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Autonomic Nervous System Pharmacology
The autonomic nervous system (ANS) maintains homeostasis by integrating signals from peripheral and central sensors to modulate organ perfusion and function. Autonomic “tone” maintains cardiac muscle, visceral organs, and vascular smooth muscle in a state of intermediate function. From this state, rapid increases or decreases in autonomic outflow can adjust blood flow and organ activity in response to the environment. The rapidity of the ANS response is impressive considering that neurotransmitters must be released from terminals, cross a synaptic cleft to an effector site, bind to a receptor, and initiate an intracellular event. For example, in just a few seconds, ANS activation can double heart rate (HR) and arterial blood pressure (BP). In a nearly similar time frame it can cause sweating, nausea, loss of bladder control, and fainting. The sympathetic nervous system (SNS) has been called the “fight-or-flight” response system and is activated under stress. In contrast, the parasympathetic nervous system is responsible for “rest and digest.” The anatomy and physiology of the ANS are discussed in Chapter 12 .
In the perioperative and intensive care settings, multiple factors disrupt the typically tight ANS control of organ and vascular homeostasis. Thus pharmacologic manipulation of the ANS is commonplace in these settings. For example, both general and regional anesthesia have powerful influences on normal ANS function. When an inhaled anesthetic acts to directly relax vascular smooth muscle and lower BP, the ANS reacts to counteract hypotension via baroreflex adjustments of ANS activity. However, a second effect of volatile anesthetics is to impair baroreflex function. The net effect of these influences requires treatment of unwanted hypotension with sympathomimetic or vagolytic drugs. Laryngoscopy and tracheal intubation or surgical incision powerfully activate the SNS; adrenergic receptor blocking drugs are used to dampen these responses.
Historical Perspective
The sympathomimetic properties of the ma huang plant were appreciated in China as early as 3000 bc . Ma huang was used as a diaphoretic, circulatory stimulant, antipyretic, and sedative for cough. Ephedrine, the main alkaloid of ma huang, was isolated in 1886. Over the next 25 years, adrenal extracts were described and analyzed and the term sympathomimetic was coined. Adrenergic receptors were identified and subdivided into two primary types (α and β) according to their responses to epinephrine and norepinephrine. The β receptors were further divided into β 1 , β 2 , and β 3 receptors based on their actions at receptors and sensitivities to inhibitors. The α receptors were similarly subdivided into α 1 andα 2 receptors, but they have been further subdivided into α 1a , α 1b , α 1d , α 2a , α 2b , and α 2c receptors based on their pharmacology and associated second-messenger systems.
The history of parasympatholytic drugs dates back to ancient times when Mandragora , the mandrake plant, was used for wounds and sleeplessness. Henbane, which contains atropine, was used in ancient Egyptian times as a mydriatic. In the Middle Ages, henbane extract was used to enhance the inebriating qualities of beer and by “witches” to produce flushed skin and vivid hallucinations.
Muscarine, the first parasympathomimetic drug, derives from the fungus Amanita muscaria and was described in 1869. It was found to bind receptors that would be called muscarinic and had the same effect on the heart as did stimulation of the vagus nerve. Originally discovered by Loewi, the “heart-inhibiting” substance that decreased HR and contractility was acetylcholine (ACh). Muscarinic receptors are activated by ACh and are thus called cholinergic .
Structure and Mechanism of Adrenergic Receptors
The basic catecholamine structure consists of an aromatic phenylethylamine with two hydroxyl groups. The name catecholamine derives from the molecule 3,4-dihydroxylphenyl, known as catechol . Epinephrine and norepinephrine have a chiral center at the hydroxyl group on the β- carbon, where the L-isomer is active, while dopamine has no chiral center ( Fig. 14.1 ). Intravenous formulations of epinephrine and norepinephrine consist of the L-isomer; a racemic formulation of epinephrine is available for inhalation.
Epinephrine and norepinephrine are predominantly charged molecules at physiologic pH owing to their amine moiety and are unable to cross lipid cellular membranes on their own (although they can cross via transporters). Their actions are mediated following signal transduction by transmembrane receptors that initiate intracellular signaling events. Adrenergic receptors are coupled to guanine nucleotide binding proteins (G proteins) that couple the receptor to an effector system (see Chapter 1 ). Adrenergic G-protein–coupled receptors (GPCRs) are classified according to their actions on adenylyl cyclase and their sensitivity to pertussis toxin. The structure of the β-adrenergic receptor is consistent with most GPCRs, with seven transmembrane segments. The signaling cascade of β 1 - andβ 2 -adrenergic receptors begins with ligand binding to the amino terminus of the receptor on the extracellular surface, then proceeds to the intracellular carboxyl terminal loop of the receptor coupling to G s -proteins, which stimulate adenylyl cyclase to convert adenosine triphosphate (ATP) to the second-messenger cyclic adenosine monophosphate (AMP). The resulting phosphorylation by cyclic AMP (cAMP)-dependent protein kinase produces cellular responses. The atomic resolution structure of the β 2 -receptor bond to G s has recently been determined and shows the involvement of the amino- and carboxy-terminal alpha helices of G s as the main interaction between the two proteins. The activated receptor demonstrates outward movement of the sixth transmembrane segment and the presence of a second intracellular loop between the β 2 -adrenergic receptor/G s complex. The receptor is stabilized extracellularly by fusion of the amino terminus to T4 lysozyme, and intracellularly by numerous interactions with G s . The Gβ and Gγ subunits of G s do not directly interact with the β 2 -adrenergic receptor.
The α 2 receptors are coupled to G i -proteins to inhibit adenylyl cyclase. The α 1 receptors are coupled to G q -proteins activating phospholipase C that hydrolyzes phosphatidylinositol diphosphates (PIP 2 ) to the second messengers inositol trisphosphate (IP 3 ) and diacylglycerol (DAG). IP 3 activates calcium ion (Ca 2+ ) release from intracellular stores via IP 3 receptors, while DAG activates lipid mediated signaling pathways including members of the protein kinase C family.
Dopamine receptors also are GPCRs and are classified as D1-type (D1 and D5) and D2-type (D2, D3, and D4) receptors. These receptors are located throughout the central nervous system (CNS), on SNS postganglionic nerve terminals, on afferent and efferent arterioles of the nephron, and in the adrenal glands. D1-like receptors stimulate adenylyl cyclase via G s , and D2-like receptors inhibit adenylyl cyclase via G i . D1-receptors are postsynaptic and stimulation mimics β 2 effects, leading to regional vascular dilation. D2-like receptors occur at presynaptic and postsynaptic sites. Presynaptic D2-like receptor activation inhibits norepinephrine release from sympathetic terminals, an effect similar to the presynaptic effects of ACh and α 2 -agonists. Postsynaptic sites mimic α1 and α 2 vasoconstriction on blood vessels, but this action is relatively weak.
The α 1 adrenoceptors are activated by the selective α 1 -receptor agonists phenylephrine and methoxamine and are inhibited by low concentrations of the antagonist prazosin. The α 1 -receptors are widely distributed, and when stimulated mediate primarily arterial and venous vascular constriction ( Table 14.1 ). The α 2 -adrenoceptors are activated by the selective α 2 -receptor agonists clonidine and dexmedetomidine and are blocked by the antagonist yohimbine; they exist as three subtypes: α 2a , α 2b , and α 2c . The α 2 receptors are located presynaptically on sympathetic neurons where they inhibit the release of norepinephrine. Postsynaptic α 2 receptors are located on blood vessels and in tissues, including liver, pancreas, platelets, kidney, adipose tissue, and the eye ( Fig. 14.2 ). Within the CNS, receptors in the locus coeruleus likely account for the sedative properties of α 2 agonists, and receptors in the medullary dorsal horn area for the reduction in sympathetic outflow. The α 2 receptors are also on the vagus nerve and in the intermediolateral cell column and the substantia gelatinosa. The dorsal horn of the spinal cord contains α 2a adrenoceptors colocalized with opioid receptors that modulate afferent pain signals.
TABLE 14.1
Relative Adrenergic Drug Effects on Peripheral Resistance and Capacitance Vessels a
| VASOCONSTRICTION | ||
|---|---|---|
| α 1 Arterial | α 1 Venous | |
| Norepinephrine | +++++ | +++++ |
| Phenylephrine | ++++ | +++++ |
| Epinephrine | 0/++++ b | 0/++++ b |
| Dopamine | 0/++++ c | +++ |
| Methoxamine, metaraminol | +++++ | ++++ |
| Ephedrine | ++ | +++ |
| Dobutamine | +/0 | ? |
| Isoproterenol | 0 | 0 |
a Drugs are listed in descending order of potency within each vascular region.
b Dose-dependent; β effects of epinephrine predominate at low doses.
c Dose-dependent; dopamine and β effects predominate at low doses.
Both β 1 - and β 2 -adrenergic receptors are characterized by their stimulation by epinephrine and norepinephrine and are heavily expressed in myocardial tissue, including atria, ventricular papillary muscle, sinoatrial and atrioventricular nodes, left and right bundles, and Purkinje fibers. They have inotropic (increased contractility), chronotropic (increased HR), and dromotropic (increased conduction velocity) effects ( Fig. 14.3 ). Activation of β 1 receptors increases renin and aqueous humor production. The β 2 -receptors are the major β receptors in arterioles and the only β receptors in the vena cava, aorta, and pulmonary artery. Activation of β 2 receptors leads to uterine smooth muscle relaxation and relaxation of vascular smooth muscle, including splanchnic, muscular, and renal vasculature, resulting in a reduction in diastolic pressure and decreases in systemic vascular resistance. Activation of β 2 adrenoceptors causes relaxation of bronchial smooth muscle and increased liver glycogenolysis. β 2 Receptor activation also reduces the plasma [potassium ion (K + ) concentration by promoting uptake into skeletal muscle and reducing aldosterone secretion, leading to renal losses of K + (see Fig. 14.3 ). The β 3 receptors are expressed in visceral adipocytes, gallbladder, and colon. Their activation mediates lipolytic and thermogenesis in brown and white adipose tissue.
Endogenous Catecholamines
The biosynthesis of the naturally occurring catecholamines (epinephrine, norepinephrine, and dopamine) begins with the conversion of tyrosine to 3,4-dihydroxyphenylalanine (DOPA) (see Fig. 14.1 ). The rate-limiting step in catecholamine synthesis is conversion of tyrosine to DOPA by the enzyme tyrosine hydroxylase.
Epinephrine
Epinephrine, also known as adrenaline, is an endogenous monoamine with broad clinical applications. Epinephrine is present in chromaffin cells in the adrenal medulla, where it is synthesized, stored, and released upon sympathetic stimulation. On average, 80% of the secreted catecholamine in the adrenal medulla is epinephrine and 20% is norepinephrine. The normal resting rate of secretion by the adrenal medulla is about 0.2 µg/kg per minute of epinephrine and about 0.05 µg/kg per minute of norepinephrine. These rates are sufficient to support arterial BP fully if the SNS is denervated. Because of slow removal from the circulation, the effects of secreted epinephrine and norepinephrine on organ function last 5 to 10 times longer than the effect from a burst of sympathetic activity to an organ or vascular bed. Epinephrine has a large β-receptor effect that increases cardiac function (i.e., HR and contractility) far more than norepinephrine ( Table 14.2 ). The β-receptor effect also constricts precapillary blood vessels and large veins. Epinephrine has a weaker effect on blood vessels in skeletal muscle than norepinephrine because of the greater affinity of epinephrine for β 2 - (relaxation) than α 1 -receptors (contraction). The β effects of epinephrine can increase the metabolic rate to twice normal and promote glycogenolysis in liver and muscle, thereby raising blood glucose levels.
TABLE 14.2
Relative Potency of Common, Naturally Occurring, and Synthetic Adrenergic Agonists
| Sympathomimetics | RECEPTORS | Dose Dependence a | |||||
|---|---|---|---|---|---|---|---|
| α 1 | α 2 | β 1 | β 2 | D1 | D2 | ||
| Phenylephrine | +++++ | ? | ± | 0 | 0 | ++ | |
| Norepinephrine | +++++ | +++++ | +++ | 0 | 0 | +++ | |
| Epinephrine | ++++ | +++ | ++++ | ++ | 0 | ++++ | |
| Ephedrine | ++ | ? | ++++ | ++ | 0 | ++ | |
| Dopamine | + to +++++ | ? | ++++ | ++ | +++ | ? | +++++ |
| Dobutamine b | 0 to + | ? | ++++ | ++ | 0 | ++ | |
| Isoproterenol | 0 | 0 | +++++ | +++++ | 0 | 0 | |
| Dexmedetomidine | + | +++++ | 0 | 0 | 0 | ||
| Clonidine | ++ | +++++ | 0 | 0 | 0 | ||
| Fenoldopam | 0 | 0 | 0 | 0 | +++++ | ||
b Dobutamine is a racemic mixture; (−)dobutamine is a potent α 1 agonist, and (+)dobutamine is a potent α 1 antagonist, reducing its net vascoconstrictor effect.
Infusions of epinephrine have dose-dependent actions at α and β receptors. Low doses (2–10 µg/min) predominantly stimulate β 1 and β 2 receptors (see Table 14.2 ). At higher doses of epinephrine (>10 µg/min), α receptors are activated, leading to vasoconstriction of the skin, mucosa, and renal vascular beds. Blood flow redistribution occurs away from these circulations, reversing many of the β 2 effects to vasodilate. Further stimulation of α receptors decreases skeletal muscle and splanchnic blood flow and inhibits insulin secretion.
Epinephrine has broad clinical effects and its use has often been supplanted by more selective synthetic adrenergic agonists. However, epinephrine is still commonly added to local anesthetics to prolong their duration of action. Epinephrine is also indicated in anaphylactic shock, localized bleeding, bronchospasm, and stridor related to laryngotracheal edema. Subcutaneous doses of 0.2 to 0.5 mg can be used in early anaphylaxis to stabilize mast cells and reduce degranulation. Epinephrine also stimulates cellular K + uptake via β 2 receptors and for short periods can be used to treat life-threatening hyperkalemia.
Norepinephrine
Norepinephrine is the principal endogenous mediator of SNS activity secreted from postganglionic terminals to act on adrenergic effector organs. Intravenous administration (4–12 µg/min) results in dose-dependent hemodynamic effects on α 1 and β adrenoceptors (see Table 14.2 ). Compared with the effects of epinephrine, norepinephrine has a greater effect at α 1 -receptors and no effect on β 2 receptors, thereby creating greater arterial and venous vascular constriction than epinephrine (see Table 14.1 ). In lower doses, β 1 actions predominate, and BP increases due to augmented cardiac output. Larger doses of norepinephrine stimulate the α 1 receptors and result in arterial and venous smooth muscle contraction in hepatic, skeletal muscle, splanchnic, and renal vascular systems. At these larger doses, HR and cardiac output can decrease via baroreflex mechanisms.
Intravenous administration of norepinephrine is most often used therapeutically for treatment of profound vasodilation, as in septic shock unresponsive to fluid administration. It increases BP, left ventricular stroke work index, cardiac output, and urine output. When given to patients already exhibiting marked vasoconstriction, further increases in vascular resistance can lead to compromised limb and organ blood flow, resulting in ischemia. Norepinephrine is less arrhythmogenic than epinephrine. Its effect on pulmonary α 1 receptors combined with its effect to increase venous return can result in pulmonary hypertension and right heart failure. To minimize this effect during open heart surgery, it can be given directly into the left atrium along with a selective pulmonary vasodilator such as prostaglandin E 1 .
Dopamine
Dopamine is an endogenous catecholamine that is also involved in central and peripheral neural transmission. Dopamine is synthesized from tyrosine and is the immediate precursor to norepinephrine (see Fig. 14.1 ). Parenteral administration of dopamine does not cross into the CNS; therapy of Parkinson disease requires use of the precursor L-DOPA that can cross the blood-brain barrier. When dopamine is used for hemodynamic support and maintenance of adequate perfusion during shock, it must be given via continuous infusion because of rapid metabolism. At low infusion rates (1–3 µg/kg per minute), vasodilation of coronary, renal, and mesenteric vasculature occurs and renal blood flow, glomerular filtration, and Na + excretion increase owing to D1-like receptor agonism (see Fig. 14.2 ). Although this “renal dose” of dopamine was purported to improve kidney function in patients at risk for acute renal failure, meta-analysis has failed to show improvement in renal dysfunction or mortality. At doses of 3 to 10 µg/kg per minute, β 1 -receptor stimulation leads to positive inotropic and chronotropic effects, and at presynaptic terminals promotes the release and inhibits the reuptake of norepinephrine. At higher doses (>10 µg/kg), α 1 -receptor activation causes peripheral vasoconstriction and can reduce renal blood flow.
Metabolism of Catecholamines
The catecholamines are metabolized by catechol- O- methyltransferase (COMT) and monoamine oxidase (MAO). COMT is an intracellular enzyme located in postsynaptic neurons. MAO is concentrated in the mitochondria of nerve terminals, resulting in a constant turnover of norepinephrine even in the resting nerve terminal. Metabolites can be detected in urine as metanephrines or vanillylmandelic acid. Urine collections and analysis can be useful to follow progress in treatment of pheochromocytoma. There are two primary termination routes for norepinephrine released from nerve terminals: simple diffusion (and metabolism in plasma, kidney, or liver) and reuptake into noradrenergic nerve terminals (which can be blocked by cocaine and most tricyclic antidepressants). Synthetic sympathomimetic drugs that mimic endogenous catecholamines can have longer durations of action because of their resistance to metabolism by MAO or COMT.
Synthetic Catecholamine-Like Drugs
Synthetic catecholamines, which are also included as sympathomimetic drugs, are a mainstay of critical care and perioperative medicine for support of the circulation. Depending on their selectivity and potency for different subtypes of α, β, and dopamine receptors, their route of administration, their lipid solubility, and their metabolism, sympathomimetic drugs can be used to achieve a variety of clinical effects. Certain drugs also have indirect sympathomimetic action; these include ephedrine, tyramine, and the amphetamines. They cause release of norepinephrine from its storage vesicles in the sympathetic nerve endings, thereby increasing synaptic concentration and postsynaptic effects.
D1-Receptor Agonists
Fenoldopam is a synthetic, selective D1-agonist without significant D2-, α-adrenergic, or β 2 -adrenergic effects (see Table 14.2 and Fig. 14.2 ). It is 10-fold more potent than dopamine at the D1 receptor. The principal use of fenoldopam is to manage hypertension in doses of 0.1 to 0.8 µg/kg per minute, with upward titration in 0.1-µg/kg per minute steps as needed. A low-dose infusion of fenoldopam (~0.1–0.2 µg/kg per minute) produces renal vasodilation and increases renal blood flow, glomerular filtration rate, and Na + excretion without changes in systemic BP. A renal protective effect has been observed in aortic and cardiac surgery involving cardiopulmonary bypass. When compared with dopamine in acute early renal dysfunction, fenoldopam is more effective at reversing renal hypoperfusion. A meta-analysis indicated that fenoldopam reduces both the need for renal replacement therapy and in-hospital death in cardiovascular surgery.
α 1 -Receptor Agonists
Agonists of α 1 adrenoceptors exert vasoconstrictor actions on arteries and veins, leading to BP increase and redistribution of blood flow (see Fig. 14.2 ). In healthy individuals, cardiac output is maintained because of increased preload. HR typically slows via the baroreflex response to increased BP. Myocardial blood flow and oxygen delivery can be improved owing to the longer diastolic filling time from the lower HR and from improved diastolic coronary blood flow because of the increased aortic BP. In patients with impaired ventricular function, increases in afterload can impair myocardial function. Topical use of α 1 agonists can be used for vasoconstriction (e.g., on nasal mucosa).
Phenylephrine
The effects of phenylephrine were described in the 1930s, and it was first used to maintain BP during spinal anesthesia. It is a nearly pure α 1 -selective agonist, only affecting β receptors at very high doses (see Table 14.2 ). It has similar potency to norepinephrine for α 1 receptors but has a longer duration of action. Phenylephrine produces greater venoconstriction than arterial vasoconstriction and therefore increases venous return and stroke volume. Cardiac output typically does not change owing to baroreflex slowing of HR. Phenylephrine can be useful as a bolus or continuous infusion for treatment of hypotension, and can be used to reverse unwanted right-to-left shunt in tetralogy of Fallot. Newer evidence suggests that phenylephrine is not detrimental to fetal oxygen delivery in pregnant patients who are hypotensive after neuraxial blockade. However, although not harmful, it still might be inferior to ephedrine in maintaining placental blood flow during cesarean delivery. A 0.25%, 0.5%, or 1% phenylephrine solution can be used topically as a nasal decongestant; 2.5% or 10% phenylephrine solutions are used to produce mydriasis when administered into the eye. Both these routes can raise BP. Rarely more serious side effects such as pulmonary edema and adverse cardiac events result. Thus α 1 -adrenergic antagonists, such as phentolamine or tolazoline, or direct vasodilating drugs, such as hydralazine or nicardipine, should be available. β-Blockers are contraindicated to treat a hypertensive crisis from phenylephrine (such as an accidental overdose). β-Blockers in this situation can reduce myocardial contractility and produce acute pulmonary edema in the face of high afterload.
Methoxamine
First described in 1948 and used to maintain BP during spinal anesthesia, methoxamine has a longer duration of action, more arterial vasoconstriction, and less venoconstriction compared with phenylephrine. It is not typically used to support BP acutely because it can increase afterload and has a long half-life. Doses of 1 to 5 mg every 15 minutes are described. Untoward hypertension can occur following its use to treat regional anesthetic-induced hypotension because sympathetic tone returns as the spinal anesthetic recovers before the action of methoxamine dissipates.
Midodrine
Midodrine is an orally absorbed α 1 agonist with a half-life of about 3 hours and duration of action of 4 to 6 hours. It is used to treat dialysis-related hypotension or autonomic failure resulting in postural hypotension, but hypertension is a possible effect when patients are supine.
α 2 Receptor Agonists
Agonists of α 2 receptors such as clonidine were originally used as antihypertensive agents because of their central effect to decrease sympathetic outflow from the CNS and to reduce presynaptic norepinephrine release. The α 2 receptor mediates sedation and hypnosis, sympatholysis, neuroprotection, diuresis, and inhibition of insulin and growth hormone secretion. Rapid intravenous administration of α 2 agonists such as dexmedetomidine can transiently increase BP through vasoconstriction at postsynaptic α 2b receptors on arteries and veins. This receptor subtype might also account for their antishivering effect. Postsynaptic α 2 receptors exist in a number of other tissues and organs, including liver, pancreas, platelets, kidney, fat, and eye (see Fig. 14.2 ).
Within the CNS, a large density of α 2 receptors is located in the medullary dorsal motor complex and in the locus coeruleus. The locus coeruleus is an important modulator of wakefulness and the major site of the sedative/hypnotic actions of the α 2 agonists. Among the many desirable properties of α 2 agonists that promote their use in the perioperative period are anxiolysis, sedation, reductions in minimal alveolar concentration (MAC) of volatile anesthetics, reduced chest wall rigidity from opioids, reduction in intraoperative BP variability from intubation, extubation and surgical stress response, and reductions in postanesthetic shivering. A meta-analysis found that α 2 -receptor agonists reduce perioperative cardiac mortality and ischemia, a benefit likely attributable to reduced sympathetic outflow and reduced shivering. Side effects include sedation, dry mouth, and bradycardia via reduced sympathetic “tone” and a slight vagomimetic effect. It is likely that some of the effects from α 2 -receptor agonists are from actions at nonadrenergic imidazoline receptors.
Clonidine
Clonidine, first synthesized in the 1960s, has an onset time after oral administration of 30 to 60 minutes, with a half-life of 6 to 24 hours. The α 2 -:α 1 -receptor affinity is ~220 : 1 ( Table 14.3 ). It is available in 100-, 250-, and 300-µg tablets for oral administration, a transdermal patch releasing 150 to 200 µg over 24 hours, and an injectable solution of 150 µg/mL. Oral dosing is typically every 8 hours. Clonidine should not be withheld before surgery because acute withdrawal can result in rebound hypertension. Neuraxial administration can be used to lessen the requirement for opioids when treating acute and chronic pain. Epidural clonidine is indicated for treatment of severe cancer pain (0.5 µg/kg per hour). When given in this manner, bradycardia and sedation can occur but respiratory drive is maintained. Clonidine also is beneficial in the treatment of opioid withdrawal in an intensive care unit (ICU) setting.
TABLE 14.3
Classification of α-Receptors and the Relative α1/α2 Selectivity
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