Anti-Hypertensive Drugs in Pregnancy

Present Scenario

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.

Further, treatment of PIH often involves adjustment between

competing concerns for maternal health, gestational age of the infant and fetal

exposure to antihypertensive drugs.

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

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

Some Basic Considerations...

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)

Definition

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.

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

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

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

Preeclampsia/eclampsia definitions

Preeclampsia: Hypertension >140/90 with proteinuria of at least 0.3g/24hSevere preeclampsia: Preeclampsia with hypertension >160/110 or proteinuria >5g/24h or multiorgan involvementEclampsia: Convulsions in any woman who has, or then presents with, hypertension in pregnancy of any cause

Symptoms other than hypertension and proteinuria in severe preeclampsia

Oliguria (<400 ml/24h)Cerebral signs (headache, blurred vision, altered consciousness)Pulmonary edema, cyanosisEpigastric or right upper quadrant painImpaired liver functionHepatic ruptureTrombocytopeniaHELLP syndrome

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

Hypertension in Pregnancy:When to treat?

When to treatControversy in mild to moderate

hypertensionB’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.

When to treat…

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.

T Podymow, August P. Update on the Use of Antihypertensive Drugs in Pregnancy .Hypertension 2008; 51: 960-969.

When to treat…

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.

T Podymow, August P. Update on the Use of Antihypertensive Drugs in Pregnancy .Hypertension 2008; 51: 960-969.

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 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

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.

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.

By What To Treat

• Sympatholytics:• Adrenergic receptor Blocker• Vasodilators• Ca Channel blockers• ACE Inhibitors• Angiotensin receptor blockers

MANAGEMENTOf

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, LabetalolNifedipine

Are acceptable oral antihypertensive agents for this scenario.

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 death

Marked obesity

Older than 35 years

Hypertension for more than !5 years.

Classes Of Drugs Useful in Treatment

DIURETICS

Furosemide

Thiazides

DRUGS that Decrease Cardiac output

Beta Blockers

Propanolol

VasopdilatorsVasopdilators

LabetalolLabetalol

FenoldopamFenoldopam

NicardipineNicardipine

NifidepineNifidepine

PrazosinPrazosin

HydralazineHydralazine

CENTRALLY CENTRALLY ACTING ACTING DRUGSDRUGS

Methyl DopaMethyl Dopa

Methyldopa

METHYL DOPA

0.5 to 3.0 g/d in 2 divided doses

Safety after first trimester well documented, including 7 years follow-up of offsprings

Drug of first choice

for control of mild to moderate'

hypertension in Pregnancy

Most commonly Prescribed

Best documented safety record

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.

Alpha methyl Dopa

• When to start BP > 110 mm of Hg diastolicInitial Dose: 250 mg 3-4 times /day Maximum dose 2gm/day BP not controlled : add other

drug

Alpha Methyl Dopa

• Side Effects: Postural Hypertension(dose reduction) Depression Headache Fatigue Depression Drowsiness Salt And water retention----Rebound Htn ( add diuretics) Abnormal LFT

2nd Line Drugs

Calcium channel Blockers

Useful In late pregnancyUseful 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

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

Labetalol Combined alpha & beta adrenergic blockerCombined alpha & beta adrenergic blocker Is a peripheral vascular dilator As effective as Methyldopa in pre-eclamptic and

non-proteinuric hypertension in pregnancy. PROBABLY as safe as methyl dopa Long term safety not established 2nd Line drug for this reason

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•

Labetalol

200 to 1200 mg/d in 2 to 3 divided doses

May be associated with fetal growth restriction

Labetalol • Side Effects:Side Effects: Tremors Headache Asthma CCF Fetal hypoglycemia• Contrindications: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-induced hypertension while methyldopa

and nifedipine are equally effective in controlling blood

pressure.

IJBCP International Journal of Basic & Clinical Pharmacology.

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.

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 of severe hypertension in pregnancy concluded that there is insufficient data to favor one agent over another.

Management of severe hypertension

Hydralazine (I.V.) Labetalol (I.V) Sublingual Nifidepine I.V.Isradepine Diazoxide Sodium Nitroprusside

Drugs useful in parenteral route

1.Labetalol2.Hydralazine3.Nifedepine4.Diazoxide5.Nitroprusside

Who require par-entral treatmentWho require par-entral treatmentHypertensive 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

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

cause fetal distress.

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

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

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

 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;

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.

Nifedipine

Oral/sublingual has been reported to be as safe and effective as

intravenous hydralazine for the acute treatment of severe

hypertension in pregnancy.

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

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

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.

Special Consideratrions

Eclampsia

Prevention of Pre- Eclampsia

Ecosprin, Antioxidants, Calcium Supp

Pre Conceptional Counselling

Impending eclampsia

Severe preeclampsia with signs of cerebral affection like visual disturbancies, headache, increased reflexes, and clonus

BJA 1996: 76: 133-148

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)

Magnesium Sulphate

Drug of Choice for T/t

Of

Eclampsia

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 paralysis

seen at >13 mEq/L

Serum Concentrari

ons between

3.5-7 meq/l are

therapeutic

Normal serum concentrations of Mg2+ are 1.5 to 2.5 mEq/L (1.8 to 3.0 mg/dL),

”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

Prevention Of Pre-eclampsia

ASPIRIN MAY PREVENT

Low-dose acetylsalicylic acid (aspirin, 75 mg) is recommended for theprevention of pre-eclampsia in women at

high risk of developing theCondition

WHO Guidelibes 2010

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

Rest May Not help in preventionweak Evidence

Advice to rest at home is not recommended as an intervention for

the primary prevention of pre-eclampsia

and hypertensive disorders of pregnancy in womenconsidered to

be at risk of developing those condition

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