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 Antihypertensives

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Chronic Hypertension (CHTN)

CHTN during pregnancy is associated with an increased risk for for superimposed preeclampsia , fetal growth restriction , stillbirth,  and placental aruption.   In addition, women with significant renal disease (serum creatinine > 1.4 mg/dL)  may experience deterioration of renal function during pregnancy [6,8] .

Evaluation

Evaluation for identifiable causes of HTN , comorbid disorders(e.g., cardiovascular disease, renal disease or pre-existing diabetes mellitus), and end organ damage that may affect prognosis and treatment is recommended [3,6,8].

  • In addition to a history and physical recommended baseline laboratories should include serum creatinine, and 24-hour urine evaluation for total protein and creatinine clearance [3,11], potassium ,hematocrit, hemoglobin, platelet count, uric acid [3], and ALT, AST [2].

  • For long standing HTN 12-lead electrocardiography, echocardiography, ophthalmologic examination, and renal ultrasonography should be considered [8].

  • Test for secondary causes of HTN if blood pressure control is not achieved or the clinical and routine laboratory evaluation strongly suggests an identifiable secondary cause (i.e., vascular bruits, symptoms of catecholamine excess, hypokalemia, or  hypercalcemia ).

  • An initial sonogram of the fetus to assess the fetal age should be performed at 18 to 20 weeks. Assessment of fetal growth should be performed at 28 to 32 weeks' and monthly thereafter. If there is evidence of fetal growth restriction, then the fetus should be assessed nonstress tests or biophysical profile as indicated [3].


Treatment

Women on multiple antihypertensive agents, End Organ Damage , or Comorbid Conditions

    The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) advises antihypertensive medication should be continued as needed to control blood pressure in women on multiple antihypertensive agents, end organ damage , or comorbid conditions [6].

Mild Hypertension

    The JNC7 advises that women with mild hypertension are at low risk for cardiovascular complications during pregnancy and are candidates for lifestyle modification [6].

    Regarding lifestyle modifications:

    • Avoidance of inter-pregnancy weight gain, increased rest at home in the third trimester, and reduction of workload or stress may be helpful in preventing preeclampsia in women at increased risk for developing preeclampsia [2].
    • New dietary salt restriction is not recommended  [2].
    • Aerobic exercise is not recommended [2,6]
    • Weight loss during pregnancy is not recommended[2,6]
    • Use of alcohol and tobacco must be strongly discouraged [2,6]

    There is no evidence that pharmacological treatment improves neonatal outcomes in women with mild hypertension[9]. However, treatment-induced reduction in mean arterial pressure may increase the frequency of small for gestational age (SGA) infants [10].

"In all cases, treatment should be re-instituted once BP reaches 150–16mmHg
systolic or 100–110 mmHg diastolic, in order to prevent increases in BP to very high levels during pregnancy." [6]

The SOGC recommends [1] :

  • For women without comorbid conditions, should be used to keep systolic BP at 130–155 mmHg and diastolic BP at 80–105 mmHg. (III-C)
     
  • For women with comorbid conditions, should be used to keep systolic BP at 130–139 mmHg and diastolic BP at 80–89 mmHg.

Medications

Antihypertensives

For patients already on antihypertensive medications it is recommended that atenolol , angiotensin-converting enzyme (ACE) inhibitors, and AII receptor antagonists should be discontinued [3,6,8]. Except for rare conditions such as renal crisis associated with scleroderma [12] ACE inhibitors should not be used during pregnancy, because the use of ACE inhibitors during pregnancy has been associated with birth defects, fetal renal failure, and fetal death [8,13].

Methyldopa and labetalol are considered first-line antihypertensive therapies during pregnancy  by the American Congress of Obstetricians and Gynecologists (ACOG) [8]. Long-acting oral nifedipine may also be used [2,8,14]. Diuretics are not contraindicated in pregnancy except in settings where uteroplacental perfusion is already reduced (preeclampsia and intrauterine growth restriction [3]

Preeclampsia Prevention

The SOGC recommends low dose aspirin (75 to 100 mg) in women at increased risk of preeclampsia [2,15]. Calcium supplementation (of at least1 g/d) is recommended for women with low calcium intake [2,16].

Postpartum [2]

  • Blood pressure should be monitored closely during  the three to six days after delivery when blood pressure is at its peak postpartum .

  • Hypertension should be treated to keep systolic BP < 160 mmHg and diastolic BP < 110 mmHg.

  • Antihypertensive agents compatible with  breastfeeding include nifedipine XL, labetalol, methyldopa,  and enalapril.

  • Non-steroidal anti-inflammatory drugs (NSAIDs) should not be given post partum if hypertension is difficult to control or if there is oliguria, an elevated creatinine, or platelets < 50 X 109/L.


Methyldopa [14,19]
Antihypertensive. MW: 238.24,
Central nervous system α2-adrenergic agonist agonist

  • Treatment of hypertension

    Starting dosage is 250 mg orally two to three times a day in the first 48 hours.
    The maximum decrease in blood pressure occurs four to six hours after oral dosage.
    Adjust dose, preferably, at intervals of not less than two days
    The usual daily dosage of methyldopa is 500 mg to 2 g in two to four divided doses.
    The maximum recommended daily dosage is 3 grams.
    Occasionally tolerance may occur, usually between the second and third month of therapy.


Contraindicated in patients with active hepatic disease, or liver disorders previously associated with methyldopa therapy

  • Positive Coombs test, hemolytic anemia, liver disorders , and rarely granulocytopenia may occur.
  • May interfere with the diagnosis of pheochromocytoma since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines.
     

(250, 500 mg tablets)

 


Labetalol [14,20]
Antihypertensive MW 364.87
Adrenergic receptor blocking agent that has both selective alpha1- and nonselective beta-adrenergic receptor blocking actions.

  • Treatment of hypertension

    Initial dose is 100 mg orally twice daily.
    Full antihypertensive effect of labetalol is usually seen within the first 1 to 3 hours of the initial dose
    Dosage may be titrated in increments of 100 mg b.i.d. every 2 or 3 days.
    Titration increments should not exceed 200 mg twice daily.
    The usual maintenance dosage of labetalol is between 200 and 400 mg twice daily.
    Should side effects (principally nausea or dizziness) occur with these doses administered twice daily, the same total daily dose administered three times daily may improve tolerability and facilitate further titration.
    Patients with severe hypertension may require 1200  mg per day.


    Contraindicated in bronchial asthma, overt cardiac failure, greater-than-first-degree heart block, cardiogenic shock, severe bradycardia, other conditions associated with severe and prolonged hypotension,
    Use with caution in patients with impaired hepatic function since metabolism of the drug may be diminished.
     
  • Pheochromocytoma: Labetalol HCl has been shown to be effective in lowering the blood pressure and relieving symptoms in patients with pheochromocytoma. However, paradoxical hypertensive responses have been reported in a few patients with this tumor; therefore, use caution when administering labetalol HCl to patients with pheochromocytoma.

(100,200,300 mg tablets)


Nifedipine Extended Release [14,21]
Long Acting Calcium channel blocker. MW: 346.3
  • Treatment of hypertension

    Starting dosage is 30 or 60 mg orally once daily swallowed (tablets should not be bitten or divided).
    Plasma drug concentrations plateau at approximately six hours after the first dose. Steady-state plasma levels are achieved on the second day of dosing.
    Titration should proceed over a 7–14 day period .
    Maximum dose 120 mg

     
  • Headache common side effect. Mild to moderate peripheral edema may occur in a dose dependent manner .
  • Transient, but occasionally significant elevations of enzymes such as alkaline phosphatase, CPK, LDH, SGOT and SGPT may also occur .
(30 mg, 60 mg,  and 90 mg tablets )

 
Hydrochlorothiazide [14, 22,23]
Diuretic and antihypertensive M.W. 297.74
  • Treatment of hypertension

    12.5 to 25 mg daily given as a single dose. The dose may be increased to 50 mg daily, given as a single or two divided doses. Doses above 50 mg are often associated with marked reductions in serum potassium
     
  • Thiazides are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy

    The usual adult dosage is 25 to 100 mg daily as a single or divided dose. Many patients with edema respond to intermittent therapy, i.e., administration on alternate days or on three to five days each week. With an intermittent schedule, excessive response and the resulting undesirable electrolyte imbalance are less likely to occur.
    After oral use diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.

    Contraindicated in anuria, hypersensitivity to this product or to other sulfonamide-derived drugs.
     

  • Use with caution in severe renal disease. In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics
  • All patients receiving diuretic therapy should be observed for evidence of fluid or electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia
  • Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.

(25 mg tablets)


POSTPARTUM [2,24]

  • Blood pressure should be monitored closely during  the three to six days after delivery when blood pressure is at its peak postpartum .

  • Hypertension should be treated to keep systolic BP < 160 mmHg and diastolic BP < 110 mmHg.

  • Ergometrine should not be given in any form.

  • The choice of antihypertensive to use should take into account the drugs compatibility with breast feeding, and the presence of associated conditions in which there are compelling indications for use of a particular treatment.
  • Antihypertensive agents compatible with breastfeeding include nifedipine XL, labetalol, methyldopa,and enalapril.


Enalapril [25]
Angiotensin converting enzyme inhibitor M.W. 492.53

  • Treatment of hypertension postpartum

    Initial dose in patients not on diuretics is 5 mg once a day.
    For patients on diuretics or with creatinine clearance ≤ 30 mL/min (serum creatinine ≥ 3 mg/dL), an initial dose of 2.5 mg should be used under medical supervision for at least two hours
    Onset of antihypertensive activity in most patients is one hour with peak reduction of blood pressure achieved by four to six hours.
    Dosage should be adjusted according to blood pressure response.
    The usual dosage range is 10 to 40 mg per day administered in a single dose or two divided doses.
    In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients, an increase in dosage or twice daily administration should be considered.

    CONTRAINDICATED in  patients with a history of angioedema and pregnant patients . Use during pregnancny may cause fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Use with caution in patients with renal artery stenosis

    Side effects may include angioedema of the face, extremities, lips, tongue, glottis and/or larynx , cough, headache, rash, weakness, hypotension in patients on diuretics, hyperkalemia, neutropenia, diarrhea, and dizziness.
     

 (2.5 mg, 5 mg, 10 mg or 20 mg tablets)


REFERENCES:

2. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. Society of Obstetricians and Gynaecologists of Canada (SOGC)Clinical Practice guideline. J Obstet Gynaecol Can. 2008 Mar;30(7):S http://www.sogc.org/guidelines/documents/gui206CPG0803_001.pdf Accessed 7/12/2010

3. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol  2000;183:S1–S22  PMID: 10920346

4. Martin JN Jr
et al., Stroke and severe preeclampsia and eclampsia: a paradigm shift focusing on systolic blood pressure. Obstet Gynecol. 2005 Feb;105(2):246-54.PMID: 15684147

5. Why mothers die 1997-1999. The confidential enquiries into maternal
deaths in the UK. London: RCOG Press;2001.

6. Chobanian AV, et al. ; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee.Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003 Dec;42(6):1206-52. Epub 2003 Dec 1.PMID: 14656957

7. Lim KH, et al. The clinical utility of serum uric acid measurements in hypertensive diseases of pregnancy. Am J Obstet Gynecol. 1998 May;178(5):1067-71.PMID: 9609585

8 ACOG Practice Bulletin. Chronic hypertension in pregnancy. ACOG Committee on Practice Bulletins. Obstet Gynecol. 2001 Jul;98(1):suppl 177-85. PMID: 11508256

9.Abalos E, et al. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD002252. Review.
PMID: 17253478

10. von Dadelszen P, Magee LA.Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: an updated metaregression analysis.J Obstet Gynaecol Can. 2002 Dec;24(12):941-5.PMID: 12464992

11. Côté AM, Monitoring Renal Function in Hypertensive Pregnancy.Hypertens Pregnancy. 2009 Nov 27. PMID: 19943769

12. Steen VD.Pregnancy in scleroderma.Rheum Dis Clin North Am. 2007 May;33(2):345-58, vii. Review. PMID: 17499711

13 Cooper WO, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med. 2006 Jun 8;354(23):2443-51. PMID: 16760444

14. Podymow T and August P. Update on the use of antihypertensive drugs in pregnancy.Hypertension. 2008 Apr;51(4):960-9. Epub 2008 Feb 7. PMID: 18259046

15.Duley L, Henderson-Smart DJ, Knight M, King JF. Antiplatelet agents for
preventing pre-eclampsia and its complications. Cochrane Database Syst
Rev 2004;CD004659.

16. Hofmeyr GJ, Atallah AN, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev 2006;3:CD001059

17. Walters BN, Walters T.  Hypertension in the puerperium.Lancet. 1987 Aug 8;2(8554):330. PMID: 2886783

18. Ferrazzani S, De Carolis S, Pomini F, Testa AC, Mastromarino C, Caruso A. The duration of hypertension in the puerperium of preeclamptic women: relationship with renal impairment and week of delivery. Am J Obstet Gynecol 1994;171:506-12.

19. 1. Package insert Mylan Pharmaceuticals Inc. March 2006
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=4814

20. Package insert Watson Laboratories, Inc. July 2007 http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=8802

21. Package insert Procardia XL Pfizer February 2010
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=16918

22. Unichem Laboratories August 2008 http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=18964

23. Collins R, Yusuf S, Peto R. Overview of randomized trials of diuretics in pregnancy. Br Med J (Clin Res Ed) 1985; 290:17–23
24.  American Academy of Pediatrics. Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics. 2001;108:776-89. PMID: 11533352

25. Package insert Merck Sharp & Dohme Ltd. March 2008http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=11894
 

26. Ahn HK, et al. Exposure to amlodipine in the first trimester of pregnancy and during breastfeeding. Hypertens Pregnancy. 2007;26(2):179-87. PMID: 17469008

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