Fenoldopan: a new parenteral anti-hypertensive; an alternative to nitroprusside

Abstracts

JUSTIFICATIVA E OBJETIVOS: O fenoldopam é um agonista dopaminérgico seletivo para os receptores dopaminérgicos tipo 1 (DA-1) que causa vasodilatação periférica e o objetivo deste artigo é reunir as informações clínicas sobre este fármaco. CONTEÚDO: Neste artigo foram revisadas as experiências em urgências e emergências hipertensivas, mostrando que o fenoldopam apresenta vantagens sobre o nitroprussiato de sódio (NPS) no tratamento das mesmas. Ao contrário do NPS, o fenoldopam causa vasodilatação periférica, ao mesmo tempo que induz diurese e natriurese em pacientes com hipertensão grave sem causar os efeitos deletérios pelo tiocianato. CONCLUSÕES: O fenoldopam parenteral, pelos seus efeitos renais e menor impacto de efeitos colaterais, pode ser considerado uma boa alternativa ao nitroprussiato de sódio no tratamento de emergências hipertensivas.

ANTIHIPERTENSIVO

MISCELLANEOUS

Fenoldopan: a new parenteral anti-hypertensive; an alternative to nitroprusside?^*

Fenoldopam: nuevo antihipertensivo parenteral; alternativa al nitroprusiato?

Daniel Sousa César, M.D.^I; Erika Miyoshi, M.D.^II; Hélio Halpern, TSA, M.D.^III; José Otávio Costa Auler Junior, M.D.^IV

^IAluno de Graduação da FMUSP

^IIMédica Assistente da Divisão de Anestesia do HC-FMUSP

^IIIDoutor em Medicina pela FMUSP

^IVProfessor Titular da Disciplina de Anestesiologia do Departamento de Cirurgia da FMUSP

Correspondence

SUMMARY

BACKGROUND AND OBJECTIVES: Fenoldopan is a selective dopaminergic agonist for dopaminergic receptors type 1 (DA-1), which induces peripheral vasodilation. This review aimed at collecting clinical information about this drug.

CONTENTS: This study reviewed experiences in hypertensive urgencies and emergencies and has shown the advantages of fenoldopan as compared to sodium nitroprusside. As opposed to sodium nitroprusside, fenoldopan induces peripheral vasodilation at the same time that induces diuresis and natriuresis in severely hypertensive patients without the harmful effects of thiocyanate.

CONCLUSIONS: Parenteral fenoldopan, for its renal effects and less adverse effects, is an interesting alternative to sodium nitroprusside in treating hypertensive emergencies.

Key Words: ANTI-HYPERTENSIVE: fenoldopan

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: El fenoldopam es un agonista dopaminérgico selectivo para los receptores dopaminérgicos tipo 1 (DA-1) que causa vasodilatación periférica y el objetivo de este artículo es reunir las informaciones clínicas sobre este fármaco.

CONTENIDO: En este articulo fueron revisadas las experiencias en urgencias y emergencias hipertensivas, mostrando que el fenoldopam presenta ventajas sobre el nitroprusiato de sodio (NPS) en el tratamiento de las mismas. Al contrario del NPS, el fenoldopam causa vasodilatación periférica, al mismo tiempo que induce diuresis y natriuresis en pacientes con hipertensión grave sin causar los efectos deletérios por el tiocianato.

CONCLUSIONES: El fenoldopam parenteral, por sus efectos renales y menor impacto de efectos colaterales, pode ser considerado una buena alternativa al nitroprusiato de sodio en tratamiento de emergencias hipertensivas.

INTRODUCTION

In the USA, 2.4% to 5.2% of hypertensive patients suffer from hypertensive crises. Hypertensive crises are generally associated to diastolic blood pressure (DBP) above 115 mmHg and require immediate intervention to prevent target-organ damage or even death¹.

So, hypertensive urgencies may be defined as high blood pressure (BP) (diastolic above 120 mmHg) without target-organ damage². In general , they are treated with oral medication, however, certain situations including perioperative hypertension, abnormal nose bleeding and hypertension associated to serum catecholamine increase require parenteral medication^1,3.

Hypertensive emergencies are defined as high diastolic and systolic blood pressure with acute and progressive involvement of the target-organ². These should be immediately treated with intensive care, parenteral hypertensive drugs and invasive BP monitoring. Traditionally, SNP is the drug of choice. Sodium nitroprusside is a potent vasodilator with fast onset, short half-life, low tolerance rate and high response rate. It has some disadvantages, including thiocyanate toxicity, potential renal function deterioration and poor coronary perfusion due to its potent arterial and venous vasodilating effect². Fenoldopan and other selective dopaminergic agonists for type 1 receptors (DA-1) may be an alternative for SNP in hypertensive emergencies with potentially less side-effects and some advantages. It is also effective in treating severe hypertension following non cardiac surgery and myocardial revascularization¹.

CHEMICAL CHARACTERISTICS

Fenoldopan, or 6-chlorine-2,3,4,5-tetrahydrate-4- hydroxyphenyl-1H-3-benzazepine-7,8-diolmetha-nosulphonate⁴, has an asymmetric carbon and is constituted of two active enantiomers, SK&F R-82526 and SK&F S-82526 (Figure 1). Its pharmacological effect in rats has shown that virtually all activity in DA-1 receptors is produced by R enantiomers. Similar pattern was found in the splenic artery of rabbits but with a much lower vessel stereoselectivity being enantiomer R 10 times more potent than S¹.

Brazilian Journal of Anesthesiology, 2001; 51: 6: 528-536

Fenoldopan: a new parenteral anti-hypertensive; an alternative to nitroprusside?

Daniel Sousa César; Erika Miyoshi; Hélio Halpern; José Otávio Costa Auler Junior

PHARMACODYNAMIC PROPERTIES

Fenoldopan is a selective agonist for DA-1 dopaminergic receptors which, among other effects shown in vitro ^6,7 and in vivo^8-10, induces vasodilation⁵.

The intracoronary administration of 20 nmol/L fenoldopan in dogs has increased coronary blood flow, mainly by vasodilation. However, in high doses (> 500 nmol/L), the increase in coronary blood flow was mainly due to its positive inotropic effect^11,12. Mesenteric vascular resistance decreased and blood flow increased to a maximum of 69% after intravenous 30 µg.kg^-1 fenoldopan in spontaneously hypertensive rats¹³.

Fenoldopan doses high enough to significantly reduce BP in dogs had minor effects on renal blood flow, while SNP doses similarly decreasing BP caused a significant decrease in renal blood flow¹⁴. Low fenoldopan doses not decreasing blood pressure in dogs produced renal vasodilation related to DA-1 receptor-mediated doses, diuresis and natriuresis when directly administered in the renal artery¹⁵.

The infusion of 0.025 to 0.5 µg.kg^-1.min^-1 fenoldopan in healthy volunteers has caused minor diastolic blood pressure (DBP) decrease and heart rate increase without affecting systolic blood pressure (SBP)¹⁶. In severely hypertensive patients, however, 0.8 µg.kg^-1.min^-1 or less has shown a dose-dependent BP decrease¹². In those patients, 0.1 to 0.9 µg.kg^-1.min^-1 has decreased SBP (baseline value above 180 mmHg) and DBP (baseline value above 120 mmHg), from 18.5% to 28% and from 22% to 31.5%, respectively^18,19. In a different study, an SBP decrease of approximately 30% was followed by a 35.6% decrease in total peripheral resistance and 33% in pulmonary pressure, with a 6% increase in heart rate²⁰.

Venous infusions of therapeutic doses, both in healthy volunteers and hypertensive patients, have significantly increased renal blood flow while decreasing renal vascular resistance without changing glomerular filtration rate^21,22. During extremely steep BP decrease, fenoldopan has increased creatinin clearance, urinary flow and sodium and potassium excretion. On the other hand, SNP has decreased creatinin clearance and had minor effects on remaining renal functions²¹.

In a dose-dependent manner, fenoldopan infusion has increased plasma renin activity and the levels of angiotensin II in healthy volunteers²³, but did not increase plasma renin activity or aldosterone and prolactin levels in severely hypertensive patients^24,25. Since the simultaneous administration of enalapril has caused an additive anti-hypertensive but not synergistic effect, it seems that the activation of the renin-angiotensin-aldosterone system does not significantly antagonizes fenoldopan effects²⁶.

In addition to those characteristics, fenoldopan had also an important role in renal protection in patients submitted to mechanical ventilation with PEEP (positive-end expiratory pressure), promoting a decrease in renal vascular resistance and an increase in renal plasma flow, diuresis and natriuresis²⁷.

PHARMACOKINETIC PROPERTIES

After Oral Administration

Fenoldopan is rapidly absorbed after oral administration²⁸ and undergoes extensive pre-systemic metabolism to produce sulfate, methyl and gycuronite conjugates¹⁶. Clancy et al. have studied the effects of food in the drug's systemic availability in healthy volunteers and have observed that it significantly decreases the area below the curve of plasma concentration and maximum plasma concentration while significantly increases the time to reach maximum plasma concentration. In addition, approximately 1% of the oral dose is excreted by the kidneys without undergoing any change²⁹.

Oral fenoldopan in hypertensive patients induces marked BP decrease, but the effect is brief due to drug's fast metabolic excretion. So, it would be necessary a frequent administration to obtain sustainable pharmacological effects³⁰.

After Parenteral Administration

Weber et al. have observed that fenoldopan has a fast peak of action (15 min.) in essential hypertension patients. In addition, they have shown distribution volume of 582 ml.kg^-1, total body clearance of 30.3 ml.kg^-1 and elimination half-life of 9.8 minutes. BP decrease was linearly related to fenoldopan's plasma concentration and infusion rate logarhythms³¹.

Alison et al. have shown that an apparent balanced plasma concentration is reached after 30 to 60 minutes and is maintained during infusion. Plasma levels seem to be linear to infusion rate. When the infusion is interrupted, plasma levels decrease very rapidly and no trace of the drug is found two hours after infusion¹⁶.

TOLERANCE

Fenoldopan's adverse effects in treating hypertensive emergencies and urgencies are related to vasodilation. They are generally seen during the first 24 hours of infusion; in 50% patients, such effects are seen during the first 4 hours of infusion³².

Headache has been described in 11% to 36% of patients, rash in 7% to 11%, nausea in 20%, dizziness in 10% and asymptomatic ST segment changes in 6% to 33%^2,33-35. In addition, fenoldopan infusion, as opposed to SNP, produces mild intra-ocular pressure increase in severe hypertensive patients, varying from 14 ± 1 to 20 ± 2 mmHg³⁶.

During continuous infusion, the incidence of adverse effects increases with doses equal to or higher than 0.8 µg.kg^-1.min^-1. Other less frequent adverse effects (<1%) include palpitations, transient hypotension, astenia and sinusoidal bradycardia³².

DRUG INTERACTIONS

The simultaneous administration of bolus doses of 100 mg fenoldopan and 1000 mg paracetamol in 12 healthy volunteers resulted in a 32% increase in maximum plasma concentration of fenoldopan and 50% in the area below the curve of plasma concentration. After premedication with 1000 mg paracetamol every 8 hours for 7 days, fenoldopan bolus increased maximum plasma concentration and the area below the curve of plasma concentration in 73% and 66%, respectively³⁰.

Panacek et al., in a comparative, prospective, randomized, open and multicentric international study have evaluated the safety of fenoldopan and SNP (75 patients receiving fenoldopan and 78 receiving SNP). Fenoldopan was administered in an initial dose of 0.1 µg.kg^-1.min^-1 with increments up to 0.2 µg.kg^-1.min^-1. Twenty-two patients (10 using fenoldopan and 12 SNP) were excluded due to adverse effects. No patient has developed chest pain, syncope or infarction. Several patients from both groups presented minor side-effects and there was no need to exclude them from the study. Adverse effects common to both groups were headache, dizziness, rash, hypotension, nausea and vomiting. Hyperhidrosis was seen in 2.2% of patients under fenoldopan and in 6.5% of those under SNP, while hypokalemia was seen in 7.8% and 3.2% of patients, respectively. Differences in potassium serum levels in the fenoldopan group were not clinically relevant³⁷.

In ten congestive heart failure patients submitted to treatment with digoxin and receiving 100 mg oral fenoldopan every 8 hours for 9 days, there were no significant changes in digoxine's pharmacokinetic properties³⁸.

An increase in renal plasma flow induced by fenoldopan has been described after the simultaneous administration of intravenous alopurinol. However, further studies are needed to evaluate whether this interaction is clinically important³⁹.

DOSE AND ADMINISTRATION

For treating severely hypertensive patients or postoperative hypertension when the oral route is not recommended, fenoldopan should be administered in intravenous continuous infusion, in an initial dose of 0.1 µg.kg^-1.min^-1 which should be adjusted to reach the desired BP decrease. Increments should not exceed 0.1 µg.kg^-1.min^-1 in intervals of at least 20 minutes. Maximum recommended dose is 1.7 µg.kg^-1.min^-1. When the desired response is reached, infusion may be gradually or abruptly interrupted because no BP rebound has been observed. Oral anti-hypertensive agents may be indicated before or after fenoldopan infusion³².

CLINICAL EXPERIENCE IN ARTERIAL HIPERTENSION

Both oral and parenteral fenoldopan have shown to be very effective in decreasing BP. However, due to little drug bioavailability and the lack of a sustainable effect after oral administration, several studies are targeting and proving the efficacy of the parenteral route for acutely treating severe hypertensive crises^{18,25,33,34,37,40-43}.

Study models were similar. Fenoldopan was infused in increasing doses until DBP reached 110 mmHg for patients with baseline DBP of 120 to 150 mmHg, or decreased 40 mmHg for those with baseline DBP between 150 and 170 mmHg. After reaching the expected DBP, infusions were maintained and gradually decreased with the administration of oral anti-hypertensive agents, if necessary¹.

Comparative studies on hypertensive urgencies have shown that fenoldopan and SNP decrease BP to similar levels and reach target-BP for most severely hypertensive patients^33-35,37. Time elapsed for target-BP was similar for both drugs, with values varying from 81 to 90 minutes for fenoldopan and from 59 to 120 minutes for SNP^33,34,37. No agent has evidenced tolerance to the anti-hypertensive effect³⁷ or rebound effects after infusion^33,34,37.

Hypertension after non-cardiac surgery is, in general, considered an urgency and is better treated with parenteral agents¹. A randomized double-blind and controlled study evaluated the efficacy of fenoldopan in this type of situation and involved 16 patients⁴⁴. Fenoldopan has significantly decreased BP to the therapeutic target in all 8 patients, while placebo has decreased BP in only four out of 8 patients. It was also effective in increasing heart index and systolic volume without decreasing diuresis and potassium clearance, as opposed to SNP.

On the other hand, Elliott et al.¹⁸, in comparing hemodynamic effects of fenoldopan and SNP in hypertensive emergencies have observed that both were effective in reaching and maintaining target-BP (between 100 and 110 mmHg) for at least one hour during continuous infusion.

Hypertension after myocardial revascularization is considered a hypertensive emergency. Fenoldopan was evaluated in a prospective and randomized study involving 20 patients³⁶. Both fenoldopan and SNP have caused a fast and significant BP and peripheral vascular resistance decrease.

Fenoldopan may replace dopamine in a dopa dose of 1.5 to 3 µg.kg^-1.min^-1 administered in approximately 25% of non-cardiac surgeries in cardiac patients, since dopamine, for interacting with multiple receptors, has variable renal effects with less renal protection potential as compared to fenoldopan, which specifically interacts with DA-1 receptors⁴⁵.

FENOLDOPAN VERSUS SODIUM NITROPRUSSIDE IN ANTI-HYPERTENSIVE THERAPY

Based on all those studies, fenoldopan may be considered a safe and effective parenteral anti-hypertensive agent. In addition, it has proven to be as effective as sodium nitroprusside in acute BP decrease in severely hypertensive patients, with a fast peak of action, good dose-response correlation and short duration^{1,16,32,33,46,47}.

Another important fact is that, in comparative studies, fenoldopan has induced diuresis and natriuresis in severely hypertensive patients as opposed to SNP. Actually, SNP infusion is associated to a decrease in urinary flow and, in some cases, to renal function deterioration³⁴. Fenoldopan's diuretic and natriuretic effects may be extremely useful in hypertensive emergencies with possible renal damage and in patients with hypertension associated to volume overload, such as in congestive heart failure or chronic renal failure¹.

Moreover, SNP has several disadvantages. Its interaction with sulfhydryl groups in erythrocytes promotes the formation of cyanide ions and methemoglobulin which is bound to one cyanide ion forming cyanomethemoglobin, which is not toxic. The remaining cyanide is converted into thiocyanate in the liver being excreted by the kidneys. In patients receiving high SNP doses, cyanide may accumulate and combine with respiratory chain cytochromes, interfering in the aerobic metabolism and potentially causing metabolic acidosis; it also interferes in SNP vasodilating action and may lead to tachyphylaxis. The risk for thiocyanate toxicity is increased when SNP is administered in high doses for a long period, especially in the presence of previous renal damage. Toxicity symptoms are: fatigue, nausea, headache, disorientation, psychotic behavior, rash and anorexia. So, the risk for toxicity limits SNP treatment duration and requires a careful monitoring of thiocyanate levels. There is still the additional disadvantage of photosensitivity, which requires SNP to be stored in opaque packagings¹.

Moreover, fenoldopan has proven to be a good alternative to SNP in patients submitted to myocardial revascularization because the latter worsens myocardial ischemia and increases alveolar-arterial oxygen gradient and intrapulmonary short-circuit⁴⁸ in addition to, due to its potent venous and arterial vasodilation, leading to coronary perfusion pressure decrease resulting in worsening of myocardial ischemia^1,45.

CONCLUSIONS

For what has been said, parenteral fenoldopan, for its renal effects and less side-effects, may be considered a good alternative to sodium nitroprusside in the treatment of hypertensive emergencies. It has also shown to be effective in the treatment of hypertension after myocardial revascularization or even non-cardiac surgeries and may in the future play an important role in such situations.

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*

Recebido da Disciplina de Anestesiologia do Departamento de Cirurgia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP

Publication Dates

• Publication in this collection
  10 Nov 2010
• Date of issue
  Dec 2001

History

• Accepted
  02 May 2001
• Received
  02 Feb 2001