydralazine (I.V.)



Labetalol (I.V)



Sublingual Nifidepine



I.V.Isradepine

...
Drugs useful in parenteral
route
1.Labetalol
2.Hydralazine
3.Nifedepine
4.Diazoxide
5.Nitroprusside
Who require par-entral treatment
Hypertensive encephalopathy,
 Hemorrhage, or
 Eclampsia

Target is :
To lower
Mean Art...
Those with hypertensive encephalopathy, hemorrhage, or eclampsia require
treatment with parenteral agents to lower mean ar...
Hydarlazine
Drug of first choice for severe HTN
ADVANTAGES ARE

No adverse effects on fetal circulation,

Long experience...
Hydarlazine
Laimed to be Drug of first choice for
severe HTN
ADVANTAGES ARE

No adverse effects on fetal circulation,

Lo...
Disadvantages of Hydralazine


Adverse effects
Mimicking HEELLP Syndrome



Maternal hypotension



Fetal heart rate de...
 Hydralazine
50 to 300 mg/d in 2 to 4 divided doses

Few controlled trials,
long experience with few adverse
events docume...
Labetalol
Experience with labetalol in the acute
treatment of severe hypertension in
pregnancy is less well documented.

...
Nifedipine

Oral/sublingual has been reported to
be as safe and effective as
intravenous hydralazine for the
acute treatme...
Nifedipine With MgSO4
Has been associated with maternal
hypotension (and fetal distress).

Neuromuscular Blockade has bee...
Isradipine
....a new weapon
Intravenous Isradipine has also been
shown to be effective in severe
pregnancy-associated hype...
Diazoxide

Diazoxide is a potent
antihypertensive

Can interfere with glucose
metabolism.

Should be reserved for patien...
Special Consideratrions
Eclampsia
Prevention of Pre- Eclampsia
Supp

Ecosprin, Antioxidants, Calcium

Pre Conceptional Cou...
Impending eclampsia
Severe preeclampsia with signs of cerebral
affection like visual disturbancies, headache,
increased re...
The treatment of choice for eclampsia
and prophylaxis against recurrent
convulsions is magnesium sulphate
(Lancet 1995: 34...
Magnesium Sulphate
Drug of Choice
for T/t
Of
Eclampsia
Normal serum
concentration
s of Mg2+ are
1.5 to 2.5
mEq/L (1.8 to
3...
”Delivery of the fetus and placenta is the
definitive management of severe
preeclampsia. Once severe disease has
been esta...
Prevention Of Pre-eclampsia
ASPIRIN MAY PREVENT
Low-dose acetylsalicylic acid
(aspirin, 75 mg) is recommended for the
prevention of pre-eclampsia in w...
Calcium Supplementation

In areas where dietary calcium intake
is low, calcium supplementation
during pregnancy (at doses ...
Rest May Not help in prevention
weak Evidence

Advice to rest at home is not
recommended as an intervention for
the primar...
Pre Conceptional Counselling
Indicated in
Patients who are chronic Hypertensive, Planning to
have pregnancy.
ACE Inhibitor...
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Ysg final ppt 27

  1. 1. Anti-Hypertensive Drugs in Pregnancy Present Scenario
  2. 2. PRE TEXT….. Hypertension complicates almost 10% of pregnancies. Progression from mild to severe forms of hypertension during pregnancy is unpredictable and can be rapid. The use of antihypertensive drugs in pregnancy is controversial.
  3. 3. Further, treatment of PIH often involves adjustment between competing concerns for maternal health, gestational age of the infant and fetal exposure to antihypertensive drugs.
  4. 4. During pregnancy, the priority regarding hypertension is in making the correct diagnosis, with the emphasis on distinguishing preexisting (chronic) from pregnancy induced (gestational hypertension and the syndrome of preeclampsia).  American Heart Assoc. Guidelines 2008
  5. 5. Role of Antihypertensive in Pregnancy Antihypertensive agents are mainly used to prevent and treat severe hypertension; to prolong pregnancy for as long as safely possible, thereby maximizing the gestational age of the infant; and to minimize fetal exposure to medications that may have adverse effects. American Heart Assoc. Guidelines 2008
  6. 6. Some Basic Considerations...
  7. 7. Definition Hypertension in pregnancy is Sustained diastolic BP (DBP) ≥90mm Hg; (most accepted) Systolic BP ≥140mm Hg (less commonly accepted) Relative rise in DBP > 15 mm of Hg (Least accepted)
  8. 8. In general, mild to moderate hypertension in pregnancy reflects a DBP between 90 and 109mm Hg; severe hypertension is usually defined as SBP ≥170mm Hg and/or DBP ≥110mm Hg.
  9. 9. Chronic hypertension diagnosed before pregnancy or within the first 20 weeks' gestation, Gestational hypertension diagnosed after 20 weeks' not associated with proteinuria Pre-eclampsia diagnosed after 20 weeks' gestation associated with proteinuria
  10. 10. Classification of Hypertensive disorders in pregnancy Chronic hypertension Gestational hypertension Develops in 2nd half of pregnancy Without significant proteinuria BP normalizes by 6 weeks post partum. Risk of developing preeclampsia is 15-25%. Pre-eclampsia / Eclampsia
  11. 11. Pre Eclampsia-Eclampsia • Preeclampsia-eclampsia is a syndrome that manifests clinically as new-onset hypertension in later pregnancy (any time after 20 weeks, but usually closer to term. With associated • Proteinuria: 1 on dipstick or (300 mg /24 hr Urine) Occurs in 5% to 8% all pregnancies and is thought to be a consequence ofabnormalities in the maternal vessels supplying the placenta
  12. 12. Preeclampsia/eclampsia definitions Preeclampsia: Hypertension >140/90 with proteinuria of at least 0.3g/24h Severe preeclampsia: Preeclampsia with hypertension >160/110 or proteinuria >5g/24h or multiorgan involvement Eclampsia: Convulsions in any woman who has, or then presents with, hypertension in pregnancy of any cause
  13. 13. Symptoms other than hypertension and proteinuria in severe preeclampsia Oliguria (<400 ml/24h) Cerebral signs (headache, blurred vision, altered consciousness) Pulmonary edema, cyanosis Epigastric or right upper quadrant pain Impaired liver function Hepatic rupture Trombocytopenia HELLP syndrome
  14. 14. Hypertension in Pregnancy: When to treat? CONTROVERSIES ARE…. At what level of BP treatment should be initiated? What is target BP for patient undergoing treatment? No evidence to suggest that treatment of gestational or chronic hypertension prevents development of Pre Eclampsia
  15. 15. When to treat Controversy in mild to moderate hypertension B’COZ Most Anti-hypertensives are in Category C of FDA safety list. which states that human studies are lacking, animal studies are either positive for fetal risk or are lacking.
  16. 16. When to treat… consensus that severe hypertension There is in pregnancy, defined as >160/110 mm Hg, requires treatment, because these women are at an increased risk of intracerebral hemorrhage, and that treatment decreases the risk of maternal death. T Podymow, August P. Update on the Use of Antihypertensive Drugs in Pregnancy .Hypertension 2008; 51: 960-969.
  17. 17. When to treat… consensus that severe hypertension There is in pregnancy, defined as >160/110 mm Hg, requires treatment, because these women are at an increased risk of intracerebral hemorrhage, and that treatment decreases the risk of maternal death. T Podymow, August P. Update on the Use of Antihypertensive Drugs in Pregnancy .Hypertension 2008; 51: 960-969.
  18. 18. Choice of drugs The choice of antihypertensive drugs in pregnancy is often limited due to fetal safety concerns.
  19. 19. Factors affecting choice of anti-hypertensive Drugs  Efficacy  Familiarity and experience with the drug  Knowledge of doses and interactions with the drug  Fetal and maternal adverse effects  Effect on utero-placental blood flow  Onset of action  Duration of action  Ease of administration
  20. 20. Drugs administered during gestational days 0 to 17 (during fertilisation and implantation) or days 18 to 55 (when organogenesis takes place) can critically interrupt fetal structural development. After day 55, the developing fetus is more resistant to drugs although noxious agents can cause fetal deformation by decreasing cell size and number.
  21. 21. General Principles for Anti Hypertensive drugs in Pregnancy When possible, drugs should be avoided in the first trimester    Monotherapy with older and familiar antihypertensives known to have minimal or no maternal or fetal adverse effects is preferred Episodic treatment should be avoided All antihypertensive drugs affect the mother and the fetus.
  22. 22. By What To Treat • • • • • • Sympatholytics: Adrenergic receptor Blocker Vasodilators Ca Channel blockers ACE Inhibitors Angiotensin receptor blockers
  23. 23. MANAGEMENT Of MILD TO MODERATE HYPERTENSION BP <160-170 Systolic < 100-110 Diastolic
  24. 24. There is no clear consensus on the management of mild to moderate hypertension Methyldopa, Labetalol Nifedipine Are acceptable oral antihypertensive agents for this scenario.
  25. 25. Patients with mild Hypertension who may be candidate for Therapy
  26. 26. History of severe HTN in Previous pregnancy History of abruptio Placenta History of still birth or unexplained neonatal death Marked obesity Older than 35 years Hypertension for more than !5 years.
  27. 27. Classes Of Drugs Useful in Treatment DIURETICS Furosemide Thiazides CENTRALLY ACTING DRUGS Methyl Dopa DRUGS that Decrease Cardiac output Beta Blockers Propanolol Vasopdilators Labetalol Fenoldopam Nicardipine Nifidepine Prazosin Hydralazine
  28. 28. Methyldopa
  29. 29. METHYL DOPA 0.5 to 3.0 g/d in 2 divided doses Safety after first trimester well documented, including 7 years followup of offsprings
  30. 30. Drug of first choice r control of mild to moderate' fo ypertension in Pregnancy h Most commonly Prescribed st documented safety record Be Maternal and Fetal safety record, (4.5 to 7.5 year) Follow up data. Does not alter maternal Cardiac output Uterine blood flow and Renal blood flow.
  31. 31. Alpha methyl Dopa • When to start BP > 110 mm of Hg diastolic Initial Dose: 250 mg 3-4 times /day Maximum dose 2gm/day BP not controlled : add other drug
  32. 32. Alpha Methyl Dopa • Side Effects: Postural Hypertension(dose reduction) Depression Headache Fatigue Depression Drowsiness Salt And water retention----Rebound Htn ( add diuretics) Abnormal LFT
  33. 33. 2 Line Drugs nd
  34. 34. Calcium channel Blockers Useful In late pregnancy, Good control of maternal BP Including those with pre-eclampsia, No adverse fetal or perinatal effects.   Little data regarding their safety in early pregnancy Nifidepine is Most Commonly used drug
  35. 35. Nifedipine/Calcium channel Blockers 30 to 120 mg/d of a slow-release preparation ..May inhibit labor ..Has synergistic action with magnesium sulfate in BP lowering; ..Little experience with other calcium entry blockers
  36. 36. Labetalol  Combined alpha & beta adrenergic blocker  Is a peripheral vascular dilator  As effective as Methyldopa in pre-eclamptic and non-proteinuric hypertension in pregnancy. as safe as methyl dopa  PROBABLY  Long term safety not established  2nd Line drug for this reason
  37. 37. Labetlol • Non selective B blocker • Mechanism of action Blocks –alpha 1 , Beta 1 & 2 receptors Decreases peripheral Vascular resistance No effect on utero-placental blood flow Cardiac output not affected •
  38. 38. Labetalol 200 to 1200 mg/d in 2 to 3 divided doses May be associated with fetal growth restriction
  39. 39. Labetalol • Side Effects: Tremors Headache Asthma CCF Fetal hypoglycemia • Contrindications: Hepatic disorders Asthma CCF
  40. 40. Choice Between Alpha Methyl Dopa Labetalol Nifedipine
  41. 41. Labetalol was more effective than methyldopa and nifedipine in controlling blood pressure in patients with pregnancy-induced hypertension while methyldopa and nifedipine are equally effective in controlling blood pressure. IJBCP International Journal of Basic & Clinical Pharmacology.
  42. 42. Severe Hypertension There is consensus that severe hypertension in pregnancy, defined as >160/110 mm Hg, requires treatment, because these women are at an increased risk of intracerebral hemorrhage, and that treatment decreases the risk of maternal death.
  43. 43. Which Drug Is to be used ? Do We Have any Choice Preferrence ?
  44. 44. A recent meta-analysis of 24 trials (2949 women) in which different antihypertensive drugs were compared for the treatment of severe hypertension in pregnancy concluded that there is insufficient data to favor one agent over another.
  45. 45. Management of severe hypertension  Hydralazine (I.V.)  Labetalol (I.V)  Sublingual Nifidepine  I.V.Isradepine  Diazoxide  Sodium Nitroprusside
  46. 46. Drugs useful in parenteral route 1.Labetalol 2.Hydralazine 3.Nifedepine 4.Diazoxide 5.Nitroprusside
  47. 47. Who require par-entral treatment Hypertensive encephalopathy,  Hemorrhage, or  Eclampsia Target is : To lower Mean Arterial Pressure by 25% over minutes to hours and then to further lower BP to 160/100 mm Hg over subsequent hours Caution: Avoid Hypotension
  48. 48. Those with hypertensive encephalopathy, hemorrhage, or eclampsia require treatment with parenteral agents to lower mean arterial pressure by 25% over minutes to hours and then to further lower BP to 160/100 mm Hg over subsequent hours. In treating severe hypertension, it is important to avoid hypotension, because the degree to which placental blood flow is autoregulated is not established, and aggressive lowering may
  49. 49. Hydarlazine Drug of first choice for severe HTN ADVANTAGES ARE No adverse effects on fetal circulation,  Long experience with the drug in this clinical setting,  Convenient administration 
  50. 50. Hydarlazine Laimed to be Drug of first choice for severe HTN ADVANTAGES ARE No adverse effects on fetal circulation,  Long experience with the drug in this clinical setting,  Convenient administration 
  51. 51. Disadvantages of Hydralazine  Adverse effects Mimicking HEELLP Syndrome  Maternal hypotension  Fetal heart rate deceleration   Possible increased tendency to cause serious ventricular arrhythmias compared with labetalol May cause neonatal thrombocytopenia
  52. 52.  Hydralazine 50 to 300 mg/d in 2 to 4 divided doses Few controlled trials, long experience with few adverse events documented; useful in combination with sympatholytic agent;
  53. 53. Labetalol Experience with labetalol in the acute treatment of severe hypertension in pregnancy is less well documented.  Studies suggest that parenteral use of labetalol is at least effective and safe as hydralazine.  Fetal distress and neonatal bradycardia have been reported. 
  54. 54. Nifedipine Oral/sublingual has been reported to be as safe and effective as intravenous hydralazine for the acute treatment of severe hypertension in pregnancy.
  55. 55. Nifedipine With MgSO4 Has been associated with maternal hypotension (and fetal distress).  Neuromuscular Blockade has been reported.    While the drugs should be used together with caution, their combined use is common practice in some delivery suites. Short-acting nifedipine capsules have been withdrawn in some countries
  56. 56. Isradipine ....a new weapon Intravenous Isradipine has also been shown to be effective in severe pregnancy-associated hypertension, although it has not been extensively studied in this clinical setting
  57. 57. Diazoxide Diazoxide is a potent antihypertensive  Can interfere with glucose metabolism.  Should be reserved for patients with severe hypertension unresponsive to hydralazine, nifedipine or labetalol. 
  58. 58. Special Consideratrions Eclampsia Prevention of Pre- Eclampsia Supp Ecosprin, Antioxidants, Calcium Pre Conceptional Counselling
  59. 59. Impending eclampsia Severe preeclampsia with signs of cerebral affection like visual disturbancies, headache, increased reflexes, and clonus BJA 1996: 76: 133-148
  60. 60. The treatment of choice for eclampsia and prophylaxis against recurrent convulsions is magnesium sulphate (Lancet 1995: 345: 1456-1463) Magnesium sulphate is also the drug of choice for seizure prophylaxis in patients with preeclampsia (Lancet 2002: 359: 1877-1890)
  61. 61. Magnesium Sulphate Drug of Choice for T/t Of Eclampsia Normal serum concentration s of Mg2+ are 1.5 to 2.5 mEq/L (1.8 to 3.0 mg/dL), Has Narrow Range of Therapeutic Safety Areflexia, particularly loss of the patellar deep tendon reflex, has been observed at 8 to 10 mEq/L Respiratory Serum paralysis Concentrari seen at ons >13 mEq/L between 3.5-7 meq/l
  62. 62. ”Delivery of the fetus and placenta is the definitive management of severe preeclampsia. Once severe disease has been established and is progressing, delivery of the fetus and placenta must be accomplished to limit maternal risk.” Int Care Med 1997: 23: 248-255
  63. 63. Prevention Of Pre-eclampsia
  64. 64. ASPIRIN MAY PREVENT Low-dose acetylsalicylic acid (aspirin, 75 mg) is recommended for the prevention of pre-eclampsia in women at high risk of developing the Condition WHO Guidelibes 2010
  65. 65. Calcium Supplementation In areas where dietary calcium intake is low, calcium supplementation during pregnancy (at doses of 1.5–2.0 g elemental calcium/day) is recommended for the prevention of pre-eclampsia in all women, but especially those at high risk of developing pre-eclampsia
  66. 66. Rest May Not help in prevention weak Evidence Advice to rest at home is not recommended as an intervention for the primary prevention of preeclampsia and hypertensive disorders of pregnancy in womenconsidered to be at risk of developing those condition
  67. 67. Pre Conceptional Counselling Indicated in Patients who are chronic Hypertensive, Planning to have pregnancy. ACE Inhibitors may be replaced with other drugs as they are fetotoxic
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