1 Describe the autonomic nervous system

The autonomic nervous system (ANS) is a network of nerves and ganglia that controls involuntary physiologic actions and maintains internal homeostasis and stress responses. The ANS innervates structures within the cardiovascular, pulmonary, endocrine, exocrine, gastrointestinal, genitourinary, and central nervous systems (CNS) and influences metabolism and thermal regulation. The ANS is divided into two parts: the sympathetic (SNS) and parasympathetic (PNS) nervous system. When stimulated, the effects of the SNS are widespread across the body. In contrast, PNS stimulation tends to produce localized, discrete effects. The SNS and PNS generally have opposing effects on end-organs, with either the SNS or the PNS exhibiting a dominant tone at rest and without exogenous stimulating events (Table 1-1). In general the function of the PNS is homeostatic, whereas stimulation of the SNS prepares the organism for some stressful event (this is often called the fight-or-flight response).

TABLE 1-1 Autonomic Dominance Patterns at Effector Sites

2 Review the anatomy of the sympathetic nervous system

Preganglionic sympathetic neurons originate from the intermediolateral columns of the thoracolumbar spinal cord. These myelinated fibers exit via the ventral root of the spinal nerve and synapse with postganglionic fibers in paravertebral sympathetic ganglia, unpaired prevertebral ganglia, or a terminal ganglion. Preganglionic neurons may ascend or descend the sympathetic chain before synapsing. Preganglionic neurons stimulate nicotinic cholinergic postganglionic neurons by releasing acetylcholine. Postganglionic adrenergic neurons synapse at targeted end-organs and release norepinephrine (Figure 1-1).

Figure 1-1 Neuronal anatomy of the autonomic nervous system with respective neurotransmitters. Ach, Acetylcholine; NE, norepinephrine.

(Moss J, Glick D: The autonomic nervous system. In Miller RD, editor: Miller’s Anesthesia, ed 6, Philadelphia, 2005, Churchill Livingstone, p 618.)

3 Elaborate on the location and names of the sympathetic ganglia. Practically speaking, what is the importance of knowing the name and location of these ganglia?

Easily identifiable paravertebral ganglia are found in the cervical region (including the stellate ganglion) and along thoracic, lumbar, and pelvic sympathetic trunks. Prevertebral ganglia are named in relation to major branches of the aorta and include the celiac, superior and inferior mesenteric, and renal ganglia. Terminal ganglia are located close to the organs that they serve. The practical significance of knowing the location of some of these ganglia is that local anesthetics can be injected in the region of these structures to ameliorate sympathetically mediated pain.

4 Describe the postganglionic adrenergic receptors of the sympathetic nervous system and the effects of stimulating these receptors

There are α₁, α₂, β₁, and β₂ adrenergic receptors. The A1, A2, and B2 receptors are postsynaptic and are stimulated by the neurotransmitter norepinephrine. The A2 receptors are presynaptic, and stimulation inhibits release of norepinephrine, reducing overall the autonomic response. Molecular pharmacologists have further subdivided these receptors, but this is beyond the scope of this discussion. Dopamine stimulates postganglionic dopaminergic receptors, classified as DA1 and DA2. The response to receptor activation in different sites is described in Table 1-2.

TABLE 1-2 End-Organ Effects of Adrenergic Receptor Stimulation

5 Review the anatomy and function of the parasympathetic nervous system

Preganglionic parasympathetic neurons originate from cranial nerves III, VII, IX, and X and sacral segments 2-4. Preganglionic parasympathetic neurons synapse with postganglionic neurons close to the targeted end-organ, creating a more discrete physiologic effect. Both preganglionic and postganglionic parasympathetic neurons release acetylcholine; these cholinergic receptors are subclassified as either nicotinic or muscarinic. The response to cholinergic stimulation is summarized in Table 1-3.

TABLE 1-3 End-Organ Effects of Cholinergic Receptor Stimulation

SNS, Sympathetic nervous system.

6 What are catecholamines? Which catecholamines occur naturally? Which are synthetic?

Catecholamines are hydroxy-substituted phenylethylamines and stimulate adrenergic nerve endings. Norepinephrine, epinephrine, and dopamine are naturally occurring catecholamines, whereas dobutamine and isoproterenol are synthetic catecholamines.

7 Review the synthesis of dopamine, norepinephrine, and epinephrine

The amino acid tyrosine is actively transported into the adrenergic presynaptic nerve terminal cytoplasm, where it is converted to dopamine by two enzymatic reactions: hydroxylation of tyrosine by tyrosine hydroxylase to dopamine and decarboxylation of dopamine by aromatic l-amino acid decarboxylase. Dopamine is transported into storage vesicles, where it is hydroxylated by dopamine β-hydroxylase to norepinephrine. Epinephrine is synthesized in the adrenal medulla from norepinephrine through methylation by phenylethanolamine N-methyltransferase (Figure 1-2).

Figure 1-2 The catecholamine synthetic pathway.

(From http://www.answers.com/topic/epinephrine.)

8 How is norepinephrine metabolized?

Norepinephrine is removed from the synaptic junction by reuptake into the presynaptic nerve terminal and metabolic breakdown. Reuptake is the most important mechanism and allows reuse of the neurotransmitter. The enzyme monoamine oxidase (MAO) metabolizes norepinephrine within the neuronal cytoplasm; both MAO and catecholamine O–methyltransferase (COMT) metabolize the neurotransmitter at extraneuronal sites. The important metabolites are 3-methoxy-4-hydroxymandelic acid, metanephrine, and normetanephrine.

9 Describe the synthesis and degradation of acetylcholine

The cholinergic neurotransmitter acetylcholine (ACh) is synthesized within presynaptic neuronal mitochondria by esterification of acetyl coenzyme A and choline by the enzyme choline acetyltransferase; it is stored in synaptic vesicles until release. After release, ACh is principally metabolized by acetylcholinesterase, a membrane-bound enzyme located in the synaptic junction. Acetylcholinesterase is also located in other nonneuronal tissues such as erythrocytes.

10 What are sympathomimetics?

Sympathomimetics are synthetic drugs with vasopressor and chronotropic effects similar to those of catecholamines. They are commonly used in the operating room to reverse the circulatory depressant effects of anesthetic agents by increasing blood pressure and heart rate; they also temporize the effects of hypovolemia while fluids are administered. They are effective during both general and regional anesthesia.

11 Review the sympathomimetics commonly used in the perioperative environment

Direct-acting sympathomimetics are agonists at the targeted receptor, whereas indirect-acting sympathomimetics stimulate release of norepinephrine. Sympathomimetics may be mixed in their actions, having both direct and indirect effects. Practically speaking, phenylephrine (direct acting) and ephedrine (mostly indirect acting) are the sympathomimetics commonly used perioperatively. Also, epinephrine, dopamine, and norepinephrine may be used perioperatively and most often by infusion since their effects on blood pressure, heart rate, and myocardial oxygen consumption can be profound. Dopamine is discussed in Chapter 15.

12 Discuss the effects of phenylephrine and review common doses of this medication

Phenylephrine stimulates primarily A1 receptors, resulting in increased systemic vascular resistance and blood pressure. Larger doses stimulate A2 receptors. Reflex bradycardia may be a response to increasing systemic vascular resistance. Usual intravenous doses of phenylephrine range between 50 and 200 mcg. Phenylephrine may also be administered by infusion at 10 to 20 mcg/min.

13 Discuss the effects of ephedrine and review common doses of this medication. Give some examples of medications that contraindicate the use of ephedrine and why

Ephedrine produces norepinephrine release, stimulating mostly A1 and B1 receptors; the effects resemble those of epinephrine although they are less intense. Increases in systolic blood pressure, diastolic blood pressure, heart rate, and cardiac output are noted. Usual intravenous doses of ephedrine are between 5 and 25 mg. Repeated doses demonstrate diminishing response known as tachyphylaxis, possibly because of exhaustion of norepinephrine supplies or receptor blockade. Similarly, an inadequate response to ephedrine may be the result of already depleted norepinephrine stores. Ephedrine should not be used when the patient is taking drugs that prevent reuptake of norepinephrine because of the risk of severe hypertension. Examples include tricyclic antidepressants, monoamine oxidase inhibitors, and acute cocaine intoxication. Chronic cocaine users may be catecholamine depleted and may not respond to ephedrine.

14 What are the indications for using β-adrenergic antagonists?

β-Adrenergic antagonists, commonly called β-blockers, are antagonists at β₁– and β₂– receptors. β-blockers are mainstays in antihypertensive, antianginal, and antiarrhythmic therapy. Perioperative β-blockade is essential in patients with coronary artery disease, and atenolol has been shown to reduce death after myocardial infarction.

15 Review the mechanism of action for β₁-antagonists and side effects

β₁-Blockade produces negative inotropic and chronotropic effects, decreasing cardiac output and myocardial oxygen requirements. β₁-Blockers also inhibit renin secretion and lipolysis. Since volatile anesthetics also depress contractility, intraoperative hypotension is a risk. β-Blockers can produce atrioventricular block. Abrupt withdrawal of these medications is not recommended because of up-regulation of the receptors; myocardial ischemia and hypertension may occur. β-Blockade decreases the signs of hypoglycemia; thus it must be used with caution in insulin-dependent patients with diabetes. β-Blockers may be cardioselective, with relatively selective B1 antagonist properties, or noncardioselective. Some β-Blockers have membrane-stabilizing (antiarrhythmic effects); some have sympathomimetic effects and are the drugs of choice in patients with left ventricular failure or bradycardia. β-Blockers interfere with the transmembrane movement of potassium; thus potassium should be infused with caution. Because of their benefits in ischemic heart disease and the risk of rebound, β-blockers should be taken on the day of surgery.

16 Review the effects of β₂-antagonism

β_2-Blockade produces bronchoconstriction and peripheral vasoconstriction and inhibits insulin release and glycogenolysis. Selective β₁-blockers should be used in patients with chronic or reactive airway disease and peripheral vascular disease because of respective concerns for bronchial or vascular constriction.

17 How might complications of β-blockade be treated intraoperatively?

Bradycardia and heart block may respond to atropine; refractory cases may require the β₂-agonism of dobutamine or isoproterenol. Interestingly, calcium chloride may also be effective, although the mechanism is not understood. In all cases expect to use larger than normal doses.

18 Describe the pharmacology of α-adrenergic antagonists

α₁-Blockade results in vasodilation; therefore α-blockers are used in the treatment of hypertension. However, nonselective α-blockers may be associated with reflex tachycardia. Thus, selective α₁-blockers are primarily used as antihypertensives. Prazosin is the prototypical selective α₁-blocker, whereas phentolamine and phenoxybenzamine are examples of nonselective α-blockers. Interestingly, labetalol, a nonselective β-blocker, also has selective α₁-blocking properties and is a potent antihypertensive.

19 Review α₂-agonists and their role in anesthesia

When stimulated, α₂-receptors within the CNS decrease sympathetic output. Subsequently, cardiac output, systemic vascular resistance, and blood pressure decrease. Clonidine is an α₂-agonist used in the management of hypertension. It also has significant sedative qualities. It decreases the anesthetic requirements of inhaled and intravenous anesthetics. It has also been used intrathecally in the hopes of decreasing postprocedural pain, but unacceptable hypotension is common after intrathecal administration, limiting its usefulness. Clonidine should be continued perioperatively because of concerns for rebound hypertension.

20 Discuss muscarinic antagonists and their properties

Muscarinic antagonists, also known as anticholinergics, block muscarinic cholinergic receptors, producing mydriasis and bronchodilation, increasing heart rate, and inhibiting secretions. Centrally acting muscarinic antagonists (all nonionized, tertiary amines with the ability to cross the blood-brain barrier) may produce delirium. Commonly used muscarinic antagonists include atropine, scopolamine, glycopyrrolate, and ipratropium bromide. Administering muscarinic antagonists is a must when the effect of muscle relaxants is antagonized by acetylcholinesterase inhibitors, lest profound bradycardia, heart block, and asystole ensue. Glycopyrrolate is a quaternary ammonium compound, cannot cross the blood-brain barrier, and therefore lacks CNS activity. When inhaled, ipratropium bromide produces bronchodilation.

21 What is the significance of autonomic dysfunction? How might you tell if a patient has autonomic dysfunction?

Patients with autonomic dysfunction tend to have severe hypotension intraoperatively. Evaluation of changes in orthostatic blood pressure and heart rate is a quick and effective way of assessing autonomic dysfunction. If the autonomic nervous system is intact, an increase in heart rate of 15 beats/min and an increase of 10 mm Hg in diastolic blood pressure are expected when changing position from supine to sitting. Autonomic dysfunction is suggested whenever there is a loss of heart rate variability, whatever the circumstances. Autonomic dysfunction includes vasomotor, bladder, bowel, and sexual dysfunction. Other signs include blurred vision, reduced or excessive sweating, dry or excessively moist eyes and mouth, cold or discolored extremities, incontinence or incomplete voiding, diarrhea or constipation, and impotence. Although there are many causes, it should be noted that people with diabetes and chronic alcoholics are patient groups well known to demonstrate autonomic dysfunction.

22 What is a pheochromocytoma, and what are its associated symptoms? How is pheochromocytoma diagnosed?

Pheochromocytoma is a catecholamine-secreting tumor of chromaffin tissue, producing either norepinephrine or epinephrine. Most are intra-adrenal, but some are extra-adrenal (within the bladder wall is common), and about 10% are malignant. Signs and symptoms include paroxysms of hypertension, syncope, headache, palpitations, flushing, and sweating. Pheochromocytoma is confirmed by detecting elevated levels of plasma and urinary catecholamines and their metabolites, including vanillylmandelic acid, normetanephrine, and metanephrine.

23 Review the preanesthetic and intraoperative management of pheochromocytoma patients

These patients are markedly volume depleted and at risk for severe hypertensive crises. It is absolutely essential that before surgery, α-blockade and rehydration should first be instituted. The α₁-antagonist phenoxybenzamine is commonly administered orally. β-Blockers are often administered once α-blockade is achieved and should never be given first because unopposed α₁-vasoconstriction results in severe, refractory hypertension. Labetalol may be the β-blocker of choice since it also has α-blocking properties.

Intraoperatively intra-arterial monitoring is required since fluctuations in blood pressure may be extreme. Manipulation of the tumor may result in hypertension. Intraoperative hypertension is managed by infusing the α-blocker phentolamine or vasodilator nitroprusside. Once the tumor is removed, hypotension is a risk, and fluid administration and administration of the α-agonist phenylephrine may be necessary. Central venous pressure monitoring will assist with volume management.