VASOACTIVE DRUGS

PHARMACOLOGY

Vasodilator Drugs
Jrg Dziersk
Case Synopsis A 90-year-old man with severe aortic stenosis, stable angina, and pulmonary hypertension has surgery under general anesthesia for a femoral neck fracture. Owing to the associated cardiac morbidities, the anesthesiologist inserts a pulmonary artery catheter. Despite maintenance of normoxemia and mild hypocapnia, the patients pulmonary artery pressure rises from 60/25 to 70/35 mm Hg and is associated with signs of right ventricular strain. A nitroglycerin infusion is started at 0.2 g/kg per minute. The pulmonary artery pressure returns to near baseline values, and the systemic blood pressure decreases from 125/90 to 75/30 mm Hg.

PROBLEM ANALYSIS Definition

Left-sided heart disease (e.g., mitral valve disease, aortic stenosis, left ventricular failure) often causes significant pulmonary venous pressure elevation and leads to compensatory pulmonary artery (PA) hypertension. Chronic elevation of PA pressure promotes compensatory right ventricular (RV) hypertrophy and pulmonary vascular remodeling. This, in turn, results in increased pulmonary vascular resistance (PVR). For such patients, acute (or acute-on-chronic) increases in PA pressure are often poorly tolerated. The consequences are RV dilatation, significant tricuspid regurgitation, and reduced cardiac output secondary to reduced venous return and impaired left ventricular filling. Together, they may lead to a downward spiral. When RV systolic pressure exceeds aortic blood pressure, RV coronary perfusion is limited to diastole, which may further impair RV performance. Vasodilating drugs act by reducing the contraction of vascular smooth muscle cells through a reduction in cytoplasmic Ca2+ concentration [Ca2+]. Vascular smooth muscle relaxation may be mediated by the following:

Increased intracellular cyclic adenosine monophosphate (e.g., 2-adrenoceptor agonists, epoprostenol) Increased intracellular cyclic guanosine monophosphate (e.g., nitric oxide, nitroglycerin, sodium nitroprusside, brain natriuretic peptide) KATP channel-opening-related hyperpolarization (e.g., diazoxide) 1-Adrenoceptor antagonism (e.g., phentolamine) Ca2+ channel blockade (e.g., diltiazem, nicardipine, verapamil) Reduction of central sympathetic tone (e.g., clonidine)

Properties of an ideal vasodilator for perioperative use include (1) short onset time, (2) short to intermediate duration of action, (3) elimination independent of organ function (i.e., renal or hepatic), and (4) lack of serious side

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effects or toxicity. At this time, there is no single drug that meets all these criteria. Clinical actions, mechanisms of action, and side effects of vasodilators currently available for intravenous or inhalational administration are listed in Table 1-1.

Recognition
Systemic vasodilatation causes a decline in systemic blood pressure, the extent of which depends on circulating blood volume and venous return (cardiac preload), the adequacy of compensatory mechanisms (i.e., reflex increase in heart rate and contractility), and the cardiac ejection fraction (normal or reduced). The skin appears warm and may be flushed, with a shortened capillary refill time. Organ dysfunction may occur if systemic blood pressure is below the respective autoregulation threshold or if flow in a vascular territory is pressure dependent (e.g., in the presence of coronary artery disease, renal artery stenosis, head injury). Myocardial injury, acute renal failure, or neurologic deficits are typical examples of complications of systemic hypotension. Computation of systemic vascular resistance quantifies the average degree of vasodilatation (or vasoconstriction) in the whole body, but it requires a precise measurement of mean arterial pressure and central venous pressure, as well as a determination of cardiac output. A PA catheter equipped for thermodilution cardiac output is necessary. In the presence of PA hypertension, systemic vasodilatation may allow right-to-left shunting of blood through a patent foramen ovale, leading to a diminished arterial oxygen saturation. Reduced RV preload due to venous pooling and RV myocardial perfusion pressure may compromise RV performance and result in a low cardiac output state.

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Risk Assessment
Vasodilator therapy has an increased potential to cause complications in patients with the following conditions: Hypovolemia Stenotic valvular lesions (especially severe aortic stenosis) Hypertrophic-obstructive cardiomyopathy 3

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Table 11

Vasodilators Available for Intravenous or Inhalational Administration

Terminal Half-life 5-8 hr 19 min (IV) 2.7 hr Principal Action and Mechanism of Action Arterial > venous vasodilatation Competitive adrenoceptor blockade (1: = 1:7) Competitive 1- = 2-adrenoceptor blockade Direct action on VSM Competitive 1-adrenoceptor blockade Competitive 2-adrenoceptor block Central sympathetic vasomotor tone Inhibits peripheral NE release Activation of guanylyl cyclase cGMP Inhibits platelet aggregation Pulmonary edema secondary to contaminants (NO2) and metabolites (peroxynitrite) Methemoglobinemia Tachyphylaxis Methemoglobinemia Cyanide toxicity, especially with higher doses and lengthy infusions Thiocyanate toxicity (lengthy infusions) Methemoglobinemia Reflex tachycardia Side Effects and Problems Bradycardia Drug fever Reflex tachycardia Hypoglycemia

Drug Class and Drug*

1-Antagonists
Labetalol Phentolamine Urapidil

2-Adrenoceptor Agonists
Clonidine

Nitric Oxide and

Donors Nitric oxide

Nitroglycerin

Sodium nitroprusside

Calcium Channel
Blockers Diltiazem Nicardipine Verapamil 3-6 hr

Angiotensin-Converting
Enzyme Inhibitors Enalaprilat 11 hr

Prostaglandins with VSM Relaxing Effect

Alprostadil (PGE1) Epoprostenol (PGI2) Iloprost 5-10 min 3-5 min 13-30 min 18 min

Natriuretic Peptides
Brain natriuretic peptide

Miscellaneous Agents
Adenosine <10 sec Stimulation of adenosine receptors Direct vasodilatation (A2a, A2b, A3) Reduces central sympathetic vasomotor tone (A2a) Inhibits peripheral NE release (A1) Bradycardia Bronchoconstriction Decreased glomerular filtration rate

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6 sec 2-8 hr

8-16 hr

Bradycardia Potentiates anesthetic/narcotic sedation Slow IV onset (30-60 min)

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2-8 min 3-4 min 8.6 hr (infusions 48 hr)

Venous > arterial vasodilatation NO or S-nitrosothiol release by metabolism activation of guanylyl cyclase Arterial venous vasodilatation NO release by red cell metabolism activation of guanylyl cyclase

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Block L-type Ca2+ channels Primary arterial dilators (no venodilatation at therapeutic doses)

Vasodilatation unpredictable
Little effect in PA HTN Moderate negative inotrope AV conduction blockade Does not block L-type cardiac Ca2+ channels (little or no effect on contractility or AV conduction) Significant negative inotrope Depresses sinus node Blocks AV node conduction Longer half-life with chronic use

Arterial vasodilatation Vascular remodeling Inhibits generation of angiotensin II Stimulates kallikrein-kinin system

Activation of adenylyl cyclase cAMP

Arterial and venous vasodilatation Stimulation of natriuretic peptide receptor A activation of guanylyl cyclase domain cGMP Inhibits renin-aldosterone axis

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Possibly severe (first dose) Acute renal failure K+, especially with renal failure No effect on PA HTN (given acutely) Slow IV onset (>15 min)

Severe systemic hypotension with IV dosing (common)

Inhibition of platelet aggregation and adhesion Stimulates coughing (inhalational use)

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Vasodilator Drugs

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PHARMACOLOGY

Table 11

Vasodilators Available for Intravenous or Inhalational Administrationcontd

Terminal Half-life 20-45 hr 5-10 min 2-4 min Principal Action and Mechanism of Action Opens KATP channels hyperpolarization and arteriolar vasodilatation Dopamine (DA1) agonist arteriolar vasodilatation Arterial vasodilatation only Side Effects and Problems Sodium and water retention Hyperglycemia Reflex tachycardia Hypokalemia Nausea Slow IV onset (5-15 min) Reflex tachycardia (quite common) Sodium and water retention Lupus-like syndrome (slow acetylators)

Drug Class and Drug* Diazoxide Fenoldopam Hydralazine

*Drugs with vasodilator activity used principally for their sympathomimetic effects (e.g., 2-adrenoceptor agonists, phosphodiesterase-3 inhibitors) are not included. Urapidil is widely used in Europe but is currently not available in the United States. AV, atrioventricular; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; HTN, hypertension; IV, intravenous; NE, norepinephrine; NO, nitric oxide; NO2, nitrogen dioxide; PA, pulmonary artery; PG, prostaglandin; VSM, vascular smooth muscle.

Intracardiac shunts Altered organ blood flow autoregulation (e.g., systemic hypertension, head injury) Perfusion territories with pressure-dependent blood flow (e.g., coronary artery disease, renal artery stenosis, aortic coarctation)

Besides their potential to cause inappropriate systemic hypotension, many vasodilators have other undesirable physiologic effects or toxicities (summarized in Table 1-1).

Implications

Systemically administered vasodilators inhibit hypoxic pulmonary vasoconstriction. They may cause or aggravate hypoxemia during one-lung ventilation or in the presence of lung pathology (e.g., atelectasis, lung contusion, pneumonia), leading to increased ventilation-perfusion mismatch or intrapulmonary shunting. Pulmonary hypertension is associated with increased perioperative morbidity and mortality in cardiac surgery. The most recent ACC/AHA guidelines on Perioperative Evaluation for Noncardiac Surgery (2002) state: although most experts agree that pulmonary hypertension poses an increased risk for noncardiac surgery, no organized study of the problem has been performed.

MANAGEMENT
Avoidance of vasodilator drug overdose is based on titration to effect with an intravenous infusion or repeated small bolus doses, depending on pharmacokinetics. Vasodilatorinduced hypotension can be treated by the following means:

Dose adjustment or (temporary) discontinuation of the responsible vasodilator Intravascular volume loading Head-down positioning or leg elevation (circumstances permitting) Judicious application of a (short-acting) vasoconstrictor

Management of PA hypertension begins with the elimination or modulation of factors known to increase PVR:

Hypoxemia Acidemia

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High sympathetic tone High intrathoracic pressure

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There is evidence that PVR begins to increase significantly when arterial PO2 falls below 60 mm Hg. Conversely, the existence of pulmonary vasodilatation with hyperoxia is controversial. However, there may be circumstances when the application of a high fraction of inspired oxygen (even 1.0) is indicated, if only to increase the margin of safety against hypoxemia. Pulmonary vasoconstriction occurs with an arterial pH of less than 7.35, irrespective of the cause of acidemia (respiratory versus metabolic). Moderate hyperventilation to an arterial PCO2 of 30 to 35 mm Hg and aggressive correction of any metabolic acidosis with sodium bicarbonate or tris(hydroxymethy) aminomethane (THAM) are advised. Extreme alkalosis (pH >7.5) may produce further pulmonary vasorelaxation but adversely affects oxygen delivery and enzyme function. High endogenous catecholamine levels cause pulmonary vasoconstriction through the stimulation of 1adrenoceptors. These high levels can be avoided or treated by providing adequate anesthetic depth and postoperative analgesia. Finally, it should be remembered that lung inflation above functional residual capacity causes a progressive increase in PVR. Ventilator settings should be adjusted, based on the patients pulmonary function, to provide adequate oxygenation and carbon dioxide elimination while keeping mean intrathoracic pressure to a minimum. Pharmacologic pulmonary vasodilatation without concomitant systemic vasodilatation, as was required in the case described here, can be attained in two ways: 1. Inhalation of a short-acting vasodilator, such as nitric oxide (NO) or prostacyclin (epoprostenol) 2. Coadministration of an intravenous pulmonary vasodilator (e.g., nitroglycerin, nitroprusside, epoprostenol) and a pulmonary vasculature-sparing vasoconstrictor (e.g., vasopressin or its synthetic analogue terlipressin). NO activates soluble guanylyl cyclase to increase cyclic guanosine monophosphate levels in vascular smooth muscle. It is inactivated by the heme moiety of hemoglobin and superoxide anions and has a blood half-life of approximately 6 seconds. Therefore, inhaled NO affects predominantly

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the tone of pulmonary vessels in ventilated lung areas but has negligible effects on systemic vascular resistance. Broader application is currently limited by its very high cost and the special equipment required for its administration. Prostacyclin (PGI2, epoprostenol) and its synthetic analogue iloprost are the most potent pulmonary vasodilators known. Their main application is continuous infusion in cases of severe pulmonary hypertension. Their vasodilator action is mediated by cyclic adenosine monophosphate. Intravenous administration frequently causes prohibitive systemic hypotension, but when administered via inhalation, the effectiveness is comparable to that of inhaled NO. Arginine vasopressin is a vasoactive nonapeptide produced in the hypothalamus. It is an agonist at three specific receptor types. Stimulation of the V1a receptor results in contraction of systemic vascular smooth muscle by means of an intracellular activation pathway shared with angiotensin II. Successful use of arginine vasopressin in vasodilatory shock after cardiopulmonary bypass and in hyperdynamic septic shock has been reported. The advanced cardiovascular life support guidelines of 2000 recommend vasopressin as an alternative to epinephrine in patients with refractory ventricular fibrillation. In contradistinction to the pulmonary vascular effects of other vasoconstrictors (e.g., 1adrenoceptor agonists, angiotensin II), vasopressin has been shown to cause pulmonary and cerebral artery vasodilatation, possibly through receptor-mediated local NO release. It may be the vasopressor drug of choice in patients with significantly elevated PVR or RV failure.

pulmonary hypertension, because it produces less relaxation of systemic resistance vessels than do other pulmonary vasodilators and does not cause a reflex tachycardia. Use of vasodilators in the perioperative period should take into account the common occurrence of hypovolemia due to preoperative fluid restriction, intraoperative fluid shifts or blood loss, and globally or regionally reduced sympathetic tone in anesthetized patients. Careful dose titration of vasodilators is advisable and is facilitated by using drugs with short half-lives. Vasodilator therapy for pulmonary hypertension coincides with the appropriate manipulation of physiologic factors known to affect PVR. Inhalational administration of NO or epoprostenol, if feasible, may help avoid unwanted systemic venodilatation or arterial vasodilatation effects. Finally, always keep in mind that adrenoceptor antagonists and vasodilators attenuate sympathetic responses, possibly masking the clinical signs of inadequate depth of anesthesia. The use of a depth-of-anesthesia monitor is encouraged, especially when neuromuscular blockers are used.

PREVENTION

Preventing the complications of vasodilator use is based on an understanding of the patients pathophysiology and the pharmacology of available drugs. Vasodilators are used to advantage based on their specific profiles, always keeping in mind any undesired or dangerous side effects. For instance, in a patient with aortic stenosis and coronary artery disease, both systemic hypotension and tachycardia must be avoided. In the case described in this chapter, nitroglycerin would be a reasonable choice for treatment of

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Further Reading
Balser JR, Butterworth J: Cardiovascular drugs. In Hensley FA Jr, Martin DE, Gravlee GP (eds): A Practical Approach to Cardiac Anesthesia, 3rd ed. Philadelphia, JB LippincottWilliams & Wilkins, 2003. Barnes PJ, Liu SF: Regulation of pulmonary vascular tone. Pharmacol Rev 47:87-131, 1995. Eagle KA, Berger PB, Calkins H, et al: ACC/AHA Guideline Update on Perioperative Cardiovascular Evaluation for Noncardiac Surgery, 2002. American College of Cardiology Web site available at http://www.acc.org/ clinical/ guidelines/perio/dirIndex.htm Frishman WH, Sonnenblick EH, Sica DH (eds): Cardiovascular Pharmacotherapeutics, 2nd ed. New York, McGraw-Hill, 2003. Katzung BG (ed): Basic & Clinical Pharmacology, 9th ed. New York, Lange Medical Books/McGraw-Hill, 2004. Malouf JF, Enriquez-Sarano M, Pellikka PA, et al: Severe pulmonary hypertension in patients with severe aortic valve stenosis: Clinical profile and prognostic implications. J Am Coll Cardiol 40:789-795, 2002. Olschewski H, Rose F, Schermuly R, et al: Prostacyclin and its analogues in the treatment of pulmonary hypertension. Pharmacol Ther 102:139-153, 2004. Reich DL, Bodian CA, Krol M, et al: Intraoperative hemodynamic predictors of mortality, stroke, and myocardial infarction after coronary artery bypass surgery. Anesth Analg 89:814-822, 1999.

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