Beta-adrenergic blockers in pregnancy

CURRICULUM

IN CARDIOLOGY

Beta-adrenergic William

H. Frishman,

blockers M.D., and Michael

in pregnancy Chesner, M.D. Bronx,

The therapeutic indications for &adrenergic blocking drugs are varied. These drugs have proven efficacy in the treatment of hypertension, arrhythmias, hyperthyroidism, atherosclerotic heart disease, essential tremor, migraine headache, and glaucoma.’ Many of these conditions will manifest themselves during the reproductive years of the female patient. The desire to ensure both maternal health and normal fetal growth and development has led to questions regarding the safety of P-blocker use during pregnancy. In this review, the world experience with P-blocker treatment during pregnancy is assessed. Recommendations concerning p-blocker administration during pregnancy are proposed in light of this world experience. ADRENERGIC PHYSIOLOGY

INFLUENCE

ON MATERNAL-FETAL

/3-adrenergic activity during pregnancy assumes physiologic importance because of the direct effects the sympathetic nervous system have on umbilical blood flow and uterine tone and contract:ility (Table I). Because of the difficulty in studying humans and the need to separate direct from indirect sympathetic effects, most experimental work on umbilical blood flow has been conducted in the pregnant ewe. Oakes et a1.2 studied the effects of propranolol and isoproterenol in nonlaboring, anesthetized, pregnant sheep that were near term. During fetal or maternal infusion of the P-blocker, there was a significant decrease in umbilical blood flow and in the maternal and fetal heart rate. Uterine blood flow and systemic blood pressure remained unchanged. With isoproterenol infusion, there was an increase in umbilical blood flow and only a small increment in fetal heart rate. It may therefore be concluded that P-adrenergic tone affects basal umbilical blood flow and a disturbance in sympathetic inputs could be potentially harmful to the developing fetus. From the Department of Medicine, Einstein College of Medicine. Received Reprint Einstein

for publication

June

requests: William College of Medicine,

Division

22, 1987;

accepted

of Cardiology, Aug.

The

Albert

3, 1987.

H. Frishman, M.D., Hospital of the Albert 1825 Eastchester Road, Bronx, NY 10461.

N.Y.

a-agonists influence umbilical blood flow indirectly, through their action on uterine blood vessels. When a low dose of norepinephrine was infused directly into a uterine artery, a profound reduction in utero-placental blood flow developed.3 A direct action of norepinephrine on the umbilical circulation has not been demonstrated.4r5 In the myometrium, there are adrenergic receptors of the 01 and /3 types. Stimulation of the ,&receptor results in myometrial relaxation, whereas increased a-adrenergic stimulation potentiates contractility.‘j In animal studies, propranolol has been shown to reverse the myometrial depressant action of fi-stimulation.7 Barden et al.* also demonstrated this effect of propranolol in pregnant humans. In their study, pregnant women at term were selected for elective induction of labor. Maternal and fetal heart rates, maternal blood pressure, and intrauterine pressure were measured in all patients. After an infusion of oxytocin to eight patients, epinephrine was administered and caused a consistent inhibition of uterine activity, while accelerating maternal heart rate. These effects were completely reversed by prior propranolol treatment. Norepinephrine infusion potentiated uterine activity, while decreasing maternal heart rate and increasing blood pressure. Prior propranolol treatment had no effect, whereas the a-adrenergic blocker, phentolamine, significantly attenuated the actions of norepinephrine. After these studies, all the subjects had normal term vaginal deliveries. The influence of the autonomic nervous system on normal fetal circulation has also been studied in the fetal lamb preparation. In a report by Joelson and Barton,g isoproterenol administered to the fetus caused an increase in heart rate and a decrease in blood pressure, whereas propranolol caused only a slight drop in heart rate. It was apparent that the effects of P-adrenergic blockade in the unstressed and undisturbed fetus were minimal. However, when the fetus is stressed, stimulation of the ,& receptor may provide an important reserve for neonatal adaptation. Thus, maternal treatment with @-blockers may impair the response to fetal distress. 147

Januarrm3a American HeartJournral

14%

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and Chesner

Table

I. Effects of alpha- and beta-adrenergic receptor stimulation

and blockade

on maternal-fetal

Stimulation a-receptor

Fetal heart rate Maternal heart rate Umbilical blood Bow Myometrical activity --

physiology

Blockade @-receptor

a-receptor

P-receptor

ct+ tt

= no effect.;t = increase; 1 = decrease.

Table

II. Reported

adverse effects of beta-blocking

drugs

in pregnancy and in the neonate 1. 2. 3. 4. 5. 6.

CLINICAL

Intrauterine growth retardation Maternal and fetal bradycardia Premature labor Delayed neonatal breathing Neonatal hypoglycemia Neonatal hyperbilirubinemia

EXPERIENCE

Propranolol. Propranolol, the oldest of the available nonselective P-blockers, was the first such agent to have wide application in pregnant patients. Since its early use in the late 1960’s, many favorable reports have accumulated. The drug has been employed successfully in the treatment of gestational hypertension,‘O thyrotoxicosis,ll obstructive cardiomyopathy,12 paroxysmal atria1 tachycardia,13 dysfunctional uterine activity,14 and fetal tachycardia.15 Despite this encouraging experience in therapy, many severe adverse reactions have also been reported (Table II). The most consistent observation has been intrauterine fetal growth retardation. In a long-term study of 12 human pregnancies, during which propranolol was administered over a long period of time, Pruyn et a1.16demonstrated poor intrauterine growth in half of the cases. They suggested that the experimental model of decreased umbilical blood flow in the ewe after long-term propranolol administration could deprive the growing fetus of needed nutrients and thus impair growth. In contrast to the findings of Pruyn et a1.,16in five prospective studies with propranolol and oxpreno101,10,17-20 the incidence of retardation of uterine growth in 94 pregnancies was approximately 4%. In addition, two of the mothers whose babies were small for gestational age had normal-sized babies in subsequent pregnancies despite continued propran0101therapy.20 It would therefore seem inappropriate

to conclude that P-adrenergic blockade during pregnancy is commonly associated with retardation of intrauterine growth.21 Livingstone et a1.F2 in a 3-year randomized prospective study, compared methyldopa to proprano101 in 28 women with pregnancy-associated hypertension and found both drugs to be equally effective in the treatment of maternal hypertension. No significant difference in the birth weights of the babies in each group were reported, although one infant born to a mother receiving propranolol bad symptomatic hypoglycemia. Both this study and one by Taylor et a1.23demonstrated transfer of propran0101 into breast milk, although not in quantities that would appear to adversely affect the infant, as had been reported in the past. In a study measuring the fetal heart rate response to a controlled sound stimulus, Jensen24 has reported that a single 80 mg oral dose of propranolol given to pregnant women was of sufficient magnitude to affect the fetal heart rate response to those stimuli. While the study demonstrates a sensitive indicator of fetal drug absorption, possible long-term consequences are not addressed. Other reported adverse effects in the fetus include birth apnea,26 bradycardiaYZ6 hypoglycemia,27 polycythemia,28 hyperbilirubinemia,16 and prolonged labor,26 as well as a case report of fetal death associated with propranolol administration.2g None of the above reactions were reported consistently in studies with chronic therapy. Many of these reactions may represent the consequences of fetal distress occurring in high-risk obstetric patients. However, these isolated case reports deserve close attention and consideration. It would appear that in the presence of hypoxia or other stresses, P-blockade would be especially counterproductive in its blocking activation of the sympathetic nervous system.g On the other hand, babies born to mothers treated with propranolol in uncomplicated deliveries would not be expected to have any serious cardiac alterations attributable to pblockade. In treating any pregnant patient with

Volume Number

1 IS 1, Part t

propranolol, the benefits of this treatment can be weighed against adverse effects upon the fetus. Metoprolol. Metoprolol is a &-selective blocking agent. It is similar in its effectiveness to other nonselective /3-adrenoreceptor blocking #drugs used in the treatment of angina pectoris30 or essential hypertension. 31 Because of its primary ,&-selective properties, the drug would theoretically not interfere with &-mediated peripheral vasodilatation or & effects on uterine tone. In a large-scale clinical study?’ 1011 pregnant patients with systemic hypertension were treated with metoprolol alone or in combination with hydralazine and a diuretic for a mean Iperiod of 4 weeks during pregnancy. This group was compared with 97 hypertensive gravidas treated with hydralazine. Perinatal mortality was lower in the metopro101group, as was the rate of fetal growth retardation. No significant adverse effects were reported in the fetus. Apparently, metoprolol, like propranolol,27 crosses the placenta; however, the concentration of the drug was relatively low in the umbilical blood samples. This low drug level in the umbilical circulation was thought to be related to poor maternal drug absorption, as maternal blood levels were also comparatively low. However, there may be another possible reason for the low serum levels of metopro101. Hogstedt et al .33 have shown that metoprolol clearance during pregnancy was related to increased hepatic metabolism of the drug via the hepatic monoxygenase system. Sandstrom has shown the combination of metoprolol and hydralazine to be superior to hydralazine and thiazide for the treatment of hypertensive pregnant patients with regard to maternal well-being, fetal intrauterine growth, lo-minute Apgar scores, and perinatal mortality. Atenoloi. Atenolol, another cardioselective pblocker with a relatively long half-life and low lipid solubility, has been studied in pregnant hypertensive patients as well. Rubin et a1.35report that in a prospective, double-blind, randomized raial involving 120 pregnant women with hypert,ension that developed in their third trimester, patients received either atenolol or placebo. The results indicated that atenolol was able to successfully 1owe:r the blood pressure and improve the outcome of pregnancy. Proteinuria developed in all of the placebo patients, as compared with its development in only four patients taking atenolol. In both gra’ups, Apgar scores and birth weights of newborn infants were virtually the same. The atenolol-treated group had fewer cases of infants born with hypoglycemia, fewer deaths, and fewer cases of respiratory distress than

Beta blockers

and pregnancy

149

the control group. However, bradycardia (heart rate <120 bpm) developed in more infants in the atenolol-treated group than in the placebo group. All episodes lasted less than 10 minutes and no intervention was necessary. A case was reported by Fowler et al.36 in which atenolol successfully controlled the blood pressure in a woman with essential hypertension who had developed preeclampsia and had lost her baby during a previous pregnancy. Despite the fact that atenolol crossed the placenta, there was no evidence of any adverse effect on the fetus, despite conception during atenolol therapy and its continuation throughout pregnancy. Reynolds et a1.37performed a prospective study in which 120 women who developed hypertension during their third trimester were randomly allocated in double-blind manner to atenolo1 or placebo. The children were followed until the age of 1 year with no short- or medium-term complications in the atenolol-treated group. Oxprenolob Oxprenolol, a noncardioselective pblocker with intrinsic sympathetic activity, has been shown to be safe and effective for the treatment of pregnancy-associated hypertension. Gallery et a1.“8 compared it with methyldopa in 183 randomly assigned patients. The two groups showed equal hypertension control and greater fetal growth in the group treated with oxprenolol. A study by Fidler et a1.3gcompared oxprenolol and methyldopa in 100 pregnant women with diastolic blood pressure above 95 mm Hg. While fetal outcomes were not significantly different in the two groups, the oxprenolol-treated group required greater increments in their medication than did the methyldopa-treated group. Acebutolol. Acebutolol, a cardioselective @-blocker with sympathomimetic activity, was compared with methyldopa in the treatment of 20 pregnant women with mild to moderate hypertension.4o There were no stillbirths or neonatal deaths in either group. There was no discernible difference in the two groups in duration of pregnancy, birth weight, Apgar score or placental weight, and no evidence of bradycardia, hypoglycemia, or respiratory difficulty in the babies born to mothers taking acebutolol. Pindolol. Pindolol, a P-blocker with sympathomimetic activity, was compared with methyldopa in the treatment of 32 women with pregnancy-induced hypertension.41 There was no difference in the two groups with regard to fetal intrauterine growth estimation, fetal Apgar scores at 1 and 5 minutes, and fetal morbidity. In the pindolol group, there was a statistically significant drop in b&h systolic and diastolic blood pressure values after treatment, lev-

150

Frishman

January1988

and Chesner

els significantly lower than in patients treated with methyldopa. Furthermore, suggestive of a beneficial effect on the renal function of toxemic women was the observed decrease in serum creatinine values and the observed rise in creatinine clearance in the pindolol-treated group. Labetalol. Labetalol, like propranolol, blocks both ,&- and &-adrenoceptors.42 However, labetalol is unique in that it also has both a,-adrenergic blocking properties and direct vasodilating activity. This drug has been shown to be a potent antihypertensive agent.43,44 There have been a number of favorable reports describing the safe use of labetalol in the treatment of hypertension in pregnancy.43-47 Clinically significant fetal hypoglycemia, bradycardia, or respiratory depression was not usually associated with maternal labetalol therapy. Michael45 treated 85 women with severe hypertension complicating pregnancy with oral labetalol as single drug therapy. Effective control of the blood pressure was achieved in all but six patients with a maximum dose of 1200 mg/day. Perinatal mortality was 4.4%, and there were no congenital malformations in any of the infants delivered. In studies comparing labetalol to methyldopa in the treatment of hypertension in pregnancy, labetalol has been shown to be as effective as 46 and possibly superior to47 methyldopa in obtaining good blood pressure control. Oral labetalol (200 mg) has also been compared with intramuscular hydralazine (10 mg)48 and was found to be more acceptable to patients, equally effective, more predictable in its action, and caused no change in heart rate as compared with hydralazine. Labetalol has also been shown to be efficacious when administered intravenously in those situations in which rapid reduction of blood pressure in pregnancy is required, such as in severe preeclampsia or eclampsia.4s*52 In a study comparing intravenous dihydralazine with intravenous labetalol, labetalol appeared to offer significant advantages in the management of hypertension in pregnancy.53 A recently completed study by Michael,54 comparing intravenous labetalol with intravenous diazoxide for the treatment of hypertensive crises in pregnancy, showed that labetalol was free of fetal and maternal side effects and was a more appropriate drug for use in the management of hypertensive crises in pregnancy and labor. Since labetalol is known to cross the placenta45 and is an (Y- and @receptor blocker, the possibility that placentally-transferred labetalol might cause sympathetic blockade in the newborn infant was examined in a recent study by MacPherson et al.55 With the use of 11 infants born to mothers treated

American

Heart Journal

with labetalol and 11 carefully matched controls, measurements of systolic blood pressure, heart and respiratory rates, palmar sweating, blood glucose, and the metabolic and vasomotor responses to cold stress were used as parameters. Infants of mothers treated with labetalol showed a mild transient hypotension that disappeared within 24 hours. There were no other significant differences between the two groups, and the authors concluded that labetalol does not cause significant sympathetic blockade in mature, newborn infants, though in their discussion they recommend further study comparing labeta101’s effect on the stressed preterm infant’s sympathetic system. CONCLUSlONS

Clinical research that employs drug therapy during pregnancy is limited by ethical and practical considerations. However, the amount of available information regarding P-blockers in pregnancy is equivalent to that available for many antihypertensive drugs that are commonly used during female gestation, The current evidence would suggest that p-blockers are relatively safe if used during pregnancy, with little risk to the fetus and possible benefit to the mother. However, until data from definitive studies are available, it would be advisable to adhere to the following guidelines: (1) Avoid, whenever possible, the use of P-blocker therapy during the first trimester of pregnancy. (2) Use the lowest possible @-blocker dose. Combination of low doses of @-blockers and low doses of other agents might provide optimal drug therapy. (3) If possible, discontinue P-blocker therapy at least 2 to 3 days prior to delivery, both as a way of limiting the effects of @-blockers on uterine contractility and for preventing possible neonatal complications secondary to p-blockade. (4) Use of P-blockers with &-selectivity, intrinsic sympathetic activity, or a-blocking activity may be preferable in that these agents would be less likely to interfere with @,-mediated uterine relaxation and peripheral vasodilation. Studies are still needed to better define p-blocker pharmacokinetics in the mother and fetus. Also, studies are warranted during pregnancy to assess the safety and efficacy of ,&blockers with existing cardiovascular therapies. The generally favorable outcome seen in patients from the studies reported to date should encourage on-going investigations im this area. REFERENCES

1. Frishman W, Silverman beta-adrenergic blocking

R. Clinical pharmacology of the new drugs. Part 3. Comparative clinical

Volume Number

2. 3. 4.

5.

6. 7. 8. 9. 10. 11. 12. 13.

14. 15. 16. 17. 18. 19.

20. 21. 22. 23. 24.

115 1, Part 1

experience and new therapeutic applications. AM HEART J 1979;98:119-31. Oakes GK, Walker AD, Ehrenkranz RA, Chez RA. Effect of propranolol infusion on the umbilical and uterine circulations of pregnant sheep. Am J Obstet Gynecol1976;126:1038-42. Ladner E, Brinkman CR, Weston P, Assali NE. Dynamics of uterine circulation in pregnant and non-pregnant sheep. Am J Physiol 1970;218:257-63. Adams FH. Assali NS. Cushman M. Westerste.n A. Interrelationships of maternal and fetal circulations. 1. Flow pressure responses to vasoactive drugs in sheep. Pediatrics 1961; 27~627-35. Chez RA, Ehrenkranz RA, Oakes GK, Walke AM, Hamilton LA, Vrennan SC, McLaughlin MK. Effects of adrenergic agents on bovine umbilical and uterine blood flows. In: Longo L, Reneau DD, eds. Fetal and newborn cardiovascular physiology. vol. 2. New York Garland Publishing Inc., 19781-16. Maughan GB, Shabanah EH, Toth A. Experiments with pharmacologic sympatholysis in the gravid. Am J Obstet Gynecol 1967;97:764-76. Wansbrough H, Nakanishi H, Wood C. Effect of epinephrine on human uterine activity in vitro and in vivo. Obstet Gynecol 1967;30:779-89. Barden TP, Stander RW. Effects of adrenergic blocking agents and catecholamines in human pregnancy. Am J Obstet Gynecol 1968;102:226-35. Joelson I, Barton MD. The effect of blockade of the betareceptors of the sympathetic nervous system of the fetus. Acta Obstet Gynecol Stand 1969;3(supp1)48:75-9. Eliahou HE, Silverberg DS, Reisin E, Romem I, Mashiach S, Serr DM. Propranolol for the treatment of hypertension in pregnancy. Br J Obstet Gynaecol 1978;85:431..6. Bullock JL, Harris RE, Young R. Treatment of thyrotoxicosis during pregnancy and propranolol. Am J C’bstet Gynecol 1975;121:242-5. Turner GM, Oakley CM, Dixon HG. Management of pregnancy complicated by hypertrophic obstructh,e cardiomyopathy. Br Med J 1968;4:281-4. Schroeder JS, Harrison DC. Repeated cardioversion during pregnancy: treatment of refractory paroxysmal atria1 tachycardia during three successive pregnancies. Am J Cardiol _ 1971;27:445-6. Mitrani A, Oettinger M, Abinader EG, et al. IJse of propran0101 in dvsfunctional labor. Br J Obstet Gvnaecol 1975: 82:651-5. ” Teuscher A, Bossi E, Imhof P, Erb E, Stocker F, Weber J. Effect of propranolol on fetal tachycardia in diabetic pregnancy. Am J Cardiol 1978;42:304-7. Pruyn SC, Phelan JP, Buchanan GC. Long-term propranslol therapy in pregnancy: Maternal and fetal outcome. Am J Obstet Gynecol 1979$35:485-g. Bott-Kanner G, Schweitzer A, Reisner SH, et al. Propranolol and hydralazine in the management of essential hypertension in pregnancy. Br J Obstet Gynaecol 1980;87:1.10-14. Tcherdakoff PH, Colliard M, Berrard E, et al. propranolol in hypertension during pregnancy. Br Med J 1978;2:670. Gallery EDM, Saunders DM, Hunyer SM, G-yory AZ. Randomized comparison of methyldopa and oxprenolol for treatment of hypertension in pregnancy. Br Med J 1979;1:15914. Oakley CDG, McGary K, Limb DG, Oakley CM. Management of pregnancy in patients with hypertrophic cardiomyopathy. Br Med J 1979;1:1749-50. Rubin PC. Beta-blockers in pregnancy. N’ Engl J Med 1981;305:1323-6. Livingstone I, Craswell PW, Bevan EB, Smith MT, Eadie MJ. Propranolol in pregnancy: three year prospective study. Clin Exp Hypertens 1983;2:341-50. Tavlor EA. Turner P. Antihvnertensive theranv with nropr&rolol during pregnancy anh lactation. Post&ad Mid J 1981;57:427-30. Jensen OH. Fetal heart rate response to a controlled sound

Beta blockers

25. 26. 27.

28. 29. 30.

31.

32. 33. 34. 35. 36. 37. 38. 39.

40. 41.

42. 43. 44. 45. 46.

47.

and pregnancy

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stimulus after propranolol administration to the mother. Acta Obstet Gynecol Stand 1984;63:199-202. Turnstall MB. The effect of propranolol on the onset of breathing at birth. Br J Anesthes 1969;41:792. Habib A, McCarthy JS. Effects on the neonate of propranolol administered during pregnancy. J Pediatr 1977;91:808-11. Cottrill CM, McAllister RG, Gettes L, Noonan JA. Propran0101 therapy during pregnancy, labor, and delivery: evidence for transplacental drug transfer and impaired neonatal drug disposition. J Pediatr 1977;91:812-4. Gladstone GR, Hordof A, Gersong WM. Propranolol administration during pregnancy: effects on the fetus. J Pediatr 1975;86:962-4. Buechier AA, Palmer SK. Intrapartum fetal death associated with propranolol: case report and review of physiology. Wise Med J 1982;81:23-5. Adolfsson L, Areskog NH, Furberg C, Johnsson G. Effects of single doses of alprenolol and two cardioselective P-blockers (H 87/07 and H 93/20) on exercise induced angina pectoris. Eur J Clin Pharmacol 197$7:111-B. Bengtsson C, Johnsson G, Regardth CG. Plasma levels and effects of metoprolol on blood pressure and heart rate after acute dose and between two doses during long term treatment. Clin Pharmacol Ther 1975;17:400-8. Sandstrom B. Antihypertensive treatment with the adrenergic beta-receptor blocker metoprolol during pregnancy. Gynecol Obstet Invest 1978;9:195-204. Hogstedt S, Lindbergh B, Peng DR, Regardth CG, Rane A. Pregnancy-induced increase in metoprolol metabolism. Clin Pharmacol Ther 1985;37:688-92. Sandstrom B. Adrenergic @-receptor blockers in hypertension of pregnancy. Clin Exp Hypertens 1982;1:127-41. Rubin PC, Butters L, Low RA, Reid JL. Atenolol in the treatment of essential hypertension during pregnancy. Br J Clin Pharmacol 1982;14:279-81. Fowler MB, Brudevell M, Jackson G, Holt DW. Essential hypertension and pregnancy: successful outcome with ateno101. Br J Clin Pratt 1984;38:73-4. Reynolds B, Butters L, Evans J, Adams T, Rubin PC. First year of life after the use of atenolol in pregnancy associated hypertension. Arch Dis Child 1984:59:1061-3. Gallery ED, Ross MR, Gyory AZ. Antihypertensive treatment in pregnancy: analysis of different responses to oxprenolol and methyldopa. Br Med J 1985;291:563-6. Fidler J, Smith J, Fayers P, DeSwiet M. Randomized controlled comparative study of methyldopa and oxprenolol in treatment of hypertension in pregnancy. Br Med J 1983;286:1927-30. Williams ER, Morrissey JR. A comparison of acebutolol with methyldopa in hypertensive pregnancy. Pharmatherapeutica 1983;3:487-91. Ellenbogen A, Jaschevatzky 0, Davidson A, Anderman S, Grunstein S. Management of pregnancy induced hypertension with pindolol: comparative study with methyldopa. Int J Gynaecol Obstet 1986;24:3-7. Frishman W, Halprin S. Clinical pharmacology of the new beta-adrenergic blocking drugs. Part 7. New horizons in beta adrenoceptor blockade therapy. AM HEART J 1979;98:660-5. Mehta J, Cohn JN. Hemodynamic effects of labetalol, an alpha and beta adrenergic blocking agent in hypertensive subjects. Circulation 1977;55:370-5. Prichard BNC, Boakes AJ. Labetalol in long term treatment of hypertension. Br J Clin Pharmacol 1976;3(suppl 3):74350. Michael CA. Use of labetalol in the treatment of severe hypertension during pregnancy. Br J Clin Pharmacol 1979;8(suppl 2):211S-15s. Redman CWG. A randomized comparison of methyldopa (Aldomet) and labetalol (Trandate) for the treatment of Severe hypertension in &egnancy [Abstract]. Clin Exp Hypertens 1982;81:345. Lamming GD, Symonds EB. Use of labetalol and methyldopa

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and Chesner

in pregnancy induced hypertension. Br J Clin Pharmacol 1979;8(suppl 2):217S-22s. 48. Walker JJ, Greer I, Calder AA. Treatment of acute pregnancy-related hypertension: labetalol and hydralazine compared. Postgrad Med J 1983;59(suppl 3):168-70. 49. Lamming GD, Broughton Pipkin F, Symonds EM. Comparison of the alpha and beta-blocking drugs labetalol and methyldopa in the treatment of moderate and severe pregnancy-induced hypertension. Clin Exp Hypertens 1980;2:86595. 50. Jorge CS. Labetalol in the hypertensive states of pregnancy. Emergency treatment of severe hypertension in a pregnant patient. The European Society of Cardiology. Drug Symposium on Labetalol 1979;131.

51. Lilford RJ. Letter. Br Med J 1980;281:1635. Lunell NO, Hjemdahl P, Fredholm BB, et al. Circulatory and metabolic effects of a combined cy- and P-adrenoceptor blocker flabetaloll in hvuertension of nreenancv. Br J Clin Pharmacol 1981;12:345-8. 53. Garden A, Davey DA, Dommisse J. Intravenous labetalol and dihydralazine in severe hypertension in pregnancy. Clin Exp Hypertens 1982;1:371-83. 54. Micheal CA. Intravenous labetalol and intravenous diazoxide in severe hypertension complicating pregnancy. Aust NZ J Obstet Gynaecol 1986;26:26-9. 55. MacPherson M, Pipkin FB, Butter N. The effect of maternal labetalol on the newborn infant. Br J Obstet Gynaecol 1986;93:539-42. 52.

-I

The comparative effects of clonidine hydrochloride and nifedipine in the treatment hypertensive crises Mark

C. Houston,

From the Medical Intensive Care bilt University Medical Center. Received

152

for publication

of

M.D. Nashville, Tenn.

Although the frequency of malignant hypertension and hypertensive crises has steadily decreased in recent years,le3 severe blood pressure elevation (diastolic blood pressure L 120 mm Hg) poses a threat to the integrity of the cardiovascular system and results in high morbidity and mortality in a short period of time.3 Prompt recognition with appropriate, effective therapy must be instituted in these patients, but overly aggressive treatment of high blood pressure may actually induce serious adverse consequences, such as cerebrovascular accident, acute myocardial infarction, or acute renal failure. Numerous oral and parenteral antihypertensive agents are now available for the treatment of hypertensive crises. Several oral antihypertensive agents have recently been studied in hypertensive crises, and some of them demonstrate excellent efficacy with a low side effect profile. Two oral antihypertensive regimens that show the greatest promise in treating hypertensive crises are clonidine hydrochlo-

Reprint Vanderbilt

-

May

Unit,

11, 1987;

requests: Mark C. Houston, University Medical Center,

Department accepted

of Medicine, Aug.

Vander-

15, 1987.

M.D., Department of Medicine, Nashville, TN 37232.

ride and nifedipine. This article will discuss these two agents in detail, comparing their relative advantages and disadvantages in the clinical treatment of hypertensive crises. GENERAL

GOALS

OF

THERAPY

Blood pressure is a function of cardiac output and systemic vascular resistance (SVR).4 The hemodynamic derangement in a hypertensive crisis is a marked elevation in SVR resulting from structural and functional vasoconstricting forces with a concomitant marked reduction in cardiac output.” Reduction of SVR without reduction in cardiac output is the most logical approach for effective therapy. Reduction in blood pressure should be prompt, but the rapidity of the fall and the level of decrease must not compromise perfusion and blood flow to vital organs, such as the brain, heart, or kidneys, and induce cerebrovascular accident, myocardial infarction, or acute renal failure. Intravascular volume, which is usually reduced, should be replaced simultaneously with effective antihypertensive therapy.3 An understanding of the onset of action, maximum effect, duration of action, hemodynamic effects, adverse reactions, relative effect on organ perfusion, and clinical pharmacology of each