As described in Chapter 14, control of vascular tone in the peripheral and pulmonary circulations is a complex interplay of local metabolism, endothelial function, and regulation by the sympathetic nervous and endocrine systems. This chapter deals with the anesthetic implications of preexisting conditions and medications patients may be receiving, which affect the vasculature, as well as medications given acutely in the perioperative period in order to reduce systemic and pulmonary vascular pressures.
Systemic Hypertension
Systemic hypertension is estimated to affect 30% of adults in the United States1 and is defined as 150 to 159/90 to 99 mm Hg (stage 1) or greater than or equal to 160/100 mm Hg (stage 2).2 By far, the most common type of hypertension is “essential” or “primary” for which there is no clear unifying pathophysiology despite decades of research. What is clear, however, is that hypertension is a major risk factor for cardiovascular disease including atherosclerosis, heart failure, stroke, renal disease, and overall decreased survival. “Secondary” hypertension is much less common and can be due to a variety of causes (Table 20-1). Antihypertensive medications are used to control both primary and secondary hypertension. If more than three medications are required for consistent control, a diagnosis of secondary hypertension should be strongly suspected.
Management of essential hypertension includes alteration in lifestyle and diet (smoking cessation, weight reduction, increased physical activity, salt restriction) and use of medications. Most commonly, a thiazide diuretic is the initial therapy as increased sodium excretion results in decreased blood pressure, and these medications are inexpensive and require infrequent dosing. However, their chronic use requires potassium monitoring and supplementation. Alternatively, monotherapy with a dihydropyridine calcium channel antagonist, such as amlodipine, or an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) may be used.
Calcium channel blockade offers a direct vasodilator effect without the requirement of salt restriction and is associated with relatively few side effects. Use of an ACE inhibitor or ARB targets the renin-angiotensin system, a major contributor to blood pressure control. Decreased renal perfusion and increased sympathetic nervous system activity cause the release of renin, which then acts on “renin substrate” or angiotensin I at various sites in the body to release angiotensin II, a potent vasocontrictor and promotor of sodium and water retention.3 Inhibition of angiotensin II production (with ACE inhibitor) or blockade of its receptor (with ARB) causes a reliable and potent antihypertensive effect, with very few side effects. In addition, in patients with most types of cardiac disease, these drugs have a well-known survivial benefit. Although β-adrenergic blockade is also an option, these agents may be associated with inferior stroke protection (when compared to calcium channel blockade, ACE inhibitor, and ARB) in patients older than the age of 60 years4 and have a greater potential for systemic side effects.
Specific Antihypertensive Drugs and Anesthesia
Hypertensive patients are likely to be receiving one or more of thiazide diuretics, calcium channel blockers, ACE inhibitors/ARB medications, and β-adrenergic blockers. Less commonly, patients may be receiving other drugs which antagonize the sympathetic nervous system (centrally acting α2 agonist clonidine, peripheral α1 antagonists, or α/β antagonists such as labetalol or carvedilol, nitrates, or hydralazine) (Table 20-2). Although many other drugs have been used in the past, they will not be discussed here. In general, antihypertensive therapy should be continued until the time of surgery, as managing poorly controlled hypertension is likely to be more difficult than managing the well-controlled hypertensive patient. Severe or poorly controlled hypertension is a relatively common cause for postponement of surgery,5 although evidence supporting this practice comes from small studies mostly more than 20 years old. Specific drugs and implications for perioperative management are discussed in the following text.
Sympatholytics
β-Adrenergic Blockers
As mentioned earlier, β blockers are less commonly used as first-line agents in hypertension as other agents may have a better safety profile for this indication in those older than the age of 60 years. In addition, β blockers have a potential side effect profile which limits their use in many patients including fatique, depression, and impotence. However, β blockers are indicated for long-term treatment of patients with coronary artery disease and heart failure and for their anthypertensive action in these patients.
Mechanism of Action
β Blockers can be classified according to whether they exhibit β1 selective versus nonselective properties and whether they possess intrinsic sympathomimetic activity. A β blocker with selective properties binds primarily to β1(cardiac) receptors, whereas a β blocker with nonselective properties has equal affinity for β1 and β2 (vascular and bronchial smooth muscle, metabolic) receptors. The β blockers with intrinsic sympathomimetic activity tend to produce less bradycardia and thus are less likely to unmask left ventricular dysfunction. These drugs are also less likely to produce vasospasm and thus to exacerbate symptoms of peripheral vascular disease. The antihypertensive effect of β blockers and other vasodilators may be attenuated by nonsteroidal antiinflammatory drugs.6
In contrast to nonselective β blockers such as propranolol, cardioselective β1 blockers (acebutolol, atenolol, metoprolol, bisoprolol) administered in low to moderate doses are unlikely to produce bronchospasm, decrease peripheral blood flow, or mask hypoglycemia. For these reasons, they are the preferred drugs for patients with pulmonary disease, insulin-dependent diabetes mellitus, or symptomatic peripheral vascular disease. The nonselective agent carvedilol which also has α1 blocking action has been shown to improve survival in patients with systolic heart failure.7 The cardioselective drugs metoprolol and bisoprolol have also been shown to provide a survival benefit in this population, although not as great as carvedilol. Labetalol is another nonselective β blocker which also has significant α1blocking action. The presence of α-adrenergic blocking properties results in less bradycardia and negative inotropic effects compared with “pure” β blockers. These α properties, however, may result in orthostatic hypotension. The incidence of bronchospasm is similar to that seen with atenolol or metoprolol. Intravenous (IV) labetalol is used in hypertensive emergencies and is particularly useful in managing patients with type B aortic dissections, facilitating conversion from IV to oral medications.
Side Effects
Treatment of hypertension with β blockers involves certain risks, including bradycardia and heart block, congestive heart failure, bronchospasm, claudication, masking of hypoglycemia, sedation, impotence, and when abruptly discontinued may precipitate angina pectoris or even myocardial infarction. Patients with any degree of congestive heart failure cannot generally tolerate more than modest doses of β blockers, yet it is clear that when dosage is slowly increased and the drugs are given chronically, the antiadrenergic effect provides a signficant benefit in chronic systolic heart failure. In patients with symptomatic asthma, β blockers should be avoided. β Blockers potentially increase the risk of serious hypoglycemia in diabetic patients because they blunt autonomic nervous system responses that would warn of hypoglycemia. Nevertheless, the incidence of hypoglycemia has not been shown to be increased in diabetic patients being treated with β-adrenergic antagonists to control hypertension.8
Intravenous β Blockers
IV β blockers available in North America include metoprolol, propranolol, labetalol (an α1/nonselective β blocker), and esmolol, which is a very short-acting cardioselective agent, inactivated by plasma esterases. Perioperative β blockade can be used to continue preoperative therapy, but due to extensive first-pass activity for oral agents, the conversion to IV dosing is somewhat unpredictable. In the case of labetalol, its β:α ratio is 3:1 when taken orally and 7:1 when given IV.9
α1 Receptor Blockers
Prazosin, terazosin, and doxazocin are oral, selective postsynaptic α1-adrenergic receptor antagonists resulting in vasodilating effects on both arterial and venous vasculature. Absence of presynaptic α2receptor antagonism leaves intact the normal inhibitory effect on norepinephrine release from nerve endings. These drugs are unlikely to elicit reflex increases in cardiac output and renin release. In contrast, oral phenoxybenzamine and IV phentolamine are nonselective α blockers which also block presynaptic α2 receptors. Both of these drugs are used almost exclusively in the management of pheochromocytoma and will not be discussed further. Urapidil is a potent α1 antagonist and centrally acting serotonin antagonist which is available outside the United States in both oral and IV formulations.
In addition to treating essential hypertension, prazosin may be of value for decreasing afterload in patients with congestive heart failure. Prazosin may also be a useful drug for the preoperative preparation of patients with pheochromocytoma. This drug has been used to relieve the vasospasm of Raynaud’s phenomenon. Another useful indication for prazosin in the treatment of essential hypertension is the presence of benign prostatic hypertrophy in older males, as this drug decreases the size of the gland.10
Pharmacokinetics
Prazosin is nearly completely metabolized, and less than 60% bioavailability after oral administration suggests the occurrence of substantial first-pass hepatic metabolism. The elimination half-time is about 3 hours and is prolonged by congestive heart failure but not renal dysfunction. The fact that this drug is metabolized in the liver permits its use in patients with renal failure without altering the dose.
Cardiovascular Effects
Prazosin decreases systemic vascular resistance without causing reflex-induced tachycardia or increases in renin activity as occurs during treatment with hydralazine or minoxidil. Failure to alter plasma renin activity reflects continued activity of α2 receptors that normally inhibit the release of renin. Vascular tone in both resistance and capacitance vessels is decreased, resulting in decreased venous return and cardiac output.
Side Effects
The side effects of prazosin include vertigo, fluid retention, and orthostatic hypotension. Nonsteroidal antiinflammatory drugs may interfere with the antihypertensive effect of prazosin. Dryness of the mouth, nasal congestion, nightmares, urinary frequency, lethargy, and sexual dysfunction may accompany treatment with this drug. Hypotension during epidural anesthesia may be exaggerated in the presence of prazosin, reflecting drug-induced α1 blockade that prevents compensatory vasoconstriction in the unblocked portions of the body.11 The resulting decrease in systemic vascular resistance results in hypotension that may not be responsive to the usual clinical doses of an α1-adrenergic agonist such as phenylephrine. In this situation, administration of epinephrine may be necessary to increase systemic vascular resistance and systemic blood pressure. Conceivably, the combination of prazosin and a β blocker could result in particularly refractory hypotension during regional anesthesia due to potentially blunted responses to β1 as well as α1 agonists.
α2 Agonists
Clonidine is a centrally acting selective partial α2-adrenergic agonist (220:1 α2 to α1 activity) that acts as an antihypertensive drug by virtue of its ability to decrease sympathetic output from the central nervous system (CNS). This drug has proved to be particularly effective in the treatment of patients with severe hypertension or renin-dependent disease. The usual daily adult dose is 0.2 to 0.3 mg orally. The availability of a transdermal clonidine patch designed for weekly administration is a more convenient formulation but is not useful in the acute setting as the onset is slow (hours). Another drug of the same class is IV dexmedetomidine, a much more α2 selective drug which is approved for sedation rather than hypertension, although it does have a blood pressure–lowering action. Dexmedetomidine is discussed in Chapter 5.
Mechanism of Action
α2-Adrenergic agonists produce clinical effects by binding to α2 receptors of which there are three subtypes (α2A, α2B, α2C) that are distributed ubiquitously, and each may be uniquely responsible for some, but not all, of the actions of α2 agonists (Fig. 20-1).12 α2A Receptors mediate sedation, analgesia, and sympatholysis, whereas α2B receptors mediate vasoconstriction and possibly antishivering effects. The startle response may reflect activation of α2C receptors.
Clonidine stimulates α2-adrenergic inhibitory neurons in the medullary vasomotor center. As a result, there is a decrease in sympathetic nervous system outflow from CNS to peripheral tissues. Decreased sympathetic nervous system activity is manifested as peripheral vasodilation and decreases in systemic blood pressure, heart rate, and cardiac output. The ability of clonidine to modify the function of potassium channels in the CNS (cell membranes become hyperpolarized) may be the mechanism for profound decreases in anesthetic requirements produced by clonidine and other even more selective α2-adrenergic agonists such as dexmedetomidine. α2 Receptors on blood vessels mediate vasoconstriction and on peripheral sympathetic nervous system nerve endings inhibit release of norepinephrine. Neuraxial placement of clonidine inhibits spinal substance P release and nociceptive neuron firing produced by noxious stimulation.
Pharmacokinetics
Clonidine is rapidly absorbed after oral administration and reaches peak plasma concentrations within 60 to 90 minutes. The elimination half-time of clonidine is between 9 and 12 hours, with approximately 50% metabolized in the liver, whereas the rest is excreted unchanged in urine. The duration of hypotensive effect after a single oral dose is about 8 hours. The transdermal route requires about 48 hours to produce steady-state therapeutic plasma concentrations.
Cardiovascular Effects
The decrease in systolic blood pressure produced by clonidine is more prominent than the decrease in diastolic blood pressure. In patients treated chronically, systemic vascular resistance is little affected, and cardiac output, which is initially decreased, returns toward predrug levels. Homeostatic cardiovascular reflexes are maintained, thus avoiding the problems of orthostatic hypotension or hypotension during exercise. The ability of clonidine to decrease systemic blood pressure without paralysis of compensatory homeostatic reflexes is highly desirable. Renal blood flow and glomerular filtration rate are maintained in the presence of clonidine therapy.
Side Effects
The most common side effects produced by clonidine are sedation and xerostomia. Consistent with sedation and, perhaps more specifically, an agonist effect on postsynaptic α2 receptors in the CNS are nearly 50% decreases in anesthetic requirements for inhaled anesthetics (minimum alveolar concentration) and injected drugs in patients pretreated with clonidine administered in the preanesthetic medication.13Patients pretreated with clonidine often manifest lower plasma concentrations of catecholamines in response to surgical stimulation and occasionally require treatment of bradycardia. As with other antihypertensive drugs, retention of sodium and water often occurs such that combination of clonidine with a diuretic is often necessary. Conversely, a diuretic effect during general anesthesia has been described after administration of oral clonidine, 2.5 to 5.0 µg/kg as preanesthetic medication.14 Skin rashes are frequent, impotence occurs occasionally, and orthostatic hypotension is rare. Despite the fact that clonidine prevents opioid-induced skeletal muscle rigidity and produces skeletal muscle flaccidity, α2 agonists have no effect on the responses evoked by neuromuscular blocking drugs.15
Rebound Hypertension
Abrupt discontinuation of clonidine therapy can result in rebound hypertension as soon as 8 hours and as late as 36 hours after the last dose.16 Rebound hypertension is most likely to occur in patients who were receiving greater than 1.2 mg of clonidine daily. The increase in systemic blood pressure may be associated with a greater than 100% increase in circulating concentrations of catecholamines and intense peripheral vasoconstriction. Symptoms of nervousness, diaphoresis, headache, abdominal pain, and tachycardia often precede the actual increase in systemic blood pressure. β-Adrenergic blockade may exaggerate the magnitude of rebound hypertension by blocking the β2vasodilating effects of catecholamines and leaving unopposed their α vasoconstricting actions. Likewise, tricyclic antidepressant therapy may exaggerate rebound hypertension associated with abrupt discontinuation of clonidine therapy.17 Tricyclic antidepressants can potentiate the pressor effects of norepinephrine.
Rebound hypertension can usually be controlled by reinstituting clonidine therapy or by administering a vasodilating drug such as hydralazine or nitroprusside. β-Adrenergic blocking drugs are useful but probably should be administered only in the presence of α-adrenergic blockade to avoid unopposed α vasoconstricting actions. In this regard, labetalol with α and β antagonist effects may be useful in the management of patients experiencing rebound hypertension. If oral clonidine therapy is interrupted because of surgery, use of transdermal clonidine provides a sustained therapeutic level of drug for as long as 7 days.18 For a planned withdrawal, the clonidine dosage should be gradually decreased over 7 days or longer.
Rebound hypertension after abrupt discontinuation of chronic treatment with antihypertensive drugs is not unique to clonidine.16 For example, abrupt discontinuation of β blocker therapy has been associated with clinical evidence of excessive sympathetic nervous system activity. Antihypertensive drugs that act independently of central and peripheral sympathetic nervous system mechanisms (direct vasodilators, ACE inhibitors) do not seem to be associated with rebound hypertension after sudden discontinuation of therapy.
Other Clinical Uses
α-Adrenergic agonists (clonidine and dexmedetomidine) induce sedation, decrease anesthetic requirements, and improve perioperative hemodynamic (attenuate blood pressure and heart rate responses to surgical stimulation) and sympathoadrenal stability.12 Although a number of small studies have demonstrated these benefits, a recent large trial failed to demonstrate a cardioprotective effect when used perioperatively.19 Both clonidine and dexmedetomidine have been used to help reduce the sympathetic nervous system hyperactivity associated with alcohol and opioid withdrawal. α2 Receptors within the spinal cord modulate pain pathways resulting in analgesia, and intrathecal clonidine has been studied as an effective adjuvant to neuraxial blockade both enhancing and prolonging sensory and motor block.
Angiotensin-Converting Enzyme Inhibitors
ACE inhibitors represented a major advance in the treatment of all forms of hypertension because of their potency and minimal side effects, resulting in improved patient compliance.20 These drugs are free of many of the CNS side effects associated with other antihypertensive drugs, including depression, insomnia, and sexual dysfunction. Other adverse effects, such as congestive heart failure, bronchospasm, bradycardia, and exacerbation of peripheral vascular disease, are not seen with ACE inhibitors either. Similarly, metabolic changes induced by diuretic therapy, such as hypokalemia, hyponatremia, and hyperglycemia, are not observed. Rebound hypertension, as seen with clonidine, has also not been observed with ACE inhibitors.
ACE inhibitors are most effective in treating systemic hypertension secondary to increased renin production. These drugs have been established as first-line therapy in patients with systemic hypertension, congestive heart failure, and mitral regurgitation. ACE inhibitors are more effective and possibly safer than other antihypertensive drugs in the treatment of hypertension in diabetics.21 There is also evidence that ACE inhibitors delay the progression of diabetic renal disease.22 As mentioned earlier, ACE inhibitors have been shown to provide a survival benefit in patients who have suffered a myocardial infarction and in patients with heart failure.23
Mechanism of Action
Angiotensin II normally binds to a specific cell membrane receptor (AT1) that ultimately leads to increased release of calcium from sarcoplasmic reticulum to produce vasoconstriction. Decreased generation of angiotensin II due to the administration of an ACE inhibitor results in reduced vasoconstrictive effects. In addition, plasma concentrations of aldosterone are decreased resulting in less sodium and water retention. ACE inhibitors also block the breakdown of bradykinin, an endogenous vasodilator substance, which contributes to the antihypertensive effects of these drugs. ACE inhibitors, like statins, reduce activation of low-density lipoprotein (LDL) receptors and thus decrease plasma concentrations of LDL cholesterol. If the concentration of LDL cholesterol is already sufficiently low, ACE inhibitors may no longer be effective in reducing the rate of cardiovascular events.24
ACE inhibitors can be classified according to the structural element that interacts with the zinc ion of the enzyme as well as the form in which the drug is administered (prodrug or active form). Administration of ACE inhibitors as prodrugs increases oral bioavailability prior to their hepatic metabolism to the active drug. Enalapril is the prodrug of the active ACE inhibitor, enalaprilat, and conversion may be altered in patients with hepatic dysfunction. Captopril and lisinopril are not prodrugs. The major difference among clinically used ACE inhibitors is in duration of action.25
Side Effects
Cough, upper respiratory congestion, rhinorrhea, and allergic-like symptoms seem to be the most common side effects of ACE inhibitors.26 It is speculated that these airway responses reflect potentiation of the effects of kinins due to drug-induced inhibition of peptidyl–dipeptidase activity and subsequent breakdown of bradykinin. If respiratory distress develops, prompt injection of epinephrine (0.3 to 0.5 mL of a 1:1,000 dilution subcutaneously) is advised. Angioedema is a potentially life-threatening complication of treatment with ACE inhibitors. Decreases in glomerular filtration rate may occur in patients treated with ACE inhibitors. For this reason, ACE inhibitors are used with caution in patients with preexisting renal dysfunction and are not recommended for patients with renal artery stenosis. Hyperkalemia is possible due to decreased production of aldosterone. The risk of hyperkalemia is greatest in patients with recognized risk factors (congestive heart failure with renal insufficiency).28 Measurement of plasma concentrations of potassium may be indicated in these patients.
Preoperative Management
Adverse circulatory effects during anesthesia are recognized in patients chronically treated with ACE inhibitors leading some to recommend that these drugs be discontinued 12 to 24 hours before anesthesia and surgery.29 A recent retrospective study of more than 75,000 patients (9,900 taking ACE inhibitors) suggested that although continuation of these drugs until the time of surgery is associated with more intraoperative hypotension, there were no adverse consequences.30 The recent American College of Cardiology/American Heart Association guidelines for perioperative management suggests it is “reasonable” to continue these drugs until the time of surgery.31 That being said, in small single center studies, the incidence of hypotension during induction of anesthesia in hypertensive patients chronically treated with ACE inhibitors was greater when ACE inhibitor therapy was continued until the morning of surgery compared with patients in whom therapy was discontinued at least 12 hours (captopril) or 24 hours (enalapril) preoperatively.32 Exaggerated hypotension attributed to continued ACE inhibitor therapy has been responsive to crystalloid fluid infusion and/or administration of a catecholamine or vasopressin infusion. ACE inhibitors may increase insulin sensitivity and hypoglycemia, which is a concern when these drugs are administered to patients with diabetes mellitus. Nevertheless, there is no evidence that the incidence of hypoglycemia is greater in diabetics being treated with ACE inhibitors for control of hypertension.8
Specific Agents
Perioperative implications of different ACE inhibitors are similar; it is not clear that any one agent has more or less effect on perioperative blood pressure control. The only IV ACE inhibitor is enalaprilat; however, there is little published information to guide its use in this setting. It is not used as an infusion (i.e., dosing recommendations are for intermittent injection) and has a less predictable onset and duration of action as well as antihypertenisve action than short-acting direct vasodilators. Oral agents commonly seen are captopril, enalapril, lisinopril, and ramipril with the latter agents having a longer duration of action that captopril.
Angiotensin II Receptor Inhibitors
Angiotensin II receptor inhibitors produce antihypertensive effects by blocking the vasoconstrictive actions of angiotensin II without affecting ACE activity. Agents commonly used include losartan, candesartan, and valdesartan, all of which have a relatively long duration of action (one or twice daily dosing). There is no IV agent available. These agents have similar antihypertensive actions and benefits in patients with heart failure as ACE inhibitors, although the evidence is somewhat less robust. They also have similar side effect profile but do not inhibit breakdown of bradykinin, one of the benefits of ACE inhibitors and which may be a reason that ACE inhibitors are generally preferred as first-line therapy. A major difference between ACE inhibitors and ARBs is that ARBs do not cause cough, one of the reasons ACE inhibitors may not be tolerated (more than 10% of patients).
As with ACE inhibitors, hypotension following induction of anesthesia has been observed in patients being treated with ARBs causing some to recommend these drugs be discontinued on the day before surgery.29
Calcium Channel Blocking Drugs
Calcium channel blocking drugs used as antihypertensives inhibit calcium influx through the voltage-sensitive L-type calcium channels in vascular smooth muscle. They are arterial specific, with little effect on venous circulation. The calcium channel drugs are broadly categorized into drugs of the dihydropyridine class (nifedipine, amlodipine, nicardipine, clevidipine) and those of the nondihydropyridine class (verapamil and diltiazem). Verapamil and diltiazem are less potent vasodilators and both have negative inotropic and chronotropic activity limiting their use in patients with cardiac disease. In current practice, these drugs are more used for their antiarrhythmic action than antihypertensive action (see Chapter 21, Antiarrhythmic Drugs)
The dihydropyridines are potent vasodilators and are relatively safe to use in patients with heart failure and cardiac conduction defects, with the exception of large doses of short-acting nifedipine which may acutely lower the blood pressure and cause myocardial ischemia. As mentioned earlier, calcium channel blockers are particularly successful in treating hypertension in the elderly, African Americans, and salt-sensitive patients. The use of calcium channel blockers does not require concurrent sodium restriction, which makes these drugs unique antihypertensive drugs and perhaps the drugs of choice for patients who find sodium restriction unacceptable. The once-daily dosing of amlodipine is of particular appeal.
Nicardipine is available as an IV preparation for continuous infusion, and other shorter acting IV drugs such as clevidipine have been developed (clevidipine is broken down by plasma esterases). The use of IV nicardipine in the perioperative setting is well studied, and it also has been used in the treatment of hypertensive emergencies.33 Clevidipine is also very effective in this setting but at the time of writing is not widely used in the United States.
Phosphodiesterase Inhibitors
The phosphodiesterases (PDEs) are a broad family of 11 isoenzymes which variably inhibit the breakdown of intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP).34 Although the many noncardiovascular actions of these enzymes are beyond the scope of this chapter, drugs of this class likely to be encountered by the anesthesiologist include the PDE3 inhibitors amrinone and milrinone and the PDE5 inhibitors sildenafil, tadalafil, and vardenafil. Inhibition of PDE causes vascular smooth muscle relaxation and, in the case of PDE III inhibitors, positive inotropy on intracellular calcium mobilization.
The IV PDE3 inhibitor milrinone has replaced amrinone due to its reduced side effect profile. Breakdown of both cAMP and cGMP are inhibited in myocardial cells and vascular smooth muscle by this enzyme. Its combined inotropic and vasodilator actions make it an ideal drug in the short-term treatment of heart failure, both in the intensive care and operative settings. An extensive literature documents its short-term hemodynamic benefits, whereas long-term oral use was associated with cardiovascular adverse effects and increased mortality. Although milrinone would not be a first-choice IV vasodilator in the absence of cardiac dysfunction, its vasodilation actions provide a significant benefit in the setting of heart failure.
The PDE5 inhibitors selectively inhibit the breakdown of cyclic cGMP, more in vascular smooth muscle than in other cardiovascular sites. Due to a high level of PDE5 in the lung, these drugs are effective pulmonary vasodilators, and they are also effective for erectile dysfunction. They are only available in oral formulations. Although peripheral (systemic) vascular effects are modest, when combined with other vasodilators, there can be significant lowering of blood pressure. Concurrent administration of nitroglycerin and erectile dysfunction drugs within 24 hours is not recommended as life-threatening hypotension from exaggerated systemic vasodilation may occur.35
Nitric Oxide and Nitrovasodilators
Nitric Oxide
Nitric oxide is recognized as a chemical messenger in a multitude of biologic systems, with homeostatic activity in the modulation of cardiovascular tone (see Chapter 14, Circulatory Physiology), platelet regulation, and a neurotransmitter function in the CNS. In addition, it has roles in gastrointestinal smooth muscle relaxation and immune regulation. Therapeutically, nitric oxide (NO) is administered by inhalation (iNO) to produce relaxation of the pulmonary arterial vasculature.
Nitric oxide is synthesized in endothelial cells from the amino acid L-arginine by nitric oxide synthetase, a constitutively expressed enzyme. It then diffuses into precapillary resistance arterioles where it induces guanylate cyclase to increase the cGMP concentration, which in turn results in vasodilation. It is formerly known as “endothelial-derived relaxing factor.” NO production has a large role in regulation of vascular tone throughout the body. There is evidence to support deficiency in NO production being related to various vascular diseases including essential hypertension. As a result of stress, an inducible form of NO synthetase can produce large amounts of NO contributing to excessive vasodilation. NO binds to the iron of heme-based proteins and thus is avidly bound and inactivated by hemoglobin leading to a half-time of less than 5 seconds under normal physiologic conditions.
As a therapeutic agent, inhaled NO affects the pulmonary circulation but not the systemic circulation due to its extremely rapid uptake by hemoglobin. Nitrovasodilators (nitrates and nitroprusside) work through generation of NO (see the following discussion) throughout the vasculature.
Nitric Oxide as a Pulmonary Vasodilator
Inhaled NO causes pulmonary arterial vasodilation that is proportional to the degree of pulmonary vasoconstriction (Fig. 20-2). It has less effect on pulmonary vascular resistance if pulmonary vascular tone is not increased such as in types of pulmonary hypertension other than “primary.” By dilating vessels in alveoli where it is locally delivered, iNO usually improves oxygenation by improving ventilation-perfusion matching.
In the United States, the only approved indication for inhaled NO is in pediatric lung injury. Inhaled NO, 10 to 20 ppm, has been used for therapy of persistent pulmonary hypertension of the newborn.36,37Inhalation of NO in premature infants with respiratory distress syndrome decreases the incidence of chronic lung disease and death.38
In the adult population, NO is used “off label” in managing severe pulmonary hypertension especially in the setting of acute right heart dysfunction or failure and in perioperative management of heart and lung transplant recipients. In acute lung injury and acute respiratory distress syndrome, inhaled NO will often provide a modest improvement in pulmonary hemodynamics and oxygenation, but clinical trials have failed to demonstrate an outcome benefit in this setting.
Toxicity
Inhaled NO increases methemoglobin levels as NO combines with hemoglobin. The increases in methemoglobin concentrations are usually modest. Life-threatening rebound arterial hypoxemia and pulmonary hypertension may accompany discontinuation of inhaled NO therapy.39 Because of the variability in rebound pulmonary hypertension, it is important to wean patients from inhaled NO slowly. NO is oxidized to nitrogen dioxide (NO2) especially in the presence of high concentrations of oxygen. NO2 is a known pulmonary toxin (“silo-filler’s disease”) and is a possible product of the interaction of NO with oxygen. It is conceivable that NO2 concentrations could produce pulmonary toxicity during treatment with NO. Continuous monitoring of inspired NO and NO2 concentrations provided in the current delivery system is important to provide an early warning of possible pulmonary toxicity. In the presence of left heart dysfunction or failure, the increased pulmonary blood flow caused by iNO can precipitate acute left heart failure and pulmonary edema.
Nitrodilators
Sodium nitroprusside and IV nitroglycerin are historically the vasodilators most widely used by anesthesiologists. As described earlier, these agents work through the generation of NO, which then augments cyclic cGMP in vascular smooth muscle, both arteries and veins, leading to vasodilation. The more recent availability of IV nicardipine and other arterial-specific dilators such as clevidipine and fenoldopam has to some degree replaced the use of the nitrodilators, especially nitroprusside due to its potential toxicities discussed later.
Sodium Nitroprusside
Sodium nitroprusside (SNP) is a direct-acting, nonselective peripheral vasodilator that causes relaxation of arterial and venous vascular smooth muscle.40 It is composed of a ferrous ion center complexed with five cyanide (CN−) moieties and a nitrosyl group. The molecule is 44% cyanide by weight and is soluble in water. SNP lacks significant effects on nonvascular smooth muscle and on cardiac muscle. Its onset of action is almost immediate, equipotent on arteries and veins, and its duration is transient, requiring continuous IV administration to maintain a therapeutic effect. The extreme potency of SNP necessitates careful titration of dosage as provided by continuous infusion devices and frequent monitoring of systemic blood pressure, often by intraarterial monitoring.
Mechanism of Action
When infused IV, SNP interacts with oxyhemoglobin, dissociating immediately and forming methemoglobin while releasing cyanide and NO.40 Once released, NO activates the enzyme guanylate cyclase present in vascular smooth muscle, resulting in increased intracellular concentrations of cGMP.40 cGMP inhibits calcium entry into vascular smooth muscle cells and may increase calcium uptake by the smooth endoplasmic reticulum to produce vasodilation.41As such, NO is the active mediator responsible for the direct vasodilating effect of SNP. In contrast to the organic nitrates (nitroglycerin), which require the presence of thio-containing compounds to generate NO, SPN spontaneously generates this product, thus functioning as a prodrug.
Metabolism
Metabolism of SNP begins with the transfer of an electron from the iron of oxyhemoglobin to SNP, yielding methemoglobin and an unstable SNP radical.40 This electron transfer is independent of electron activity. The unstable SNP radical promptly breaks down, releasing all five cyanide ions, one of which reacts with methemoglobin to form cyanomethemoglobin. The remaining free cyanide ions are available to rhodanese enzyme in the liver and kidneys for conversion to thiocyanate. Rhodanese uses thiosulfate ions as sulfur donors, and most adults can detoxify approximately 50 mg of SNP using existing sulfur stores. Normal adult methemoglobin concentrations (about 0.5% of all hemoglobin) are capable of binding the cyanide released from 18 mg of SNP. Cyanomethemoglobin remains in dynamic equilibrium with free cyanide and is nontoxic. The nonenzymatic release of cyanide from SNP is not inhibited by hypothermia as may be present during cardiopulmonary bypass, whereas enzymatic conversion of cyanide to thiocyanate may be delayed.42
Dose and Administration
Patients receiving SNP should have blood pressure monitored continuously via an arterial catheter. The recommended initial dose of SNP is 0.3 µg/kg/minute IV titrated to a maximum rate of 10 µg/kg/minute IV, with the maximum rate not to be infused longer than 10 minutes.43 SNP infusion rates of greater than 2 µg/kg/minute IV result in dose-dependent accumulation of cyanide and the risk of cyanide toxicity must be considered. Therefore, as other less toxic drugs are widely available, a reasonable approach might be to change to a different medication if the required dose approaches 2 µg/kg/minute. Delivery of the SNP infusion as protected from light by aluminum foil is most often via an infusion pump.
Organ-Specific Effects
Cardiovascular
Baroreceptor-mediated reflex responses to SNP-induced decreases in systemic blood pressure manifest as tachycardia and increased myocardial contractility. These reflex-mediated responses may oppose the blood pressure–lowering effects of SNP. Although decreased venous return would tend to decrease cardiac output, the net effect is often an increase in cardiac output due to reflex-mediated increases in peripheral sympathetic nervous system activity combined with decreased impedance to left ventricular ejection. In the setting of left ventricular failure, SNP decreases systemic vascular resistance, pulmonary vascular resistance, and right atrial pressure, whereas the effect on cardiac output depends on the initial left ventricular end-diastolic pressure. There is no evidence that SNP exerts direct inotropic or chronotropic effects on the heart.
SNP may increase the area of damage associated with a myocardial infarction through a phenomenon called “coronary steal.”44 SNP dilates resistance vessels in nonischemic myocardium, resulting in diversion of blood flow away from ischemic areas where collateral blood vessels are already maximally dilated. Decreases in diastolic blood pressure produced by SNP may also contribute to myocardial ischemia by decreasing coronary perfusion pressure and associated coronary blood flow.45
Renal
SNP-induced decreases in systemic blood pressure may result in decreases in renal function. Release of renin may accompany blood pressure decreases produced by SNP and contribute to blood pressure overshoots when the drug is discontinued.46 Pretreatment with a competitive inhibitor of angiotensin II prevents blood pressure overshoots after discontinuation of SNP, thus confirming the participation of the renin-angiotensin system in this response.47Increased plasma concentrations of catecholamines also accompany hypotension produced by SNP.
Hepatic
In animals, SNP-induced decreases in systemic blood pressure do not result in hepatic hypoxia or changes in hepatic blood flow.45 Furthermore, hepatic blood flow does not change when cardiac output is maintained in anesthetized patients, despite 20% to 60% decreases in systemic blood pressure produced by SNP.48
Cerebral
SNP increases cerebral blood flow and cerebral blood volume. In patients with decreased intracranial compliance, this may increase intracranial pressure (greater than the increase produced by nitroglycerin). It is likely that the rapidity of systemic blood pressure decrease produced by SNP exceeds the capacity of the cerebral circulation to autoregulate its blood flow such that intracranial pressure and cerebral blood flow change simultaneously but in opposite directions.49 Nevertheless, increases in intracranial pressure produced by SNP are maximal during modest decreases (<30%) in mean arterial pressure. When SNP-induced decreases in mean arterial pressure are greater than 30% of the awake level, the intracranial pressure decreases to below the awake level.50 Furthermore, decreasing blood pressure slowly over 5 minutes with SNP in the presence of hypocarbia and hyperoxia negates the increase in intracranial pressure that accompanies the rapid infusion of nitroprusside.51 Patients with known inadequate cerebral blood flow as associated with dangerously increased intracranial pressure or carotid artery stenosis should probably not be treated with SNP. During cardiopulmonary bypass, SNP has been shown to have no direct effect on cerebral vasculature and autoregulation is preserved.52 The potential adverse effects of SNP on intracranial pressure are not present if the drug is administered after the dura has been surgically opened.
Pulmonary
Decreases in the PaO2 may accompany the infusion of SNP and other peripheral vasodilators used to produce controlled hypotension. Attenuation of hypoxic pulmonary vasoconstriction by peripheral vasodilators is the presumed mechanism.53 Addition of propranolol to the vasodilator regimen does not alter the magnitude of decrease in PaO2.54 Furthermore, peripheral vasodilator-induced decreases in blood pressure are more likely to increase the shunt fraction in patients with normal lungs than in those with chronic obstructive pulmonary disease.55 It is speculated that hypotension in normal patients leads to decreased pulmonary artery pressure such that preferential perfusion of dependent but poorly ventilated alveoli occurs. In contrast, patients with chronic obstructive pulmonary disease may develop destructive vascular changes that prevent alterations in the distribution of pulmonary blood flow in response to vasodilation. The addition of positive end-expiratory pressure may reverse vasodilator-induced decreases in the PaO2.56
Hematologic
Increased intracellular concentrations of cGMP, as produced by SNP and nitroglycerin, have been shown to inhibit platelet aggregation.57 Infusion rates of SNP of greater than 3 µg/kg/minute may result in decreases in platelet aggregation and increased bleeding time.58 The postoperative stress-induced increase in platelet aggregation is absent in SNP-treated patients.59 Increased bleeding time could also be the result of vasodilation secondary to a direct effect of SNP on vascular tone. However, clinical measures of intraoperative bleeding are not increased in SNP-treated patients, suggesting that decreased ability of platelets to aggregate during and after controlled hypotension does not have an adverse clinical effect.59
Toxicity
Cyanide Toxicity
Clinical evidence of cyanide toxicity may occur when the rate of IV SNP infusion is greater than 2 µg/kg/minute or when sulfur donors and methemoglobin are exhausted, thus allowing cyanide radicals to accumulate. Because any free cyanide radical may bind inactive tissue cytochrome oxidase and prevent oxidative phosphorylation, increased cyanide concentrations may precipitate tissue anoxia, anaerobic metabolism, and lactic acidosis. Children may be less able to mobilize thiosulfate stores despite increasing cyanide concentrations, leading to accelerated toxicity.
Regardless of the SNP infusion rate or total administered dose, cyanide toxicity should be suspected in any patient requiring an increasing dose especially more than 2 µg/kg/minute or in a previously responsive patient who becomes less or unresponsive to the drug. Mixed venous Po2 is increased in the presence of cyanide toxicity, indicating paralysis of cytochrome oxidase and inability of tissues to use oxygen. At the same time, metabolic acidosis (plasma lactate concentrations of >10 mM, which correlates with blood cyanide concentrations of >40 µM) develops as a reflection of anaerobic metabolism in the tissues. Decreased cerebral oxygen use is evidenced by the increased cerebral venous oxygen content. In awake patients, CNS dysfunction (mental status changes, seizures) may occur.
Treatment of Cyanide Toxicity
Appearance of tachyphylaxis in a previously sensitive patient in association with metabolic acidosis and increased mixed venous Po2 mandates immediate discontinuation of SNP and administration of 100% oxygen despite normal oxygen saturation. Sodium bicarbonate is administered to correct metabolic acidosis. Sodium thiosulfate, 150 mg/kg IV administered over 15 minutes, is a recommended treatment for cyanide toxicity.40 Thiosulfate acts as a sulfur donor to convert cyanide to thiocyanate. If cyanide toxicity is severe, with deteriorating hemodynamics and metabolic acidosis, the recommended treatment is slow IV administration of sodium nitrate, 5 mg/kg. Sodium nitrate converts hemoglobin to methemoglobin, which acts as an antidote by converting cyanide to cyanomethemoglobin. Alternatively, hydroxocobalamin (vitamin B12a), which binds cyanide to form cyanocobalamin (vitamin B12), can be administered (25 mg per hour IV to a maximum of 100 mg) to treat cyanide toxicity. In addition to being expensive, hydroxocobalamin may produce a reddish discoloration of the skin and mucous membranes.60 Another treatment is methylene blue, 1 to 2 mg/kg IV, administered over 5 minutes, to facilitate the conversion of methemoglobin to hemoglobin.
Thiocyanate Toxicity
Thiocyanate is cleared slowly by the kidneys, with an elimination half-time of 3 to 7 days.40 Clinical thiocyanate toxicity is rare, as thiocyanate is 100-fold less toxic than cyanide. In patients with normal renal function, 7 to 14 days of SNP infusion in the 2 to 5 µg/kg/minute range may be required to produce potentially toxic thiocyanate blood concentrations. SNP infusions for 3 to 6 days may result in thiocyanate toxicity in patients with chronic renal failure who are not undergoing periodic hemodialysis.
Nonspecific symptoms of thiocyanate toxicity include fatigue, tinnitus, nausea, and vomiting. Clinical evidence of neurotoxicity produced by thiocyanate includes hyperreflexia, confusion, psychosis, and miosis. Toxicity may progress to seizures and coma. Increased thiocyanate concentrations competitively inhibit uptake and binding of iodine in the thyroid gland, sometimes producing clinical hypothyroidism. Thiocyanate clearance can be facilitated by dialysis. Oxyhemoglobin can slowly oxidize thiocyanate back to sulfate and cyanide, but this is insufficient to cause cyanide toxicity.
Methemoglobinemia
Adverse effects from methemoglobinemia produced by SNP breakdown are unlikely even in patients with a congenital inability to convert methemoglobin to hemoglobin (methemoglobin reductase deficiency).40 The total SNP dose required to produce 10% methemoglobinemia exceeds 10 mg/kg. Patients receiving such high doses of SNP who present with evidence of impaired oxygenation despite an adequate cardiac output and arterial oxygenation should have methemoglobinemia included in the differential diagnosis. Measurement of methemoglobin via cooximetry may be helpful in these patients.
Clinical Use
The use of SNP, as mentioned earlier, has significantly declined with the introduction of more selective arterial agents which have a greater margin of safety and much less or absent toxicity. In addition, selective arterial agents do not generally have such a dramatic or acute effect on blood pressure due to preservation of venous tone. Before the availability of these drugs, SNP was used widely and well studied in the settings of controlled hypotension, hypertensive emergencies, aortic and cardiac surgery, and heart failure. In this latter population, the combined preload and afterload effect is still a possible advantage but at the cost of blood pressure lability and systemic toxicity. It is likely the use of SNP will continue to decline as experience grows with the newer agents.
Nitrates
Nitroglycerin is an organic nitrate that acts principally on venous capacitance vessels and large coronary arteries to produce peripheral pooling of blood and decreased cardiac ventricular wall tension.61,62However, as the dose of nitroglycerin is increased, there is also relaxation of arterial vascular smooth muscle. Nitroglycerin can produce pulmonary vasodilation equivalent to the degree of systemic arterial vasodilation. The most common clinical use of nitroglycerin is sublingual or IV administration for the treatment of angina pectoris as a result of either atherosclerosis of the coronary arteries or intermittent vasospasm of these vessels. Controlled hypotension can also be achieved with the continuous infusion of nitroglycerin.
Mechanism of Action
Nitroglycerin, like SNP, generates NO, which stimulates production of cGMP to cause peripheral vasodilation (see earlier discussion). In contrast to SNP, which spontaneously produces NO, nitroglycerin requires the presence of thio-containing compounds. In this regard, the nitrate group of nitroglycerin is biotransformed to NO through a glutathione-dependent pathway involving both glutathione and glutathione S-transferase. Nitroglycerin is not recommended in patients with hypertrophic obstructive cardiomyopathy or in the presence of severe aortic stenosis, and venous pooling may be followed by syncope.
Route of Administration
Nitroglycerin is most frequently administered by the sublingual route, but it is also available as an oral tablet, a buccal or transmucosal tablet, a sublingual spray, and a transdermal ointment or patch. Sublingual administration of nitroglycerin results in peak plasma concentrations within 4 minutes. Only about 15% of the blood flow from the sublingual area passes through the liver, which limits the initial first-pass hepatic metabolism of nitroglycerin. In contrast, nitroglycerin is well absorbed after oral administration but it is largely inactive because of first-pass hepatic metabolism.
Transdermal absorption of nitroglycerin, 5 to 10 mg over 24 hours, provides sustained protection against myocardial ischemia. The plasma concentration resulting from transdermal absorption of nitroglycerin is low, but tolerance to the drug effect occurs when the patches are left in place for longer than 24 hours. It is possible that removing the patches after 14 to 16 hours will prevent the development of tolerance.
Continuous infusion of nitroglycerin, via special delivery tubing to decrease absorption of the drug into plastic, is a useful approach to maintain a constant delivered concentration of nitroglycerin.
Pharmacokinetics
Nitroglycerin has an elimination half-time of about 1.5 minutes.62 There is a large volume of distribution, reflecting tissue uptake, and it has been estimated that only 1% of total body nitroglycerin is present in the plasma. For this reason, plasma nitroglycerin concentrations may vary widely because of differences in tissue binding.
Methemoglobinemia
The nitrite metabolite of nitroglycerin is capable of oxidizing the ferrous ion in hemoglobin to the ferric state with the production of methemoglobin.63,64
In particular, high doses of nitroglycerin may produce methemoglobinemia in patients with hepatic dysfunction. Treatment of methemoglobinemia is as discussed earlier with SNP toxicity.
Tolerance
A limitation to the use of all nitrates is the development of tolerance to their vasodilating effects. Tolerance is dose-dependent and duration-dependent, usually manifesting within 24 hours of sustained treatment. If ischemia occurs during continuous administration of nitroglycerin, responsiveness to the antiischemic effects of the nitrate can usually be restored by increasing the dose. The mechanism of tolerance is not well understood but may reflect a change in the vasculature that limits the vasodilating effects of the nitrates. A drug-free interval of 12 to 14 hours is recommended to reverse tolerance to nitroglycerin and other nitrates. Rebound myocardial ischemia may occur during the drug-free interval.
Clinical Use
Perioperatively, nitroglycerin in all its forms is used to treat suspected myocardial ischemia as well as volume overload in the setting of heart failure (preload reduction). As a systemic antihypertensive, both for treatment and achieving controlled hypotenion, nitroglycerin infusion can be effective but its preferential effect on veins rather than arteries can make it less effective in severe hypertension than drugs which preferentailly act on the arteries. Although nitroglycerin has no “toxicity” (other than possible methemoglobinemia with high doses), its use for hypertension has declined with the availability of IV nicardipine and fenoldopam.
Isosorbide Dinitrate
Isosorbide dinitrate is a commonly administered oral nitrate for the prophylaxis of angina pectoris and for preload reduction in patients with heart failure. Its effects are very similar to that of nitroglycerin but as an oral agent, isosorbide dinitrate is well absorbed from the gastrointestinal tract and it is not subject to the extensive first-pass metabolism that limits oral use of nitroglycerin. It exerts a physiologic effect lasting up to 6 hours when taken in large doses of 60 to 120 mg. The longer acting sustained release form provides a prolonged antianginal effect and improves exercise tolerance for up to 6 hours. Isosorbide dinitrate may also be administered sublingually, producing an effect lasting up to 2 hours. The metabolite of isosorbide dinitrate, isosorbide-5-mononitrate, is more active than the parent compound. Orthostatic hypotension accompanies acute administration of isosorbide dinitrate, but tolerance to this and other pharmacologic effects seems to develop with chronic therapy.
Hydralazine
Hydralazine is a direct systemic arterial vasodilator which both hyperpolarizes smooth muscle cells and activates guanylate cyclase to produce vasorelaxation.65 Arterial vasodilation by hydralazine produce reflex sympathetic nervous system stimulation with resulting increases in heart rate and myocardial contractility so this drug is not generally recommended for patients with myocardial ischemia or coronary disease. It is an effective afterload-reducing agent and is still used in combination with nitrates for outpatient treatment of congestive heart failure and for intermittent IV dosing in the perioperative period or critical care setting. Although it has been widely used in hypertensive disorders associated with pregnancy, other agents may be associated with less adverse outcomes.66 Long-term hydralazine is associated with a systemic lupus syndrome, limiting its widespread use. Acute IV administration has a slightly delayed onset making it less appealing than other immediate-onset medications.
Fenoldopam
Fenoldopam is a dopamine type 1 receptor agonist, causing systemic arterial dilation through increasing cyclic cAMP. It has a particular action of increasing renal blood flow and increasing urine output and also increasing splanchnic blood flow due to the density of dopamine type 1 receptors in these beds.67 Because of this action, it has been viewed by some as a possible “new renal dopamine” which might have a renal protective effect, but evidence to support this hypothesis is weak. There is no question, however, that when compared to other IV antihypertensive drugs such as SNP or nicardipine, there is greater urine output with fenoldopam for the same degree of antihypertensive action. Fenoldopam is only available in an IV preparation, it has a rapid onset and 10-minute elimination half-life. As is the case with other arterial dilators, there is a baroreflex-mediated increase in heart rate and plasma catecholamine level associated with its use. Adverse effects are limited to an increase in intraocular pressure, making this drug unsuitable for patients with glaucoma.
Diuretics
As discussed earlier, diuretics continue to be first-line oral agents used for essential hypertension. Patients are most likely to be prescribed a thiazide drug, with more potent loop diuretics (furosemide, bumetanide) reserved for patients where thiazides are less effective such as patients with renal insufficiency or heart failure. Diuretics are not, strictly speaking, vasodilators although there is evidence for a venodilating effect of IV furosemide.68
Both thiazide and loop diuretics cause potassium loss and their use generally mandates supplementation with potassium and often magnesium. This is true both for oral outpatient use and acute IV dosing in the perioperative or critical care setting.
Aldosterone antagonists or “potassium-sparing” agents are less potent than loop diuretics but have a clear role in patients with heart failure where their addition to other antihypertensive drugs (e.g., ACE inhibitors) confers a survival benefit. This is possibly due to blocking aldosterone effects on the heart.
Drugs Not Discussed
The earlier discussion of antihypertensive drugs and vasodilators has not included a number of older agents which are rarely used now for this indication in clinical practice in North America. These include trimethaphan, diazoxide, alphmethyldopa, and adenosine. The reader is referred to old texts for a discussion of these agents.
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