PockedtEdu Anesthesia Infographics: Sympathetic nervous system 6.1.

Fig 1. Schematic representation of the autonomic nervous system depicting the functional innervation of peripheral effector organs and the anatomic origin of peripheral autonomic nerves from the spinal cord. Although both paravertebral sympathetic ganglia chains are presented, the sympathetic innervation to the peripheral effector organs is shown only on the right side of the figure, whereas the parasympathetic innervation of peripheral effector organs is depicted on the left. The roman numerals on nerves originating in the tectal region of the brainstem refer to the cranial nerves that provide parasympathetic outflow to the effector organs of the head, neck, and trunk. (From Ruffolo R. Physiology and biochemistry of the peripheral autonomic nervous system. In Wingard L, Brody T, Larner J, et al, eds. Human Pharmacology: Molecular to Clinical. St. Louis: Mosby-Year Book; 1991:77.)

Fig. 2 Schematic diagram of the peripheral autonomic nervous system. Preganglionic fibers and postganglionic fibers of the parasympathetic nervous system release acetylcholine (ACh) as the neurotransmitter. Postganglionic fibers of the sympathetic nervous system release norepinephrine (NE) as the neurotransmitter (exceptions are fibers to sweat glands, which release ACh). (From Lawson NW, Wallfisch HK. Cardiovascular pharmacology: a new look at the pressors. In Stoelting RK, Barash J, eds. Advances in Anesthesia. Chicago: Year Book Medical Publishers; 1986:195-270.)

Fig 3. Schematic depiction of the postganglionic sympathetic nerve ending. Release of the neurotransmitter norepinephrine (NE) from the nerve ending results in stimulation of postsynaptic receptors, which are classified as α1, β1, and β2. Stimulation of presynaptic α2-receptors results in inhibition of NE release from the nerve ending. (Adapted from Ram CVS, Kaplan NM. Alpha- and beta-receptor blocking drugs in the treatment of hypertension. In Harvey WP, ed. Current Problems in Cardiology. Chicago: Year Book Medical Publishers; 1970.)

Fig 4. Biosynthesis of norepinephrine and epinephrine in sympathetic nerve terminal (and adrenal medulla). (A) Perspective view of molecules. (B) Enzymatic processes. (From Tollenaer. JP. Atlas of the Three-Dimensional Structure of Drugs. Amsterdam: Elsevier North-Holland; 1979, as modified by Vanhoutte PM. Adrenergic neuroeffector interaction in the blood vessel wall. Fed Proc. 1978;37:181.)

Fig.5 Release and reuptake of norepinephrine at sympathetic nerve terminals. Solid circle, Active carrier; aad, aromatic l-amino acid decarboxylase; DβH, dopamine β-hydroxylase; Dopa, l-dihydroxyphenyalanine; NE, norepinephrine; tyr hyd, tyrosine hydroxylase. (From Vanhoutte PM. Adrenergic neuroeffector interaction in the blood vessel wall. Fed Proc. 1978;37:181, as modified by Shepherd J, Vanhoutte P. Neurohumoral regulation. In Shepherd S, Vanhoutte P, eds. The Human Cardiovascular System: Facts and Concepts. New York: Raven Press; 1979:107.)

PockedtEdu Anesthesia Infographics: Parasympathetic nervous system 6.2.

2. ADRENERGIC PHARMACOLOGY

Norepinephrine

Norepinephrine, the primary adrenergic neurotransmitter, binds to α- and β-receptors. It is used primarily for its α1-adrenergic effects that increase systemic vascular resistance. Like all the endogenous catecholamines, the half-life of norepinephrine is short (2.5 minutes), so it is usually given as a continuous infusion at rates of 3 μg/min or more and titrated to the desired effect. The increase in systemic resistance can lead to reflex bradycardia. Additionally, because norepinephrine vasoconstricts the pulmonary, renal, and mesenteric circulations, infusions must be carefully monitored to prevent injury to vital organs. Prolonged infusion of norepinephrine can also cause ischemia in the fingers and toes because of the marked peripheral vasoconstriction.

Epinephrine

Like norepinephrine, epinephrine binds to α- and β- adrenergic receptors. Exogenous epinephrine is used intravenously in life-threatening circumstances to treat cardiac arrest, circulatory collapse, and anaphylaxis. It is also commonly used locally to decrease the systemic absorption of local anesthetics and to reduce surgical blood loss. Among the therapeutic effects of epinephrine are positive inotropy, chronotropy, and enhanced conduction in the heart (β1); smooth muscle relaxation in the vasculature and bronchial tree (β2); and vasoconstriction (α1). The effects that predominate depend on the dose of epinephrine administered. Epinephrine also has endocrine and metabolic effects that include increasing the levels of blood glucose, lactate, and free fatty acids.

An intravenous dose of 1 mg can be given for cardiovascular collapse, asystole, ventricular fibrillation, pulseless electrical activity, or anaphylactic shock to constrict the peripheral vasculature and maintain myocardial and cerebral perfusion. In less acute circumstances, epinephrine can be given as a continuous infusion. The response of individual patients to epinephrine varies, so the infusion must be titrated to effect while the patient is monitored for signs of compromised renal, cerebral, or myocardial perfusion. In general, an infusion rate of 1 to 2 μg/min should primarily stimulate β2-receptors and decrease airway resistance and vascular tone. A rate of 2 to 10 μg/min increases heart rate, contractility, and conduction through the atrioventricular node. When doses larger than 10 μg/min are given, the α1-adrenergic effects predominate, resulting in generalized vasoconstriction, which can lead to reflex bradycardia. Epinephrine also can be administered as an aerosol to treat severe croup or airway edema. Bronchospasm is treated with epinephrine administered subcutaneously in doses of 300 μg every 20 minutes with a maximum of three doses. Epinephrine treats bronchospasm both via its direct effect as a bronchodilator and because it decreases antigen-induced release of bronchospastic substances (as may occur during anaphylaxis) by stabilizing the mast cells that release these substances. Because epinephrine decreases the refractory period of the myocardium, the risk of arrhythmias during halothane anesthesia is increased when epinephrine is given. The risk of arrhythmias seems to be less in children but increases with hypocapnia.

Dopamine

In addition to binding to α- and β-receptors, dopamine binds to dopaminergic receptors. Besides its direct effects, dopamine acts indirectly by stimulating the release of norepinephrine from storage vesicles. Dopamine is unique in its ability to improve blood flow through the renal and mesenteric beds in shock-like states by binding to postjunctional D1 receptors. Dopamine is rapidly metabolized by MAO and COMT and has a half-life of 1 minute, so it must be given as a continuous infusion. At doses between 0.5 and 2.0 μg/ kg/min, D1 receptors are stimulated and renal and mesenteric beds are dilated. When the infusion is increased to 2 to 10 μg/kg/min, the β1-receptors are stimulated and cardiac contractility and output are increased. At doses of 10 μg/kg/min and higher, α1-receptor binding predominates and causes marked generalized constriction of the vasculature, negating any benefit to renal perfusion. In the past, dopamine was frequently used to treat patients in shock. The belief was that infusions of dopamine, by improving renal blood flow, could protect the kidney and aid in diuresis. Subsequently, dopamine was not found to have a beneficial effect on renal function in shock states. Its routine use for patients in shock is questionable because it may increase mortality risk and the incidence of arrhythmic events. (1,2)

Synthetic Catecholamines

Isoproterenol

Isoproterenol (Isuprel) provides relatively pure and nonselective β-adrenergic stimulation. Its β1-adrenergic stimulation is greater than its β2-adrenergic effects. Its popularity has declined because of adverse effects such as tachycardia and arrhythmias. It is no longer part of the Advanced Cardiac Life Support protocols , and its principal uses now are as a chronotropic drug after cardiac transplantation and to initiate atrial fibrillation or other arrhythmias during cardiac electrophysiology ablation procedures. With larger doses, isoproterenol may cause vasodilation due to β2-adrenergic stimulation. Because isoproterenol is not taken up into the adrenergic nerve endings, its half-life is longer than that of the endogenous catecholamines.

Dobutamine

Dobutamine, a synthetic analog of dopamine, has predominantly β1-adrenergic effects. When compared with isoproterenol, inotropy is more affected than chronotropy. It exerts less of a β2-type effect than isoproterenol does and less of an α1-type effect than does norepinephrine. Unlike dopamine, endogenous norepinephrine is not released, and dobutamine does not act at dopaminergic receptors. Dobutamine is potentially useful in patients with congestive heart failure (CHF) or myocardial infarction complicated by low cardiac output. Doses smaller than 20 μg/kg/min usually do not produce tachycardia. Because dobutamine directly stimulates β1-receptors, it does not rely on endogenous norepinephrine stores for its effects and may still be useful in catecholamine-depleted states such as chronic CHF. However, prolonged treatment with dobutamine causes downregulation of β-adrenergic receptors. If given more than 3 days, tolerance and even tachyphylaxis may occur and can be avoided by intermittent infusions of dobutamine. However, there are no controlled trials demonstrating improved survival. (3)

Fenoldopam

Fenoldopam is a selective D1 agonist and potent vasodilator that enhances renal blood flow and diuresis. Because of mixed results in clinical trials, fenoldopam is no longer used for treatment of chronic hypertension or CHF. Instead, intravenous fenoldopam, at infusion rates of 0.1 to 0.8 μg/kg/min, has been approved for treatment of severe hypertension. Fenoldopam is an alternative to sodium nitroprusside with fewer side effects (e.g., no thiocyanate toxicity, rebound effect, or coronary steal) and improved renal function. Its peak effect takes 15 minutes.

Noncatecholamine Sympathomimetic Amines

Most noncatecholamine sympathomimetic amines act at α- and β-receptors through both direct (binding of the drug by adrenergic receptors) and indirect (release of endogenous norepinephrine stores) activity. Mephentermine and metaraminol are rarely used currently, so the only widely used noncatecholamine sympathomimetic amine at this time is ephedrine.

Ephedrine

Ephedrine increases arterial blood pressure and has a positive inotropic effect. Because it does not have detrimental effects on uterine blood flow in animal models, ephedrine became widely used as a pressor in hypotensive pregnant patients. However, phenylephrine is now the preferred treatment for hypotension in the parturient because of a decreased risk of fetal acidosis. As a result of its β1-adrenergic stimulating effects, ephedrine is helpful in treating moderate hypotension, particularly if accompanied by bradycardia. The usual dose is 2.5 to 10 mg given intravenously or 25 to 50 mg administered intramuscularly. Tachyphylaxis to the indirect effects of ephedrine may develop as norepinephrine stores are depleted. In addition, although drugs with indirect activity are widely used as a first-line therapy for intraoperative hypotension, repeat doses of ephedrine administration in life-threatening events (instead of switching to epinephrine) may contribute to morbidity. (4)

3. SELECTIVE Α-ADRENERGIC RECEPTOR AGONISTS

4. Β2-ADRENERGIC RECEPTOR AGONISTS

5. Α-ADRENERGIC RECEPTOR ANTAGONISTS

6. Β-ADRENERGIC ANTAGONISTS

β-Adrenergic antagonists (i.e., β-blockers) are frequently taken by patients about to undergo surgery. Clinical indications for β-adrenergic block include ischemic heart disease, postinfarction management, arrhythmias, hypertrophic cardiomyopathy, hypertension, heart failure, migraine prophylaxis, thyrotoxicosis, and glaucoma. In patients with heart failure and reduced ejection fraction, β-blocker therapy has been shown to reverse ventricular remodeling and reduce mortality rate. (10) In the 1990s, a study by the Perioperative Ischemia Research Group demonstrated the value of initiating β-block perioperatively in patients at risk for coronary artery disease. (11) Study subjects given perioperative β-blockers had a markedly reduced all-cause 2-year mortality rate (68% survival rate in placebo group vs. 83% in atenolol-treated group). The presumed mechanism for this improved survival rate was a diminution of the surgical stress response by the β-blockers. These and other confirmatory findings led to tremendous political and administrative pressure to increase the use of β-blockers perioperatively. Subsequent studies, however, have questioned the value of perioperative β-block, including a large study of oral metoprolol started on the day of surgery and continuing for 30 days (POISE trial), which demonstrated increased mortality rate in the β-blocker group. (12) A systematic review on perioperative β-block from the American College of Cardiology/American Heart Association (ACC/AHA) states that although perioperative continuation of β-block started 1 day or less before noncardiac surgery in high-risk patients prevents nonfatal myocardial infarctions, it increases the rate of death, hypotension, bradycardia, and stroke. In addition, there is insufficient data regarding continuation of β-block started 2 days or more before noncardiac surgery. (13) The 2014 ACC/ AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery recommends that patients on chronic β-blocker therapy continue this therapy in the perioperative period, but β-blocker therapy should not be started on the day of surgery. (14)

The most widely used β-adrenergic blockers in anesthetic practice are propranolol, metoprolol, labetalol, and esmolol because they are available as intravenous formulations and have well-characterized effects. The most important differences among these blockers are tied to cardioselectivity and duration of action. Nonselective β-blockers act at the β1- and β2-receptors. Cardioselective β-blockers have stronger affinity for β1-adrenergic receptors than for β2-adrenergic receptors. With β1-receptor selective block, velocity of atrioventricular conduction, heart rate, and cardiac contractility decrease. The release of renin by the juxtaglomerular apparatus and lipolysis at adipocytes also decrease. With larger doses, the relative selectivity for β1-receptors is lost and β2- receptors are also blocked, with the potential for bronchoconstriction, peripheral vasoconstriction, and decreased glycogenolysis.

Adverse Effects of β-Adrenergic block

Life-threatening bradycardia, even asystole, may occur with β-adrenergic block, and decreased contractility may precipitate heart failure in patients with compromised cardiac function. In patients with bronchospastic lung disease, β2-block may be fatal. Diabetes mellitus is a relative contraindication to the long-term use of β-adrenergic antagonists because warning signs of hypoglycemia (tachycardia and tremor) can be masked and because compensatory glycogenolysis is blunted. To avoid worsening of hypertension, use of β-blockers in patients with pheochromocytomas should be avoided unless α-receptors have already been blocked. Overdose of β-blocking drugs may be treated with atropine, but isoproterenol, dobutamine, or glucagon also may be required along with cardiac pacing to maintain an adequate rate of contraction.

Undesirable drug interactions are possible with β-blockers. The rate and contractility effects of verapamil are additive to those of β-blockers, so care must be taken when combining these drugs. Similarly, the combination of digoxin and β-blockers can have powerful effects on heart rate and conduction and should be used with special care.

Specific β-Adrenergic Blockers

Propranolol

Propranolol (Inderal, Ipran), the prototypical β-blocker, is a nonselective β-blocking drug. Because of its high lipid solubility, it is extensively metabolized in the liver, but metabolism varies greatly from patient to patient. Clearance of the drug can be affected by liver disease or altered hepatic blood flow. Propranolol is available in an intravenous form and was initially given as either a bolus or an infusion. Infusions of propranolol have largely been supplanted by the shorter-acting esmolol. For bolus administration, doses of 0.1 mg/kg may be given, but most practitioners initiate therapy with much smaller doses, typically 0.25 to 0.5 mg, and titrate to effect. Propranolol shifts the oxyhemoglobin dissociation curve to the right, which might account for its efficacy in vasospastic disorders. (15) Additionally, propranolol is commonly used in the treatment of hyperthyroidism to mitigate tachycardia that may result.

Metoprolol

Metoprolol (Lopressor), a cardioselective β-adrenergic blocker, is approved for the treatment of angina pectoris and acute myocardial infarction. No dosing adjustments are necessary in patients with liver failure. The usual oral dose is 100 to 200 mg/day taken once or twice daily for hypertension and twice daily for angina pectoris. Intravenous doses of 2.5 to 5 mg may be administered every 2 to 5 minutes up to a total dose of 15 mg, with titration to heart rate and blood pressure.

Labetalol

Labetalol (Trandate, Normodyne) acts as a competitive antagonist at the α1- and β-adrenergic receptors. Metabolized by the liver, its clearance is affected by hepatic perfusion. Labetalol may be given intravenously every 5 minutes in 5- to 10-mg doses or as an infusion of up to 2 mg/min. It can be effective in the treatment of patients with aortic dissection (16) and in hypertensive emergencies. Because vasodilation is not accompanied by tachycardia, labetalol has been given to cardiac patients postoperatively. It may be used to treat hypertension in pregnancy both on a long-term basis and in more acute situations. (17) Uterine blood flow is not affected, even with significant reductions in blood pressure (18).

Esmolol

Because it is hydrolyzed by blood-borne esterases, esmolol (Brevibloc) has a uniquely short half-life of 9 to 10 minutes, which makes it particularly useful in anesthetic practice. It can be used when β-block of short duration is desired or in critically ill patients in whom the adverse effects of bradycardia, heart failure, or hypotension may require rapid withdrawal of the drug. Esmolol is cardioselective, and the peak effects of a loading dose are seen within 5 to 10 minutes and diminish within 20 to 30 minutes. It may be given as a bolus of 0.5 mg/kg or as an infusion. When used to treat supraventricular tachycardia a bolus of 500 μg/kg is given over 1 minute, followed by an infusion of 50 μg/kg/min for 4 minutes. If the heart rate is not controlled, a repeat loading dose followed by a 4-minute infusion of 100 μg/kg/min is given. If needed, this sequence is repeated with the infusion increased in 50-μg/kg/min increments up to 300 μg/kg/min. Esmolol is safe and effective for the treatment of intraoperative and postoperative hypertension and tachycardia. If continuous use is required, it may be replaced by a longer-lasting cardioselective β-blocker such as metoprolol.

7. CHOLINERGIC PHARMACOLOGY