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Cardiovascular Drugs in Pregnancy

Josef Widerhorn, MD, * J. Nathan Rubin, MD, * William H. Frishman, MD, t and Uri Elkayam, MD:j:

Pregnant women often require medical therapy for treatment of various coexisting cardiovascular conditions. The effects of the cardiovascular drugs in pregnant women are discussed in this article. .

PHARMACOLOGIC CONSIDERATIONS IN PREGNANCY

Complex physiologic changes occurring during pregnancy in the cardiovascular, pulmonary, renal, gastrointestinal, and endocrine systems may affectthe pharmacokinetics of drugs, with severalconsequences on the fetomaternal unit. 107, 150. 173. 198

Drug absorption may be influenced by thedecreased motility of the gastrointestinal tract thatoccurs during pregnancy. Reduced gastric motilitymay cause stagnation of drugs in the stomach.170Diminished acid secretion, combined with increased production of alkaline mucus, can affectgastric pH and, consequently, the degree of ionization and solubility of drugs. 150. 173 The prolongation of transit timethrough the small bowel may lead to increasedmetabolism of drugs in the gut wa1l41 or, con-versely, .may allow a more complete absorptionwith increased bioavailability. 53, 107 In addition, the administration of opiate analgesics or antacids, frequently used during labor, also may delay ordecrease drug absorption. 162. 193

During pregnancy, the distribution of

drugs is modified by increased plasma volume, total body water, and total body fat.l07, 150. 198 Serum concentration of albumin, the principal drug binding protein, decreases progressively throughout pregnancy. 46 This change, along with altered binding to alacid glycoprotein,78. 254 increase in fatty acids and lipids, and hormonal changes, may lead to an increase of the unbound drug frac-tion.107 Furthermore, the difference in fetal and 'maternal plasma binding capacity produces a complex situation that also has to be considered in the interpretation of therapeutic and toxIC drug concentrations}8. 107. 150, 198. 254

The metabolism of many drugs is altered during pregnancy; however, these changes are not necessarily clinically significant. 107 The liver h;,ls an important role in drug metabolism. Hepatic clearance is dependent on the binding affinity of drugs, hepatic blood flow, and hepatic enzymatic systems. Sex hormones may have opposite effects on the hepatic microsomal oxidase system.42. 44. 59 For example, estrogens inhibit the microsomal oxidase system for ethylmorphine and hexabarbitone44; on the other hand, progesterone enhances hepatic enzymatic acti vi ty. 42. 59

The fetoplacental unit plays an active role in metabolism of various drugs. The placenta contains many enzymatic systems that transform several drugs into toxic or nontoxic products.

*Clinical Instructor. of Medicine, University of Southern California School of Medicine; and Section of Cardiology, Department of Medicine, Los Angeles County-University of Southern California Medical Center, Los Angeles, California

tProfessor of Medicine, Albert Einstein College of Medicine; and Director of Medicine, Hospital of the Albert Einstein College of Medicine, Bronx, New York *Associate Professor of Medicine, University of Southern California School of Medicine; and Director of In-Patient Cardiology, Section of Cardiology, Department of Medicine, Los Angeles County-University of Southern California Medical Center, Los Angeles, California

Cardiology Clinics-Vol. 5, No.4, November 1987 651

652 Josef Widerhom et aI.

The fetus also participates in drug metabolism after6 to 8 weeks of gestation.l75 Placental transfer ofdrugs depends on maternal and fetal drugconcentratipq;,gegree of protein binding; placentalblood flow; anatomy, and metabolism; and acid-base equilibrium. 117. 150. 154. 198 The acidic pH of amniotic fluid, for example, can function as an "ion trap"for weak basic drugs. 150 Other important parameters are molecular weight of the drugs,degree of ionization, and lipid solubility. 206

The excretion of drugs that primarily are clearedby the kidney may be enhanced during pregnancy.Both renal blood flow and glomerular filtration rate are increased markedly. 45. 52.215 Posturalchanges that occur late in pregnancy also may influence hemodynamics and drug clearance. 150

A modem concept of teratogenesis has to embrace not only the anatomic malformations notedat birth, but also biochemical, physiologic, and behavioral modifications, which are more subtleand may manifest first during childhood or adult life. 107 Teratogenic effects depend on the chemical nature of drugs, duration of exposure, dosage, genetic susceptibility, andgestational age. During blastogenesis (first 14days), severe insults may result in abortion;however, the blastocyst is relatively resistant to teratogenic agents and there are no known viablemalformations generated during this period.I07

The most vulnerable period of gestation is that ofembryogenesis (2 to 8 weeks). Various organsystems are formed during this period and injuriesto the embryo will result in morphogenetic alterations.

During fetogenesis, the effect of drugs may besimilar to that occurring during extrauterine life;however, the systems still in differentiation (that is,the central nervous system) might be damaged. Other effects can be nonspecific, manifested bygrowth retardation or system dysfunction thatbecome evident after birth.

As a general principle, all drugs should beavoided as much as possible during pregnancy. If atherapeutic decision has to be .made, the risk-benefit ratio should be evaluated carefully. Inchoosing drugs, toxicity, metabolism, andgestational age are of crucial importance inavoiding untoward effects. If a condition requires drugs potentially harmful to the fetus, the bestsolution is to avoid pregnancy for the duration oftreatment. As previously described, thepharmacokinetics of drugs is modified inpregnancy; because of a multitude of factors, thesechanges cannot always be predicted and,

therefore, close monitoring of therapy, both clinically and by laboratory methods, is necessary.

Another source of concern is the transfer of drugs into breast milk and, consequently, to neonates. Again, this is dependent on the physicochemical characteristics of the compound. 206 Generally, only 1 to 2 per cent of maternal dose appears in milk. Except for some drugs that clearly are contraindicated, there is not enough evidence to allow or to prohibit breast feeding in mothers undergoing drug treatment.25O Most data regarding drug excretion in human milk are available from case reports. Because of the complexity of mechanisms involved in drug excretion into breast milk, various models and formulas used to estimate plasma milk ratios have limited clinical value. Close monitoring of the infant's ingested dose and plasma levels, as well as close observation for adverse effects or toxicity, th.erefore are necessary to assure safety.l50 .

CARDIAC GLYCOSIDES

Cardiac glycosides have been known to humanity since the ancient Egyptian and Roman era. Used for centuries for different purposes, digitalis emerged as one of the major drugs in the therapy of congestive heart failure, as well as for terminating paroxysmal supraventricular tachycrdia and controlling rapid ventricular rates in patients with atrial fibrillation and flutter. .

Among various digitalis preparations, digoxin is the most accepted and widely used. During pregnancy, the most common maternal and fetal indications for digoxin use are congestive heart failure and/or supraventricular tachyarrhythmias.6. 31. 68. 74. 81. 121. 130. 189. 196. 201. 211. 223 Only 60 to 80 per cent of an oral dose is absorbed, mostly in the proximal small intestine. As with other drugs, the presence of food or delayed gastric emptying that may occur in pregnancy may retard its absorption.107. 150. 170 Digoxin is only 20 to 25 per cent bound to proteins; the decreased albumin level seen during pregnancy, therefore, should not affect its serum concentration significantly. Peak level and maximal effect following oral administration are reached after 2 to 3 hours and 4 to 6 hours, respectively. The intravenous (IV) preparation has a rapid onset of action (within 5 to 20 minutes) and a maximal effect within 1.5 to 3 hours. The half life of digoxin is 36 to 40 hours. The volume of distribution (V D) is increased significantly dur

r Cardiovascular Drugs in Pregnancy 653

ing pregnancy.134 For rapid digitalization, the dosage is similar to that in the nonpregnant state-that is, 0.75 to 1.5 mg IV. Digoxin is excreted primarily by the kidneys. During pregnancy, there is a linear correlation between digoxin and creatinine clearance; the dosage, therefore, has to be adjusted when renal function is impaired. The maintenance dose has to be approximately 35 per cent of total body stores; it may need adjustments throughout pregnancy in order to obtain optimal therapeutic effect.

In 1972, Rogers and coworkersl96 reported that serum digoxin level at term was lower than 4 weeks post delivery in mothers treated with the same maintenance dose. These data could not be confirmed by other authors,6. 31, 130 however, who found digoxin concentration in the therapeutic range at the time of delivery. Luxford and colleagues130 demonstrated that despite increased digoxin and creatinine clearance and increased 24-hour urinary digoxin elimination, serum digoxin level was higher during the third trimester of pregnancy than during the postpartum period.

Several studies79. 104. 240 recently have dem-onstrated the existence of endogenous digoxinlike substances in pregnant women and neonates. These substances interfere with the radioimmunoassay for exogenous digoxin, leading to reading errors ranging from 0.1 J.Lg per L to more than 2 J.Lg per L. To complicate the situation further, the concentration of these digoxin-like substances changes with gestational age, making it extremely difficult to assses therapeutic levels.240 These data cast doubts on the utility of monitoring digoxin serum concen-tration during pregnancy and suggest the need to use electrocardiographic and clinical criteria to determine adequacy of digoxin dosing during gestation.

Treatment of fetal conditions is based on the ability of digoxin to cross the placenta. Although' this property was well documented by numerous authors, 6, 31. 68. 74. 81. 121. 130. 189, 196. 201. 211. 223 the magnitude of digoxin transfer to the fetus is somewhat conflicting. Rogers and coworkersl96 found similar concentrations of digoxin in both maternal and fetal blood at the time of delivery. Chan and colleagues31 found lower levels in fetal blood and postulated the. existence of a placental barrier or digoxin. Allonen and

. coworkers6 also noted lower digoxin concentration in fetuses but at a different gestational age (12 to 16 weeks). In light of the new reports on endogenous digoxin-like substances and their

effect on digoxin measurement, it is difficult to interpret these data.

In a study using radioisotopes, Saarikosky and associates201 demonstrated that placental transfer of digoxin occurs fairly rapidly. Five minutes following the injection of H3-digoxin in maternal blood, radioactivity was demonstrated in umbilical cord blood, and by 30 minutes, fetal and maternal blood concentrations of radioisotopes were approximately equal. They also demonstrated that the fetal heart binds digoxin much less avidly than the infant heart. Based on these reports, the fetomaternal digoxin concentration ratio probably ranges from 0.5 to 1.0.

During the past decade, digoxin has been employed with increasing frequency to treat fetal supraventricular tachycardia and congestive heart failure.68. 74. 81. 121. 189. 223 Digoxin may be adequate alone in treating fetal tachycardia.68.81 In refractory cases, it m~y be necessary . to add a seco)ld drug such as verapamiP21 or quinidine..223 As in the Jlonpregnant state, the addition of quinidine or verapamil may increase the digoxin level significantly. The same precaution regarding drug interactions therefore applies during pregnancy as in the nonpregnant state.

To date, few adverse effects have been observed in fetuses of mothers treated chronically with digoxin. Low birth weight infants occasionally have been born of mothers with cardiac conditions treated with digitalis. It has been postulated that digoxin may affect amino acid transport through the placenta, with consequent growth retardation.248 However, the duration of pregnancy and labor has been noted to be shorter in mothers on long term digoxin therapy.245 Therefore, it is conceivable that the low birth weight reported with digoxin treatment is secondary to prematurity rather than to intrauterine growth retardation.

Despite the above concerns, digoxin is con-sidered a safe drug to use in pregnancy and, to date, there are no reports of teratogenesis in humans. Caution is advised in digitalis administration, however, because overdose can be detrimental to the mother and may be lethal to the fetus. 211

Digoxin is excreted in the breast milk and the milk-plasma ratio ranged from 0.59 to 0.9.31. 124 The total amount of digoxin ingested daily by the infant has been estimated to be approximately 1/100 of the pediatric recommended dose of 12.5 J.Lg per kg per day. 124 No apparent clinical effects were demonstrated in newborns;

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654 Josef Widerhorn et ai.

digoxin therapy of the mother therefore should not affect breast feeding decisions.31. 124

ANTIARRHYTHMIC DRUGS .,.1 >,

Quinidine

Quinidine, a class Ia antiarrhythmic drug, is a dextrostereoisomer of quinine. Both alkaloids have similar properties and spectrum of action; quinidine, however, is more effective in sup-pressing both supraventricular and ventricular arrhythmias. It is used for cardioversion, as well as for prophylaxis against recurrences of paroxysmal supraventricular tachycardia, atrial flutter, atrial fibrillation, and re-entrant arrhythmia associated with Wolff-Parkinson-White syndrome. It frequently is employed in suppressing ventricular premature beats and ventricular tachycardia. .

Quinidine has a depressant effect .on the myocardium that is directly proportional to plasma concentration.77 It decreases myocardial automaticity, excitability, and conduction velocity and increases the fibrillation threshold. The diminished conduction velocity and the increased effective refractory period induced by quinidine are very useful in terminating reentry.58 Because of its vagolytic effects, the atrioventricular (A V) conduction may be enhanced in some patients. Quinidine also has (Xadrenergic blocking effects.

Approximately 70 to 80 per cent of an oral dose of quinidine is absorbed.37 Food and antacid may delay the absorption. In patients with congestive heart failure, the decreased volume of distribution (V D) may lead to higher drug levels despite diminished absorption.4o Maximum serum levels are attained within 60 to 90 minutes and the half-life is 6 to 8 hours. Eighty percent is bound to protein and the unbound fraction, therefore, increases during hypoalbuminemic conditions such as gestation.150 Quinidine is metabolized primarily in the liver and some of the metabolites are active. Ten to 20 percent is eliminated unchanged by the kidney251 and alkalinization of the urine may decrease urinary excretion.94 The therapeutic level is 2.5 to 5 !Jog per ml; levels greater than 7 to 8 !Jog per ml are associated with increased toxicity.

Unfortunately, quinidine has many adverse effects. Nausea, vomiting, and diarrhea can be disabling. Some patients may develop skin rashes, thrombocytopenia, hemolytic anemia, or fever. In 3 to 4 per cent of patients, QT

prolongation may lead to polymorphic ventricular tachycardia ("torsade de pointes"), which has a reported mortality of 10 per cent.48 Among interactions with other drugs, of particular im-portance is the potentiation of warfarin . and augmentation of digoxin concentration. In up to 30 per cent of patients, side effects are serious enough to discontinue therapy.

Quinidine has been used during pregnancy since 1930.144 Several recent reports have documented its transplacental transfer.35, 50, 223 Hill and coworkers80 reported a case of quinidine treatment throughout the pregnancy to prevent maternal ventricular tachycardia. During preg-nancy, maternal quinidine levels are approximately constant; that is, 5.1 and 7.8 !Jog per ml. At delivery, the level in the neonate was 2.3 !Jog per ml and in the amniotic fluid, 9.3 !Jog per ml. Five days postpartum the mother's level rose to 9 !Jog per ml. The authors hypothesized that the high levels found in the amniotic fluid may have b~en because of fetal voiding or a technical error in measurement of quinidine metabolites.

Spinnato and associates223 described three cases of fetal supraventricular tachycardia treated with digoxin and quinidine. In all three cases, the addition of quinidine to digoxin was successful in controlling fetal arrhythmia and, in two of these fetuses, ascites as well. At delivery, quinidine maternal levels were 0.7 to 2.1 !Jog per ml; cord blood levels, 0.5 to 1.6 !Jog per ml; and amniotic fluid level, 0.9 !Jog per ml. The low levels may be explained by the fact that quinidine was discontinued 24 hours prior to delivery. No side effects were noted; fetal development was normal and the labor was uneventful.

Quinidine has a minimal oxytocic effect144. 231 that manifests mainly after the onset of spontaneous uterine contraction.231 Fetal thrombocy topenia also was associated with quinidine treat-ment.135 Toxic doses may cause premature labor, 14 abortion, 141 or damage of the fetal eighth cranial nerve. 140

However, the large clinical experience with use of this drug in pregnancy has shown an extremely low incidence of side effects and no known teratogenic effects. Quinidine use appears to be safe for both maternal and fetal indications. Quinidine is secreted in the breast mild, and the milk-plasma ratio is 0.71. 8e

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Procainamide

Procainamide, synthesized from procaine by substituting an ester linkage with an amide

--;,Cardiovascular Drugs in Pregnancy

group, was introduced as an antiarrhythmic agent in 1951.133 The drug is very effective in abolishing premature ventricular contractions, ventricular tachycardia, and supraventricular tachycardia associated with Wolff-ParkinsonWhite syndrome,82 although it is less effective than quinidine for supniveritticular arrhythmia.

It has a depressant effect on the heart, similar to that of quinidine; it decreases automaticity, excitability, conduction velocity, and contractility. The effective refractory period is prolonged and the fibrillation threshold increased. Its anticholinergic activity is less than that of quinidine.

Procainamide can be given orally and paren-terally. Following oral administration, approxi-mately 75 to 95 per cent of the dose is absorbed. The absorption may be retarded with delayed gastric emptying, decreased intestinal motility, or intestinal pH changes.18 Only 10 .to 20 per cent is bound to plasma proteins. Peak levels are reached in 45 to 75 minutes after an oral capsule dose. Half-life is' about 2.5 to 5.0 hours in patients with no evidence of heart or kidney failure. Therapeutic levels are 4 to 8 J.Lg per ml. Approximately 40 to 70 per cent of a procainamide dose is eliminated unchanged by the kidneys; renal impairment, therefore, may decrease elimination markedly, with a consequent increase in serum levels. Ten to 34 percent of the drug is metabolized in the liver to N-acetylprocainamide (NAPA)64 at a rate that varies depending on acetylator status. NAPA has less antiarrhythmic potency and its efficacy is limited. The treatment with NAPA probably does not induce antinuclear antibody formation or lupus syndrome,62 however, as does procainamide. NAPA is eliminated predominantly by the kidneys; its therapeutic range is 9.4 to 19.5 J.Lg per ml. Congestive heart failure and renal impairment prolong both procainamide and NAPA half-lives.95 In order to avoid toxicity, both procainamide and NAPA levels have to be monitored closely.

Procainamide can be administered intravenously as 100 mg boluses (25 mg per minute) every 5 to 10 minutes until therapeutic effects are obtained or 1 g is given. Intravenous administration may produce hypotension, QT interval prolongation, and, serious arrhythmias.159 Nausea, vomiting, and diarrhea are noted more frequently with the oral route but are less pronounced than with quinidine. Central ner-vous system (CNS) toxicity may manifest as 'mental depression, hallucinations, and psychosis. Hypersensitivity reaction such as drug fever, agranulocytosis, and skin rashes may oc

655

cur and drug-induced lupus may develop in 20 to 40per cent of the patients. 159

Transplacental transfer of procainamide is well documented in two reports of treatment of fetal supraventricular tachycardia. 51. 66 Dumesic and coworkers51 reported successful control of fetal supraventricular tachycardia and heart failure when procainamide was administered to the mother in addition to digoxin. The fetal arrhythmia was refractory to previous treatment with digoxin a10ne or in combination with propranolol. After 4 weeks of treatment, the arrhythmia recurred and became more difficult to control, despite increased dose of digoxin and procainamide. Cesarean section was performed and, at delivery, although digoxin levels were equal in the maternal and neonate blood (0.8 J.Lg per ml), procainamide level was higher in maternal blood (15.6 J.Lg per ml versus 4.3 J.Lg per ml in fetus).

A similar therapeutic approach was reported by Given and coworkers.66 Again, fetal supra-ventricular t~chycardia resistant to the combination of digoxin and propranolol converted with digoxin and procainamide. In this case, fetal tachyarrhythmia also recurred. But the digoxin and procainamide levels at delivery were discordant with those found by Dumesic's team. Fetal levels were 30 per cent higher for procainamide and 50 per cent lower for digoxin. NAPA levels in the maternal and fetal blood were 3.0 J.Lg per ml and 3.7 J.Lg per ml, respectively. In both cases, it is unclear whether the therapeutic success was because of synergistic digoxin-procainamide action or procainamide effect alone.

At the present time, there are no data available on procainamide pharmacokinetics in the maternofetal unit. There is no evidence of teratogenic effects76. 142 and the drug appears to be safe in pregnancy. 36, 143, 144 Because of limited information and serious potential side effects, however, procainamide should be used only when drugs with a better safety record, such as quinidine, fail or cannot be used.

Translactal passage of procainamide was reported by Pittard and Glazier.lso They found a milk-plasma ratio of 4.3 :t 2.4 for procainamide and of 3.8 :t 1.8 for NAPA. Although the high ratio may suggest accumulation in the milk of both procainamide and NAPA, the amount ingested daily by the infant is not expected to produce significant plasma levels. ISO

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Disopyramide

Disopyramide, a relatively recent class Ia antiarrhythmic drug, was approved in the

656 Josef Widerhorn et al.

United States in 1977 for the treatment of ventricular arrhythmias. In suppression of pre-mature ventricular contractions, it appears equal to or better than quinidine or procainamide.75 During mYC9<;ardial infarction, it is use ful in reducing PVCs and the frequency of ventricular tachycardia; it is not clear if it can prevent ventricular fibrillation, however. 90 In Europe, it was found to be equal to quinidine in the treatment and prophylaxis of supraventricular arrhythmias.73, 128

Disopyramide has electrophysiologic properties similar to other class I antiarrhythmic agents; it decreases excitability, conduction velocity, automaticity, and contractility. It also prolongs the effective refractory period and action potential duration. It has marked negative inotropic effects and increases systemic vascular resistance.106. 157 These hemodynamic effects, while not .clinically evident in patients with normal ventricular function, may be deleterious in patients with limited cardiac function.182 Disopyramide has 10 per ceD:t of the anticholinergic effects of atropine.149 Approxi-mately 80 to 90 per cent of an oral dose is absorbed; peak plasma levels are reached by 1 to 2 hours, and the half-life is about 6 to 9 hours. Approximately 30 per cent was found to be bound to plasma proteins at a concentration of 3 f.Lg per ml; the binding varies directly with serum concentration, however, and may be as high as 90 per cent.159 Forty to 90 percent is eliminated in the urine unchanged; dosage has to be adjusted in renal failure. The remainder of the drug is metabolized in the liver via dealkylation.69 Therapeutic levels are 3 to 6 f.Lg per ml. The oral dose is 300 to 800 f.Lg per day; this dose has to be reduced in hepatic, cardiac, or renal insufficiency.

The majority of untoward effects of disopyr-amide are caused by its anticholinergic activity and include include dry mouth, constipation, blurred vision, and urinary retention. It may precipitate congestive heart failure in patients with ventricular dysfunction182 and, similar to quinidine, can induce QT prolongation, ventriculartachycardia, or "torsade de pointes. "139. 161

Animal studies have shown that disopyramide crosses the placenta. With very high doses, an increased incidence of low birth weight fetuses was observed, but there were no teratogenic effects.

There is very little information regarding disopyramide treatment in pregnant women. Shaxted and colleagues210 described a 26-week pregnant patient treated with 600 mg per day for symptomatic ventricular tachycardia. At de

livery, the maternal and fetal levels were 2.3 f.Lg per ml and 0.9 f.Lg per ml, respectively. No adverse effects were noted, and the delivery was normal. Leonard and coworkers,115 however, reported the treatment of refractory su-praventricular tachycardia in a pregnant woman with mitral valve prolapse in which the admin-istration of disopyramide initiated uterine con-tractions that resolved when the drug was dis-continued.

Disopyramide is secreted in the breast milk in concentrations similar to those in plasma; no adverse effects were noted in the infant. 11

Because of the limited information, the use of disopyramide in pregnancy should be reserved for patients refractory to quinidine.

Lidocaine

Lidocaine is a local anesthetic of the amide type that has been used as an antiarrhythmic agent since 1950. During the fifties, lidocaine was employed mainly In the cardiac catheterization laboratory; today it is one of the drugs most commonly used in intensive cardiac care units. Lidocaine is very effective in suppressing ventricular premature beats and ventricular tachyarrhythmias, particularly during acute myocardial infarction, cardiac surgery, and digitalis toxicity. 65 It is of little benefit for supraventricular arrhythmias. Lidocaine depresses automaticity in Purkinje fibers and increases the threshold for ventricular fibrillation.19 The action potential duration is decreased significantly as is, to a lesser extent, the effective refractory period (ERP) in both Purkinje fibers and ventricular muscle. The effect on the ERP of A V node is variable. Lidocaine effectively decreases conduction velocity and suppresses ventricular re-entry in ischemic myocardium. There is no apparent effect on blood pressure or contractility. 165

Lidocaine is administered parenterally; oral administration is ineffective because of extensive metabolism during first pass through the liver. It has immediate onset of action and its half-life is approximately 100 minutes. A loading dose of 1 to 1.5 f.Lg per kg of body weight is followed by continuous infusion. A second dose, usually half of the first dose, may be necessary. Lidocaine is 70 per cent bound to proteins, principally to (Xl-acid glycoprotein, and its clearance approximates hepatic blood flow. Any condition or drug that decreases hepatic blood flow, such as liver disease, congestive heart failure, propranolol,23 or cimetidine10I; therefore, it may


decrease lidocaine clearance. Prolonged infusion of lidocaine for several days also may decrease itshepatic clearance; the dose therefore should be adjusted after 24, 48, and 72 hours. 13. 28

Lidocaine is metabolized in the liver to twocompounds, glycinexylidide and monoethylgly-cinexylidide. Both metabolites are less active thanlidocaine,93 but they may contribute to itsantiarrhythmic activity and CNS toxicity. 20 About 10 per cent oflidocaine undergoes kidneyexcretion unchanged.

Lidocaine in toxic doses may produce myo-cardial depression and hypotension; however, CNSside effects most commonly are observed.Paresthesias, blurred vision, dizziness, drowsiness, hallucination, tremor, and seizures may manifestwhen levels are 5 J.l.g per ml or above. 159

Lidocaine mainly has been used during preg-nancy for epidural or local anesthesia. Stokes andcolleagues227 reported the use of lidocaine as anant,iarrhythmic agent in an 18-week pregnant woman who suffered an acute _myocardialinfarction and cardiac arrest. The infant wasdelivered at 38 weeks of gestation with somegrowth retardation but had normal neurologicexamination at birth and at 17 months.

The drug crosses the placenta rapidly.17. 213Following maternal administration, it can bedetected in the umbilical cord in 2 minutes,237 andthe maternofetal plasma concentration ratio is 0.5 to0.7. The lower fetal drug concentration may beattributed to lower fetal concentration of (Xl-acid glycoprotein, which is approximately one-third of maternal levels. 254 This hypothesis is supported by Tucker,237 who has found a lower bindingcapacity of fetal plasma for lidocaine. Shnider andcoworkers213 using ultrafiltration techniques,however, demonstrated similar binding capacities inboth fetal and maternal plasma. Lidocaine'smetabolism in the fetus also is hepatic.

Shnider and colleagues,212 in a study of 57mothers treated with lidocaine, observed five infants with CNS depression at birth. Three of these infants had a lidocaine level greater than 3J.l.g per m!. No apparent evidence of CNS toxicitywas noted when the fetal .level was below 2.5 J.l.g per ml. The therapeutic range oflidocaine in the nonpregnant state is 1 to 5 J.l.g perml. If the fetal plasma concentration is 50 to 60 percent of the maternal level, it probably is safe tohave maternal levels below 4 J.l.g per ml in order to avoid maternofetal toxicity.

As a weak base, lidocaine may be trapped by theslightly acidic environment of amniotic

657

fluid. Several studies 1., 25, 178 have shown higher fetal drug concentration during fetal acidosis. In addition, acidosis may increase the unbound fraction of lidocaine, facilitating further fetal trapping. 27

Kim and coworkers97 described a case of accidental lidocaine injection of the fetal scalp during local anesthesia or episiotomy. Fifteen minutes after birth, the newborn manifested severe toxicity, demonstrated by apnea, hypotonia, fixed dilated pupils, and then at 1 hour, seizures. The fetal lidocaine level was 14 J.l.g per m!. With appropriate treatment, the neonate recovered completely, with normal neurologic and behavioral examination at 3 days and at 7 months of age.

The Collaborative Perinatal Project surveyed 293 of 50,282 mothers who had exposure to lidocaine during their first trimester.76 Lidocaine administration could not be associated with increased risk of any major group of malformations. Anomalies of the respiratory system (three cases), tumors (two cases), and inguinal herni~s (eight cases), qowever, had greater frequency than expected. .

Several studies showed that lidocaine does not have deleterious neurobehavioral effects on neonates. 2, 96 Despite the paucity of information of lidocaine's use as an antiarrhythmic agent during pregnancy, study data indicate that lidocaine is safe as long as blood levels are monitored closely.

Mexiletine

Mexiletine (see Medical Clinics of North America, Vol. 72, No.2, 1988), a class Ib antiarrhythmic drug, structurally is very similar to lidocaine. Initially studied as an anticonvulsant drug, it soon became evident that mexiletine possessed antiarrhythmic properties resembling those of lidocaine. It is efficacious in suppressing ventricular premature beats and ventricular tachycardia, but it may not prevent ventricular fibrillation during acute myocardial infarction.229 Its antiarrhythmic activity seems to be independent of the nature of underlying cardiac condition-that is, it has equal effectiveness in acute and chronic ischemic heart disease, as well as in cardiomyopathy.30 MexiIe tine has a membrane stabilizing effect, a manifestation of its local anesthetic properties. It slows the maximal rate of depolarization of the action potential and shortens the action potential duration in Purkinje fibers.3O, 151, 163. 176. 181, 229. 236, 2S5 In patients with a compromised A V


node or His-Purkinje systems, the conduction velocities are decreased and the effective refractory periods may be increased. It has no effect on the normal sinus node, but patients with diseased sinus.-ngdes may develop sinus arrest.3O Mexiletine has no apparent hemodynamic effects, 30. 181 and does not significantly affect the ejection fraction in patients with left ventricular dysfunction. 225

Mexiletine is absorbed almost completely in the proximal small bowel. The delayed gastric emptying that occurs in pregnancy may retard the absorption. The peak level is reached after 1.5 hours.255 Seventy-five percent of the drug is protein bound. First pass hepatic metabolism is only 10 per cent, with bioavailability of 90 per cent following oral administration. The drug is metabolized in the liver. The renal clearance of the unchanged drug is highly dependent on urinary pH, varying from 35 per cent in acid urine to 1 per cent'in alkaline urine.1~1 The halflife is 8 to 10 hours in the normal subject but may be prolonged to 15 hours in patients with myocardial infarction.176 The therapeutic range is 0.75 to 2 mg per ml, and it has a narrow toxic-therapeutic window. Following a loading oral dose of 400 to 600 mg, a daily dose of 600 to 120 mg should be sufficient to achieve therapeutic levels. The dosage has to be reduced in patients with chronic liver disease. 163

The adverse effects of mexiletine may occur in 30 to 70 per cent of the patients and are related to plasma concentration. Tremor, diplopia, nausea, and vomiting particularly are frequent. Ataxia, sleep disturbances, fatigue, headache, psychosis, seizures, fever, and rashes also have been reported. Thrombocytopenia and hepatitis are rare complications. Mexiletine also is arrhythmogenic; several authors reported induction of "torsade de pointes. "34. 181

In 1980, Timis and coworkers236 reported a case of ventricular tachycardia in a 32-week pregnant patient treated successfully with a daily dose of propranolol 120 mg and mexiletine 600 mg. On this regimen, the trough plasma concentration of mexiletine was 0.3 to 0.6 !J.g per L. At 39 weeks of pregnancy, the patient went into spontaneous labor and delivered a normal child. For 6 hours post delivery, however, the infant heart rate was only 90 beats per minute; thereafter, it rose to 120 beats per minute and remained stable throughout puerperium. The fetal-maternal ratio of mexiletine plasma concentration was 1. 0, Indicating free transplacental transfer. Mexiletine is secreted in breast milk; however, the daily quantity ingested by the infant is minimal and, therefore,

not detectable in plasma.236 Because of very limited experience with this drug, no recom-mendation can be made until its safety in preg-nancy is documented further.

Amiodarone

Amiodarone (see Medical Clinics of North America, Vol. 72, No.2, 1988),' a benzofuran derivative, was introduced in the late 1960s as an antianginal drug. Since introduction, however, its unusual class III antiarrhythmic properties became evident and it has been widely employed in the management of various supraventricular and ventricular arrhythmias. Amiodarone prolongs the duration of action potential and reduces the maximum rate of depolarization.218 It increases the refractory period and prolongs repolarization.217 It does not affect resting membrane potential. It depresses the

sinus. node 1md prol~ngs PR, QRS, and QTc intervals. 60. 156 In patients with Wolff-

ParkinsonWhite syndrome, it increases refractoriness in both the retrograde and antegrade pathways. 246

Amiodarone has noncompetitive a- and 13-adrenergic blocking activity, and is a potent coronary and systemic vasodilator.32 It also reduces myocardial contractility and heart rate and may lower the blood pressure.

Absorption of amiodarone following oral administration is variable and unpredictable; however, it is estimated to be approximately 40 per cent. Its oral bioavailability ranges from 22 to 86 per cent. 114. 192 Peak plasma concentration is reached within 2 to 10 hours, but a therapeutic effect may take up to 21 days to occur. The metabolism of amiodarone is not fully elucidated. After absorption, the drug is widely distributed into various tissues. Being lipophilic, it accumulates mostly in adipose tissue but also is taken up extensively by the lung, the liver, and cardiac and skeletal muscle.114 The drug undergoes hepatic metabolism and, of its metabolites, desethylamiodarone (DEA) accumulates in plasma during chronic therapy. Only 1 per cent of the dose is excreted unchanged in the urine. Biliary excretion probably plays an important role.114 Protein binding is about 96 per cent. 192 The elimination half-life ranges from 13 to 100 days, with an average of 40 to 50 days.114 To initiate oral treatment, a loading dose of 800 mg to 1600 mg per day is given for 1 to 3 weeks, then decreased to 600 to 800 mg per day for 1 month, and, thereafter, to a maintenance dose of 400 mg per day. The

Cardiova~cular Drugs in Pregnancy ,

therapeutic plasma levels are 1 to 2.5 mg perml. 114

Amiodarone has numerous adverse effects;70 themost severe is pulmonary fibrosis that carries a 10 per cent mortality and may be reversible if the drugis discontinued. Amiodarone may produce sinusbradycardia, A V block, QT prolongation, and"torsade de pointes." Anorexia, nausea, vomiting,and elevation of transaminases are common.Amiodarone has a high iodide content-that is, 75 mg of elemental iodide in a 200 mg dose of drug;both hypoand hyperthyroidism may occur. Cornealmicrodeposits may affect the patient's vision. Pho-tosensitivity and bluish gray discoloration of theskin develop not infrequently. CNS toxicity(tremor, ataxia, and dizziness) or peripheralneuropathy is uncommon, but reported. The adverseeffects may persist months after discontinuation of drug.

Amiodarone interacts with numerous drugsl31; jtpotentiates the effects of warfarin and increasesserum concentration of digoxin,

diltiazem, quinidine, procainamide, and phen ytoin. .

Transplacental transfer of amiodarone has beendocumented in several reports. 7. 129. 137. 179.195 McKenna and coworkers137 treated a 34 week pregnant patient who had paroxysms of atrial flutter-fibrillation associated with Wolff-Parkinson-White syndrome and resistant toquinidine. A loading dose of 800 mg per day for 1week was followed by a maintenance dose of 400mg per day. At 41 weeks, the patient delivered anormal child that was slightly bradycardic for 48hours (104 to 120 beats per minute). Amiodaroneand DEA plasma levels in the infant at birth wereapproximately 25 per cent of the mother's levels.

Pitcher and colleagues179 also reported a case ofa patient with atrial tachycardia resistant topropranolol, digoxin, and verapamil, treatedsuccessfully with amiodarone during the last 3 weeks of pregnancy. Transplacental transfer of amiodarone and DEA was 10 per cent and 25 per cent, respectively. Neither the mother nor the child had untoward effects.

Robson and associates195 described two addi-tional cases in which amiodarone was administered during pregnancy for longer time periods. In thefirst caSe, amiodarone. was given at a dose of 200mg per day to control atrial fibrillation associatedwith mitral stenosis. The patient became pregnantwhile on treatment, and the drug was continuedthrough the pregnancy. At 34 weeks, she delivereda healthy baby. Maternal drug levels throughpregnancy were

659

0.5 to 0.7 mg per ml. The cord drug level was 0.05 mg per ml and the amniotic fluid level was 0.02 mg per ml. Desethylamiodarone levels in maternal plasma, cord blood, and amniotic fluid were 0.8 mg per L, 0.15 mg per Land 0.11 mg per L, respectively. In the second case, amiodarone (400 mg per day) was given in addition to metoprolol (50 mg per day) to control atrial tachycardia in a 22-week pregnant patient. At 39 weeks, she delivered a healthy child. Again, amiodarone and DEA levels in cord blood were 10 and 20 per cent of maternal levels, respectively.

Treatment of fetal supraventricular tachycardia with amiodarone during pregnancy was attempted in two cases. 7. 129 Armoux and coworkers7 described a patient with fetal supraventricular tachycardia and congestive heart failure resistant to digoxin alone or in combination with either sotalol or verapamil who was successfully treated with digoxin and amiodarone. Started at 31 weeks of pregnancy, amiodarone was continued until term (38 weeks). A normal infantwas delivered with an amiodarone level at 12.7 per cent" of maternal level. The comparison of doses and fetomaternal levels shows a linear concentration-dosage relation. Maternal levels, therefore, may be used as an indicator for fetal levels.

The conclusion from the above reports is that amiodarone crosses the placenta; however, fetal levels are approximately 10 per cent of maternal levels. The concentration of amiodarone in the placenta is higher than in adipose tissue, but the significance of this finding is not clear.

In the previously described case reports, no harmful effects on the fetus were observed. Until more data are available, however, caution is recommended regarding the use of amiodarone during pregnancy.

Amiodarone is secreted in breast milk in quantities significant enough to be detected in infant blood. 137 The effect of chronic amiodarone exposure in neonates is unknown; breast feeding, therefore, is not recommended to women who are treated with amiodarone.

Verapamil

Verapamil (see Medical Clinics of North America, Vol. 72, No.1, 1988) a papaverine derivative, initially was used in the 1960s as an antianginal agent. The drug was approved in the United States in 1981 for angina pectoris and supraventricular tachyarrhythmias. It is very effective in terminating A V nodal and

660 Josef Widerhorn et aI.

bypass tract re-entrant tachycardias.244 In patients with atrial flutter or fibrillation and multifocal atrial tachycardia, verapamil slows the ventricular response :and sometimes causes conversion to' sinus rhythm.244 It generally is not used for ventricular arrhythmias unless they are precipitated by coronary spasm. Other indications are angina, hypertension, and hypertrophic cardiomyopathy.

Verapamil blocks the slow influx of calcium and probably of sodium in the sinus and A V nodes.I03 It decreases the conduction velocity and increases the refractory period in nodal tissue. The direct effect of slowing the sinus node generally is overwhelmed by sympathetic activation secondary to peripheral vasodilation.

Oral verapamil is absorbed quite completely, is 9Q per cent bound to proteins, and reaches peak levels in l.to 2 hours. During first pass through the liver, however, it is eliminated extensively, so the drug has a bioavailability of only 10 to 20 per cent. In the liver, the drug is metabolized to several compounq.s,. of which' norverapamil is most active. The elimination half-lives of verapamil and norverapamil are 3 to 7 hours and 8 to 10 hours, respectively. The hepatic metabolism of verapamil may decrease with chronic administration. In the patient with advanced liver disease (that is, cirrhosis), the half-life of verapamil may increase dramatically, up to 14 to 16 hours or more.221 The onset of action with IV preparation is 10 to 15 minutes and its duration is approximately 6 hours. 216 The usual dose employed is 0.15 mg per kg given intravenously at 1 mg per minute.

In patients with compromised sinus or A V node, verapamil may precipitate bradycardia, asystole, hypotension, or A V block. It may increase digoxin levels. The most frequent non-cardiac side effects are headache, dizziness, nausea, constipation, and peripheral edema. It may induce galactorrhea and hyperprolactinemia.57. 207

The majority of reports regarding verapamil administration during pregnancy are from Europe. The drug was used for different indications: maternal and fetal supraventricular arrhythmia,99. 252, 2S3 premature labor,IS:.or severe pre-eclampsia, 209

Klein and colleagues99 described a 38-yearold pregnant hyperthyroid patient treated with verapamil for supraventricular tachycardia re sistant to digoxin and propranolol. The arrhythmia converted to sinus rhythm after 5 mg of IV verapamil. The fetal monitoring tracing showed a transient decrease in fetal heart rate but no decelerations. One month later, the patient

delivered uneventfully. Wolff2S3 also studied six pregnant patients who were administered a single oral dose of 80 mg of verapamil 49 to 564 minutes prior to delivery. The umbilical vein levels were 17 to 26 per cent of maternal concentration. The same investigator also re ported one case of successful cardioversion of fetal supraventricular tachycardia with digoxin and verapamil without adverse effects. Successful fetal cardioversion With verapamil also was described by other authors.5. 16, 100

Despite several reports demonstrating no fetal side effects or teratogenesis, the experience with chronic verapamil therapy is limited. Further studies are therefore necessary in order to assess its safety. Verapamil is secreted in breast milk, but the total daily dose ingested by the baby is very small and no apparent neonatal effects have been noted.88. 148

t I

~-ADRENERGIC BLOCKERS

The therapeutic indications for ~-adrenergic blocking drugs are varied. These agents have proven efficacious in multiple conditions occurring during pregnancy, including dysfunctional labor,152 hypertension, 21, 22, 54, 123, 184,232 thyrotoxicosis,26, 112. 184 hypertrophic cardiomyopathy, 166, 238 migraine headache, glaucoma, and maternap9. 184. 208. 2S3 and fetal51. 66. 100, 208, 252 supraventricular tachyarrhythmias. With some exceptions,233 however, the treatment of fetal tachyarrhythmias has been rather disappointing. 153

The desire to ensure both maternal health and normal fetal growth has led to questions regarding the safety of ~-blocker use during pregnancy. In this article, the world experience with ~-adrenergic blockers in pregnancy is reviewed and recommendations regarding their clinical use are proposed. The effects of ~blockers on the fetus and neonate are reviewed elsewhere in this issue (see article by Kornbluth and colleagues) and the drugs them-selves are discussed extensively by Frishman in the Medical Clinics of North America (Vol. 72, No.1, 1988).

I t

~ b t I .

Adrenergic Influences on Maternal-Fetal Physiology62

~-Adrenergic activity during pregnancy assumes physiologic importance because of the direct effects the sympathetic nervous system has on umbilical blood flow and uterine tone and contractility (Table 1). Because of the dif


Table 1. Adrenergic Influences on Maternal-Fetal Physiology STIMULATION BLOCKADE

a-Receptor f.-Receptor a-Receptor f.-Receptor

Fetal heart rate - t - -!Maternal heart rate - t - ! Umbilical blood flow .".... :,. - t - !

1\ I yometrial activity- t ! ! t - No effect; t increases; ! decreases.

661

ficulty 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 and coworkersl65 studied the effects of propranolol and isoproterenol in nonlaboring, anesthetized pregnant sheep that were near term. During fetal or maternal infusion of the j3-blocker, there was a significant decrease in umbilical blood flow and in the maternal and fetal heart rates. Uterine blood flow and systemic blood pressure' remained unchanged. With isoproterenol infusion, there was _ an increase in umbilical blood flow and oniy a small increment in fetal heart rate. It, therefore, may be concluded that j3-adrenergic tone affects basal umbilical blood flow and a disturbance in sympathetic inputs potentially could be harmful to the developing fetus.

a-Agonists influence umbilical blood flow in-directly through their action on uterine blood vessels. When a low dose of norepinephrine was infused directly into a uterine artery, a profound reduction in uteroplacental blood flow developed. 110 A direct action of norepinephrine on the umbilical circulation has not been demonstrated.3. 33

In the myometrium, there are adrenergic receptors of the a- and j3-types. Stimulation of the j3-receptor results in myometrial relaxation, whereas increased a-adrenergic stimulation po-tentiates contractility.136 In animal studies, pro-pranolol has been shown to reverse the myometrial depressant action of j3-stimulation.242 Barden and colleagues70 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 decreas

ing 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 of the subjects had normal term vaginal deliveries.

The influence of the autonomic nervous system on normal fetal circulation also has been studied in the fetal lamb preparation. In a report by J oelson and Barton,91 isoproterenol administered to the fetus caused an increase in heart rate and a decrease in blood pressure,

whereas pfopr'anolol caused only a slight drop in heart rate. It was apparent that the effects of

j3-adrenergic blockade in the unstressed and undisturbed fetus were minimal. When the fetus is stressed, however, stimulation of the 13receptor may provide an important reserve for neonatal adaptation. Thus, maternal treatment with j3-blockers may impair the response to fetal distress.

Clinical Experience

Different j3-adrenergic blocking drugs have been used in pregnancy. Despite their growing use, several adverse reactions have been reported (Table 2).

Propranolol. Propranolol, the oldest of the available nonselective j3-blockers, has been studied the longest in pregnancy. The drug is a class II antiarrhythmic agent, and j3-blockade appears to be the main mechanism for its an-tiarrhythmic effect.81. 159 A membrane stabilizing effect also may be involved, however, particularly at higher concentrations. 8, 65

During pregnancy, propranolol can affect uterine contractility (see Table 1). Barden and coworkersl66 have demonstrated that proprano

Table 2. Reported Adverse Reactions to I3-Adrenergic Blocking Drugs in Pregnant Women

Bradycardia Premature labor Prolonged labor


Ii,. ", i:

101, given to pregnant women, blocks the inhib-itory effects of epinephrine on myometrial ac-tivity. The administration of propranolol therefore may facilitate an increase in uterine contractility. ""

:-.

The pharmacokinetics of propranolol during pregnancy are similar to those in the nonpregnant state. O'Hare and colleagues169 administered propranolol to six healthy pregnant volunteers between 32 and 36 weeks of gestation. There were no significant changes in elimination half-life, clearance, VD, and bioavailability. Perruca and coworkers,142 however, found that the protein binding of propranolol decreased during pregnancy.

Propranolol readily crosses the placenta39. 43. 67. 112. 184. 233 and, at delivery, the fetal serum concentration is equal t039. 184 or less than233 the maternal concentration. The unbound fraction of propranolol is .higher in fetal plas~a, how ever, probably because of low concentration of (Xl-acid glycoprotein. Because of decreased he patic metabolism and altered protein binding, the serum concentration and half-life' of pro pranolol may be increased in the neonate during thefirst days of life. 67. 184

Several fetal and neonatal adverse effects were reported.21. 43. 54. 132. 166. 166. 184. 232. 239 Pruyn and associatesl84 noted that 10 to 11 neonates frommothers treated chronically with propranolol had intrauterine growth retardation. Extrapolating data from an animal study,l65 they suggested thatpropranolol may decrease umbilical blood flow and, consequently, fetal nu trition. While reported by many other authors21. 54. 132. 166. 187.232 the true incidence of intrauterinegrowth retardation is unclear. In some prospective studies,21. 54. 166. 232 the incidence of intra-uterine growth retardation was only 3 to 4 per cent(4 of 94 pregnancies). Furthermore, two of thesefour mothers who had small babies deliverednormal babies in subsequent pregnancies, despite continuous treatment with propranolol. 166 Redmond,187 in an extensive review of human andanimal literature, concluded that the evidenceimplicating propranolol in growth retardation issuggestive but inconclusive.

There are many hypothetical mechan~sms bywhich propranolol may induce growth'retardation. A decrease in cardiac output combined with plasmavolume contraction and increased systemic vascular resistance occurring duringhypertension in pregnancy may decrease uterine blood flow.187 Propranolol has been shown toreduce umbilical blood flow in pregnant ewes.165 Other postulated mechanisms may in-volve a decreased peripheral conversion of T4

,I '!H

to T3 and a theoretical effect on neurotransmitters that may affect the brain's influence on fetal growth. 187

Turnstall and colleagues239 described a delay in the onset of respiration of newborns when propranolol was administered to the mother prior to cesarean section. Another major source of concern is the effect of propranolol and of 13-blockade therapy in general on the fetal response to hypoxia. During asphyxia, several hormonal, metabolic, and circulatory adaptive mechanisms are activated. Most responses are mediated through catecholamines and l3-receptors. As has been demonstrated in experimental animal studies,85. 91 propranolol therapy may be particularly deleterious during these circumstances of fetal distress. l3-blockade also may be responsible for lack of fetal heart acceleration provoked by sound stimulationl66 and persistently negative throughout the nonstress test and contraction stress test. 132

To date, propranolol has not been demonstrated to be teratogenic. However, three cases of congenital malformatibns have been associated with propranolol therapy during preg nancy; for example, pyloric stenosis, crepitus of the hip, and tracheoesophageal fistula. 22. 29. 167 It is not clear at all if this is a casual occurrence or a true teratogenic effect of propranolol. In any case, if the last hypothesis is correct, these malformations probably are very rare.

Although the information concerning use of propranolol during pregnancy has expanded steadily, its safety is still somewhat controversial. Despite favorable reviews,l23. 199 there is a potential for side effects29. 184. 187. 205 that should be anticipated by the clinician.

Propranolol is excreted in breast milk. 12. 93. 116 Karlberg and coworkers93 showed that propranolol is secreted into the breast milk in a dosedependent manner and the milk-plasma ratio is approximately 1.0. Bauer and colleagues12 found a milk-plasma ratio of 0.4 to 0.6; they estimated that the daily dose ingested by the infant probably is 1 per cent of the recommended pediatric daily dose. No adverse effects were observed in infants breast fed by mothers treated with propranolol. However, the newborn hepatic microsomal enzyme systems are immature and propranolol may accumulate. Careful observation of these infants is therefore recommended.

Metoprolol. Metoprolol is a I3cselective blocking agent. It is similar in its effectiveness to other nonselective l3-adrenoreceptor blocking drugs used in the treatment of angina pectoris4 or essential hypertension. 15 Because of its primary 131-selective properties, the drug

i

Cardiovascular Drugs in Pregnancy 663

theoretically would not interfere with 132-me-diated peripheral vasodilatation or 132 effects on uterine tone.

In pregnancy, metoprolol has been used pri-marily to control hypertension61. 84. 202. 203 or tachyarrhythmias.24 Its metaQ.olism during preg-nancy is increased and, therefore, half-life, serum concentration, and bioavailability are de-creased.83 The most plausible explanation is that steroid hormones increase the activity of the hepatic mono-oxygenase system, which is involved in metoprolol metabolism.83 Protein binding is not altered during pregnancy.

Metoprolol crosses the placenta, and the fe tomaternal serum concentration ratio is approx-imately 1.0.122.203 Because of redistribution and! or relative immaturity of hepatic enzymatic systems in the newborn, the serum concentration of metoprolol increases four-fold during the first hours of life, but then declines over 5 to 20 hours. 122 ' .

Metoprolol alone or combined with hydralazine was studied in 101 pregnant hypertensive patients.203 The metoprolol group experienced lower perinatal mortality (2 per cent versus 8 per cent) and a lower incidence of intrauterine growth retardation (11.7 per cent versus 16.3 per cent). Theoretically, this might be explained by metoprolol's lack of action on uterine tone (132 effect) and l3-mediated vasodilatation. No differences in Apgar score, gestational age, or birth weight were noted.

Hogstedt and colleagues,84 in a recent con-trolled trial, compared the combination of me-toprolol and hydralazine with non pharmacologic management of hypertension in 161 pregnant patients. The outcome for the neonates with respect to birth weight, head Cfircumference, Apgar score, incidence of respiratory distress, bradycardia, and hypoglycemia was similar in both groups, confirming the results previously reported.220 There was one case of fetal malfor mation in each group. This may be an unrelated event because the combination metoprolol-hydralazine was started during the second and third trimesters. To date, no cases of fetal malformation induced by metoprolol have been reported, but experience during the first trimester is lacking.

Sandstrom204 has shown the combination of metoprolol and hydralazine to be superior to hydralazine and thiazide for the treatment of pregnant hypertensive patients with regard to maternal well-being, fetal intrauterine growth, 10-minute Apgar scores, and perinatal mortality.

Despite encouraging data, caution is recom

mended. Kjellmer and associates,98 in an animal study, showed that 131-adrenoreceptor blockade is potentially dangerous in cases of fetal asphyxia. These data are in agreement with previous experimental results obtained with the nonselective l3-blocker propranolol. 29.85

Metoprolol is secreted in breast milk,1I9 but the daily fetal quantity ingested by the neonate is very small. Unless hepatic function. in the newborn is markedly impaired, breast feeding should not be discouraged. Finally, metoprolol appears to be safe in

pregnancy, but the data are still limited. Pending further studies assessing metoprolol's safety in

pregnancy, caution is recommended. Atenolol. Atenolol is another relatively selective

I3cadrenergic blocking agent used to treat hypertension during pregnancy. 113. 127. 138.200,220. 23S Its fetal effects are described in the article by Kornbluth and colleagues in this issue.

Like metoprolol, atenolol has negative ino

tropic and chronotropic activity. However, it , has insignificant partial ~1 mimetic activity and weak membrane stabilizing properties. 194

Transplacental transfer of atenolol is well documented. 113. 138 Although there is a three- or six-fold individual variation in plasma atenolol concentration in each patient studied, its con-centration was found to be equal in maternal and fetal blood (ratio 1.0).138 Atenolol is secreted in breast milk and no effects were noted in atenolol-exposed babies; breast feeding, therefore, need not be discontinued. 119

Pindolol. Pindolol is a l3-adrenergic blocking agent that has partial intrinsic sympathomimetic activity. It also has some membrane stabilizing

effects, but much less than propranolol's. 8

The potential advantage of intrinsic agonist activity in a l3-blocker is that the decrease in heart rate and cardiac output at rest is not as pronounced as with nonagonistic l3-blocking drugs. The exercise-induced increase in heart rate and cardiac output still is blunted, however.204 This may be of particular benefit in patients with ventricular dysfunction or those prone to bradycardia.6S

Theoretically, pindolol may be particularly advantageous in pregnancy because the lack of effects on resting heart rate and cardiac output, combined with a direct vasodilator effect, are not expected to compromise uterine blood flOW197 or to decrease basal fetal heart rate.87

Pindolol crosses the placenta, and the feto-maternal concentration ratio is less than 1. 0.71 Elimination half-lives in fetus and mother are 1.6 hours and 2.2 hours, respectively. Dubois and coworkersso compared acebutolol, pindolol,

.1'

664 Josef Widerhom et ai.

and atenolol in 56, 38, and 31 pregnant hyper-tensive patients, respectively. In the pindolol group, the birth weight was significantly higher than in the atenoloLgrgup (3345 g versus 2745 g). Apgar score, gestational ages, fetal heart rate, and frequency of hypoglycemia were not affected by pindolol treatment. Two cases of malformation were reported in the pindolol group, however: cleft palate (pindolol started at 29 weeks of gestation) and vesicoureteral reflux (second full pregnancy on pindolol in a mother with asymmetrical segmental renal hypoplasia).

In another study, 55 pindolol was compared with methyldopa in 32 consecutive patients with pregnancy-induced hypertension. Maternal blood pressure was controlled better in the pindolol group. Furthermore, a drop in creatinine levels and an increase in creatinine clearance was noted in mothers treated With pindolol. No difference was observed between the two groups in regard to intrauterine growth, Apgar score, or fetal morbidity. The birth weight was similar in the two groups (2850 g). Nonstress tests were normal and no bradycardia was observed in the pindolol group.

Rosenfeld and coworkers197 randomly assigned 44 consecutive pregnant hypertensive patients to two treatment groups: hydralazine alone (21 patients) or hydralazine and pindolol (23 patients). These investigators found a lower incidence of maternal side effects such as dizziness or headaches in the combination therapy group. No differences were noted in the two groups concerning birth weight, gestational ages, hypothermia, hypoglycemia, Apgar score, or mode of delivery. Two major malformations were noted in the hydralazine group and neonatal thrombocytopenia was noted in the combination group.

Although preliminary reports are favorable for recommending the use of pindolol in pregnancy, the information available is still limited. Additional experience is needed to confirm the safety of pindolol during pregnancy.

Labetalol. Labetalol, like propranolol, blocks both I3c and 132-adrenergic receptors. But la-betalol is unique in that it also has both a1-adrenergic blocking properties and direct va-sodilatory activity. Labetalol' crosses the pla-centa.I64. 190 The fetomaternal concentration ra tio is 0.5. Its clearance and volume of distribution are not altered during pregnancy.

There have been a number of favorable reports describing the safe use of labetalol in pregnancy.

Lamming and coworkerslll randomized 26 patients with pregnancy-induced hypertension

in two groups: one treated with labetalol (14 patients) and one treated with methyldopa (12 patients). Improvement of renal function and a better control of blood pressure were observed in the labetalol group. The incidence of spontaneous labor and Bishop score also were higher in the labetalol group. Theoretically, the higher incidence of spontaneous labor could be caused by myometrial relaxation induced by acblocking and the 132-mimetic activity. of labetalol. Furthermore, Nylund and colleaguesl64 dem onstrated that uterine blood flow was not affected despite significant reduction in blood pressure. There also is evidence that labetalol may promote fetal lung maturation. Michaep45 observed higher than expected lecithin-sphin gomyelin ratio in amniotic fluid as early as 31 weeks of gestation in patients treated with labetalol. This effect probably is mediated by 132mimetic activity because salbutamol has similar effects.l60 Several studiesl46, 186, 230 showed that no fetal adverse effects were associated with labetalol treatment.

Labetalol also is useful in the management of severe pre-eclampsia or eclampsia. 63. 147 Michaep47 randomly assigned 90 patients with severe hypertension (diastolic blood pressure greater than 105 mm Hg) to receive IV labetalol (45 patients) or IV diazoxide (45 patients). The control of blood pressure was better in the labetalol group. A precipitous drop in blood pressure (60/40 mg Hg) was noted only in the diazoxide group (eight patients). No fetal brady-cardia, hypoglycemia, hypothermia, or malfor mations were noted. There was a higher operative delivery rate in the diazoxide group. The results obtained in several studies regarding the use of labetalol for all types of hypertension during pregnancy, including hypertensive emergencies, are very encouraging. However, more information concerning its safety is warranted and, therefore, caution is recommended.

Labetalol is secreted in breast milk and no adverse effects were noted in neonates.l25 The nursing babies should be monitored closely, however.

Other I3-Blockers. The experiences with ace-butolol, oxprenolol, and sotalol are reviewed in the article by Kornbluth and coworkers.

t Ir

Recommendations

The evidence currently available regarding the safety of l3-blocking agents in pregnancy is inconclusive. It, therefore, appears preferable to offer other effective drugs already proven

I


safe during pregnancy, prior to using ~-blockers. If a ~-blocker is to be used, the following guidelines may be useful.

1. Consider the pregnant woman (and the fetus) receiving ~-blockers to be a high-risk patient, deserving special. -c:ire during both pregnancy and labor. 2. Whenever possible, avoid the use of ~ blocker therapy during the first trimester.

3. Use the lowest possible therapeutic dose; combinations of low doses of ~-blockers and other agents may be the optimal drug therapy.

4. When possible, taper drug therapy at least 2 to 3 days prior to delivery, both as a way of limiting the effects of ~-blockers on uterine contractility and of preventing neonatal compli-cations secondary to ~-blockade.

5. The use of ~-blockers with ~1-selectivity or intrinsic sympathomimetic activity, or the use of an a-~-blocker (that is, labetalol) may be preferable, in that these. drugs theoretically would be less likely to interfere with -~2mediated uterine relaxation and peripheral vasodilation.

A comprehensive recommendation regarding the use of ~-blockers is extremely difficult to state because of the absence of any large scale clinical use of these agents in pregnant patients. Further studies are needed to define drug pharmacokinetics in mother and fetus. Future trials hopefully will address these questions and further clarify the role ~-blocking agents should playas therapy in controlling maternal disease states, as well as their effects on fetal and neonatal well-being.

SODIUM NITROPRUSSIDE

Sodium nitroprusside (SN) is one of the most potent drugs available for treatment of hyper-tensive emergencies. It was approved in the United States in 1974. Chemically, sodium nitroprusside is disodium pentacyanonitrosylferrate. The hypotensive component of sodium nitroprusside is the free nitroso (NO) group which interferes with calcium influx and activation, producing relaxation of vascular smooth muscle but not of uterine smooth muscle. SN directly relaxes arteriolar and venous smooth muscle, decreasing preload and afterload. Blood pressure decreases and heart rate increases slightly. Renal blood flow and glomerular filtration rate are preserved; plasma renin activity is increased. Nitroprusside reacts rapidly with hemoglobin, yielding methemoglobin and cyanide. The latter compound undergoes metabo

665

lism in the liver or kidney to thiocyanate, which is excreted in the urine. Cyanide also may be eliminated as cyanomethemoglobin or cyano-cobalamine. In case of liver diseases, hepatic immaturity, and excessive administration, cyanide ions may poison the cytochrome oxidase system, leading to anaerobic metabolism and, clinically, metabolic acidosis.

SN is given intravenously in light-protected tubing. The initial rate of infusion should be 0.1 to 0.2 J.Lg per kg per minute and slowly increased (5 to 10 J.Lg every 5 to 10 minutes) until the desired effect is obtained or a dose of 10 J.Lg per kg per minute is reached. Cyanide, thiocyanate, methemoglobin level, and arterial pH should be monitored periodically.

Prolonged use of SN and/or renal failure may result in excessive thiocyanate formation and/or accumulation that initially manifests with CNS symptoms (tinnitus, blurred vision, confusion, psychosis). Plasma,thiocyanate above 10 mg per 100 ml is toxic ana above ~O mg per 100 ml, fatal. Other adverse effects are methemoglobinemia, increased intracranial pressure, headache, rash, nausea, abdominal pain, and muscle twitching.

During pregnancy, SN has been used to control the blood pressure during intracranial aneurysm surgery"9. 249 or severe gestational hy-petension.174 SN was demonstrated to cross the placenta in both human21. 226 and animal studies.56.

11S. 156. 191. 247

The experimental data concerning the phar-macodynamic effects of SN in pregnant animals still are conflicting. 56. l1S, 156, 191. 247 Ring and coworkers191 compared SN with hydralazine in phenylephrine-induced hypertension in nearterm pregnant ewes. Both agents were equally effective in lowering the blood pressure. However, only hydralazine counteracted the effects of phenylephrine-that is, increasing uterine blood flow, heart rate, and cardiac output. Wheeler and associates247 found that nitroglycerin and nitroprusside have similar effects on uterine flow, that is, mostly increased or, in a few cases, unchanged. Ellis and coworkersS6 found that SN increases uterine blood flow in pregnant ewes, whereas Lieb and coworkers11S noted a significant (25 to 35 per cent) decrement. Naulty and colleagues156 observed a decrease in blood pressure without any changes in uterine blood flow.

Paull and coworkers174 described four severe pre-eclamptic patients with hypertension resis tant to diazoxide and other "conventional methods" treated successfully with nitroprusside. The only fetus alive at the onset of therapy was


delivered uneventfully. Four other patients with severe pregnancy-induced hypertension and refractory congestive heart failure were treated successfully with SN. 226 One premature infant expired. The 'other infants were free of side effects or malformations. The infusion rate varied from 0.013 /Lg per kg per minute to 2.75 /Lg per kg per minute. Measurements made in one case showed equal but negligible (0.1 ILg per ml) concentrations of cyanide in maternal and fetal blood.

Shoemaker and coworkers214 described a 24-week pregnant patient with severe pre-eclampsia not controlled by hydralazine and magnesium sulfate. Blood pressure was controlled with SN and labor was induced with pitocin. Fifteen hours after the onset of SN therapy, the patient delivered a 478 g stillborn infant. The nitroprusside dose was 3.9 /Lg per kg' per ml. The level of cyanide in the fetal liver was less than 10 /Lg per ml, with toxic levels reported to be 30 to 40 /Lg per ml. The authors speculate that fetal death was caused by severe eclampsia.

In summary, nitroprusside is a very effective but toxic drug.' Until further studies clarify its pharmacodynamics, kinetics, and safety during pregnancy, caution is recommended.

HYDRALAZINE

Hydralazine has been used extensively during pregnancy since the early 1950s. It is one of the agents of choice in the management of hypertensive emergencies as well as for main-tenance therapy, alone or in combination with other antihypertensive drugs.

It has a direct relaxing effect on arteriolar vascular smooth muscle, producing a decrease in systemic vascular resistance and vasodilatation.102 The hydralazine effects appear to be mediated through guanosine 3' ,5' -monophosphate (cyclic GMP).

Peripheral vasodilatation triggers compensatory sympathetic discharge, which increases the heart .rate and cardiac OUtpUt.102 Plasma renin activity is increased and, consequently, sodium and water retention may lead to edema formation. Regional vasodilatation is not equal; splanchnic, cerebral, coronary, and renal vascular beds are more dilated than skin and muscle vascular beds. Venous dilatation is minimal and, therefore, postural hypertension is infrequent.

When given orally, the drug is absorbed almost completely from the gastrointestinal tract. The systemic bioavailability of hydralazine

after its first pass through the liver depends on acetylator type. Obviously, slow acetylators will have a higher blood level and will be more prone to toxicity. Peak plasma concentration is reached within 0.5 to 2 hours, and the hypotensive effect lasts 6 to 8 hours. Parenteral administration is less influenced by acetylator type; onset of action is within 10 to 20 minutes and may last 2 to 4 hours. For the treatment of hypertensive emergency during pregnancy, Pritchard and colleaguesl83 suggested an initial IV dose of 5 mg that can be increased by 5 to 10 /Lg every 20 minutes.

With IV administration, flushing, headache, dizziness, and palpitations may be prominent. Nasal congestion, nausea, vomiting, diarrhea, fatigue, and sleep disturbances also may be common. Approximately 5 to 10 per cent of the patients may develop a lupus erythematosuslike syndrome. The syndrome is more common in slow acetylators and when doses of more than 200 mg per ~ day are used. It may become evident after 2 months of treatment and resolve slowly (6 months to years) after withdrawal of drug. Other rare complications are blood dyscrasias, rash, and fever.

Experimental data from animal models con-cerning the effect of hydralazine on uterine blood flow have been controversial. 9. 109. 191 Ring and associates191 reported an increase in uterine blood flow in pregnant hypertensive sheep, whereas Ladner and coworkers109 showed the opposite effect in normotensive pregnant sheep. Several studies92. 126, 228 investigated the effects of drugs on intervillous blood flow in hypertensive pregnant women. In all of these studies, the administration of IV hydralazine did not change the mean intervillous blood flow significantly. Looking at individual results, however, uterine blood flow was descreased in 9 of 13 patients in the Lunell study,126 in contrast to the Suomo study,228 in which the flow decreased in only 4 of 10 patients.

Vink and coworkers241 investigated the effect of IV administration of dihydralazine on maternal blood pressure, uterine activity, fetal heart rate, and growth retardation in 33 hypertensive pregnant patients. Dihydralazine, 12.5 mg, lowered the diastolic blood pressure from more than no mm Hg to 70 to 90 mm Hg in 5 minutes in 30 of 33 patients. Nineteen fetuses had deceleration in fetal heart rate concomitantly with the decrease in blood pressure; 13 of these 19 fetuses had intrauterine growth retardation; and three fetuses were stillborn. Only one fetus from the group without deceleration had intrauterine growth retardation.


Uterine activity was not influenced by hydralazine administration. According to the authors, fetal deceleration was caused by inability of the uteroplacental unit to compensate for the acute reduction in blood pressure.

Spinnato and colleagues27 also observed a higher incidence of cesarean section deliveries secondary to fetal distress in pre-eclamptic or eclamptic patients treated with hydralazine.

Kuzniar and coworkers108 obseved that the hemodynamic effects of hydralazine are more pronounced in patients with pregnancy-induced hypertension than in those with essential hy-pertension during pregnancy. Patients with se vere pre-eclampsia have high systemic vascular resistance, decreased cardiac output, and di-minished plasma volume. In these patients, vasodilator agents such as hydralazine, are more likely to induce marked hypotension and, con-sequently, fetal distress. In contrast, the response to hydralazine is less dramatic in patients with pregnancy-associated hypertension. These observations indicate that lower doses and a gradual decrease in blood pressure are particularly beneficial in the high risk group of patients with pre-eclampsia.

In summary, the use of IV hydralazine in hypertensive emergencies such as pre-eclampsia and eclampsia is very effective in lowering the blood pressure and preventing hypertensive encephalopathy or intracranial hemorrhages. Hydralazine therapy is associated with the risk offetal distress, however, particularly in patients with a reduced uteroplacental reserve. In these patients, aprecipitous decrease in blood pressure clearly isassociated with fetal distress and should be avoided.Some authorslSS believe that the reduction inuterine blood flow is caused by catecholamine-induced vasoconstriction rather than a reduction inperfusion pres sure alone. They suggest that the concomitantadministration of antiadrenergic agents, such asmethyldopa, as well as avoidance of unnecessary reduction in blood pressure may explain the lowincidence of fetal distress noted in their patients.

Hydralazine crosses the placenta freely and alsoappears in small amounts in milk. ~20 To date, no teratogenic effects of hydralazine have beenreported.

NITRATES

Organic nitrates, esters of nitric acid, have been used extensively for more than a century for the treatment of the symptoms of ischemic

heart disease. Their use more recently was extended to congestive heart failure. Nitrates are very potent dilators, predominantly of venous vessels; arterial dilatation increases at high doses. Nitrate effects lead to a decrease in venous return and, consequently, to lower right and left ventricular end diastolic pressures. Systemic vascular resistance is not changed significantly, heart rate is unchanged or increased, and cardiac output usually is un changed. In higher doses, nitrates may lower the blood pressure and cardiac output, which triggers a compensatory sympathetic activation with reflex tachycardia and vasoconstriction. Nitroglycerin also decreases pulmonary vascular resistance. The antianginal effects mostly are because of a decrease in myocardial oxygen requirements by reducing pre- and afterload. Nitrates are metabolized in the liver. Nitroglycerin metabolites have only 10 per cent of nitroglycerin's potency and their half-life is approximately 40 minutes. Following sublingual administration, the peak plasma concentration is reduced in 4 minutes and half-life is 1 to 3 minutes. Intravenous administration is used mostly in acute ischemic syndromes and conges-tive heart failure.89 It also is used to control systemic hypertension after and during coronary artery bypass surgery.

Continuous exposure to nitrates may lead to early development of tolerance. 1. 171. 172. 188. 234 These problems probably may be avoided by increasing the dosing interval and allowing nitrate-free intervals of at least 10 hours over 24 hours.ll. 171. 172 Most common side effects are headache, dizziness, and postural hypotension; syncopal episodes are not common. During pregnancy, IV nitroglycerin was used to control severe pregnancy-induced hypertension. 86. 219 Having a very small molecular weight and being uncharged, nitroglycerin easily crosses the pla-centa.38 Experimental data in pregnant ewes47 showed a fetomaternal arterial blood concentration ratio of 0.15. The authors advanced the hypothesis that the low fetal levels probably are caused by rapid metabolism, poor placental transfer, or widespread binding.

Snyder19 and Hood86 and their colleagues used nitroglycerin to control the elevation of blood pressure that occurs during tracheal intubation in pre-eclamptic patients. Nitroglycerin not only successfully lowered the basal blood pressure, but also blunted the hyperten sive response to intubation. No evidence of fetal compromise was noted.

Cotton and colleagues38 studied the hemo-dynamic effect of IV nitroglycerin coupled with


blood volume expansion in six pre-eclamptic patients. The mean gestational age was 37.3 :!: 3.6 weeks. Nitroglycerin alone effectively reduced the mean arterial blood pressure by 27.5 per cent. The hypotepsive effect was blunted by volume expansion. In two patients in whom blood pressure was lowered suddenly, fetal deceleration and bradycardia were observed. In the other three patients, a flat fetal heart rate with an average beat-to-beat variability of less than 5 beats per minute was noted. The authors suggested that this probably is because of a loss of cerebral autoregulation and increased intracranial pressure induced by nitroglycerin.

In summary, it appears that nitrate treatment is not free of side effects, and the information available regarding their use during pregnancy is very limited. Of particular concern are the effects. on uterine blood flow, oxygen'delivery, and fetal hemodynamics. Further studies are needed to clarify their effects and safety during pregnancy; therefore, no recommendation can be made at this time.

CONCLUSION

There are many clinical situations that require the use of cardiovascular medications in pregnancy. It is hard to evaluate drugs during pregnancy, so the safety experiences with many medications are limited, but certain drugs (digoxin, quinidine, (3-blockers, a-methyldopa, hydralazine) have been used with relative safety to both mother and fetus. It always is best to avoid medications in pregnancy but, when necessary, drugs for cardiovascular disease may be used when the risk-benefit ratio is favorable.

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