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    • 788 Current Drug Targets, 2009, 10, 788-798 Acute Severe Arterial Hypertension: Therapeutic Options A.R. De Gaudio†,*, C. Chelazzi+, G. Villa+ and F. Cavaliere# † University of Florence, Department of Critical Care, Section of Anesthesiology and Intensive Care. Azienda Ospedaliero-Universitaria Careggi, Viale Morgagni 85, 50134 Florence Italy + University of Florence, Department of Critical Care Medicine, Section of Anesthesiology, Florence, Italy # Institute of Anaesthesia and Intensive Care of Catholic University of Rome, Rome, Italy Abstract: Arterial hypertension is a very common condition. Cerebral, coronary and renal vessels are mainly affected by the deleterious effect of this condition, and both acute and chronic organ failure may ensue. Exacerbation of underlying pathophysiologic conditions or new precipitating factors can lead to hypertensive crisis, either urgencies or emergencies. During hypertensive emergencies, a quick raise in arterial pressure may lead to acute and significant organ dysfunction, such as aortic dissection, acute myocardial infarction, intracranial bleeding or acute renal failure. Perioperative hypertension often takes the shape of a crisis and it can be related to hypothermia, pain, neuro-hormonal response to surgical trauma or antihypertensive drugs withdrawal. Treatment for hypertensive crisis should achieve a progressive control of blood pressure, avoiding any abrupt decrease in organ blood supply. Therapeutic options are many and different in terms of pharmacokinetics and pharmacodynamic profiles. The best option should be based upon the characteristics of the patient and the pathophysiology of the hypertensive crisis . Of particular interest, some agents are metabolized by blood esterase and have a very short half life (e.g., clevidipine). This allows tight titration of their effect, which is advisable when carefully lowering blood pressure. This is of particular importance when treating hypertensive crisis in surgical patients both intra-operatively or in critical care. Keywords: Cardiovascular homeostasis, perioperative hypertension, antihypertensive treatment, hypertensive emergency. INTRODUCTION are affected, while 7.1 million deaths are related to it. Of all the affected population, it is proved that 1% will develop an According to the seventh Joint National Committee on hypertensive crisis during the disease course [4]. Following Detection, Evaluation and Treatment of High Blood Pressure JNC 7 definitions, an hypertensive crisis occurs when SBP (JNC 7), arterial hypertension is defined as a systolic blood raises above 180 mmHg or a DBP above 120 mmHg. Those pressure (SBP) 140 mmHg or a diastolic blood pressure crisis can be further distinguished in hypertensive urgencies, (DBP) 90 mmHg (Table 1) [1]. Patients with systolic if there is no evidence of ongoing end-organ damage, and values between 139 and 120 mmHg or diastolic values hypertensive emergencies, when the raise in blood pressure between 89 and 80 mmHg are considered as having pre - is associated to organ damage or pending organ failure. hypertension, and will have a tendency to develop hypertension later during lifetime. However it is not always possible to recognize a precise cause of hypertension and hypertensive crisis, many Table 1. Blood Pressure Definitions secondary causes need to be ruled out (Table 2) [5]. These secondary forms of hypertension expose affected patients to BP Definitions Systolic BP Diastolic BP develop hypertensive crisis more easily than essential forms [6]. The aim of this paper is to review literature data about Normal <120 mmHg <80 mmHg the complex physiopathology which leads from the chronic Pre-hypertension 120-139 mmHg 80-89 mmHg hypertensive state to an acute crisis and the appropriate therapies available for these conditions. Hypertension >140 mmHg >90 mm Hg Hypertensive crisis >180 mmHg >120 mmHg Physiopathology of Arterial Hypertension Blood pressure is the driving force of tissue perfusion. It Hypertension affects an estimated 72 million people in is defined as the product of cardiac output (CO) and United States and its prevalence in the US population aged peripheral vascular resistance. Main determinants of CO are cardiac preload and afterload, myocardial contractility and more than 20 is 30% [2, 3]. Worldwide, one billion people heart rate, while vascular resistance is regulated by a highly integrated system including sympathetic activity and renin- *Address correspondence to this author at the University of Florence, angiotensin-aldosterone (RAA) system [7]. Endothelial Department of Critical Care, Section of Anesthesiology and Intensive Care. function plays a major role in tightly regulating tissue Azienda Ospedaliero-Universitaria Careggi, Viale Morgagni 85, 50134 perfusion pressures and oxygen supply [8]. Florence Italy; E-mail: 1389-4501/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.
    • Acute Severe Arterial Hypertension Current Drug Targets, 2009, Vol. 10, No. 8 789 Table 2. Causes of Secondary Hypertension increase in CO (Fig. 1) [9]. Chronic adrenergic stimulation induces vascular remodelling and smooth muscular cells • Autonomic hyperactivity (spinal cord injury, Guillain-Barré proliferation, thus increasing diastolic pressure, while arterial syndrome, diabetes mellitus) vessels thicken and stiffen due to lipid, calcium and collagen accumulation and deposition in vascular walls [7]. • Intracranial hypertension and brain edema Moreover, chronically increased vascular tone leads to • Pheochromocytoma increased myocardial mass (e.g., left ventricular hypertro- • Tumors secreting renin or aldosterone phy) and oxygen consumption, which in turn can lead to • Eclampsia and preeclampsia chronic ischemia or acute myocardial infarction. At renal level, increased sympathetic activity enhances sodium and • Vasculitis and scleroderma water retention, further contributing to maintain elevated • Parenchymal renal disease (e.g., acute glomerulonephritis) blood pressure. • Renal vascular disease (e.g., renal artery stenosis or thrombosis) Renin-Angiotensin-Aldosterone System • Drugs (e.g., cocaine, amphetamine, phencyclidine) • Drug interaction (e.g., monoamine oxydase inhibitor with The RAA system greatly influences cardiovascular tyramine, tryciclics antidepressants or sympathomimetics) homeostasis (Fig. 2). Angiotensin II (AT-II) acts as direct vasoconstrictor on systemic and renal vessels, thus • Abrupt withdrawal of anti-hypertensive drugs (e.g., clonidine) contributing to initiate and maintain elevated blood pressure. • Alcohol withdrawal Moreover, AT-II stimulates adrenaline and noradrenaline release at pre-synaptic level. It also contributes to left Sympathetic Activity ventricular hypertrophy and myocardial ischemia through increased left ventricular wall tension. On renal vessels, AT- Noradrenaline and adrenaline, either from sympathetic II-induces alterations of arterial and capillary walls and leads neurons or epirenal medullar cells, interact with peripheral to progressive glomerular ischemia, parenchymal damage, smooth cell- 1 adrenergic receptors increasing vascular tone proteinuria and end-stage renal failure [10]. AT-II stimulates at pre-capillary level. They also increase heart rate and aldosterone and antidiuretic hormone release, which both contractility through interaction with cardiac- 1 adrenergic contribute to hypervolemia and hypertension. This condition receptors. The net effect of sympathetic stimulation is an Sympatetic activity Increases Increases Induces Increases vascular tone at sodium and vascular heart rate precapillary water remodelling and contractility level reabsorption Vasoconstriction Increased left Increase Increase increasing ventricular diastolic cardiac output peripheral vascular hypertrofy and pressure resistances oxygen consumption Chronic Ischemia Increase BP and AMI Fig. (1). Effect of increased sympathetic activity cardiovascular homeostasis.
    • 790 Current Drug Targets, 2009, Vol. 10, No. 8 De Gaudio et al. Renin Angiotensin II Vasoconstriction Alteration of renal Aldosterone ADH on systemic and arterial and capillary renal vassels vessels’ wall Increase left Glomeruar ischemia, Sodium and ventricular wall parenchymal damage, water renal tension proteinuria, end-stage retention renal failure Left ventricular hypervolemia hypertrophy and myocardial ischemia Increase BP Fig. (2). Effect of renin-angiotensin system on cardiovascular homeostasis. contributes to myocardial remodelling and cell fibrosis. increase of blood pressure raises shear stress on arteriolar Aldosterone leads to increased sodium and water renal and capillary vessels and leads to endothelial inflammation retention, with hypokalemia and metabolic alkalosis [7]. and fibrosis with altered permeability [10]. In sustained Hyperaldosteronism “per se” promotes renal vessel inflam- crisis, endothelial damage occurs, and coagulation cascade mation and fibrosis, leading to microvascular renal injury activates [15]. This can further impair tissue hypoperfusion [11, 12]. Furthermore, during hypertensive crisis, abrupt and precipitate acute organ damage. increase in renal vessels shear forces leads to reflex glomerular capillary constriction and renal hypoperfusion End-Organ Damage in Hypertensive Crisis which, in turn, can be responsible for a further increase of Hypertensive associated end-organ damage can be the RAA system activity with sudden worsening of renal acute complication of chronic hypertension or the clinical function [13]. manifestation of a hypertensive emergency (Table 3). Endothelial Function Table 3. End Organ Damage in Arterial Hypertension Vascular endothelium plays a role in regulating • Hypertensive encephalopathy microvascular tone (Fig. 3). Nitric oxide exhibits vasodilating activity, while endothelin-1 is a powerful • Stroke vasoconstrictor. In physiological condition the two effects • Subarachnoid and intraparenchymal haemorrhage are well balanced. In hypertensive patients, increase in • Hypertensive retinopathy arteriolar and capillary shear forces, due to peripheral • Myocardial ischemia transmission of elevated blood pressure, leads to an increased endothelin-1 release by the endothelium, with a • Acute congestive heart failure and pulmonary oedema progressive increase in vasoconstriction. The consequent reduction in blood-oxygen supply can lead to tissue • Aortic dissection hypoperfusion/ischemia and organ dysfunction [8]. In insulin resistant patients hyperinsulinemia inhibits endothelial nitric • Renal injury and chronic renal failure oxide release thus leading to a predominant endothelin-1 effect [14]. Vasoconstrictive endothelial tone might contri- • Eclampsia bute to maintain high blood pressure and precipitate renal injury [13]. During hypertensive emergencies, an abrupt
    • Acute Severe Arterial Hypertension Current Drug Targets, 2009, Vol. 10, No. 8 791 Activation of coagulative Hypertensive states cascade Endothelial Increased shear inflammation forces on arterioles and fibrosis and capillaries Increased endothelin-1 Alterated vasocostrictive effect Hyperinsulinemia permeability Unbalanced vasoconstrictive tone Organ chronic hypoperfusion, ischemia and dysfunction Organ damage Fig. (3). Effects of hyperinsulinemia on endothelial dysfunction. Heart Brain and Retina Chronically elevated peripheral vascular resistance leads Normotensive individuals maintain a normal cerebral to increased left ventricular mass because of the increased blood flow between mean arterial pressures (MAP) of 60 and left wall tension [7]. Aldosterone and angiotensin II can 120 mm Hg [16]. A chronically high MAP induces cerebral directly stimulate left ventricular hypertrophy and microvascular thickening and stiffening, increasing cerebral vascular resistance. Consequently hypertensive patients are remodelling. Thickening of the ventricular wall increases myocardial oxygen consumption, limiting diastolic blood more prone to suffer from cerebral hypoperfusion when flow and myocardial oxygen delivery. These phenomena blood pressure lowers [17]. On the other hand, an abrupt lead to a chronic myocardial ischemia, with progressive wor- increase in blood pressure leads to elevated cerebral blood sening of left ventricular function and deposition of inters- flow and intracranial pressure, with consequent blood brain titial collagen, with further impairment of myocardial oxy- barrier disruption, fluid leakage and brain oedema [7, 18]. Clinical manifestation of such hypertensive encephalopathy gen delivery [20]. Left ventricular hypertrophy can lead to mitral regurgitation, left atrial dilatation and atrial fibrilla- is an acute neurologic syndrome associated to severe hyper- tion, which further reduce blood flow to the coronaries. tension. Clinical manifestations include headache, nausea During hypertensive crisis, a raise in myocardial serum and vomiting which are associated to elevated blood troponin-I is commonly observed as the result of impaired pressure. If the syndrome is left untreated, confusion, myocardial cells oxygen supply, even in absence of overt delirium or seizures can manifest, and risk of stroke or cerebral haemorrhage is high [13]. On the retina, chronic ischemia or infarction [21]. However, during acute crisis, shear stress on coronary walls leads to intimal damage and hypertension leads to arterial narrowing and intimal accelerated atherosclerosis which can precipitate plaque thickening. In hypertensive crisis, blood-retina disruption rupture and intravascular thrombosis causing myocardial occurs, with necrosis, retinal ischemia and optic disk oede- infarction [13]. Both left ventricular hypertension and ma. Fundoscopic examination reveals haemorrhage, “cotton myocardial ischemia lead to left ventricular failure and wool spots” and papilledema [19]. congestive heart failure. In hypertensive crisis, the already
    • 792 Current Drug Targets, 2009, Vol. 10, No. 8 De Gaudio et al. failing left ventricle can be overcome by acutely increased of surgery and usually requires treatment for no more than 6 vascular resistance and acute congestive failure with pulmo- hours [27]. Cardiothoracic, vascular, head and neck surgery nary edema [22]. Clinically, patients are hypoxic and crack- and neurosurgical procedures are most commonly involved les are heard on chest auscultation, limbs can be cool as a [28]. Perioperative neuro-hormonal stress response leading sign of hypo-perfusion and oedematous as fluid overload to increased sympathetic tone is thought to be responsible occurs [18]. [29]. Other involved factors include activation or RAA system, baroreceptor dysfunction or withdrawal of central Aorta acting antihypertensive therapies [18]. Anaesthetic factors include poorly controlled postoperative pain, hypothermia, Untreated hypertension may lead to aortic dilation and urinary distention and discontinuation of anaesthetic drugs. intimal tearing, i.e. aortic dissection [13]. Blood flows into the aortic media and false and true aortic lumen become Postoperative crisis require aggressive treatment in case of the fear of vascular suture leak and rupture [13, 30]. evident. Dissection can involve the ascending aorta (proximal, type A of Stanford) or not (distal, type B of Therapeutic Options Stanford) [23]. In type A dissection, tearing can involve carotid artery, with stroke and/or syncope as clinical Arterial hypertension without signs of acute organ manifestations. Coronary arteries can be involved, and damage can be managed conservatively [4]. Control of myocardial infarction can be seen [18]. If aortic rupture precipitating factors and wait for a progressive reduction of occurs, massive intra - pericardial bleeding leads to cardiac blood pressure values is the more rational approach. In tamponade, obstructive shock and cardiac arrest. When already hypertensive patients, reinitiating oral therapy may aortic valve is involved in dissection, acute regurgitation can be the key to restore normal blood pressure. In the lead to pulmonary edema and acute heart failure. In type B postoperative period, pain, anxiety, hypothermia, hypoxia, dissection limbs ischemia or anuria can occur as a hypercapnia and hypoglycaemia have all to be ruled out and consequence of involvement of aortic branch vessels [23]. treated in order to control the hypertensive status that can be associated to them [18]. Because of the risk of organ Kidneys hypoperfusion associated to the use of parenteral hypotensive drugs, postoperative volume status should be Acute glomerulonephritis, renal artery stenosis or optimized before starting the intravenous therapy [28]. cyclosporine use in renal transplant patients, may lead to arterial hypertension and hypertensive crisis [13]. On the In the setting of hypertensive emergencies, when organ other hand, kidneys are usually involved as target organs of damage is pending or actual, there is a general consensus that chronic hypertensive status. Afferent arterioles of lowering blood pressure may limit damage [4, 13]. However, hypertensive patients tend to progressively narrow in the even in this case, arterial pressure should be lowered slowly, attempt of limiting overflow to glomerular capillaries. targeting a 20% reduction in mean arterial pressure over Moreover, chronic stimulation from the adrenergic system several minutes-hours [6]. To rapidly lower high blood and AT-II leads to vessel wall thickening. Vessel structural pressure values, can be harmful in chronic hypertensive changes are seen that lead to progressive reduction of patients, where autoregulation thresholds of the brain are glomerular blood flow and filtration rate. Microalbuminuria higher than normotensive individuals. In this case, brain is the landmark of progressive glomerular damage [10]. End- hypoperfusion can complicate institution of anti-hyperten- stage renal failure and need for dialysis may follow. sive therapy [17]. Moreover, there is not enough evidence Moreover, chronic glomerular ischemia stimulates renin that anti-hypertensive treatment reduces mortality or associa- release and the consequent activation of the RAA system ted morbidity in hypertensive emergencies [31]. The only leads to further renal vasoconstriction and fluid retention, situation in which blood pressure should be quickly lowered, thus maintaining and worsening hypertension [24]. As auto - is aortic dissection, in order to reduce tearing forces on aortic regulatory renal system is lost, glomerular blood flow starts wall, thus limiting the extension of dissection itself [23]. to vary directly with variations of systemic arterial pressure. Many different pharmacological options are available, and At this point, any abrupt reduction in blood pressure may each patient should have the treatment tailored to the aim of lead to acute renal failure. lowering blood pressure in a safe manner. Evidence in terms of best drug and best infusion regimen is still lacking [31]. Preeclampsia and Eclampsia Calcium Antagonists: Nicardipine and Clevidipine The preeclamptic syndrome is characterized by hyperten- sion associated to interstitial oedema and proteinuria, while Nicardipine is a second-generation dihydropyridine in eclamptic syndrome, neurological signs, such as visual calcium-channel antagonist (Table 4). It shows high vascular alterations and seizures, ensue [18, 25]. Altered trophoblast selectivity and a strong cerebral and coronary vasodilatory implantation seems to initiate a cascade in which placental activity, with no negative inotropic properties. Nicardipine vessels vasoconstriction induces a raise in peripheral reduces both cardiac and cerebral ischemia [32]. Nicardipine resistances, leading to hypertension. Moreover, endothelial increases stroke volume and coronary blood flow, thus dysfunction, with activation of coagulative pathways and contributing to a better oxygen supply to the heart [4]. This inhibition of fibrinolisis, occurs as well [26]. might be useful in patients suffering from coronary heart diseases and congestive heart failure. Its use has been Postoperative Arterial Hypertension advocated in hypertensive patients undergoing vascular surgery, either abdominal, neuro- or cardiovascular [33]. Postoperative Arterial hypertension is defined as an Moreover, it has been used to prevent cerebral vasospasm in hypertensive crisis which occurs within 2 hours from the end
    • Acute Severe Arterial Hypertension Current Drug Targets, 2009, Vol. 10, No. 8 793 Table 4. Drugs Receptor Interaction and Mechanism of Action Calcium Channel Alfa 1 Alfa 2 Beta 1 Beta 2 D1 5-HT NO Nicardipine Antagonist Clevidipine Antagonist Antagonist Partial Agonist Antagonist Agonist Urapidil (+++) (++) (+) (++) Agonist Agonist Agonist Clonidine (+++) (+) (+) Antagonist Antagonist Antagonist Phentolamine (+++) (+++) (+) Antagonist Antagonist Antagonist Antagonist Labetalol (+++++++) (+++++++) (+) (+) Esmolol Antagonist Nitroglycerine Donors Sodium Donors Nitroprusside Antagonist Antagonist Agonist Fenoldopam (+) (+) (+++) subarachnoid hemorrhage. Nicardipine has been recommen- advantage when treating patients suffering from ischemic ded as agent of choice to reduce blood pressure in patients heart disease, in whom any reflex tachycardia can increase with ischemic stroke when DBP > 120 mmHg or SBP > 220 myocardial oxygen consumption. Similarly, clevidipine was mmHg [34]. When administered intravenously, nicardipine’s found to reduce blood pressure without influencing cardiac onset ranges from 5 to 15 minutes, and its action lasts index or filling pressures [39]. The drug showed both a rapid between 4 to 6 hours [4]. Patient weight does not influence onset and offset in patients admitted to postoperative nicardipine dose, which starts from 5mg/h, up to a 15 mg/h, intensive care. Authors concluded that clevidipine may be with an increasing rate of 2.5 mg/h every 5 minutes (Table useful in treatment of acute postoperative hypertension. The 5). The main adverse effect is abrupt reduction in blood same results were found in the ECLIPSE trials on acute pressure and reflex tachycardia, which can be harmful in hypertension treatment in cardiac surgery patients [40]. patients with coronary heart disease. Clevidipine showed to be more effective than nitroglycerin (p=0.0006) and sodium nitroprusside (p=0.003) in maintai- Clevidipine is a third-generation dihydropyridine calcium- channel antagonist [4, 35] (Table 4). Acting as arteriolar ning a blood pressure target. Compared to nicardipine, it showed the same efficacy, but more stability in terms of less smooth muscle cells relaxant, clevidipine reduces peripheral blood pressure excursions. No differences were found in the vascular resistance. As a result, blood pressure lowers and incidence of myocardial infarction, stroke or postoperative cardiac output increases. Being metabolized by the esterases renal dysfunction. of red blood cells, it exhibits an ultra short activity, with an half life of about 2 minutes (Table 5). This makes Alpha-Adreno Receptors Agonists and Antagonists: clevidipine very suitable in those conditions when blood Urapidil, Phentolamine and Clonidine pressure needs to be tightly controlled, such as in intensive care and perioperative care [35]. Moreover, clevidipine Urapidil acts as a peripheral 1 post-synaptic receptor exerts a protective role in ischemic tissues limiting antagonist and as a central 5-hydroxytryptamine receptor reperfusion injury, either scavenging oxygen free radicals or agonist [4, 41] (Table 4). It induces a reduction in both reducing intracellular calcium overflow toxicity [36]. preload and afterload, thus lowering cardiac output and Clevidipine is effective in reducing blood pressure in blood pressure, without reflex effects on heart rate (Table 5). hypertensive crises in surgical and intensive care patients It is used to control hypertensive crisis either in surgical and at the emergency department [37]. In hypertensive patients or during pregnancy [41]. Urapidil has been patients scheduled for cardiac surgery, pre-operative compared to nitroprusside in its efficacy in reducing blood clevidipine was given to control high blood pressure [38]. It pressure during hypertensive emergencies [42]. It showed to showed to rapidly decrease blood pressure without be as effective as nitroprusside, with a slower effect and a significant increases in heart rate (median of 6 minutes, CI lower incidence of adverse hypotensive events. In light of 95% 6-8 min.). This last effect must be taken as an this, Authors recommended its use in patients with
    • 794 Current Drug Targets, 2009, Vol. 10, No. 8 De Gaudio et al. Table 5. Antihypertensive Agents’ Synopsis Drug Dynamic Dose Onset (min) Metabolism Offset Adverse Effects 5mg/h, up to a 15 mg/h, with 5-15 calcium-channel abrupt reduction in blood pressure Nicardipina an increasing rate of 2.5 hepatic 4-6 h antagonist and reflex tachycardia mg/h every 5 minutes 0.4 g/kg/min doubling 1-2 esterases of calcium-channel Clevidipine every 90 seconds to a red blood 5-15 min antagonist maximum of 8 g/kg/min cells peripheral 1 post- bolus of 10-50 mg or 2 2-5 synaptic receptor Urapidil mg/min titrated up to 9 hepatic 1-2 h hypotension, cardiac arrhythmias antagonist and central mg/min 5HT receptor agonist tachyphylaxis, reflex thachycardia, -1 and -2 2-5 mg 1-2 hours before an increase of circulating levels of Phentolamine adrenoreceptors pheochromocytoma surgery 1-2 hepatic 15-30 min noradrenaline cardiac arrhythmias, antagonist repeating if necessary ischemic cardiac events abdominal pain, nausea Clonidine starting at 0.2 mg/kg/min 2-adrenergic receptors bradycardia and hypotension, dry and titrated up to a 5-10 hepatic 6-8 h agonist mouth and sedation maximum of 0.5 mg/kg/min initial dose of 20 mg,20-80 1-adrenergic and mg can follow every 10 nonselective - minutes. Continuous Labetalol 2-5 hepatic 2-4 h bradycardia and bronchospasm adrenergic blocking infusion starting at 1-2 agent mg/hrs after the loading dose of 20mg bolus of 0.5 to 1 mg/kg followed by a 1-adrenergic red blood continuous infusion starting Esmolol 1 cells 10-20 min bradycardia and bronchospasm blocking agent at 50 g/kg/min and titrated esterases up to 300 g/kg/min 5 g/min, titrated by 5 hypotension, tachycardia, Nitroglycerine NO donors g/min every 5-10 min to 2-5 hepatich 10-20 min hypoxemia , tachyphylaxis and maximum of 60 g/min headache starting at 0.5 g/kg/min, cyanide toxicity Sodium breaken down NO donors and titrated up to a <1 1-2 min Nitroprusside in erythrocyte maximum of 2 g/kg/min increase intraocular dopamine-1 receptor starting dose of 0.1 Fenoldopam 5 hepatic 40 min pressure,tachycardia, hypotension agonist g/kg/min and hypokaliemia cerebrovascular and cardiovascular diseases, in whom a drug. Phentolamine can be used for short-term control of gradual and cautious reduction of blood pressure is hypertension in patients with Pheochromocytoma [44]. To indicated. Urapidil-mediated 1-block proved to be useful in control high blood pressure, 5 mg of the drug are injected patients undergoing laparoscopic surgery for pheocromo- intravenously 1 or 2 hours before surgery and repeated if cytoma. The drug prevented cathecolaminergic crises during necessary (Table 5). Tachyphylaxis, reflex thachycardia and gland manipulation and resection [43]. Urapidil use is an increase in circulating levels of noradrenaline counter contraindicated in aortic stenosis [18]. indicate its use for prolonged blood pressure control in peri- Phentolamine is a competitive receptor antagonist that operative period [45]. shows affinity for both -1 and -2 adreno-receptors (Table Rapid infusions of phentolamine may cause severe 4). It exerts also an 5-HT and K+ channels blocking effect. hypotension, and the drug should be administered cautiously. Phentolamine has an half-life of 19 minutes following In addition, reflex cardiac stimulation may cause alarming intravenuos administration and approximately 13 % of a tachycardia, cardiac arrhythmias, and ischemic cardiac single intravenous dose appears in the urine as unchanged events, including myocardial infarction. GI stimulation may
    • Acute Severe Arterial Hypertension Current Drug Targets, 2009, Vol. 10, No. 8 795 result in abdominal pain, nausea, and exacerbation of peptic Due to the rapid onset and offset, esmolol is considered as ulcer. the anti-hypertensive of choice in intensive care and postoperatively, when a tight control on blood pressure has Clonidine is a direct and selective agonist of 2- to be kept [53]. This hemodynamic stabilizing effect was adrenergic receptors (Table 4). Intravenous administration of clonidine leads to an acute and transient elevation in blood recently evidenced in neurosurgical patients treated with esmolol during emergence from general anesthesia [57]. pressure, due to peripheral post-sinaptic 2-adrenergic Authors found that a loading dose of the drug followed by a stimulation [46]. However this effects is followed by a continuous infusion, effectively treated tachycardia and prolonged hypotensive effect which is related to its hypertension (p<0.05). The same effect has been observed adrenergic stimulation on brain stem receptors. Both heart during endotracheal intubation or skin incision, when rate and contractility are reduced by clonidine. Secondary effects are linked to excessive sympathetic block, such as esmolol can prevent any raise in intracranial pressure associated to excessive adrenergic stimulation [58]. A bradycardia and hypotension (Table 5). Clonidine exerts “myocardial sparing effect” has been observed in brain dead analgesic and sedative effects [47]. Those combined effects organ donors, in whom esmolol can be used to avoid the make clonidine useful in controlling the postoperative effect of associated “autonomic storm” [59]. hypertension associated to pain and agitation [46]. Moreover it has shown to reduce anesthetic requirements both in non As an antiarrhythmic drug, esmolol has been employed to cardiac and cardiac surgery [48, 49]. Clonidine infusion reduce heart rate in supraventricular tachyarrhtymias [60] leads to hemodynamic stability due to the sympathetic block and its use has been recommended particularly in decreasing and it seems to reduce perioperative cardiac risk for patients ventricular rate in high rate atrial fibrillation in post-CABG undergoing non cardiac surgery [50]. Interestingly, patients patients [61]. undergoing regional anesthesia for carotid endoarterectomy Perioperatively, esmolol infusion contributes to a better treated with clonidine had a significantly reduced cortisol, pain control, reducing opioid requirements. Recently, it has epinephrine and norepinephrine plasma concentration been used as a continuous infusion in hypertensive patients (p<0.05) [51]. Same results were observed in hypertensive undergoing laparoscopic cholecystectomy [62]. In this trial, patients undergoing general anesthesia for major vascular Authors found that esmolol exerted an opiod-sparing effect, surgery [52], in whom clonidine showed to reduce anesthetic both intraoperatively (p=0.001) and post-operatively requirements and plasma level of adrenergic stress (p=0.012). Esomolol is administered as a slow (one minute mediators. This blunt in adrenergic response to surgical long) bolus of 0.5 to 1 mg/kg, followed by a continuous stress, might be helpful when managing peri-operative infusion starting at 50 g/kg/min and titrated up to 300 hypertensive crises. g/kg/min, targeting a desired blood pressure [4]. As with labetalol, bradycardia and bronchospasm may follow its Beta-Blockers: Labetalol and Esmolol administration, and its use in congestive heart failure must be Labetalol is a -blocker with selective 1 -adrenergic and judicious [18]. nonselective -adrenergic blocking activity, with a / - blocking ratio of 1:7 [53] (Table 4). Following intravenous Nitroglycerin administration, labetalol exerts its effects in 2-5 minutes, Nitroglycerin is a venous dilator which reduces dilate peaking at 5-15 minutes and lasting 2-4 hrs (Table 5). Reflex arterioles only at high doses [63] (Table 4). It reduces blood tachycardia is blunt by the -blocking effect, and heart rate pressure reducing preload and, thus, cardiac output. can also be slightly reduced [54]. Labetalol reduces the Nitroglycerin onset starts in 2-5 minutes after administration, systemic vascular resistance without, thus increasing cardiac and lasts 10-20 minutes after withdrawal [4, 53]. Its output. Moreover, it maintains cerebral, renal, and coronary elimination is hepatic (Table 5). When administered to blood flow [55]. Its use is safe in pregnancy, due to little volume depleted patients (e.g., postoperative patients), placental transfers [55]. Labetalol is administered as an Nitroglycerin tends to cause hypotension and reflex initial dose of 20 mg. Next doses of 20-80 mg can follow tachycardia, particularly harmful in the setting of coronary every ten minutes, targeting a desired BP. Continuous heart disease [27]. Moreover, reduction of cardiac output can infusion is suitable as well, starting at 1-2 mg/hr after the impair peripheral blood flow, particularly to kidneys and loading dose of 20 mg, and titrating it to the desired blood brain. Due to its potential detrimental effects, use of pressure values [4, 53]. Adverse effects include bradycardia nitroglycerin in critical care patients must be cautious, and a and bronchospasm, while caution must be used in treating low-dose administration is advised only in patients with patients with congestive heart failure to avoid acute heart hypertensive emergencies associated with acute coronary failure [18]. syndromes or acute pulmonary edema [18]. Dosing regimens Esmolol is cardioselective, -adrenergic blocking agent start at 5 g/min, titrated by 5 g/min every 5-10 min to (Table 4). Following its administration, the effect starts maximum of 60 g/min [4]. Adverse effect include within one minute and lasts up to 10-20 minutes [56] Table hypotension and tachycardia, hypoxemia due to ventilation- 5. Esmolol reduces blood pressure reducing heart rate and perfusion mismatch (it blunts hypoxemic vasoconstriction in myocardial contractility, thus reducing cardiac output. lungs), tachyphylaxis and headache. However, peripheral blood flow is maintained. Esmolol exerts no vasodilating effect [56]. Being metabolized by the Sodium Nitroprusside red blood cells esterases, its elimination is not dependant on Sodium nitroprusside acts as arterial and venous hepatic or renal function. However, any reduction in the vasodilator, decreasing cardiac after-load and preload [4, 64] number of circulating red cells might prolong its half-life. (Table 4). Nitroprusside is a very effective anti-hypertensive
    • 796 Current Drug Targets, 2009, Vol. 10, No. 8 De Gaudio et al. agent. Its effect begins seconds after starting the intravenous reducing blood pressure while maintaining organ blood flow, infusion and lasts for 1-2 minutes after its withdrawal. e.g., avoiding coronary, brain or renal hypo-perfusion. In Nitroprusside use should be limited to manage very severe order to do so, many different agents are suitable, and hypertensive crisis, starting as an infusion rate of 0.5 therapeutic strategies must be undertaken considering both g/kg/min, and up to a maximum of 2 g/kg/min [4, 18] severity of the crisis and clinical features of the single Table 5. Due to its direct vasodilatory effects, nitroprusside patients. Faster agents, like clevidipine, might be of tends to decrease peripheral blood flow to tissues. 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