Vasodilators

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 α₁ blocking 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 α₂ receptor 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 (α_2A, α_2B, α_2C) 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 α_2A Receptors mediate sedation, analgesia, and sympatholysis, whereas α_2B receptors mediate vasoconstriction and possibly antishivering effects. The startle response may reflect activation of α_2C 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.¹³ Patients 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 β₂ vasodilating 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.