Untoward effects of rapid-acting antihypertensive agents

Best Practice & Research Clinical Obstetrics and Gynaecology Vol. 15, No. 4, pp. 491±506, 2001

doi:10.1053/beog.2001.0196, available online at http://www.idealibrary.com on

1 Untoward e€ects of rapid-acting antihypertensive agents Fathima Paruk

FCOG (SA)

Consultant

Jack Moodley

MD

Professor and Head of Department of Obstetrics and Gynaecology MRC/UN Pregnancy and Hypertension Research Unit and Department of Obstetrics and Gynaecology, Nelson R. Mandela School of Medicine, University of Natal, South Africa

Cerebral haemorrhage remains a major cause of hypertensive cerebral mortality. Lowering of raised blood pressure is therefore crucial in the clinical management of hypertensive disorders of pregnancy. This article reviews rapid-acting agents employed in life-threatening situations. Key words: hypertensive nifedipine.

urgency;

hypertensive

emergency;

dihydralazine;

labetalol;

Pre-eclampsia/eclampsia is an unpredictable multi-organ disorder unique to human pregnancy. It is a cause of signi®cant maternal and fetal morbidity and mortality worldwide. A third of the maternal deaths are attributed to cerebral haemorrhage. Thus, appropriate control of elevated blood pressure is important. As its aetiology remains unestablished, treatment is empirical. The pregnant hypertensive patient constitutes a unique individual. She is usually young in age, with a contracted blood volume. In addition, she has to contend with the attendant physiological cardiovascular changes which occur with pregnancy. Current management of severe hypertension constitutes an individualized approach which involves haemodynamic stabilization and an appropriately timed delivery. The reason for lowering blood pressure is to reduce maternal complications, such as cardiovascular accidents and pulmonary oedema. It is important to note that hypertensive emergencies are physiologically diverse and, consequently, clinicians ought to be familiar with a few rapid-acting antihypertensive agents used in the management of this potentially fatal scenario. CLASSIFICATION The recently updated classi®cation of hypertension in pregnancy according to the American College of Obstetricians and Gynecologists1 is as follows: . gestational hypertension; . chronic hypertension; 1521±6934/01/040491‡16 $35.00/00

c 2001 Harcourt Publishers Ltd. *

492 F. Paruk and J. Moodley

. pre-eclampsia; . chronic hypertension with superimposed pre-eclampsia. Pre-eclampsia is generally de®ned on the basis of new-onset hypertension and proteinuria developing after 20 weeks of pregnancy. According to Higgins and de Swiet2, women who do not have proteinuria but who do have hypertension and other features, such as headache, thrombocytopenia, hyperuricaemia, deranged liver function or fetal compromise, are likely to have pre-eclampsia. This concept is suggested in the new Australasian and American College de®nition of pre-eclampsia.2 Transient hypertension constitutes the occurrence of hypertension in pregnancy near term or within 24 hours post-delivery. It is usually a retrospective diagnosis. A hypertensive emergency is de®ned as a scenario that warrants immediate blood pressure reduction in order to prevent or limit acute target organ damage. A systolic blood pressure 4169 mmHg or a diastolic blood pressure 4109 mmHg is regarded as a hypertensive emergency. It di€ers from a hypertensive urgency where blood pressure reduction is achieved gradually over a period of a few hours. Moodley and Rajagopal3, quote a 7% incidence of hypertensive crises of pregnancy. This is a high incidence but the ®gures are hospital-based and probably re¯ect the referral nature of the institution. Hypertensive encephalopathy constitutes a complication of malignant hypertension ± usually it occurs in the scenario of a diastolic blood pressure in excess of 130 mmHg. It is characterized by the occurrence of severe hypertension with neurological symptoms and/or signs. There is a school of thought that believes that eclampsia represents a form of hypertensive encephalopathy4 while others maintain that this cannot be the case as all eclamptic patients do not exhibit severe hypertension. There appears to be a shift in thinking that both eclampsia and hypertensive encephalopathy are considered to be part of reversible posterior leucoencephalopathy syndrome (PLS) which is diagnosed clinicoradiologically. It is important to note that PLS has multifactorial causes, many of which are non-hypertensive in origin.

PATHOPHYSIOLOGY It has been suggested that hypertension may not be central to the pathogenesis of preeclampsia as changes such as increased sensitivity to vasopressors, reduced plasma volume, altered proximal tubular function, activation of the thromboxane-prostaglandin imbalance, endothelial dysfunction, insucient production of blocking antibodies, genetic predisposition and coagulation system changes antedate overt hypertension.5±9 The development of hypertension re¯ects an imbalance of cardiac output [CO] and systemic vascular resistance [SVR]. The pregnant hypertensive has a raised SVR in addition to a raised CO. Thus, blood pressure (which is equal to SVR  CO) is raised. It is important to note, however, that the haemodynamics are in¯uenced by the interplay of multiple factors ± which results in altered blood vessel characteristics and lumen diameter. These factors include structural changes in calibre, hormones, neurogenic mechanisms, nitric oxide, endothelin and the thromboxane±prostaglandin system. The pathophysiology of a hypertensive crisis is not yet completely understood. Figure 1 illustrates the proposed sequence of events in a hypertensive emergency. The pathophysiological origin of cerebral lesions in severe pre-eclampsia/eclampsia remains a debatable issue. The theories of vasogenic oedema and cytotoxic oedema constitute the two polarized theories that have emerged. According to the theory of cytotoxic oedema, the cerebral lesions occur due to cerebral arterial over-regulation with severe hypertension and generalized vasoconstriction, local ischaemia, arteriolar

Rapid-acting antihypertensive agents 493

SEVERE HYPERTENSION

Raised SVR due to humoral factors Vasoconstrictive factors Cytosolic (calcium)

Endothelial injury Vasoactive factors

Fibrinoid necrosis Perivascular oedema

Ischaemia

Loss of autoregulation Platelet/fibrin deposition Figure 1. Pathophysiology of a hypertensive emergency.

necrosis and disruption of the blood±brain barrier. Di€usion weighted imaging in regions of cytotoxic oedema reveal reduces coecients compared to normal white matter, while magnetic resonance angiography shows focal or di€use vasospasm. Naidu et al10 suggest, in a study which utilized single photon emission computed tomography (SPECT), CT scan and transcranial Doppler ultrasound, that the pathophysiological mechanism of eclamptic seizures may be primary cerebral vasospasm. The alternative theory of vasogenic oedema proposes that cerebral lesions occur on the basis of loss of cerebral arterial autoregulation in response to acute severe hypertension with passive arteriolar dilatation, disruption of tight junctions between endothelial cells, extravascation between macromolecules, diapedesis of red blood cells and disruption of the blood±brain barrier. Recent studies have supported this pathophysiological mechanism in eclampsia.11,12 MEASUREMENT OF BLOOD PRESSURE IN PREGNANCY An accurate assessment of blood pressure is integral in the appropriate management of the pregnant hypertensive patient. The following issues need to be considered: . Equipment ± the equipment ought to be functional. The width of the cu€ should cover one-third of the circumference at the midpoint of the upper arm. . Patient position ± a standardized position is important. Blood pressure should be measured with the patient lying on her side at 15±308 to the horizontal. The sphygmomanometer cu€ should be at the level of the patient's heart. Currently, the Korotko€ phase V is recommended to assess diastolic blood pressure. The shift away from the use of Korotko€ phase IV is due to its limited reproducibility, its absence in 17±57% of pregnant patients and the technical diculty experienced in determining it.13,14 Korotko€ phase V appears to be closer to true intra-arterial blood

494 F. Paruk and J. Moodley

pressure and it is reported to be very rarely low or zero.14 A prospective randomized controlled trial constituting 220 pregnant hypertensive patients has addressed the concerns regarding safety of a change from Korotko€ phase IV to Korotko€ phase V.15 The trial did not show any clinically signi®cant di€erences in outcome with the use of phase IV rather than phase V. INDICATIONS FOR RAPID LOWERING OF HIGH BLOOD PRESSURE In pregnancy, a diastolic blood pressure of 110 mmHg or a systolic blood pressure of 170 mmHg, or greater, is regarded as a hypertensive crisis. It has been found that young women may develop complications such as encephalopathy with a diastolic blood pressure of 120 mmHg.16,17 It is thus important to lower high blood pressure once it reaches 110 mmHg in the pregnant patient. However, one should be aware of the fact that blood pressures are often labile (especially in the severe pre-eclamptic/eclamptic patient) and in addition, sensitivity to acute acting antihypertensive agents should be taken into account. Very high blood pressure values should therefore be reduced promptly but slowly, in a gradual manner, as marked hypotension may complicate an overzealous attempt at blood pressure control. The recommendation is that diastolic blood pressure should not be reduced by more than 30 mmHg and that neither should the mean arterial pressure (MAP) be reduced by more than 25%. It is important to administer the drugs in small doses intermittently or by utilization of a controlled infusion method. One should avoid the simultaneous use of more than one acute antihypertensive agent as a compound e€ect may be elicited. Postural hypotension would have a similar result; therefore, patients should be nursed on their sides or tilted with the aid of a pelvic wedge. MANAGEMENT The management of acute severe hypertension with target organ damage or hypertensive encephalopathy usually constitutes patient stabilization and delivery. Recent advances in obstetric care have seen the emergence of conservative management prior to 32 weeks' gestation. This is reviewed elsewhere.18 It is important to note that treatment is based on experience and consensus rather than being evidence-based. This is mainly because there are no large randomized controlled trials on the issue of what constitutes optimal therapy for hypertensive emergencies in obstetric practice. The experienced obstetrician thus needs to individualize patient care based on blood pressure readings, as well as the presence or absence of end-organ damage. Important issues to consider constitute the following: 1. maternal evaluation; 2. fetal evaluation; 3. maternal monitoring; (a) invasive haemodynamic monitoring (b) intravenous ¯uid management (c) radiological investigations 4. fetal monitoring; 5. speci®c drug therapy.

Rapid-acting antihypertensive agents 495

Maternal evaluation This should entail the following: (a) An appropriate history . details on duration and severity of previous hypertension; . previous end-organ damage (cardiovascular and renal); . previous antihypertensive therapy; . use of over-the-counter drugs (sympathomimetic agents); . illicit drug use (cocaine); . symptoms of target-organ damage chest pain back ache dyspnoea vaginal bleeding seizures visual loss headaches (b) Clinical evaluation (c) Investigations . Urine analysis; . haemoglobin; . urea/electrolytes; . liver function test; . coagulation screen; . peripheral smear; . chest radiograph; . electrocardiograph; . electrocardiogram ± to exclude left ventricular hypertrophy; . echocardiography ± in the scenario of pulmonary oedema to evaluate chamber size, wall thickness, systolic function and valvular function. Fetal evaluation This entails: . clinical assessment; . fetal ultrasonography; . fetal heart rate monitoring. Maternal monitoring (a) Invasive haemodynamic monitoring; (b) Intravenous ¯uid management; (c) Radiological investigations CT MRI SPECT TCD

496 F. Paruk and J. Moodley Table 1. Rapid-acting antihypertensive agents. Drugs used as acute-acting antihypertensives: 1. Dihydralazine 2. Labetalol 3. Nifedipine 4. Sodium nitroprusside Drugs being evaluated for use as acute-acting antihypertensive agents 1. Isradipine 2. Nimodipine 3. Nicardipine 4. Nitrendipine 5. Ketanserin 6. Urapidil

GENERAL PRINCIPLES Maternal monitoring It is important to note that plasma volume and cardiac output are markedly decreased in severe pre-eclampsia. There is a state of low oncotic pressure and leaky blood capillaries. This predisposes patients to pulmonary oedema. Thus the patient with a hypertensive crisis requires meticulous cardiovascular monitoring. Central venous pressure (CVP) monitoring, despite its shortcomings in that it does not re¯ect left ventricular pressures, should probably be used prior to parenteral antihypertensive agent administration. The use of the pulmonary capillary wedge pressure monitor to detect pulmonary oedema is currently a controversial issue. Its use is not without side-e€ects and it is not available in all centres. The optimal ¯uid, viz. crystalloid versus colloid, is also a subject of debate as crystalloids alone may decrease oncotic pressure, while the use of colloids results in an increase in CVP and is associated with pulmonary oedema. Crystalloids administered are titrated to achieve an acceptable CVP level. Colloid use ought to be individualized. The use of the Swan±Ganz catheter (SGC) may be considered in uncontrollable hypertension, pulmonary oedema and severe oliguria not responding to appropriate ¯uid administration in the scenario of multi-organ failure. However, one should be particularly aware of speci®c complications such as cardiac arrhythmias, pulmonary haemorrhage and pulmonary infarction. Fetal monitoring An important fear concerning antihypertensive drug use is the possible reduction in placental blood ¯ow and, subsequently, the e€ect on the developing fetus. Even with appropriate blood pressure control, the fetus remains at risk. It is thus of paramount importance to monitor the fetus when a rapid-acting antihypertensive agent is prescribed. This may be in the form of real-time ultrasound, fetal heart rate monitoring, biophysical pro®le, and/or Doppler ultrasound. RAPID-ACTING AGENTS Table 1 lists the drugs that are currently used as rapid-acting antihypertensive agents and those that are being evaluated for their use as rapid-acting antihypertensives in pregnancy.

Rapid-acting antihypertensive agents 497

Dihydralazine Intravenous dihydralazine remains the most commonly used agent for the reduction of acute blood pressure in pregnancy.19,20 It has gained widespread acceptance as an e€ective agent for this purpose. It acts directly on smooth muscle to cause vasodilation and a reduction in total peripheral vascular resistance. It also interferes with the movement of cellular calcium, which is responsible for initiating or maintaining the contractile site of vascular smooth muscle. It is more e€ective in lowering diastolic blood pressure than systolic blood pressure. Dihydralazine may be administered as a continuous infusion or in the form of intermittent boluses of low doses of 5 mg. Following intravenous administration, the e€ect begins within 5±20 minutes and lasts for 2±6 hours. The antihypertensive e€ect begins within 10±30 minutes and lasts for 2±6 hours, following intramuscular administration. The preferred method of dihydralazine administration is by intermittent intravenous bolus doses. Dihydralazine exhibits a considerable number of adverse e€ects. Its action of direct inhibition of the contractile activity of vascular smooth muscle results in dilatation of the capacitance vessels causing an increase in intracranial blood pressure in the cerebral circulation. This may account for severe headaches and may mimic impending eclampsia. Subsequently, the cerebral resistance vessels dilate and cerebrovascular ¯ow increases. A marked tachycardia invariably occurs. This is probably attributed to the increased cardiac output, resulting in an increased venous return. Dihydralazine is also believed to cause a prolonged release of noradrenaline, and this might explain the anxiety, restlessness and hyper-re¯exia which also mimic impending eclampsia.21 Other maternal adverse e€ects include palpitations, hypotension, ¯ushing, tremors, nausea, vomiting, anxiety, restlessness and epigastric pain. Dihydralazine is also contraindicated in patients with an initial heart rate of 100 beats/minute because of re¯ex tachycardia. The dihydralazine-induced release of noradrenaline is also responsible for the associated uteroplacental vasoconstrictions observed with its use. Fetal distress with intrauterine growth retardation is a documented phenomenon with dihydrallazine infusion.22,23 Vink et al22 suggested that the risk of abnormal fetal heart rate patterns detected by electroning fetal heart rate monitoring is reduced by correction of hypovolaemia and the use of intermittent small doses (5 mg) of the drug intravenously. Thus, monitoring of the viable fetus is essential with the use of dihydralazine. The adverse e€ects of the drug may be reduced by co-administration of an adrenergic blocking agent which reduces sympathetic nervous system activity. Thus, a loading dose of methyldopa (1 mg orally) with hydrallazine given as an intermittent bolus dose (5 mg) is an option that is recommended. Paterson-Brown et al24 have shown that the use of 5 mg boluses of dihydralazine represents a safe and e€ective method of treating severe hypertension in pre-eclampsia. According to a systematic review by Magee et al25, intravenous dihydralazine should no longer be considered as the agent of choice as its use is associated with greater perinatal and maternal adverse e€ects compared to other agents, particularly labetalol and nifedipine. It is obvious that dihydralazine is not the ideal drug for acute lowering of blood pressure in the pregnant patient. However, it is the most commonly used drug for this purpose ± mainly because it is easy to administer, ecacious, has been in use for a long time, does not require intra-arterial monitoring, is relatively inexpensive and most clinicians are familiar with its use.

498 F. Paruk and J. Moodley

Labetalol Labetalol is an agent which confers antagonist activity at both a and b adrenoreceptor receptors. It is 4±8 times more potent at b-than at a-adrenoceptors.26 It produces its antihypertensive e€ect without compromising the maternal CVS by producing peripheral vasodilatation. This may help to maintain renal and uterine blood ¯ow. Intravenous labetalol administered at 0.5 to 2 mg/kg produces an almost immediate fall in blood pressure27±29 with a minimal increase or decrease in heart rate. It is usually administered as a concomitant infusion which is initiated at 20 mg/hour. This may be increased by 20 mg increments every 10±20 minutes until appropriate blood pressure control is achieved, or a maximum total dose of 300 mg is administered. Bhorat et al30 compared labetalol with dihydralazine in a randomized trial. Their ®ndings showed a signi®cant reduction in maternal heart rate in patients receiving labetalol compared to those who received dihydralazine. They concluded that the badrenergic blockade signi®cantly reduced the incidence of dangerous ventricular arrhythmias. The maternal adverse e€ects of this drug include tremulousness, tingling, headache and hepatotoxicity. Studies comparing labetalol to dihydralazine have either found both drugs to be ecacious31,32, or labetalol to be more e€ective in reducing blood pressure.33,34 Feto-placental blood ¯ow remains unaltered with the use of labetalol.35 Jouppila and Rasonen36 have demonstrated that intravenous labetalol is not associated with a change in pulsatility indices in the main uterine, placental arciate, umbilical and fetal middle cerebral and renal arteries. In addition, parameters re¯ecting fetal cardiac functions were not a€ected. b-Adrenergic blockade symptoms in the fetus have been reported to be associated with the use of intravenous labetalol.37 The long-term use of labetalol has, however, been associated with small-for-gestational-age38 and severe b-adrenergic blockade.39 Although obstetricians are less familiar with the use of labetalol compared to dihydralazine, labetalol remains a reasonable choice for the treatment of hypertension in pregnancy. The advantages associated with its use include its ecacy in lowering blood pressure and lack of a negative e€ect on uteroplacental blood ¯ow. Labetalol is particularly useful in the scenario of ventricular tachycardia associated with high levels of circulating catecholamines, or myocardial ischaemia, or if dihydralazine fails to lower the blood pressure. Nifedipine Nifedipine is a type 2 calcium-channel antagonist that inhibits the entry of calcium ions through a slow channel in the cell membranes of cardiac and smooth-muscle cells. Its primary e€ect is to cause smooth muscle relaxation. Nifedipine may be administered orally or sublingually. Administration of the drug results in a 20% lowering of the systolic, diastolic and mean arterial blood pressure.40 Blood pressure falls following 5± 10 minutes of sublingual administration of the drug or 10±30 minutes following its oral administration. Nifedipine is administered as an initial oral dose of 10±20 mg every 30 minutes when utilized as a rapid-acting antihypertensive agent. Feto-maternal adverse e€ects associated with Nifedipine These include palpitations, tachycardia, headaches, cutaneous ¯ushing, constipation, diarrhoea, dyspnoea, chest pain and heart burn. These are, however, rare. Nifedipine

Rapid-acting antihypertensive agents 499

does not alter uteroplacental blood ¯ow. Doppler studies have not shown any changes in uterine artery velocity waveforms.42,43 In a small prospective study, Scardo et al43 have shown no fetal heart rate changes with the use of nifedipine in pre-eclamptic hypertensive emergencies. A prospective multicentre study by Magee et al,44 which assessed the risk of fetal anomalies following exposure to calcium channel-blocking agents in the ®rst trimester, found one infant with congenital abnormalities and delay in development (among a cohort of 44 exposed patients). This infant's mother was, however, also exposed to anti-epileptic agents, steroids, b-blockers and immunosuppressants during her pregnancy.44 The exposure of animals to high doses of nifedipine is associated with digital abnormalities.45 In general, the fetal adverse e€ects appear to be minimal. There is a suggestion in the literature from a case report by Hata et al46 that the adverse e€ect of nifedipine on fetal circulation may occur in the growth-retarded fetus. Nifedipine's ecacy and safety as compared to dihydralazine has been addressed in a few trials.47±49 Jegasothy and Paranthaman47 compared sublingual nifedipine (5 mg) to intravenous dihydralazine (5 mg) in 200 patients. They concluded that sublingual nifedipine was comparable to intravenous dihydralazine in the treatment of acute hypertension of pregnancy. Further, nursing sta€ were able to administer the sublingual nifedipine without any diculty. Randomized studies have shown less tachycardia and fewer episodes of hypotension with nifedipine compared to dihydralazine.48,49 There was no di€erence in fetal outcome in both groups of patients. Seabe et al48 demonstrated in a cohort of 33 primigravidae, that nifedipine is as e€ective as dihydralazine and in addition that nifedipine exhibits an earlier onset of action. Vermillion et al50 compared nifedipine with labetalol in a double-blind randomized controlled trial consisting of a cohort of 50 patients. They demonstrated that nifedipine and labetalol are ecacious in the management of acute hypertensive emergencies of pregnancy; however, nifedipine controls hypertension more rapidly, and fewer doses of nifedipine were required compared to labetalol. The trial also demonstrated that nifedipine has the ability to enhance urine output. This has been attributed to selective renal vasodilatation. In the context of pre-eclampsia which predisposes a patient to a contracted intravascular volume, nifedipine's ability to increase renal perfusion and urine output would appear to be bene®cial. Visser and Wallenburg51, in a prospective comparative study of 240 patients, showed that nifedipine and dihydralazine exhibit similar ecacy with respect to blood pressure reduction. Fetal distress occurred in ®ve patients treated with dihydralazine compared to none treated with nifedipine. From a haemodynamic viewpoint, they found nifedipine to be a useful agent in the treatment of hypertensive emergencies in pregnancy. Dekker and Sibai52 recommend that dihydralazine be no longer considered as the primary drug as most studies show a preference for calcium-channel blockers. Although the shift towards the use of nifedipine is evidence-based, dihydralazine remains currently a popular choice in developing countries. This is mainly attributed to the cost and vast experience with the use of dihydralazine. There is a concern that nifedipine, when used in conjunction with magnesium sulphate, may result in marked hypotension because of the compounded e€ects of the magnesium ion on calcium-channel functions.51 Some authors have experienced no adverse e€ects with the simultaneous use of both of these drugs53; however, it must be borne in mind that, in a woman with cardiac disability, the use of two negative inotropic agents simultaneously may be a compromising factor. An issue that is often raised with respect to the use of nifedipine is its potential to prolong the duration of labour in patients undergoing a trial of labour, owing to its tocolytic e€ect. However,

500 F. Paruk and J. Moodley

it should be noted that, usually, patients require only one or two doses of medication to e€ect blood pressure control and this represents a small concentration of nifedipine compared to that used to achieve tocolysis. A more recent concern with the use of nifedipine is its possible association with mortality in the scenario of coronary artery disease. A meta-analysis by Furberg et al54 indicates a statistically signi®cant increased risk of mortality in patients (with coronary artery disease) treated with nifedipine with a relative risk of 1.16 (1.01±1.33). One must take cognisance of the fact that these data may not be applicable to pregnant patients without coronary artery disease. However, pregnancy is associated with an expansion in plasma volume, increase in cardiac output and an increase in myocardial oxygen demand. Thus, theoretically, even in the absence of coronary artery disease, the pregnant patient may be at risk with the use of nifedipine. The elderly pregnant patient may be at additional risk if she has underlying occult coronary artery disease. It is thus recommended that a long-acting preparation of nifedipine be used instead of the short-acting formulation. Nifedipine is an e€ective antihypertensive agent that is easy to administer with relatively few fetomaternal adverse e€ects based on the few small available trials conducted on this drug. There is a need for further randomized trials in the scenario of the pregnant hypertensive patient in order to formulate ®rm recommendations about its use in clinical obstetrics. Until then, one should exercise the necessary caution required when prescribing this drug. Sodium nitroprusside Sodium nitroprusside (SNP) is an arterial and venous vasodilatory drug. It is potent, has a rapid onset of action, and its e€ect is of a short duration. The drug acts in a dosedependent manner and decreases systolic and diastolic blood pressures.55 In pregnancy, the use of sodium nitroprusside is reserved for the management of an acute hypertensive crisis which is not responding to safer agents. The potentially dangerous side-e€ects necessitate its use in an intensive-care setting. The dosage recommended is 0.5±5 mg/kg/minute.56 The fetomaternal adverse e€ects associated with sodium nitroprusside include fetal cyanide poisoning, transient fetal bradycardia, fetal metabolic acidosis and maternal hypotension.57,58 The concern of fetal and maternal cyanide toxicity is an important issue if SNP is administered for more than 2±3 hours. In non-pregnant individuals, cyanide toxicity is prevented by the co-administration of sodium thiosulphate in highrisk individuals. In pregnancy, there are no studies in humans on co-administration of sodium thiosulphate with SNP. Curry et al59 have recently demonstrated in gravid ewes that the co-administration of sodium thiosulphate with SNP prevents cyanide toxicity in the mother and the fetus. It is recommended that one delivers the fetus following control of the acute hypertensive crisis and stabilization of the patient. It is important to note that SNP should be administered only if it is indicated and under meticulous fetomaternal surveillance. SNP remains a drug of last resort for the treatment of hypertension in pregnancy. Its use is limited to speci®c situations in which there is no response to preferred agents, or in an ICU setting or just prior to endotracheal intubation for a general anaesthetic. Diazoxide Diazoxide is a potent arteriolar vasodilator. In pregnant individuals it is administered as a 300 mg bolus injection. An important maternal adverse e€ect is severe precipitous

Rapid-acting antihypertensive agents 501

hypotension. The adverse fetomaternal haemodynamic consequences of diazoxide administration can be improved by slow infusion of the drug. Diazoxide usage ought to be restricted to scenarios where the patient is unresponsive to dihydralazine, labetalol or nifedipine.

Isradipine Isradipine is a second-generation dihydropyrine calcium. It inhibits calcium in¯ux and blocks transmembrane in¯ux of calcium into muscle cells. Isradipine has been shown to increase renal plasma ¯ow and to maintain or increase glomerular ®ltration rate. Thus it may be speci®cally bene®cial in pre-eclampsia. Intravenous isradipine is thus being evaluated for its safety and ecacy as a rapid-acting antihypertensive agent. Maharaj et al60 have calculated the appropriate dosage regimen to comprise an initial dose of 0.15 mg/kg/minute with increments of 0.0025 mg/kg/minute every 15 minutes, until a diastolic ¯ow of 95 mmHg is obtained. They then commence a maintenance infusion at 0.15 mg/kg/minute. Ingermarsson et al61 have demonstrated changes in Doppler velocimetry of the umbilical or uterine arteries, while Maharaj et al62 detected fetal heart rate deceleration in two patients among a cohort of 20 patients. The use of oral isradipine has not been shown to have any adverse e€ects on the fetus.63,64 Isradipine needs to be investigated in larger randomized trials before it can be advocated for routine use, especially as there is a suggestion in the literature that it may not be e€ective in proteinuric hypertension as compared to non-proteinuric hypertension.64

Nimodipine Nimodipine is a calcium-channel antagonist. It stabilizes calcium channels, resulting in a calcium blockade. The drug is selective for cerebral vasculature. Intravenous (15± 45 mg/kg infusion) or sublingual administration (0.3 mg/kg) results in a decrease in blood pressure. Belforte et al65 have demonstrated a reduction in pulsatility index in maternal ophthalmic and central retinal arteries as well as reduction in systolic/ diastolic ratios in the fetal middle cerebral arteries. The associated decrease in cerebral vasospasm is used to advantage in the treatment of patients with severe pre-eclampsia and eclampsia.

Nicardapine This calcium-channel antagonist inhibits transmembrane in¯ux of calcium ions into cardiac muscle and vascular smooth muscle. The intravenous formulation is currently being evaluated for use in hypertensive crises in pregnancy. Theoretically, it would be safer to use nicardapine as compared to nifedipine as nicardapine exerts a less negative inotropic e€ect and it acts more selectively on peripheral vasculature. Aya et al66 have demonstrated, in a cohort of 20 patients, that intravenous nicardapine is ecacious±reporting a 15±30% decrease in MAP within 15±20 minutes in all patients. Two patients did develop severe tachycardia and decelerations did occur. However, no severe fetal or neonatal adverse e€ects were observed.

502 F. Paruk and J. Moodley

Ketanserin Ketanserin is a competitive serotonin antagonist. The intravenous form is being evaluated for its use as a rapid-acting antihypertensive agent. Intravenous ketanserin has been found to reduce blood pressure e€ectively in severe hypertension in pregnancy.67,68 Bolte et al69 have compared ketanserin to dihydralazine in an open randomized multicentre prospective trial involving 44 patients. They concluded that both agents exhibit comparable ecacies but signi®cantly fewer maternal complications were noted with the use of ketanserin. Steyn et al70 compared ketanserin to dihydralazine in a cohort of 70 patients. Dihydralazine was found to be more e€ective in lowering blood pressure. The authors attribute this di€erence in ecacy to a possibility that the dosage of ketanserin (10 mg) was insucient. Fetal distress did not di€er in the two groups of patients. Urapidil Urapidil is an arterial and venous vasodilator. It acts at peripheral vessels by combined a adrenoceptor blockade and on the central venous system by an a adrenoreceptor blockade on the tractus solitarius nucleus. The reduction in peripheral resistance causes a decrease in blood pressure. Wacker et al71,72 initially demonstrated its safety and ecacy in hypertension in pregnancy in two pilot studies. Recently, Wacker et al73 have compared urapidil to dihydralazine in a randomized trial involving 26 patients. They found that urapidil decreases blood pressure without any serious adverse e€ects. The haemodynamic e€ects of urapidil were found to be more predictable compared to those of dihydralazine. In their opinion, urapidil is superior to dihydralazine.

CONCLUSION In a hypertensive crises the main aims of therapy are to prevent cerebrovascular complications and to avoid progression of chronic hypertension into superimposed pre-eclampsia, which has a worse prognosis. The following factors need to be considered when choosing an appropriate antihypertensive agent: . . . . . . .

e€ectiveness and safety; familiarity and experience with the agent; knowledge of doses and drug interactions; lack of maternal and fetal adverse e€ects; maintenance of uteroplacental blood ¯ow; rapid onset of action; ease of administration of the drug.

After initial treatment with a rapid-acting agent it is recommended that oral therapy be introduced to maintain control of arterial blood pressure. Although delivery of the fetus is usually the de®nitive management of severe hypertension in pregnancy it should be appropriately timed and planned. Currently, there is no ideal acute-acting antihypertensive for the pregnant patient. Dihydralazine, nifedipine and labetalol appear to be the most commonly used and recommended agents. Although there are many other rapid-acting antihypertensive agents, they need to be subjected to large randomized controlled trials to assess the

Rapid-acting antihypertensive agents 503

Practice points . pre-eclampsia causes signi®cant morbidity and mortality. Maternal morbidity and mortality is related to cerebrovascular accidents in part. It is important to di€erentiate hypertensive urgencies from hypertensive emergencies. The pregnant patient with a systolic pressure 4169 mmHg or a diastolic blood pressure 4109 mmHg requires prompt, but gradual, reduction of high blood pressure . it is recommended that diastolic blood pressure be not reduced by more than 30 mmHg, and neither should the mean arterial pressure be reduced by more than 25% . appropriate fetomaternal evaluation is important prior to instituting antihypertensive therapy. Intravenous dihydralazine remains the most widely used rapid-acting antihypertensive agent as it is easy to administer, ecacious, inexpensive and most clinicians are familiar with its use . recent studies suggest that nifedipine be considered the agent of choice in hypertensive emergencies. Labetalol is particularly useful in the scenario of ventricular tachycardia, or if dihydralazine fails to lower raised blood pressure. The use of sodium nitroprusside and diazoxide should be reserved for speci®c situations. Ketanserin and urapidil are newer agents; initial studies suggest that they do have a potential role as rapid-acting antihypertensive agents

Research agenda . the aetiology of pre-eclampsia/eclampsia needs to be fully elucidated . there should be an e€ort to develop appropriate antenatal care which allows for close vigilance, identi®cation of risk factors and easy referral of at-risk patients . there is a need for large randomized controlled trials comparing adalat, labetalol, ketanserin and urapidil to dihydralazine with respect to ecacy, ease of administration and fetomaternal adverse e€ects. This is essential for an evidencebased decision regarding the selection of an appropriate antihypertensive agent . the use of cerebrovascular therapies such as antithrombotic agents, thrombolytics, neuroprotective agents and gene-based therapies needs to be thoroughly researched and subjected to randomized controlled trials to establish their ecacy safety and ecacy. Until then, it is important that the clinician familiarizes himself/ herself with the drug that he/she chooses to use. REFERENCES * 1. Report of the national high blood pressure education programme working group on blood pressure in pregnancy. American Journal of Obstetrics and Gynecology 2000; 183: 511±522. 2. Higgins JR & de Swiet M. Blood pressure measurement and classi®cation in pregnancy. Lancet 2001; 357: 131±135. 3. Moodley J & Rajagopal M. Maternal and perinatal outcome associated with hypertensive crises of pregnancy. Hypertension in Pregnancy 1998; 17: 43±53. 4. Donaldson JO. The brain in eclampsia. Hypertension in Pregnancy 1990; 13: 115±133.

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