Joel O. Johnson
Noel W. Lawson
1. The autonomic nervous system (ANS) includes that part of the central and peripheral nervous system concerned with involuntary regulation of cardiac muscle, smooth muscle, glandular, and visceral functions.
2. The sympathetic and parasympathetic nervous systems (SNS, PNS) affect cardiac pump function in three ways: (1) by changing the rate (chronotropism), (2) by changing the strength of contraction (inotropism), and (3) by modulating coronary blood flow.
3. SNS nerves are by far the most important regulators of the peripheral circulation.
4. The ANS can be pharmacologically subdivided by the neurotransmitter secreted at the effector cell: acetylcholine (ACh) released by the PNS and the catecholamines epinephrine (EPI) and norepinephrine (NE) are considered the mediators of peripheral SNS activity.
5. An agonist is a substance that interacts with a receptor to evoke a biologic response. An antagonist is a substance that interferes with the evocation of a response at a receptor site by an agonist.
6. The adrenergic receptors are termed adrenergic or noradrenergic, depending on their responsiveness to epinephrine or norepinephrine.
7. The numbers and sensitivity of adrenergic receptors can be influenced by normal, genetic, and developmental factors.
8. The autonomic nervous system reflex has (1) sensors, (2) afferent pathways, (3) central nervous system integration, and (4) efferent pathways to the receptors and efferent organs.
9. The clinical application of ANS pharmacology is based on knowledge of ANS anatomy, physiology, and molecular pharmacology.
10. Clinically, anticholinesterase drugs may be divided into two types: the reversible and nonreversible cholinesterase inhibitors.
11. The net physiologic effect of a sympathomimetic is usually defined by the relative actions on the α, β, and dopamine receptors.
12. Dexmedetomidine is a more selective α2 agonist than clonidine.
13. Drugs that bind selectively to α-adrenergic receptors block the action of endogenous catecholamines or moderate the effects of exogenous adrenergics.
14. Calcium channel blockers are not true pharmacologic antagonists of calcium. They interact with the cell membrane to control the intracellular concentration of calcium.
Anesthesia and the Autonomic Nervous System
Anesthesiology is the practice of autonomic medicine. Drugs that produce anesthesia also produce potent autonomic side effects. The greater part of our training and practice is spent acquiring skills in averting or using the autonomic nervous system (ANS) side effects of anesthetic drugs under a variety of pathophysiologic conditions. The success of any anesthetic depends on how well homeostasis is maintained. The numbers that we faithfully record during the course of anesthesia reflect ANS function.
The ANS includes that part of the central and peripheral nervous system concerned with involuntary regulation of cardiac muscle, smooth muscle, glandular, and visceral functions. ANS activity refers to visceral reflexes that function below the conscious level. The ANS is also responsive to changes in somatic motor and sensory activities of the body. The physiologic evidence of visceral reflexes as a result of somatic events is abundantly clear. The ANS is therefore not as distinct an entity as the term suggests. Neither somatic nor ANS activity occurs in isolation.1 The ANS organizes visceral support for somatic behavior and adjusts body states in anticipation of emotional behavior or responses to the stress of disease (i.e., fight or flight).
Afferent fibers from visceral structures are the first link in the reflex arcs of the ANS whether relaying visceral pain or changes in vessel stretch. Most ANS efferent fibers are accompanied by sensory fibers that are now commonly recognized as components of the ANS. However, the afferent components of the ANS cannot be as distinctively divided, as can the efferent nerves. ANS visceral sensory nerves are anatomically indistinguishable from somatic sensory nerves. The clinical importance of visceral afferent fibers is more closely associated with chronic pain management.
The ANS falls into two divisions by anatomy, physiology, and pharmacology. Langley divided this nervous system into two parts in 1921. He retained the term sympathetic nervous system (SNS) introduced by Willis in 1665 for the first part and introduced the term parasympathetic (parasympathetic nervous system, PNS) for the second. The term autonomic nervous system was adopted as a comprehensive name for both. Table 15-1 lists the complementary effects of SNS (adrenergic, sympathetic) and PNS (cholinergic, parasympathetic) activity of organ systems.
Central Autonomic Organization
Pure central ANS or somatic centers are not known. Integration of ANS activity occurs at all levels of the cerebrospinal axis. Efferent ANS activity can be initiated locally and by centers located in the spinal cord, brainstem, and hypothalamus. The cerebral cortex is the highest level of ANS integration. Fainting at the sight of blood is an example of this higher level of somatic and ANS integration. ANS function has also been
successfully modulated through conscious, intentional efforts demonstrating that somatic responses are always accompanied by visceral responses and vice versa.
Table 15-1 Homeostatic Balance Between Adrenergic and Cholinergic Effects
Figure 15-1. Schematic distribution of the craniosacral (parasympathetic) and thoracolumbar (sympathetic) nervous systems. Parasympathetic preganglionic fibers pass directly to the organ that is innervated. Their postganglionic cell bodies are situated near or within the innervated viscera. This limited distribution of parasympathetic postganglionic fibers is consistent with the discrete and limited effect of parasympathetic function. The postganglionic sympathetic neurons originate in either the paired sympathetic ganglia or one of the unpaired collateral plexuses. One preganglionic fiber influences many postganglionic neurons. Activation of the sympathetic nervous system produces a more diffuse physiologic response rather than discrete effects.
The principal site of ANS organization is the hypothalamus. SNS functions are controlled by nuclei in the posterolateral hypothalamus. Stimulation of these nuclei results in a massive discharge of the sympathoadrenal system. PNS functions are governed by nuclei in the midline and some anterior nuclei of the hypothalamus. The anterior hypothalamus is involved with regulation of temperature. The supraoptic hypothalamic nuclei regulate water metabolism and are anatomically and functionally associated with the posterior lobe of the pituitary (see “Interaction of Autonomic Nervous System Receptors”). This hypothalamic-neurohypophyseal connection represents a central ANS mechanism that affects the kidney by means of antidiuretic hormone. Long-term blood pressure control, reactions to physical and emotional stress, sleep, and sexual reflexes are regulated through the hypothalamus.
The medulla oblongata and pons are the vital centers of acute ANS organization. Together they integrate momentary hemodynamic adjustments and maintain the sequence and automaticity of ventilation. Integration of afferent and efferent ANS impulses at this central nervous system (CNS) level is responsible for the tonic activity exhibited by the ANS. Tonicity holds visceral organs in a state of intermediate activity that can either be diminished or augmented by altering the rate of nerve firing. The nucleus tractus solitarius, located within the medulla, is the primary area for relay of afferent chemoreceptor and baroreceptor information from the glossopharyngeal and vagus nerves. Increased afferent impulses from these two nerves inhibits peripheral SNS vascular tone, producing vasodilation and increasing vagal tone, producing bradycardia. Studies of patients with high spinal cord lesions show that a number of reflex changes are mediated at the spinal or segmental level. ANS hyperreflexia is an example of spinal cord mediation of ANS reflexes without integration of function from higher inhibitory centers.1
Peripheral Autonomic Nervous System Organization
The peripheral ANS is the efferent (motor) component of the ANS and consists of the same two complementary parts, the SNS and the PNS. Most organs receive fibers from both divisions (Fig. 15-1). In general, activities of the two systems produce opposite but complementary effects (Table 15-1). A few tissues, such as sweat glands and spleen, are innervated only by SNS fibers. Although the anatomy of the somatic and ANS sensory pathways is identical, the motor pathways are characteristically different. The efferent somatic motor system, like somatic afferents, is composed of a single (unipolar) neuron with its cell body in the ventral gray matter of the spinal cord. Its myelinated axon extends directly to the voluntary striated muscle unit. In contrast, the efferent (motor) ANS is a two-neuron (bipolar) chain from the CNS to the effector organ. The first neuron of both the SNS and PNS originates within the CNS but does not make direct contact with the effector organ. Instead, it relays the impulse to a second station known as an ANS ganglion, which contains the cell body of the second ANS (postganglionic) neuron. Its axon contacts the effector organ. Thus, the motor pathways of both divisions of the ANS are schematically a serial, two-neuron chain consisting of a preganglionic neuron and a postganglionic effector neuron (Fig. 15-2).
Preganglionic fibers of both subdivisions are myelinated with diameters of <3 mm.1 Impulses are conducted at a speed of 3 to 15 m/s. The postganglionic fibers are unmyelinated and conduct impulses at slower speeds of <2 m/s. They are similar
to unmyelinated visceral and somatic afferent C fibers (Table 15-2). Compared with the myelinated somatic nerves, the ANS conducts impulses at speeds that preclude its participation in the immediate phase of a somatic response.
Figure 15-2. Schematic diagram of the efferent autonomic nervous system. Afferent impulses are integrated centrally and sent reflexly to the adrenergic and cholinergic receptors. Sympathetic fibers ending in the adrenal medulla are preganglionic, and acetylcholine (ACh) is the neurotransmitter. Stimulation of the chromaffin cells, acting as postganglionic neurons, releases epinephrine (EPI) and norepinephrine (NE).
Sympathetic Nervous System
The efferent SNS is referred to as the thoracolumbar nervous system. Figure 15-1 demonstrates the distribution of the SNS and its innervation of visceral organs. The preganglionic fibers of the SNS (thoracolumbar division) originate in the intermediolateral gray column of the 12 thoracic (T1 through T12) and the first three lumbar segments (L1 through L3) of the spinal cord. The myelinated axons of these nerve cells leave the spinal cord with the motor fibers to form the white (myelinated) communicating rami (Fig. 15-3). The rami enter one of the paired 22 sympathetic ganglia at their respective segmental levels. On entering the paravertebral ganglia of the lateral sympathetic chain, the preganglionic fiber may follow one of three courses: (1) synapse with postganglionic fibers in ganglia
at the level of exit, (2) course upward or downward in the trunk of the SNS chain to synapse in ganglia at other levels, or (3) track for variable distances through the sympathetic chain and exit without synapsing to terminate in an outlying, unpaired, SNS collateral ganglion (Fig. 15-3). The adrenal gland is an exception to the rule. Preganglionic fibers pass directly into the adrenal medulla without synapsing in a ganglion (Fig. 15-2). The cells of the medulla are derived from neuronal tissue and are analogous to postganglionic neurons.
Table 15-2 Classification of Nerve Fibers
Figure 15-3. The spinal reflex arc of the somatic nerves is shown on the left. The different arrangements of neurons in the sympathetic system are shown on the right. Preganglionic fibers coming out through white rami may make synaptic connections following one of three courses: (1) synapse in ganglia at the level of exit, (2) course up or down the sympathetic chain to synapse at another level, or (3) exit the chain without synapsing to an outlying collateral ganglion.
The sympathetic postganglionic neuronal cell bodies are located in ganglia of the paired lateral SNS chain or unpaired collateral ganglia in more peripheral plexuses. Collateral ganglia, such as the celiac and inferior mesenteric ganglia (plexus), are formed by the convergence of preganglionic fibers with many postganglionic neuronal bodies. SNS ganglia are almost always located closer to the spinal cord than to the organs they innervate. The sympathetic postganglionic neuron can therefore originate in either the paired lateral paravertebral SNS ganglia or one of the unpaired collateral plexus. The unmyelinated postganglionic fibers then proceed from the ganglia to terminate within the organs they innervate. Many of the postganglionic fibers pass from the lateral SNS chain back into the spinal nerves, forming the gray (unmyelinated) communicating rami at all levels of the spinal cord (Fig. 15-2). They are distributed distally to sweat glands, pilomotor muscle, and blood vessels of the skin and muscle. These nerves are unmyelinated C type fibers (Table 15-2) and are carried within the somatic nerves. Approximately 8% of the fibers in the average somatic nerve are sympathetic.
The first four or five thoracic spinal segments generate preganglionic fibers that ascend in the neck to form three special paired ganglia. These are the superior cervical, middle cervical, and cervicothoracic ganglia. The last is known as the stellate ganglion and is actually formed by the fusion of the inferior cervical and first thoracic SNS ganglia. These ganglia provide sympathetic innervation of the head, neck, upper extremities, heart, and lungs. Afferent pain fibers also travel with these nerves, accounting for chest, neck, or upper extremity pain with myocardial ischemia.
Activation of the SNS produces a diffused physiologic response (mass reflex) rather than discrete effects. SNS postganglionic neurons outnumber the preganglionic neurons in an average ratio of 20:1 to 30:1.2 One preganglionic fiber influences a larger number of postganglionic neurons, which are dispersed to many organs.
Parasympathetic Nervous System
The PNS, like the SNS, has both preganglionic and postganglionic neurons. The preganglionic cell bodies originate in the brainstem and sacral segments of the spinal cord. PNS preganglionic fibers are found in cranial nerves III (oculomotor), VII (facial), IX (glossopharyngeal), and X (vagus). The sacral outflow originates in the intermediolateral gray horns of the second, third, and fourth sacral nerves. Figure 15-1 shows the distribution of the PNS division and its innervation of visceral organs.
The vagus (cranial nerve X) nerve has the most extensive distribution of all the PNS, accounting for more than 75% of PNS activity. The paired vagus nerves supply PNS innervation to the heart, lungs, esophagus, stomach, small intestine, proximal half of the colon, liver, gallbladder, pancreas, and upper portions of the ureters. The sacral fibers form the pelvic visceral nerves, or nervi erigentes. These nerves supply the remainder of the viscera that are not innervated by the vagus. They supply the descending colon, rectum, uterus, bladder, and lower portions of the ureters, and are primarily concerned with emptying. Various sexual reactions are also governed by the sacral PNS. The PNS is responsible for penile erection, but SNS stimulation governs ejaculation.
In contrast to the SNS division, PNS preganglionic fibers pass directly to the organ that is innervated. The postganglionic cell bodies are situated near or within the innervated viscera and generally are not visible. The proximity of PNS ganglia to or within the viscera provides a limited distribution of postganglionic fibers. The ratio of postganglionic to preganglionic fibers in many organs appears to be 1:1 to 3:1 compared with the 20:1 found in the SNS system. Auerbach's plexus in the distal colon is the exception, with a ratio of 8,000:1. The fact that PNS preganglionic fibers synapse with only a few postganglionic neurons is consistent with the discrete and limited effect of PNS function. For example, vagal bradycardia can occur without a concomitant change in intestinal motility or salivation. Mass reflex action is not a characteristic of the PNS. The effects of organ response to PNS stimulation are outlined in Table 15-1.
The heart is well supplied by the SNS and PNS. These nerves affect cardiac pump function in three ways: (1) by changing the rate (chronotropism), (2) by changing the strength of contraction (inotropism), and (3) by modulating coronary blood flow. The PNS cardiac vagal fibers approach the stellate ganglia and then join the efferent cardiac SNS fibers; therefore, the vagus nerve to the heart and lungs is a mixed nerve containing both PNS and SNS efferent fibers. The PNS fibers are distributed mainly to the sinoatrial and atrioventricular (AV) nodes and to a lesser extent to the atria. There is
little or no distribution to the ventricles. Therefore, the main effect of vagal cardiac stimulation to the heart is chronotropic. Vagal stimulation decreases the rate of sinoatrial node discharge and decreases excitability of the AV junctional fibers, slowing impulse conduction to the ventricles. A strong vagal discharge can completely arrest sinoatrial node firing and block impulse conduction to the ventricles.3
The physiologic importance of the PNS on myocardial contractility is not as well understood as that of the SNS. Cholinergic blockade can double the heart rate (HR) without altering contractility of the left ventricle. Vagal stimulation of the heart can reduce left ventricular maximum rate of tension development (dP/dT) and decrease contractile force by as much as 10 to 20%. However, PNS stimulation is relatively unimportant in this regard compared with its predominant effect on HR. The SNS has the same supraventricular distribution as the PNS, but with stronger representation to the ventricles. SNS efferents to the myocardium funnel through the paired stellate ganglia. The right stellate ganglion distributes primarily to the anterior epicardial surface and the interventricular septum. Right stellate stimulation decreases systolic duration and increases HR. The left stellate ganglion supplies the posterior and lateral surfaces of both ventricles. Left stellate stimulation increases mean arterial pressure and left ventricular contractility without causing a substantial change in HR. Normal SNS tone maintains contractility approximately 20% above that in the absence of any SNS stimulation.4 Therefore, the dominant effect of the ANS on myocardial contractility is mediated primarily through the SNS. Intrinsic mechanisms of the myocardium, however, can maintain circulation quite well without the ANS, as evidenced by the success of cardiac transplants (see Chapter 54). Early investigations, performed in anesthetized, open-chest animals, demonstrated that cardiac ANS nerves exert only slight effects on the coronary vascular bed; however, more recent studies on chronically instrumented, intact, conscious animals show considerable evidence for a strong SNS regulation of the small coronary resistance and larger conductance vessels.5,6
Different segments of the coronary arterial tree react differently to various stimuli and drugs. Normally, the large conductance vessels contribute little to overall coronary vascular resistance (see Chapter 10). Fluctuations in resistance reflect changes in lumen size of the small, precapillary vessels. Blood flow through the resistance vessels is regulated primarily by the local metabolic requirements of the myocardium. The larger conductance vessels, however, can constrict markedly because of neurogenic stimulation. Neurogenic influence also assumes a greater role in the resistance vessels when they become hypoxic and lose autoregulation.
The SNS nerves are by far the most important regulators of the peripheral circulation. The PNS nerves play only a minor role in this regard. The PNS dilates vessels, but only in limited areas such as the genitals. SNS stimulation produces both vasodilation and vasoconstriction, with vasoconstrictor effects predominating. The SNS effect on the vascular bed is determined by the type of receptors on which the SNS fiber terminates (see “Adrenergic Receptors”). SNS constrictor receptors are distributed to all segments of the circulation. Blood vessels in the skin, kidneys, spleen, and mesentery have an extensive SNS distribution, whereas those in the heart, brain, and muscle have less SNS innervation.
Basal vasomotor tone is maintained by impulses from the lateral portion of the vasomotor center in the medulla oblongata that continually transmits impulses through the SNS, maintaining partial arteriolar and venular constriction. Circulating epinephrine (EPI) from the adrenal medulla has additive effects. This basal ANS tone maintains arteriolar constriction at an intermediate diameter. The arteriole, therefore, has the potential for either further constriction or dilation. If the basal tone were not present, the SNS could only effect vasoconstriction and not vasodilation.7 The SNS tone in the venules produces little resistance to flow compared with the arterioles and the arteries. The importance of SNS stimulation of veins is to reduce or increase their capacity. By functioning as a reservoir for approximately 80% of the total blood volume, small changes in venous capacitance produce large changes in venous return and, thus, cardiac preload.
The lungs are innervated by both the SNS and PNS. Postganglionic SNS fibers from the upper thoracic ganglia (stellate) pass to the lungs to innervate the smooth muscles of the bronchi and pulmonary blood vessels. PNS innervation of these structures is via the vagus nerve. SNS stimulation produces bronchodilation and pulmonary vasoconstriction.8 Little else has been proven conclusively about the vasomotor control of the pulmonary vessels other than that they adjust to accommodate the output of the right ventricle. The effect of stimulation of the pulmonary SNS nerves on pulmonary vascular resistance is not ideal but may be important in maintaining hemodynamic stability during stress and exercise by balancing right and left ventricular output. Stimulation of the vagus nerve produces almost no vasodilation of the pulmonary circulation. Hypoxic pulmonary vasoconstriction is a local phenomenon capable of providing a faster adjustment to the organism needs.
Both the SNS and the vagus nerve provide active bronchomotor control. SNS stimulation causes bronchodilation, whereas vagal stimulation produces constriction. PNS stimulation may also increase secretions of the bronchial glands. Vagal receptor endings in the alveolar ducts also play an important role in the reflex regulation of the ventilation cycle. The lung has important nonventilatory activity as well. It serves as a metabolic organ that removes local mediators such as norepinephrine (NE) from the circulation and converts others, such as angiotensin 1, to active compounds.9
Autonomic Nervous System Transmission
Transmission of excitation across the terminal junctional sites (synaptic clefts) of the peripheral ANS occurs through the mediation of liberated chemicals (Fig. 15-4). Transmitters interact with a receptor on the end organ to evoke a biologic response. The ANS can be pharmacologically subdivided by the neurotransmitter secreted at the effector cell.
Pharmacologic parlance designates the SNS and PNS as adrenergic and cholinergic, respectively. The terminals of the PNS postganglionic fibers release acetylcholine (ACh). With the exception of sweat glands, NE is considered the principal neurotransmitter released at the terminals of the sympathetic postganglionic fibers (see Fig. 15-2). Cotransmission of adenosine triphosphate (ATP), neuropeptide Y, and NE has been demonstrated at vascular sympathetic nerve terminals in a number of different tissues including muscle, intestine, kidney, and skin (see “Sympathetic Nervous System Neurotransmission”). The preganglionic neurons of both systems secrete ACh.
The terminations of the postganglionic fibers of both ANS subdivisions are anatomically and physiologically similar. The terminations are characterized by multiple branchings calledterminal effector plexuses, or reticulae. These filaments surround the elements of the effector unit “like a mesh stocking.”7 Thus, one SNS postganglionic neuron, for example, can innervate ~25,000 effector cells (e.g., vascular smooth muscle).
The terminal filaments end in presynaptic enlargements called varicosities. Each varicosity contains vesicles, ~500 µm in diameter, in which the neurotransmitters are stored (Fig. 15-4). The rate of synthesis depends on the level of ANS activity and is regulated by local feedback. The distance between the varicosity and the effector cell (synaptic or junctional cleft) varies from 100 µm in ganglia and arterioles to as much as 20,000 µm in large arteries. The time for diffusion is directly proportional to the width of the synaptic gap. Depolarization on the nerve releases the vesicular contents into the synaptic cleft by exocytosis.
Figure 15-4. The anatomy and physiology of the terminal postganglionic fibers of sympathetic and parasympathetic fibers are similar.
Parasympathetic Nervous System Transmission
ACh is considered the primary neurotransmitter of the PNS. ACh is formed in the presynaptic terminal by acetylation of choline with acetyl coenzyme A. This step is catalyzed by choline acetyl transferase (Fig. 15-5). ACh is then stored in a concentrated form in presynaptic vesicles. A continual release of small amounts of ACh, called quanta, occurs during the resting state. Each quantum results in small changes in the electrical potential of the synaptic end plate without producing depolarization. These are known as miniature end-plate potentials. Arrival of an action potential causes a synchronous release of hundreds of quanta, resulting in depolarization of the end plate. Release of ACh from the vesicles depends on influx of calcium (Ca2+) from the interstitial space. ACh is not reused like NE; therefore, it must be synthesized constantly.
Figure 15-5. Synthesis and metabolism of acetylcholine.
The ability of a receptor to modulate function of an effector organ depends on rapid recovery to its baseline state after stimulation. For this to occur, the neurotransmitter must be quickly removed from the vicinity of the receptor. ACh removal occurs by rapid hydrolysis by acetylcholinesterase (Fig. 15-5). This enzyme is found in neurons, at the neuromuscular junction, and in various other tissues of the body. A similar enzyme, pseudocholinesterase or plasma cholinesterase, is also found throughout the body but only to a limited extent in nervous tissue. It does not appear to be physiologically important in termination of the action of ACh. Both acetylcholinesterase and pseudocholinesterase hydrolyze ACh as well as other esters (such as the ester-type local anesthetics), and they may be distinguished by specific biochemical tests.3
Sympathetic Nervous System Transmission
Traditionally, the catecholamines EPI and NE are considered the mediators of peripheral SNS activity. NE is released from localized presynaptic vesicles of nearly all postganglionic sympathetic nerves. Vascular SNS nerve terminals, though, also release ATP. Thus, ATP and NE are coneurotransmitters. They are released directly into the site where they act. Their postjunctional effects appear to be synergistic in tissues.
The SNS fibers ending in the adrenal medulla are preganglionic, and ACh is the neurotransmitter (see Fig. 15-2). It interacts with the chromaffin cells in the adrenal medulla, causing release of EPI and NE. The chromaffin cells take the place of the postganglionic neurons. Stimulation of the sympathetic nerves innervating the adrenal medulla, however, causes the release of large quantities of a mixture of EPI and NE into the circulation. The greater portion of this hormonal surge is normally EPI. Nevertheless, EPI and NE, when released into the circulation, are classified as hormones in that they are synthesized, stored, and released from the adrenal medulla to act at distant sites.
Hormonal EPI and NE have almost the same effects on effector cells as those caused by local direct sympathetic stimulation; however, the hormonal effects, although brief, last about 10 times as long as those caused by direct stimulation. EPI has a greater metabolic effect than NE. It can increase the metabolic rate of the body as much as 100%. It also increases glycogenolysis in the liver and muscle with glucose release into the blood. These functions are all necessary to prepare the body for fight or flight.
Figure 15-6. The chemical configurations of three endogenous catecholamines are compared with those of two synthetic catecholamines. Sympathomimetic drugs differ in their hemodynamic effects largely because of differences in substitution of the amine group on the catechol nucleus.
Catecholamines: The First Messenger
A catecholamine is any compound of a catechol nucleus (a benzene ring with two adjacent hydroxyl groups) and an amine-containing side chain. The chemical configuration of five of the more common catecholamines in clinical use is demonstrated in Figure 15-6. The endogenous catecholamines in humans are dopamine (DA), NE, and EPI. DA is a neurotransmitter present in the CNS. It is primarily involved in coordinating motor activity in the brain. It is the precursor of NE. NE is synthesized and stored in nerve endings of postganglionic SNS neurons. It is also synthesized in the adrenal medulla and is the chemical precursor of EPI. Stored EPI is located chiefly in chromaffin cells of the adrenal medulla. Eighty to eighty-five percent of the catecholamine content of the adrenal medulla is EPI and 15–20% is NE. The brain contains both noradrenergic and dopaminergic receptors, but circulating catecholamines do not cross the blood–brain barrier. The catecholamines present in the brain are synthesized there.
Catecholamines are often referred to as adrenergic drugs because their effector actions are mediated through receptors specific for the SNS. Sympathomimetics can activate these same receptors because of their structural similarity. For example, clonidine is a α2-receptor agonist that does not possess a catechol nucleus and even has two ring systems that are aplanar to each other. However, clonidine enjoys a remarkable spatial similarity to NE that allows it to activate the receptor. Drugs that produce sympathetic-like effects but lack the basic catecholamine structure are defined as sympathomimetics. All clinically useful catecholamines are sympathomimetics, but not all sympathomimetics are catecholamines. The effects of endogenous or synthetic catecholamines on adrenergic receptors can be direct or indirect Indirect-acting catecholamines (i.e. ephedrine) have little intrinsic effect on adrenergic receptors but produce their effects by stimulating release of the stored neurotransmitter from SNS nerve terminals. Some synthetic and endogenous catecholamines stimulate adrenergic receptor sites directly, whereas others have a mixed mode of action. The actions of direct-acting catecholamines are independent of endogenous NE stores; however, the indirect-acting catecholamines are totally dependent on adequate neuronal stores of endogenous NE.
Figure 15-7. Schematic of the synthesis of catecholamines. The conversion of tyrosine to DOPA by tyrosine hydroxylase is inhibited by increased norepinephrine synthesis. Epinephrine is shown in these steps but is primarily synthesized in the adrenal medulla.
The main site of NE synthesis is in or near the postganglionic nerve endings. Some synthesis does occur in vesicles near the cell body that pass to the nerve endings. Phenylalanine or tyrosine is taken up into the axoplasm of the nerve terminal and synthesized into either NE or EPI. Figure 15-7 demonstrates this synthesis cascade. Tyrosine hydroxylase catalyzes the conversion of tyrosine to dihydroxyphenylalanine. This is the rate-limiting step at which NE synthesis is controlled through feedback inhibition. Dopamine (DA) synthesis occurs in the cytoplasm of the neuron. The vesicles of peripheral postganglionic neurons contain the enzyme dopamine-b-hydroxylase, which converts DA to NE. The adrenal medulla additionally contains phenylethanolamine-N-methyltransferase, which converts NE to EPI. This reaction takes place outside the medullary vesicles, and the newly formed EPI then enters the vesicle for storage (Fig. 15-8). All the endogenous catecholamines are stored in presynaptic vesicles and released on arrival of an action potential. Excitation-secretion coupling in sympathetic neurons is Ca2+-dependent.
Figure 15-8. Schematic of the synthesis and disposition of norepinephrine (NE) in adrenergic neurotransmission. (1) Synthesis and storage in neuronal vesicles; (2) action potential permits calcium entry with (3) exocytosis of NE into synaptic gap. (4) Released NE reacts with receptor on effector cell. NE (5) may react with presynaptic α2 receptor to inhibit further NE release or with presynaptic β receptor to enhance reuptake of NE (6; uptake 1). Extraneuronal uptake (uptake 2) absorbs NE into effector cell (7) with overflow occurring systemically (8). Tyr, tyrosine; DOPA, dihydroxyphenylalanine; DA, dopamine; MAO, monoamine oxidase; COMT, catechol-O-methyltransferase.
Increased SNS nervous activity, as in congestive heart failure or chronic stress, stimulates the synthesis of catecholamines. Glucocorticoids from the adrenal cortex stimulate an increase in phenylethanolamine-N-methyltransferase that methylates NE to EPI.
The release of NE depends on depolarization of the nerve and an increase in calcium ion permeability. This release is inhibited by colchicine and prostaglandin E2, suggesting a contractile mechanism. NE inhibits its own release by stimulating presynaptic (prejunctional) α2 receptors. Phenoxybenzamine and phentolamine, α-receptor antagonists, increase the release of NE by blocking inhibitory presynaptic α2 receptors (Fig. 15-9). Other receptors are also important in NE regulation.
The catecholamines are removed from the synaptic cleft by three mechanisms (Fig. 15-8). These are reuptake into the presynaptic terminals, extraneuronal uptake, and diffusion. Termination of NE at the effector site is almost entirely by reuptake of NE into the terminals of the presynaptic neuron. This is an active, energy-requiring, and temperature-dependent process. The reuptake of NE in the presynaptic terminals is also a stereospecific process. Structurally similar compounds (guanethidine, metaraminol) may enter the vesicles and displace the neurotransmitter. Tricyclic antidepressants and cocaine inhibit the reuptake of NE, resulting in high synaptic NE concentrations and accentuated receptor response. In addition, evidence suggests that NE reuptake is mediated by a presynaptic β-adrenergic mechanism because beta-blockade causes marked elevations of EPI and NE10 (seeFigs. 15-8 and 15-9). Extraneuronal uptake is a minor pathway for inactivating NE. Effector cells and other extraneuronal tissues take up NE. The NE that is taken up by the extraneuronal tissue is metabolized by monoamine oxidase (MAO) and by catechol-O-methyltransferase to form vanillylmandelic acid. The minute amount of catecholamine that escapes these two mechanisms diffuses into the circulation, where it is metabolized by the liver and kidney. The same enzymes inactivate EPI. Reuptake is the predominant pathway for inactivation of the endogenous catecholamines, while metabolism by the liver and kidney is the predominant pathway for catecholamines given exogenously. This accounts for the longer duration of action of the exogenous catecholamines than that noted at the local synapse.
The final metabolic product of the catecholamines is vanillylmandelic acid. Vanillylmandelic acid constitutes the major metabolite (80 to 90%) of NE found in the urine. Less than 5% of released NE appears unchanged in the urine. The metabolic products excreted in the urine provide a gross estimate of SNS activity and can facilitate the clinical diagnosis of pheochromocytoma (see “Endocrine Function”).
Figure 15-9. This schematic demonstrates just a few of the presynaptic adrenergic receptors thought to exist. Agonist and antagonist drugs are clinically available for these receptors (see Table 15-5). The α2 receptors serve as a negative feedback mechanism whereby norepinephrine (NE) stimulation inhibits its own release. Presynaptic β stimulation increases NE uptake, augmenting its availability. Presynaptic muscarinic (MUSC) receptors respond to acetylcholine (ACh) diffusing from nearby cholinergic terminals. They inhibit NE release and can be blocked by atropine.
An agonist is a substance that interacts with a receptor to evoke a biologic response. ACh, NE, EPI, DA, and ATP are the major agonists of the ANS. An antagonist is a substance that interferes with the evocation of a response at a receptor site by an agonist. Receptors are therefore regarded as target sites that, when activated by an agonist, will lead to a response by the effector cell. Receptors are protein macromolecules and are located in the plasma membrane. Several thousand receptors have been demonstrated in a single cell. The enormity of this network is realized when it is considered that ~25,000 single cells can be innervated by a single neuron.
ACh is the neurotransmitter for three distinct classes of receptors. These receptors can be differentiated by their anatomic
location and their affinity to bind various agonists and antagonists. ACh mediates the “first messenger” function of transmitting impulses within the PNS, the ganglia of the SNS, and the neuroeffector junction of striated, voluntary muscle (Fig. 15-2). Cholinergic receptors are further subdivided into muscarinic and nicotinic receptors because muscarine and nicotine stimulate them selectively.3 However, both muscarinic and nicotinic receptors respond to ACh (see “Cholinergic Drugs”). Muscarine activates cholinergic receptors at the postganglionic PNS junctions of cardiac and smooth muscle throughout the body. Muscarinic stimulation is characterized by bradycardia, decreased inotropism, bronchoconstriction, miosis, salivation, gastrointestinal hypermotility, and increased gastric acid secretion (Table 15-1). Muscarinic receptors can be blocked by atropine without effect on nicotinic receptors (see “Cholinergic Drugs”). Muscarinic receptors are known to exist in sites other than PNS postganglionic junctions. They are found on the presynaptic membrane of sympathetic nerve terminals in the myocardium, coronary vessels, and peripheral vasculature (Fig. 15-9). These are referred to as adrenergic muscarinic receptors because of their location; however, ACh stimulates them also. Stimulation of these receptors inhibits release of NE in a manner similar to α2-receptor stimulation. Muscarinic blockade removes inhibition of NE release, augmenting SNS activity. Atropine, the prototypical muscarinic blocker, may produce sympathomimetic activity in this manner as well as vagal blockade. Neuromuscular blocking drugs that cause tachycardia are thought to have a similar mechanism of action. ACh acting on presynaptic adrenergic muscarinic receptors is a potent inhibitor of NE release.10 The prejunctional muscarinic receptor may play an important physiologic role because several autonomically innervated tissues (e.g., the heart) possess ANS plexuses in which the SNS and PNS nerve terminals are closely associated. In these plexuses, ACh, released from the nearby PNS nerve terminals (vagus nerve), can inhibit NE release by activation of presynaptic adrenergic muscarinic receptors (Fig. 15-9).
Nicotinic receptors are found at the synaptic junctions of both SNS and PNS ganglia. Because both junctions are cholinergic, ACh or ACh-like substances such as nicotine will excite postganglionic fibers of both systems (see Fig. 15-2). Low doses of nicotine produce stimulation of ANS ganglia, whereas high doses produce blockade. This dualism is referred to as the nicotinic effect (see “Ganglionic Drugs”). Nicotinic stimulation of the SNS ganglia produces hypertension and tachycardia by causing the release of EPI and NE from the adrenal medulla. Adrenal hormone release is mediated by ACh in the chromaffin cells, which are analogous to postganglionic neurons (Fig. 15-2). A further increase in nicotine concentration produces hypotension and neuromuscular weakness, as it becomes a ganglionic blocker. The cholinergic neuroeffector junction of skeletal muscle also contains nicotinic receptors, although they are not identical to the nicotinic receptors in ANS ganglia.
The adrenergic receptors are termed adrenergic or noradrenergic, depending on their responsiveness to EPI or NE. The dissimilarities of these two drugs led Ahlquist in 1948 to propose two types of opposing adrenergic receptors, termed alpha (α) and beta (β). The development of new agonists and antagonists with relatively selective activity allowed subdivision the β receptors into β1 and β2. α-Receptors were subsequently divided into α1 and α2, and later further subdivided using molecular cloning. The sympathomimetic adrenergic drugs in current use differ from one another in their effects largely because of differences in substitution on the amine group, which influences the relative α or β effect (Fig. 15-6).
Another major peripheral adrenergic receptor specific for DA is termed the dopaminergic receptor. Further studies have revealed not only subsets of the α and β receptors but also the DA receptor. These DA receptors have been identified in the CNS and in renal, mesenteric, and coronary vessels. The physiologic importance of these receptors is a matter of controversy because there are no identifiable peripheral DA neurons. DA measured in the circulation is assumed to result from spillover from the brain.
The function of DA in the CNS has long been known, but the peripheral DA receptor has been elucidated only within the past 25 years. The presence of the peripheral DA receptor was obscured because DA does not affect the DA receptor exclusively. It also stimulates α and β receptors in a dose-related manner. However, DA receptors function independently of α or β blockade and are modified by DA antagonists such as haloperidol, droperidol, and phenothiazines. Thus, there is a necessity for the addition of the DA receptor and its subsets (DA1and DA2).
The distribution of adrenergic receptors in organs and tissues is not uniform and their function differs not only by their location but also in their numbers and/or distribution. Adrenergic receptors are found in two loci in the sympathetic neuroeffector junction. They are found in both the presynaptic (prejunctional) and postsynaptic (postjunctional) sites as well as extrasynaptic sites (Fig. 15-10). Table 15-3 is a review of the function and synaptic location of some of the clinically important receptors and their subtypes.
The α-adrenergic receptors have been further subdivided into two clinically important classes α1 and α2. This classification is based on their response to the α-antagonists yohimbine and prazosin. Prazosin is a more potent antagonist of α1 receptors, whereas α2 receptors are more sensitive to yohimbine. Recently, the pharmacologic experiments have demonstrated the existence of two subtypes within the α1 group, namely α1A and α1B, and at least two subtypes within the α2, respectively α2A, and α2B. The importance of these subsets is still emerging with evidence that the spleen, and liver contain mainly α1B receptors, and the heart, neocortex, kidney, vas deferns, and hippocampus containing equal amounts of α1A and α1B receptors. The α1-adrenergic receptors are found in the smooth muscle cells of the peripheral vasculature of the coronary arteries, skin, uterus, intestinal mucosa, and splanchnic beds11 (Table 15-4). The α1 receptors serve as postsynaptic activators of vascular and intestinal smooth muscle as well as of endocrine glands. Their activation results in either decreased or increased tone, depending on the effector organ. The response in resistance and capacitance vessels is constriction, whereas in the intestinal tract it is relaxation. There is now a large body of evidence documenting the presence of postjunctional α1 adrenoreceptors in the mammalian heart. α1–Adrenergic receptors have been shown to have a positive inotropic effect on cardiac tissues from most mammals studied, including humans. Experimental work strongly supports the concept that enhanced myocardial α1responsiveness plays a primary role in the genesis of malignant arrhythmias induced by catecholamines during myocardial ischemia and reperfusion. Drugs possessing potent α1antagonist activity such as prazosin and phentolamine provide significant antiarrhythmic activity. The clinical mechanism and significance of these findings are not yet clear. However, there is no doubt that α1-adrenergic antagonists prevent catecholamine-induced ventricular arrhythmias.12 In contrast, studies of the effects of β antagonists in experimental and clinical myocardial infarction have provided conflicting results.
The discovery of presynaptic α adrenoreceptors and their role in the modulation of NE transmission provided the stimulus for the subclassification of α receptors into α1 and α2subtypes.
Presynaptic α1 receptors have not been identified and they appear confined only to the postsynaptic membrane. On the other hand, α2 receptors are found on both presynaptic and postsynaptic membranes of the adrenergic neuroeffector junction. Table 15-4 reviews these sites. Postsynaptic membranes contain a near equal mix of α1 and α2 receptors.
Figure 15-10. Loci of several known adrenergic receptors. The presynaptic α2 and dopamine (DA) receptors serve as a negative feedback mechanism, whereby stimulation of norepinephrine (NE) inhibits its own release. Presynaptic β2 stimulation increases NE uptake, augmenting its availability. Postsynaptic α2 and β2 receptors are extrasynaptic and are considered noninnervated hormonal receptors.
The α2 adrenoreceptors may be subdivided even further into as many as four possible subtypes. The postsynaptic α2 receptors have many actions, which include arterial and venous vasoconstriction, platelet aggregation, inhibition of insulin release, inhibition of bowel motility, stimulation of growth hormone release, and inhibition of antidiuretic hormone release.
α2 Receptors can be found in cholinergic pathways as well as in adrenergic pathways. They can significantly modulate parasympathetic activity as well. Current research implies that α2 stimulation of the parasympathetic pathways plays a role in the modulation of the baroreceptor reflex (increased sensitivity), vagal mediation of HR (bradycardia), bronchoconstriction, and salivation (dry mouth). However, cholinergic receptors can also be found in adrenergic pathways; thus, muscarinic and nicotinic receptors have been found in presynaptic and postsynaptic locations, where in turn they modulate sympathetic activity (Fig. 15-9). There is speculation that the features that are so desirable to the anesthesiologist, such as sedation, anxiolysis, analgesia, and hypnosis, are mediated through this site.
Stimulation of presynaptic α2 receptors mediates inhibition of NE release into the synaptic cleft, serving as a negative feedback mechanism. The central effects are primarily related to a reduction in sympathetic outflow with a concomitantly enhanced parasympathetic outflow (e.g., enhanced baroreceptor activity). These results in a decreased systemic vascular resistance, decreased cardiac output (CO), decreased inotropic state in the myocardium, and decreased HR. The peripheral presynaptic α2 effects are similar, and NE release is inhibited in postganglionic neurons. However, stimulation of postsynaptic α2 receptors, like the α1 postsynaptic receptor, affects vasoconstriction. NE acts on both α1 and α2receptors. Thus, NE not only activates smooth muscle vasoconstriction (postsynaptic α1 and α2 receptors) but also stimulates presynaptic α2 receptors and inhibits its own release. Selective stimulation of the presynaptic α2 receptor could produce a beneficial reduction of peripheral vascular resistance. Unfortunately, most known presynaptic α2 agonists also stimulate the postsynaptic α2 receptors, causing vasoconstriction. Blockade of α2 presynaptic receptors, however, ablates normal inhibition of NE, causing vasoconstriction. Vasodilation occurs with the blockade of postsynaptic α1 and α2 receptors.
Alpha-Adrenergic Receptors in the Cardiovascular System
Postsynaptic α1 and α2 receptors in the mammalian myocardium and coronary arteries mediate a number of responses.
The presence of postsynaptic α1 and α2 receptors in mammalian models has been demonstrated. Sympathetic nerves cause coronary vasoconstriction, which is mediated more by postsynaptic α2 than α1 receptors. The larger epicardial arteries possess mainly α1 receptors, whereas α2 receptors and some α1 receptors are present in the small coronary artery resistance vessels.13 Epicardial vessels contribute only 5% to the total resistance of the coronary circulation; therefore, α1 agonists such as phenylephrine have little influence on coronary resistance.14,15 Myocardial ischemia has been shown to increase α2 receptor density in the coronary arteries. Ischemia has also been shown to cause a reflex increase in sympathetic activity mediated by α mechanisms. This cascade may further increase coronary constriction. Postsynaptic α1 receptors do not rely upon extracellular Ca2+ to constrict the vessel, whereas the α2-constrictor response is highly dependent on extracellular influx and exquisitely sensitive to calcium channel inhibitors.16
The role of β receptors in mediating catecholamine induced inotropism and arrhythmogenesis is well known (see “Beta-Adrenergic Receptors”). Studies have shown the presence of postsynaptic myocardial α1 receptors,
which also exert a major, facilitory, positive inotropic effect on the myocardium of several species of mammals including humans. Their contribution to malignant reperfusion arrhythmogenesis has also been recognized.
Table 15-3 Adrenergic Receptors: Order of Potency of Agonists and Antagonists
Table 15-4 Adrenergic Receptors
Phenylephrine, an α1 agonist, can increase myocardial contractility two- to threefold compared with a six- to sevenfold increase produced by isoproterenol, a pure β agonist. Myocardial postsynaptic α1 receptors mediate perhaps as much as 30 to 50% of the basal inotropic tone of the normal heart.
Postsynaptic myocardial α1 receptors play a more prominent inotropic role in the failing heart by serving as a reserve to the normally predominant β1 receptors. Although the
response to both α1 and β1 agonists is reduced in the failing myocardium, the interaction between the two receptors is more apparent. Chronic heart failure is known to produce a reduced density (down-regulation) of myocardial β1 receptors as a result of high levels of circulating catecholamines. However, there is no evidence of down-regulation of either α1 or β2 receptors due to cardiac failure. The increase in density of myocardial α1 adrenoreceptors shows a relative increase with failure and myocardial ischemia.17 Thus, enhanced myocardial α1-receptor numbers, and sensitivity, may contribute to positive inotropism seen during ischemia as well as to the malignant arrhythmias that occur with reperfusion. Intracellular mobilization of cytosolic Ca2+ by the activated α1-myocardial receptors during ischemia appears to contribute to these arrhythmias. The α1 receptor also increases the sensitivity of the contractile elements to Ca2+. Drugs possessing potent α1 antagonism such as prazosin and phentolamine have been shown to possess significant antiarrhythmic activity, although of limited usefulness because of hypotension. Enhanced α1 activity with myocardial ischemia may explain why the antiarrhythmic benefits of β antagonists in patients with acute myocardial infarction are far from certain. The contribution of β receptors to positive inotropism and arrhythmogenesis during ischemia and reperfusion may be overshadowed by the α receptors during acute failure and ischemia.
Activation of the presynaptic α2-vascular receptors produces vasodilation, whereas the postsynaptic α1- and α2-vascular receptors subserve vasoconstriction. Presynaptic vascular α2receptors inhibit NE release. This represents a negative feedback mechanism by which NE inhibits its own release via the prejunctional receptor. Presynaptic α2 agonists, such as clonidine, inhibit NE release at the neurosympathetic junction producing vasodilatation. The effect of selective presynaptic α2-receptor agonists to ameliorate coronary vasoconstriction in humans is unclear. Excitation of the inhibitory presynaptic α2 receptors by endogenous or synthetic catecholamines also inhibits NE release. However, most sympathomimetics are nonselective α agonists that will excite equally presynaptic α2 vasodilators and vasoconstrictive postsynaptic α1 and α2 receptors. Postsynaptic α1 and α2receptors coexist in both the arterial and venous sides of the circulation with the relative distribution of α2 receptors being greater on the venous side.11 This may explain why pure α1agonists, such as methoxamine, produce little venoconstriction, whereas many nonselective agonists such as phenylephrine produce significant venoconstriction. NE is the most potent venoconstrictor of all the catecholamines. Clinically, venoconstriction would have the effect of preloading by shifting venous capacitance centrally, whereas stimulation of arterial postsynaptic α1 and α2 receptors would effect afterloading by increasing arterial resistance.
Alpha-Adrenergic Receptors in the Central Nervous System
All subtypes of the α, β, and DA receptors have been found in various regions of the brain and spinal cord. The functional role of the cerebral α and β receptors suggests a close association with blood pressure and HR control. Cerebral and spinal cord presynaptic α2 receptors are also involved in inhibition of presynaptic NE release. Although the brain contains adrenergic and dopaminergic receptors, circulating catecholamines do not cross the blood–brain barrier. The catecholamines in the brain are synthesized there. Many actions have been attributed to the cerebral postsynaptic α2 receptor. This includes inhibition of insulin release, inhibition of bowel motility, stimulation of growth hormone release, and inhibition of antidiuretic hormone release. Central neuraxis injection of α2 agonists, such as clonidine, induces analgesia, sedation, and cardiovascular depression. The increased duration of epidural or intrathecal anesthesia by the addition of nonselective α agonists to the local anesthetic may produce additional analgesia through this mechanism.
Alpha Receptors in the Kidney
The kidney has an extensive and exclusive adrenergic innervation of the afferent and efferent glomerular arterioles, proximal and distal renal tubules, ascending loop of Henle, and juxtaglomerular apparatus. The greatest density of innervation is in the thick ascending loop of Henle, followed by the distal convoluted tubules and proximal tube. Both α1 and α2subtypes are found in the kidney with the α2 receptor dominating. The α1 receptor is predominant in the renal vasculature and elicits vasoconstriction, which modulates renal blood flow. Tubular α1 receptors enhance sodium and water reabsorption, leading to antinatriuresis, whereas tubular α2 receptors promote sodium and water excretion.
The β-adrenergic receptors, like the α receptor, have been divided into subtypes. They are designated as the β1 and β2 subtypes. Recently, molecular cloning has demonstrated the existence of a third subtype, namely β3 receptor. Activation of all these receptors subtypes induces the activation of adenylyl cyclase and increased conversion of ATP to cyclic adenosine-3′, 5′-monophosphate (cAMP). β1 receptors predominate in the myocardium, the sinoatrial node, and the ventricular conduction system. The β1 receptors also mediate the effects of the catecholamines on the myocardium. These receptors are equally sensitive to EPI and NE, which distinguishes them from the β2 receptors. Effects of β1 stimulation are outlined in Table 15-4, which includes their effects specifically on the cardiovascular system.
The β2 receptors are located in the smooth muscles of the blood vessels in the skin, muscle, mesentery, and in bronchial smooth muscle. Stimulation produces vasodilation and bronchial relaxation. The β2 receptors are more sensitive to EPI than NE. β Receptors are found in both presynaptic and postsynaptic membranes of the adrenergic neuro effector junction (Table 15-4). β1 Receptors are distributed to postsynaptic sites and have not been identified on the presynaptic membrane. Presynaptic β receptors are of the β2 subtype. The effects of activation of the presynaptic β2 receptor are diametrically opposed to those of the presynaptic α2 receptor. The presynaptic β2 receptor accelerates endogenous NE release, whereas blockade of this receptor will inhibit NE release. Antagonism of the presynaptic β2 receptors produces a physiological result similar to activation of the presynaptic α2 receptor. The postsynaptic β1 receptors are located on the synaptic membrane and respond primarily to neuronal NE. The postsynaptic β2 receptors, like the postsynaptic α2receptor, respond primarily to circulating EPI.
Beta Receptors in the Cardiovascular System
Myocardial β receptors were originally classified as β1 receptors. Those in the vascular and bronchial smooth muscle were called the β2 subtype. However, studies have confirmed the coexistence of β1 and β2 receptors in the myocardium.18 Both β1 and β2 receptors are functionally coupled to adenylate cyclase, suggesting a similar involvement in the regulation of inotropism and chronotropism. Postsynaptic β1 receptors are distributed predominantly to the myocardium, the sinoatrial node, and the ventricular conduction system. The β2receptors have the same distribution but are presynaptic. Activation of the presynaptic β2 receptor accelerates the release of NE into the synaptic cleft. The β2 receptor approximates 20 to 30% of the β receptors in the ventricular myocardium and up to 40% of the β receptors in the atrium.
The effect of NE on inotropism in the normal heart is mediated entirely through the postsynaptic β1 receptor, whereas the inotropic effects of EPI are mediated through both the β1- and
β2-myocardial receptors. The β2 receptors may also mediate the chronotropic responses to EPI, which explains why selective β1 antagonists are less effective in suppressing induced tachycardia than the nonselective β1 antagonist propranolol.
The postsynaptic vascular β receptors are virtually all of the β2 subtype. The β2 receptors are located in the smooth muscle of the blood vessels of the skin, muscle, mesentery, and bronchi. Stimulation of the postsynaptic β2 receptor produces vasodilation and bronchial relaxation. Modest vasoconstriction occurs when subjected to blockade because the actions of the vascular postsynaptic β2 receptors no longer oppose the actions of the α1-and α-postsynaptic receptors.
Beta Receptors in the Kidney
The kidney contains both β1 and β2 receptors, with the β1 being predominant. Renin release from the juxtaglomerular apparatus is enhanced by β stimulation. The β1 receptor evokes renin release in humans. Renal β2 receptors also appear to regulate renal blood flow at the vascular level. They have been identified pharmacologically and mediate a vasodilatory response.
DA, synthesized in 1910, was recognized in 1959 not only as a vasopressor and the precursor of NE and EPI, but also as an important central and peripheral neurotransmitter. DA receptors have been localized in the CNS, on blood vessels, and postganglionic sympathetic nerves (Table 15-4). Two clinically important types of DA receptors have been recognized DA1 and DA2, while other subtypes like DA4, and DA5, are still being investigated. The DA1 receptors are postsynaptic, whereas the DA2 receptors are both presynaptic and postsynaptic. The presynaptic DA2 receptors, like the presynaptic α2 receptor, inhibit NE release and can produce vasodilatation. The postsynaptic DA2 receptor may subserve vasoconstriction similar to that of the postsynaptic α2 receptor. This effect is opposite to that of the postsynaptic DA1 renal vascular receptor. The zona glomerulosa of the adrenal cortex also contains DA2 receptors, which inhibit the release of aldosterone.
Defining specific dopaminergic receptors has been difficult because DA also exerts effects on the α and β receptors. DA receptors have not been described in the myocardium. Effects of DA are those related to activation of β1 receptors, which promote positive inotropism and chronotropism. β2 Activation would produce some systemic vasodilatation.
The greatest numbers of DA1-postsynaptic receptors are found on vascular smooth muscle cells of the kidney and mesentery, but are also found in the other systemic arteries including coronary, cerebral, and cutaneous arteries. The vascular receptors are, like the β2 receptors, linked to adenylate cyclase and mediate smooth muscle relaxation. Activation of these receptors produces vasodilatation, increasing blood flow to these organs. Concurrent activation of vascular presynaptic DA2 receptors also inhibits NE release at presynaptic α2 receptors, which may also contribute to peripheral vasodilatation. Higher doses of DA can mediate vasoconstriction via the postsynaptic α1 and α2 receptors. The constrictive effect is relatively weak in the cardiovascular system where the action of DA on adrenergic receptors is 1/35 and 1/50 as potent as that of EPI and NE, respectively.19,20
Central Nervous System
DA receptors have been identified in the hypothalamus where they are involved in prolactin release. They are also found in the basal ganglia where they coordinate motor function. Degeneration of dopaminergic neurons in the substantia nigra is the source of Parkinson disease. Another central action of DA is to stimulate the chemoreceptor trigger zone of the medulla, producing nausea and vomiting. DA antagonists such as haloperidol and droperidol are clinically effective in countering this action.
Kidney and Mesentery
Apart from their effect on the vessels of the kidney and mesentery, DA receptors on the smooth muscle of the esophagus, stomach, and small intestine enhance secretion production and reduce intestinal motility.19,20 Metoclopramide, a DA antagonist, is useful for aspiration prophylaxis by promoting gastric emptying. The distribution of DA receptors in the renal vasculature is well known, but DA receptors have other functions within the kidney. DA1 receptors are located on renal tubules, which inhibit sodium reabsorption with subsequent natriuresis and diuresis. The natriuresis may be the result of a combined renal vasodilatation, improved CO, and tubular action of the DA1 receptors. Juxtaglomerular cells also contain DA1 receptors, which increase renin release when activated. This action modulates the diuresis produced by DA1 activation of the tubules.
DA has unique autonomic effects by activating specific peripheral dopaminergic receptors, which promote natriuresis and reduce afterload via dilatation of the renal and mesenteric arterial beds. Peripheral dopaminergic activity serves as a natural antihypertensive mechanism. Its actions are overshadowed by the opposite effect of its main biologic partner, NE. Plasma NE levels are known to increase with aging, likely the result of reduced clearance, while peripheral dopaminergic activity is known to diminish. Subtle changes in the DA-NE balance with aging may account for the diminished ability of the aged kidney to excrete a salt load.
Adenosine produces inhibition of NE release. The effect of adenosine is blocked by caffeine and other methylxanthines. The physiologic function of these receptors may be the reduction of sympathetic tone under hypoxic conditions when adenosine production is enhanced. As a consequence of reduced NE release, cardiac work would be decreased and oxygen demand reduced. Adenosine has been effectively used to produce controlled hypotension.21
Serotonin (5-hydroxytryptamine) depresses the response of isolated blood vessels to SNS stimulation and decreases release of labeled NE in these preparations. Raising the external calcium ion concentration antagonizes this inhibitory action of serotonin. Thus, serotonin may inhibit neuronal NE release by a mechanism that limits the availability of calcium ions at the nerve terminal.
Prostaglandin E2, Histamine, and Opioids
Prostaglandin E2, histamine, and several opioids have been reported to act on prejunctional receptor sites to inhibit NE release in certain sympathetically innervated tissue. However, these inhibitory receptors are unlikely to play a physiologic role in limiting NE release since their direct antagonists, compounds like inhibitors of cyclo-oxygenase, histamine antagonists, and naloxone do not increase a NE release.
Histamine acts in a manner similar to the neurotransmitters of the SNS. Cell membrane has specific receptors for histamine, with the individual response being determined by the type of cell being stimulated (see Chapter 13). Two
receptors for histamine have been determined. These have been designated H1 and H2, for which it has been possible to develop specific agonists and antagonists. Stimulation of the H1 receptors produces bronchoconstriction and intestinal contraction. The major role of the H2 receptors is related to acid production by the parietal cells of the stomach; however, histamine is present in relatively high concentrations in the myocardium and cardiac conducting tissue, where it exerts positive inotropic and chronotropic effects while depressing dromotropism. The positive inotropic and chronotropic effects of histamine are H2 receptor effects that are not blocked by β antagonism. These effects are blocked by H2 antagonists, such as cimetidine, which accounts for the occasional report of cardiovascular collapse following the use of cimetidine. The negative dromotropic effect and that of coronary spasm caused by histamine are H1 receptor effects.
Adrenergic Receptor Numbers and Sensitivity
Receptors, once thought to be static entities, are now thought to be dynamically regulated by a variety of conditions and to be in a constant state of flux. Receptors are synthesized in the sarcoplasmic reticulum of the parent cell, where they may remain extrasynaptic or externalize to the synaptic membranes where they may cluster. Membrane receptors may be removed or internalized to intracellular sites for either dehydration or recycling.
The numbers and sensitivity of adrenergic receptors can be influenced by normal, genetic, and developmental factors. Changes in the number of receptors alter the response to catecholamines. Alteration in the number, or density, of receptors is referred to as either up-regulation or down-regulation. As a rule, the number of receptors is inversely proportional to the ambient concentration of the catecholamines. Extended exposure of receptors to their agonists markedly reduces, but does not ablate, the biologic response to catecholamines. For example, increased adrenergic activity occurs in response to reduced perfusion as a result of acute or chronic myocardial dysfunction. Plasma catecholamines are increased. Subsequently, the myocardial postsynaptic β1 receptors “down regulate” (see Chapter 6). This is thought to explain the diminished inotropic and chronotropic response to β1 agonists and exercise in patients with chronic heart failure. However, calcium-induced inotropism is not impaired because β2-receptor (extrasynaptic) numbers remain relatively intact. The β2 receptors may account for up to 40% of the inotropism of the failing heart compared with 20% in the normal heart.17,22 Tachyphylaxis to infused catecholamines is also thought to be the result of acute “down-regulation” of receptor numbers. There appears to be a reduction in numbers or sensitivity of β receptors in hypertensive patients who also have elevated plasma catecholamines. Down-regulation is the presumptive explanation for the lack of correlation between plasma catecholamine levels and the blood pressure elevation in patients with pheochromocytoma. Chronic use of β agonists such as terbutaline, isoproterenol, or EPI for the treatment of asthma can result in tachyphylaxis because of down-regulation. Even short-term use (1 to 6 hours) of β agonists may cause down-regulation of receptor numbers. Down-regulation is reversible on termination of the agonist. Chronic treatment of animals with nonselective beta-blockade causes a 100% increase in the number of β receptors. This accounts for the propranolol withdrawal syndrome in which the acute discontinuation of the β antagonist leaves the α receptors unopposed plus an increased number of β receptors. Clonidine withdrawal can be explained by the same mechanism. Up- or down-regulation of receptor numbers may not alter sensitivity of the receptor. Likewise, sensitivity may be increased or decreased in the presence of normal numbers of receptors. The pharmacologic factors affecting up- or down-regulation of the α and β receptors are similar.
Autonomic Nervous System Reflexes and Interactions
The ANS reflex has been compared to the computer circuit. This control system, as in all reflex systems, has (1) sensors, (2) afferent pathways, (3) CNS integration, and (4) efferent pathways to the receptors and efferent organs. Fine adjustments are made at the local level according to positive and negative feedback mechanisms. The baroreceptor is an example. The variable to be controlled (blood pressure) is sensed (carotid sinus), integrated (medullary vasomotor center), and adjusted through specific effector-receptor sites. Drugs or disease can interrupt this circuit at any point. Beta-blockers may attenuate the effector response, whereas an α agonist such as clonidine may alter both the effector and the integrator functions of blood pressure control.
There are several reflexes in the cardiovascular system, which help control arterial blood pressure, CO, and HR. The aim of the circulation is to provide blood flow to all the body organs (see Chapter 10). Yet, the most important controlled variable to which the sensors are attuned is blood pressure, a product of the blood flow and vascular resistance. Etienne Marey noted in 1859 that the pulse rate is inversely proportional to the blood pressure, and this is known as Marey's law. Subsequently, Hering, Koch, and others demonstrated that the alterations in HR evoked by changes in blood pressure depend on baroreceptors located in the aortic arch and the carotid sinuses. These pressure sensors react to alterations in stretch caused by blood pressure. Impulses from the carotid sinus and aortic arch reach the medullary vasomotor center by the glossopharyngeal and vagus nerves, respectively. Increased sensory traffic from the baroreceptors, caused by increased blood pressure, inhibits SNS effector traffic. The relative increase in vagal tone produces vasodilation, slowing of the HR, and a lowering of blood pressure. Real increases in vagal tone occur when blood pressure exceeds normal limits. The Valsalva maneuver can best demonstrate the arterial baroreceptor reflex (Fig. 15-11). The Valsalva maneuver
raises the intrathoracic pressure by forced expiration against a closed glottis. The arterial blood pressure rises momentarily as the intrathoracic blood is forced into the heart (preload). Sustained intrathoracic pressure diminishes venous return, reduces the CO, and drops the blood pressure. Reflex vasoconstriction and tachycardia ensue. Blood pressure returns to normal with release of the forced expiration, but then briefly “overshoots” because of the vasoconstriction and increased venous return. A slowing of the HR accompanies the overshoot in pressure. The cardiovascular responses to the Valsalva maneuver require an intact ANS circuit from peripheral sensor to peripheral adrenergic receptors. The Valsalva maneuver has been used to identify patients at risk for anesthesia because of ANS instability (Fig. 15-11). This was once a major concern in patients receiving drugs that depleted catecholamines, such as reserpine. Dysfunction of the SNS is implicated if exaggerated and prolonged hypotension develops during the forced expiration phase (50% from resting mean arterial pressure). In addition, the overshoot at the end of the Valsalva maneuver is absent. Dysfunction of the PNS can be assumed if the HR does not respond appropriately to the blood pressure changes.
Figure 15-11. A. The normal blood pressure response to the Valsalva maneuver is demonstrated. Pulse rate moves in a reciprocal direction according to Marey's law of the heart. B. An abnormal Valsalva response is shown in a patient with C5 quadriplegia.
Venous baroreceptors may be more dominant in the moment-to-moment regulation of CO. Baroreceptors in the right atrium and great veins produce an increase in HR when stretched by increased right atrial pressure. Reduced venous pressure decreases HR. Unlike the arterial baroreceptors, venous sensors are not thought to alter vascular tone; however, venoconstriction is postulated to occur when atrial pressures decline. Stretch of the venous receptors produces changes in HR opposite those produced when the arterial pressure sensors are stimulated. The arterial and venous pressure receptors are separately monitoring two of the four major determinants of CO, afterload and preload, respectively. Venous baroreceptors sample preload by stretch of the atrium. Arterial baroreceptors survey resistance, or afterload, as reflected in the mean arterial pressure. Afterload and preload produce opposite effects on CO; thus, one should not be surprised that the venous and arterial baroreceptors produce effects opposite those of a similar stretch stimulus, pressure.
Bainbridge described the venous baroreceptor reflex and demonstrated that it can be abolished by vagal resection. Numerous investigators have confirmed the acceleration of the HR in response to volume. However, the magnitude and direction of the HR response depend on the prevailing HR at the time of stimulation. The denervated, transplanted mammalian heart also accelerates in response to volume loading. HR, like CO, can apparently be adjusted to the quantity of blood entering the heart. The Bainbridge reflex relates to the characteristic but paradoxical slowing of the heart seen with spinal anesthesia. Blockade of the SNS levels of T1-T4 ablates the efferent limb of the cardiac accelerator nerves. This source of cardiac deceleration is obvious, as the vagus nerve is unopposed. However, bradycardia during spinal anesthesia is more related to the development of arterial hypotension than to the height of the block. The primary defect in the development of spinal hypotension is a decrease in venous return. Theoretically, the arterial hypotension should reflexly produce a tachycardia through the arterial baroreceptors. Instead, bradycardia is more common. Bridenbaugh et al.23 suggest that, in the unmedicated person, the venous baroreceptors are dominant over the arterial. A reduced venous pressure, therefore, slows HR. In contrast, humorally mediated tachycardia is the usual response to hypotension or acidosis from other causes.
Reflex modulation of the adrenergic agonists is best seen in the denervated transplant heart, which retains the recipient's innervated sinoatrial node and the donor's denervated sinoatrial node24 (see Chapter 54). NE infusion in the transplanted heart produces a slowing of the recipient's atrial rate through vagal feedback as the blood pressure rises. In the unmodulated donor heart, atrial rate increases. The baroreceptors are therefore not operant in the transplanted heart. Isoproterenol, a pure β agonist, increases the discharge rate of both the recipient and donor node by direct action, with the donor rate near doubling that of the recipient node. Atropine accelerates the recipient's atrial rate, whereas no effect is seen on the donor rate, which now controls HR.
Beta blockade produces comparable slowing of the sinoatrial node of both recipient and donor. The exercise capability of the denervated heart is conspicuously reduced by beta-blockade, presumably because of its reliance on circulating catecholamines. Propranolol has also been demonstrated to reduce the β response to chronotropic effects of NE and isoproterenol in the transplanted heart. The CO of the transplanted heart varies appropriately with changes in preload and afterload.
Interaction of Autonomic Nervous System Receptors
Strong interactions have been noted between SNS and PNS nerves in organs that receive dual, antagonistic innervation. Release of NE at the presynaptic terminal is modified by the PNS. For example, vagal inhibition of left ventricular contractility is accentuated as the level of SNS activity is raised. This interaction is termed accentuated antagonism and is mediated by a combination of presynaptic and postsynaptic mechanisms. The coronary arteries present an example of this phenomenon and deserve special attention.
The myocardium and coronary vessels are abundantly supplied with adrenergic and cholinergic fibers. Strong activity of both α and β receptors has been demonstrated in the coronary vascular bed. Selective stimulation of both the α1 and postsynaptic α2 receptors increases coronary vascular resistance, whereas selective α blockade eliminates this effect. Therefore, both β1 and α1 adrenoreceptors are present on coronary arteries and accessible to NE released by sympathetic nerves.5,14
The presynaptic adrenergic terminals of the myocardium and coronary vessels, like all blood vessels examined, contain muscarinic receptors.10 Recent observations confirm that muscarinic agents and vagal stimulation, acting on the presynaptic, SNS muscarinic receptor, inhibit the release of NE in a manner similar to that of the presynaptic α2 and DA2receptors (Fig. 15-9). Conversely, blockade of the muscarinic receptors with atropine markedly augments the positive inotropic responses to catecholamines.5 Suppression of NE release explains, in part, vagal-induced attenuation of the inotropic response to strong SNS stimulation (accentuated antagonism) and only a weak negative inotropic effect of vagal stimulation when there is low background SNS activity. This may also explain why vagal activity reduces the vulnerability of the myocardium to fibrillation during infusions of NE.
ACh may cause coronary spasm during periods of high SNS tone.5 Inhibition of NE release by presynaptic adrenergic muscarinic receptors of the smooth muscle of coronary vessels would lessen the coronary relaxation normally produced by NE on the β1 receptor (Fig. 15-9). In anesthetized dogs, the rate of NE outflow into the coronary sinus blood, evoked by cardiac SNS stimulation, is markedly diminished by simultaneous vagal efferent stimulation.25 This action is known to be prevented by atropine, which also causes coronary vasodilation.
Interaction with Other Regulatory Systems
The ANS is integrally related to several endocrine systems that ultimately summate to control blood pressure and regulate homeostasis. These include the renin-angiotensin system,
antidiuretic hormone, glucocorticoids, and insulin (see Chapter 49). Both α and β receptors have been found in the endocrine pancreas and modulate insulin release (Table 15-4). β Stimulation increases insulin release, whereas α stimulation decreases it. The overall importance of this interaction is not entirely clear, but decreased tolerance to glucose and potassium has been noted in subjects taking beta-blocking drugs. The renin-angiotensin system is a complex endocrine system that modulates both blood pressure and water-electrolyte homeostasis (Fig. 15-12). Renin is a proteolytic enzyme contained within the cells of the juxtaglomerular apparatus of the renal cortex. When released, it acts on plasma angiotensinogen to form angiotensin I. Angiotensin I is then converted to angiotensin II by converting enzyme in the lung. Angiotensin II is a powerful direct arterial vasoconstrictor. It also acts on the adrenal cortex to release aldosterone and on the adrenal medulla to release EPI. In addition to its direct effects on vascular smooth muscle, angiotensin II augments NE release via presynaptic receptors, thus enhancing peripheral SNS tone. Captopril, enalapril, and lisinopril inhibit the action of converting enzyme, thus preventing the conversion of angiotensin I to angiotensin II. Renin is released in response to hyponatremia, decreased renal perfusion pressure, and ANS stimulation via β receptors on juxtaglomerular cells. Changes in sympathetic tone may thus alter renin release and affect homeostasis in a variety of ways. The ANS is also intimately related to adrenocortical function. As previously outlined, glucocorticoid release modulates phenylethanolamine-N-methyltransferase formation and thus synthesis of EPI. Glucocorticoids are also important in regulating the response of peripheral tissues to changes in SNS tone. Thus, the ANS is intimately related to other homeostatic mechanisms.
Figure 15-12. The interactions of the renin–angiotensin and sympathetic nervous system in regulating homeostasis are shown schematically along with the physiologic variables that modulate their function. Arrows with a plus sign (+) represent stimulation, and those with a minus sign (-) represent inhibition.
Clinical Autonomic Nervous System Pharmacology
The clinical application of ANS pharmacology is based on knowledge of ANS anatomy, physiology, and molecular pharmacology. Drugs that modify ANS activity can be classified by their site of action, mechanism of action, or pathology for which they are most commonly used. Antihypertensive drugs are an example of the third category. This classification is a matter of degree because considerable functional overlap occurs. An example of classification by site relates to the ganglionic agonists or blocking agents. ANS drugs can be further categorized as those that act at the prejunctional membrane and those acting postjunctionally. They can then be more specifically classified by the predominant receptor or receptors on which they act.
Mode of Action
ANS drugs may be broadly classified by mode of action according to their mimetic or lytic actions. This may also be termed agonist or antagonist. A sympathomimetic, such as ephedrine, mimics SNS sympathetic activity by stimulation of adrenergic receptor sites both directly and indirectly. Sympatholytic drugs cause dissolution of SNS activity at these same receptor sites. β Receptor blockers are examples of sympatholytic drugs. Several modes of ANS drug action become evident when one follows the cascade of neurotransmission. Drugs that act on prejunctional membranes may therefore (1) interfere with transmitter synthesis (α-methyl paratyrosine), (2) interfere with transmitter storage (reserpine), (3) interfere with transmitter release (clonidine), (4) stimulate transmitter release (ephedrine), or (5) interfere with reuptake of transmitter (cocaine). Drugs may also (6) modify metabolism of the neurotransmitter in the synaptic cleft (anticholinesterase). Drugs acting at postjunctional sites may (7) directly stimulate postjunctional receptors and (8) interfere with transmitter agonist at the postjunctional receptor.
The ultimate response of an effector organ to an agonist or antagonist depends on (1) the drug, (2) its plasma concentration, (3) the number of receptors in the effector organ, (4) binding by the receptor, (5) the concurrent activities of other drugs and hormones, (6) the cellular metabolic status, and (7) reflex adjustments by the organism.
SNS and PNS ganglia are pharmacologically similar in that transmission through these ANS ganglia is effected by ACh (Fig. 15-2). Most ganglionic agonists and antagonists are not
selective and affect SNS and PNS ganglia equally. This nonselective property creates many undesirable and unpredictable side effects, which have limited the clinical usefulness of this category of drug.
There are essentially no clinically useful ganglionic agonists. Nicotine is the prototypical ganglionic agonist. In low doses, it stimulates ANS ganglia and the neuromuscular junction of striated muscle. High doses produce ganglionic and neuromuscular blockade. The protean side effects of nicotinic stimulation render it useful only as an investigative tool.
Drugs that interfere with neurotransmission at ANS ganglia are known as ganglionic blocking agents. Nicotine in high doses is the prototypical ganglionic blocking agent also; however, early stimulatory nicotinic activity can be blocked both at the ganglia and muscle end plates with other ganglionic blockers and muscle relaxants, respectively, without blocking muscarinic effects. Ganglionic blockers produce their nicotinic effects by competing, mimicking, or interfering with ACh metabolism. Hexamethonium, trimethaphan, and pentolinium produce a selective nondepolarizing blockade of neurotransmission at ANS ganglia without producing nicotinic neuromuscular blockade. They compete with ACh in the ganglia without stimulating the receptors. The introduction of drugs that produce vasodilation directly or by action on the SNS vasomotor center has made the ganglionic blockers obsolete. d-Tubocurare produces a competitive nondepolarizing block of both motor end plates and ANS ganglia. The action of motor paralysis predominates, but the concomitant ganglionic blockade at higher doses explains part of the hypotensive effect often seen with the use of d-tubocurare for muscle relaxation. Anticholinesterase drugs may produce nicotinic type ganglionic blockade by competition with ACh as well as by persistent depolarization via accumulated ACh.
Trimethaphan produces blockade by competition with ACh for receptors, thus stabilizing the postsynaptic membrane. However, side effects and rapid onset tachyphylaxis have markedly reduced its use in anesthesia.26 The patient's pupils become fixed and dilated during administration, which obscures eye signs, an important consideration for neurosurgery. In this regard, it is distinctly inferior to nitroprusside. The major advantage of trimethaphan is its short duration of action, which is the result of pseudocholinesterase hydrolysis.
The cholinomimetic muscarinic drugs act at sites in the body where ACh is the neurotransmitter of the nerve impulse. These drugs may be divided into three groups, the first two of which are direct muscarinic agonists. The third group acts indirectly. These groups are choline esters (ACh, methacholine, carbamylcholine, bethanechol), alkaloids (pilocarpine, muscarine), and anticholinesterases (physostigmine, neostigmine, pyridostigmine, edrophonium, echothiophate).
ACh has virtually no therapeutic applications because of its diffuse action and rapid hydrolysis by cholinesterase (see Fig. 15-5). One may encounter the use of topical ACh (1%) drops during cataract extraction when a rapid miosis is desired. Systemic effects are not usually seen because of the rapidity of ACh hydrolysis. Derivatives of ACh, other choline esters have been synthesized, which possess more selective muscarinic activity than ACh. They differ from ACh in being more resistant to inactivation by cholinesterase and thus having a more prolonged and useful action. They also differ from ACh in their relative muscarinic and nicotinic activities. The best studied of these drugs are methacholine, bethanechol, and carbamylcholine. The chemical structures of ACh and these choline esters are shown in Figure 15-13. Their pharmacologic actions are compared with those of ACh in Table 15-5. These are not important drugs in anesthesiology practice but anesthesiologists may encounter patients who are receiving them.
Figure 15-13. Chemical structures of direct-acting cholinomimetic esters and alkaloids.
ACh is a quaternary ammonium compound that interacts with postsynaptic receptors, causing conformational membrane changes. This results in increased permeability to small ions and, thus, depolarization. All the receptors translate the reversible binding of ACh into openings of discrete channels in excitable membranes, allowing Na+ and K+ ions to flow along their electrochemical gradients. Structure-activity relationships point to the presence of two important binding sites on the receptor, an esteratic site that binds the ester end of the molecule and an ionic site that binds the quaternary amine portion (Fig. 15-5). Subtle changes in the structure of the compound can markedly alter the responses among different tissue groups. The degree of muscarinic activity falls if the acetyl group is replaced, but this confers a resistance to enzymatic hydrolysis. Bethanechol is resistant to hydrolysis but possesses mainly muscarinic activity. β-Methyl substitution produces methacholine, which is less resistant to hydrolysis and is primarily a muscarinic agonist. Methacholine slows the heart and dilates peripheral blood vessels. It is used to terminate supraventricular tachydysrhythmias, especially paroxysmal tachycardia, when other measures have failed. It also increases intestinal tone. Methacholine should not be given to patients with asthma. Hypertensive patients may also develop marked hypotension. Side effects are those of PNS stimulation such as nausea, vomiting, and flushed sweating. Overdose is treated with atropine. Bethanechol is relatively selective for the
gastrointestinal and urinary tracts. In usual doses it does not slow the heart or lower the blood pressure. Bethanecol is of value in treating postoperative abdominal distention (nonobstructive paralytic ileus), gastric atony following bilateral vagotomy, congenital megacolon, nonobstructive urinary retention, and some cases of neurogenic bladder.
Table 15-5 Comparative Muscarinic Actions of Direct Cholinomimetic Agents
Direct-acting cholinomimetic alkaloids include muscarine and pilocarpine. They act at the same sites as ACh, and their effects are similar to those of ACh as described in Table 15-5. There are no uses for these drugs in anesthesiology. Pilocarpine is the only drug of this group used therapeutically in the United States. Its sole use is for the treatment of glaucoma, for which it is the standard. It is used as a topical miotic drug in ophthalmologic practice to reduce intraocular pressure in glaucoma.
Muscarinic agonists are particularly dangerous in patients with myasthenia gravis (who are receiving anticholinesterases), bulbar palsy, cardiac disease, asthma, peptic ulcer, progressive muscular atrophy, or mechanical intestinal obstruction or urinary retention because they intensify these conditions.
The indirect-acting cholinomimetic drugs are of greater importance to the anesthesiologist than are the direct-acting drugs. These drugs produce cholinomimetic effects indirectly as a result of inhibition or inactivation of the enzyme acetylcholinesterase, which normally destroys ACh by hydrolysis. They are referred to as cholinesterase inhibitors oranticholinesterases. Most of these drugs inhibit both acetylcholinesterase and pseudocholinesterase. Inhibition of acetylcholinesterase permits the accumulation of ACh transmitter in the synapse, resulting in intense PNS activity similar to that of the direct cholinomimetic agents. The accumulation of ACh by the anticholinesterases potentially can produce all of the following: (1) stimulation of muscarinic receptors at ANS effect organs, (2) stimulation followed by depression of all ANS ganglia and skeletal muscle (nicotinic), and (3) stimulation with later depression of cholinergic receptor sites in the CNS. All of these effects may be seen with lethal doses of anticholinesterase drugs, but therapeutic doses only produce the first two.
Actions of therapeutic significance of the anticholinesterase drugs to the anesthesiologist concern the eye, the intestine, and the neuromuscular junction. The effects of anticholinesterases are useful in the treatment of myasthenia gravis, glaucoma, and atony of the gastrointestinal and urinary tracts. Anticholinesterase drugs are used routinely in anesthesia to reverse nondepolarizing neuromuscular block. The most prominent pharmacologic effects of the anticholinesterase drugs are muscarinic. Their most useful actions are their nicotinic effects. Muscarinic activity is evoked by lower concentrations of ACh than are necessary to produce the desired nicotinic effect. For example, the anticholinesterase neostigmine reverses neuromuscular blockade by increasing ACh concentration at the muscle end plate, a nicotinic receptor. Nicotinic reversal of neuromuscular blockade can usually be produced safely only when the patient has been protected by atropine or other muscarinic
blockers. This prevents the untoward muscarinic effects of bradycardia, hypotension, bronchospasm, or intestinal spasm. Reversal of neuromuscular blockade in patients who have had bowel anastomosis was at one time a major controversy (see “Neuromuscular Blockers”). Some thought that the muscarinic effects of anticholinesterase drugs (hypermotility) increased the risk of anastomotic leakage whereas others found no association between their use and subsequent breakdown. National experience has favored the latter opinion.
Clinically, anticholinesterase drugs may be divided into two types: the reversible and nonreversible cholinesterase inhibitors.26 Reversible cholinesterase inhibitors delay the hydrolysis of ACh from 1 to 8 hours. Nonreversible drugs are so named because their inhibitory effects may last from days to weeks. The differences in duration of various anticholinesterases apparently depend on whether they inhibit the anionic or esteratic site of acetylcholinesterase. Therefore, the anticholinesterase drugs have also been pharmacologically subdivided. Drugs that inhibit the anionic site are called competitive inhibitors. Their action is due to competition between the anticholinesterase and ACh for the anionic site. These drugs tend to be short-acting. Edrophonium is an example of this type. Drugs that inhibit the esteratic site are called acid-transferring inhibitors. These drugs include the longer-acting neostigmine, pyridostigmine, and physostigmine.
Most of the reversible cholinesterase inhibitors are quaternary ammonium compounds and do not cross the blood–brain barrier. Physostigmine is a tertiary amine that readily passes into the CNS (Fig. 15-14). It produces central muscarinic stimulation and, thus, is not used to reverse neuromuscular blockade but can be used to treat atropine poisoning. Conversely, atropine is used to treat physostigmine poisoning. Physostigmine has also been found to be a specific antidote in the treatment of postoperative delirium (see “Central Anticholinergic Syndrome”).3
Table 15-6 Comparison of Antimuscarinic Drugs
Table 15-7 Antimuscarinic Compounds Associated with Central Anticholinergic Syndrome
Figure 15-14. Structural formulas of clinically useful reversible anticholinesterase drugs. Physostigmine is a tertiary amine and crosses the blood–brain barrier. It is useful in treating the central anticholinergic syndrome.
The irreversible cholinesterase inhibitors are mostly organophosphate compounds. The organophosphate compounds are highly lipid-soluble, readily pass into the CNS, and are rapidly absorbed through the skin. They are used as the active ingredient in potent insecticides and chemical warfare agents known as nerve gases (see Chapter 60). The only therapeutic drug of this group is echothiophate, which is available in the form of topical drops for the treatment of glaucoma. Its primary advantage is its prolonged duration of action. Topical absorption is variable but considerable. Echothiophate can remain effective for 2 or 3 weeks following cessation of therapy. A history of use of echothiophate is important in avoiding prolonged action of succinylcholine, which requires pseudocholinesterase for its hydrolysis. Organophosphate poisoning manifests all the signs and symptoms of excess ACh. The antidote cartridges dispensed to troops to counter the effects of anticholinesterase nerve gases contain only atropine, which would effectively counter the muscarinic effects of the gas; however, atropine does little to counter the high-dose nicotinic muscle paralysis or the central ventilation depression that contributes to death from nerve gases. Treatment requires high doses of atropine, 35 to 70 mg/kg intravenously (IV) every 3 to 10 minutes until muscarinic symptoms abate. Lower doses at less frequent intervals may be required for several days. Central ventilatory depression and weakness require respiratory support and specific therapy of the cholinesterase lesion. Pralidoxime has been reported to reactivate cholinesterase activity by hydrolysis of the phosphate enzyme complex. It is particularly effective with parathion poisoning and is the only cholinesterase reactivator available in the United States.26
Muscarinic antagonist refers to a specific drug action for which the term anticholinergic is widely used. Any drug that interferes with the action of ACh as a transmitter can be considered an anticholinergic agent. The term anticholinergic refers to a broader classification that also includes the nicotinic antagonists.
Atropine, scopolamine, and glycopyrrolate are the most commonly used muscarinic antagonists used in anesthesia (Fig. 15-15). The actions of these drugs include inhibition of salivary, bronchial, pancreatic, and gastrointestinal secretions and antagonism the muscarinic side effects of anticholinesterases during reversal of muscle relaxants. Historically, atropine was introduced to anesthesia practice to prevent excessive secretions during ether anesthesia and to prevent vagal bradycardia during the administration of chloroform.26Antimuscarinic agents do not inhibit transmission equally, and there are marked variations in sensitivity at different muscarinic sites owing to differences in penetration and affinities of the various receptors. Differences in relative potency between the different antimuscarinics are outlined in Table 15-6. Atropine and scopolamine are tertiary amines (Fig. 15-15) and easily penetrate the blood–brain barrier and placenta. Glycopyrrolate is a quaternary amine that, like the reversible anticholinesterase drugs, does not easily penetrate these barriers. Glycopyrrolate, a synthetic antimuscarinic, has gained popularity because it avoids the central effects of the other two drugs. Atropine and scopolamine have notable CNS effects that are dissimilar. Scopolamine differs from atropine mainly in its central depressant effects, which produce
sedation, amnesia, and euphoria. Such properties are widely used for premedication for cardiac patients in combination with morphine and a major tranquilizer. It also has been used to induce amnesia in patients who have a high risk for intraoperative awareness, such as trauma victims who are hemodynamically unstable and cannot receive adequate anesthesia. Atropine, as a premedicant, has slight effects on the CNS, including mild stimulation. Higher doses such as those given for reversal of muscle relaxants (1 to 2 mg) may produce restlessness, disorientation, hallucinations, and delirium (see “Central Anticholinergic Syndrome”).
Figure 15-15. Structural formulas of the clinically useful antimuscarinic drugs.
Atropine is useful in increasing CO when sinus bradycardia due to vagal stimulation is present. Atropine and scopolamine are noted to produce a paradoxical bradycardia when given in low doses. Scopolamine (0.1 to 0.2 mg) usually causes more slowing than atropine but also produces less cardiac acceleration at higher doses. The usual intramuscular premedicant doses of scopolamine cause either a decrease or no change in HR. Atropine may also produce sympathomimetic effects by blocking presynaptic muscarinic receptors found on adrenergic nerve terminals.27 ACh stimulation of these receptors inhibits NE release, and blockade by atropine releases this inhibition (see “Cholinergic Receptors: Muscarinic”). Atropinelike drugs that cross the blood–brain barrier also produce dilation of the pupil (mydriasis) and paralysis of accommodation (cycloplegia). Atropine-like drugs are widely used in ophthalmology as mydriatics and cycloplegics. Atropine is contraindicated in patients with narrow-angle glaucoma (see Chapter 51). Pupillary dilation thickens the peripheral part of the iris, which narrows the iridocorneal angle. This leads to impaired drainage of aqueous humor and increase of the intraocular pressure. Doses of atropine used for premedication have little effect in this regard, whereas equal doses of scopolamine cause mydriasis. Prudence would dictate avoidance of either agent in patients with narrow-angle glaucoma. The need for antimuscarinic premedication is questionable in this situation.
Atropine and scopolamine also possess antiemetic action. Atropine, however, reduces the opening pressure of the lower esophageal sphincter, which theoretically increases the risk of passive regurgitation. The belladonna alkaloids (atropine and scopolamine) also block ACh transmission to sweat glands, which, although they are cholinergic, are innervated by the SNS. Antimuscarinic agents produce antinicotinic actions at higher doses and result in important actions on CNS transmission that are pharmacologically similar to the postganglionic cholinergic function. Atropine is best avoided where tachycardia would be harmful, as may occur in thyrotoxicosis, pheochromocytoma, or obstructive coronary artery disease. Atropine should be avoided in hyperpyrexial patients because it inhibits sweating.
Central Anticholinergic Syndrome
The belladonna alkaloids have long been known to produce undesirable side effects ranging from stupor (scopolamine) to delirium (atropine). This syndrome has been calledpostoperative delirium, atropine toxicity, and the central anticholinergic syndrome. Biochemical studies have demonstrated abundant muscarinic ACh receptors in the brain that can be affected by any drug possessing antimuscarinic activity and capable of crossing the blood–brain barrier. Hundreds of drugs exist that meet these criteria with which this syndrome has been associated. Table 15-7 lists some of those drugs.3 High doses of atropinic alkaloids rapidly produce dryness of the mouth, blurred vision with photophobia (mydriasis), hot and dry skin (flushed), and fever. Mental symptoms range from sedation, stupor, and coma to anxiety, restlessness, disorientation, hallucinations, and delirium. Convulsions may occur if lethal poisoning has occurred. Although an alarming reaction may occur, fatalities are rare. Intoxication is usually short-lived and followed by amnesia. These reactions can be controlled by the intravenous injection of physostigmine. Physostigmine is an anticholinesterase that, by virtue of being a tertiary amine, readily passes into the CNS to counter antimuscarinic activity. It should be given slowly in 1-mg doses,
not exceeding 3 mg, to avoid producing peripheral cholinergic activity. Neostigmine, pyridostigmine, and edrophonium are not effective because they cannot pass into the CNS. The duration of physostigmine action may be shorter than that of the offending antimuscarinic agent and require repeated injection if symptoms recur. Physostigmine appears safe when used within dose recommendations and when indications are established. Central disorientation alone does not establish a diagnosis. Peripheral signs of antimuscarinic activity should be present in addition to a central anticholinergic syndrome.
Physostigmine has been reported to reverse the CNS effects of many of the drugs listed in Table 15-7, including antihistamines, tricyclic antidepressants, and tranquilizers. Reversal of the sedative effects of opioids and benzodiazepines has also been reported.28 However, anticholinesterase agents potentiate cholinergic synaptic transmission and increase neuronal activity, even if no receptor antagonist is present. Thus, arousal may not be a function independent of its cholinesterase activity, and claims that physostigmine is a nonspecific CNS stimulant may not be warranted and could, in fact, be dangerous. These considerations, in association with possible significant bradycardia, made the use of physostigmine fairly rare in the modern recovery rooms.
The selection of vasoactive drugs requires knowledge of both the hemodynamic disturbance and pharmacology of the available drugs. The catecholamines and sympathomimetic drugs continue to be the pharmacologic mainstay of cardiovascular support for the low-flow state. Sustained interest in the catecholamines is related to their predictable pharmacodynamics and favorable pharmacokinetic profiles. The half-life of most is short, ranging from 2 to 3 minutes. Undesirable side effects dissipate within minutes of lowering or stopping the infusion. Sympathomimetics, as a group, produce a wide range of hemodynamic effects and can be used in combination to achieve a yet wider spectrum of effects. As a result, one needs to become familiar with only a few agents to manage most clinical situations (Table 15-8).
The goal for managing the low-output or high-output shock syndrome is to establish and maintain adequate tissue perfusion. Sympathomimetics are not a substitute for volume, and are to be used in hypotensive emergencies, in order to preserve cerebral and coronary blood flow, that may be due to severe hemorrhage, spinal cord injury, antihypertensive overdose, or central nervous system depressant medication, just to name a few circumstances. Therefore, while intravascular volume is optimized, a vasoactive drug may be required to sustain CO. Aggressive fluid therapy will suffice in most instances. If, on the other hand, adequate fluid resuscitation has been achieved and hemodynamic status still requires sympathomimetics to maintain a normal arterial blood pressure, one must consider alternative causes for hypotension such as septic shock, and seek the most adequate therapy. The term inodilator has entered our lexicon during the early 1990s to supplant the more archaic term vasopressor. This neologism reflects a change in philosophy in managing low-flow states, particularly those characterized by heart failure. The new synthetic sympathomimetics have been chemically engineered to obtain inotropism and
vasodilation rather than for pressor effects. The potential for benefit or harm can best be understood in terms of receptor characteristics. For example, activation of the inotropic β1 and β2 receptors results in positive inotropism and chronotropism. Selective stimulation of the vascular β2 receptors causes vasodilatation. Left ventricular outflow may improve as a function of afterload reduction and inotropism. However, chronotropism may not be a desirable feature in a patient with mitral (valvular) stenosis or coronary artery disease.
Table 15-8 Dose Schedule and Hemodynamic Effects of the Adrenergic Agonists
Table 15-9 Actions of Adrenergic Agonists
Catecholamine Receptor-Effector Coupling
The net physiologic effect of a sympathomimetic is usually defined as the algebraic sum of its relative actions on the α, β, and DA receptors. Most adrenergic drugs activate or block these receptors to varying degrees. Each catecholamine has a distinctive effect, qualitatively and quantitatively, on the myocardium and peripheral vasculature. Table 15-9demonstrates the relative potency of the adrenergic amines on the various myocardial and vascular receptors. This relative potency is also dose-related, adding yet another variable. For many years, the emphasis on catecholamines was focused almost entirely on their actions on the myocardium and on arteriolar resistance vessels. Changes in venous resistance contribute little to total vascular resistance and blood pressure. However, small changes in venous capacitance result in large changes in venous return because 60 to 70% of the circulating blood volume is the venous circulation.4 The effect of the sympathomimetic amines on the venous circulation appears to be distributive in that acute venular constriction increases the central blood volume (preload), whereas dilatation decreases venous return by the promotion of peripheral pooling.4 The distributive effect of a catecholamine may be as important as its inotropic action and more important than its arteriolar effect.10 Further definition should elucidate some of the complex and confusing data in the literature generated when clinical observations are limited solely to adrenergic effects on the myocardium and arteriolar vasculature.
Intravenous and intra-arterial infusions of EPI in humans have been shown to cause marked constriction of the veins. Arteriolar vasoconstriction may or may not precede venoconstriction; however, stroke volume does not increase until the onset of venoconstriction. The initial increase in CO seen with the infusion of EPI is more an effect of increased preload than an arteriolar or direct cardiac effect. NE produces a similar effect, but the onset of venoconstriction is slower. The peripheral receptors of both resistance and capacitance vessels subserve vasoconstriction, but with divergent effects on afterload and preload; therefore, the α1 receptors have been subdivided into α1 arterial (α1a) and α1venous (α1v). DA has potent venoconstrictor (α1v) effect at doses at which few α1a or β1 effects are noted.
The major adverse effects of the sympathomimetic amines are related to excessive α or β activity. The potential for harm can be understood in terms of receptor characteristics. Excessive β1 activity may increase contractility but increase HR and myocardial oxygen consumption beyond supply. Severe dysrhythmias are a frequent companion of excess β1activity as a result of increased conduction velocity, automaticity, and ischemia. The β2 activity has the potential to increase CO by reducing resistance (afterload) while reducing blood pressure. An excessive decrease in diastolic pressure, however, reduces coronary perfusion pressure and may further aggravate myocardial ischemia. Unfortunately, it is difficult to separate the inotropic, dromotropic, and chronotropic effects in the clinical setting. The characteristics of the ideal positive inotropic agent are listed in Table 15-9 for comparison with each drug as it is discussed.
Drugs with prominent α1 agonist effects may produce an increase in blood pressure but at the same time can reduce total flow due to increases in arteriolar resistance (afterload). A more prominent α1 venous constriction may improve CO by increasing preload or precipitate failure if preload exceeds the contractile limits of the myocardium. In general, the α effects of the sympathomimetics are of benefit only when used for specific indications such as significant vasodilation due to different mechanisms. Other measures like fluid resuscitation are usually more effective in improving flow and are indicated before a pressor should be used. Cardiopulmonary resuscitation is the primary example where a pressor effect is necessary to create diastolic coronary perfusion during closed or open heart massage. Any drug with strong α agonist properties seems equally effective in this regard. EPI, with its added β properties, has been the first-line agent for this situation. Vasopressin has recently been added as an important agent in cardiopulmonary resuscitation.29
Tables 15-8 and 15-9 list adrenergic agonists to be discussed in this section. Phenylephrine, is considered a pure α drug, increases both venous constriction and arterial constriction in a dose-related manner. Venous constriction may be its most redeeming feature when compared with the purely arteriolar effect of methoxamine. One cannot discount the possibility of an inotropic effect now that α1 receptors are known to exist in the myocardium. Acutely, venoconstriction favors
venous return (preload), and even though arterial resistance (afterload) also increases, one may observe a rise in the arterial blood pressure. Because phenylephrine does increase the venous return and stroke volume, but at the same time induces reflex bradycardia secondary to a vagal reflex, one must be aware that CO is not increased. Phenylephrine does not change CO in normal individuals but can cause a decreased output in patients with ischemic heart disease.30 Phenylephrine is useful in reversing right-to-left shunt in tetralogy of Fallot when patients are having “spells” during anesthesia. Phenylephrine has continued to be favored in operating rooms to increase blood pressure during cardiopulmonary bypass as well as during intracranial, vascular procedures and to reverse significant vasodilatory states related to regional blocks like spinal and epidural analgesia. Its efficacy, the fact that it can be used either as a bolus, or as a peripheral infusion, made this drug one of the most commonly used medications in the operating room to reverse anesthetic hypotension from a multitude of causes. In addition, it can be used in primary vasodilatory conditions, such as incipient phases of septic shock.31
NE is the naturally occurring mediator of the SNS and the immediate precursor of EPI. It produces direct-acting hemodynamic effects on the α and β receptors in a dose-related manner when given by infusion. NE produces increased CO and blood pressure when given in low doses (Table 15-8). Higher doses reduce flow because α arteriolar constriction supersedes the β effects. Reflex baroreceptor-mediated bradycardia may occur despite active β stimulation. Increased plasma levels of the endogenous catecholamines NE and EPI are the sympathetic milieu in which exogenous sympathomimetics are ordinarily given. NE is the catecholamine standard against which other catecholamines are compared. Intravenous NE has received an unseemly reputation over the years that is not merited. Studies indicate that NE was being used in doses that are orders of magnitude greater than that necessary to obtain its best response. Complications such as tissue necrosis may be expected when NE is used. A resurgence of interest in this agent is noted and it has remained clinically useful because its effects are predictable, prompt, and potent. Objections to the use of NE for the treatment of cardiogenic shock are based on two considerations: (1) vasoconstriction increases the pressure work of the left ventricle, with an adverse effect on the oxygen economy of the ischemic pump, and (2) these drugs cause further vasoconstriction and organ ischemia in a syndrome in which intense constriction may already have occurred. For management of cardiogenic shock, other drugs are more appropriate (dobutamine and milrinone). However, the predictability of NE pharmacologic effects makes it one of the most useful drugs when intense α activity is intended. Reduced vascular tone states with or without cardiogenic shock, including separation from cardiopulmonary bypass, or situations when other vasopressors such as phenylephrine fail to maintain a steady hemodynamic state, render NE one of the most commonly used drugs.10,32 Additional undesirable effects associated with NE include renal arteriolar constriction and oliguria. These effects are secondary to persistent and untreated hypovolemia. Recently, clinicians who manage oliguria in intensive care units, after adequate fluid resuscitation to control prerenal causes, do use NE to maintain renal perfusion pressure, especially in cases of vasodilated hypotension.33
NE should only be administered in a centrally placed IV to avoid tissue necrosis from extravasation. It can be used for its inotropic effect at low doses and titrated to effect while monitoring CO. Monitoring of blood pressure alone, or titrating to a predetermined effect, is often detrimental to CO. Blood pressure increases are usually due to increases in systemic vascular resistance, and excessive increases of the afterload can diminish forward flow and contribute to cardiac failure. Even moderate doses of NE may have a detrimental effect on end-organ perfusion, which has given the drug an ill-gotten reputation when used to titrate to pressure rather than flow. However, in those clinical conditions characterized by high-ouput, low-tone states with a low perfusion pressure, NE has been shown to improve renal and splanchnic blood flow by increasing pressure, provided the patient has been volume resuscitated.
EPI is the prototypical endogenous catecholamine. It is synthesized, stored, and released from the adrenal medulla and is the key hormonal element in the fight-or-flight response. It is the most widely used catecholamine in medicine and, to date, it remains the drug of choice in cases of cardiac arrest. It is used to treat asthma, anaphylaxis, cardiac arrest, bleeding, and to prolong regional anesthesia. The cardiovascular effects of EPI, when given systemically, result from its direct stimulation of both α and β receptors. This is dose-dependent and is outlined in Table 15-8.
The effect of EPI on the peripheral vasculature is mixed. It has predominantly α-stimulating effects in some beds (skin, mucosa, and kidney) and β-stimulating actions in others (skeletal muscle). These effects are also dose-dependent. At therapeutic doses, β-adrenergic effects predominate in the peripheral vessels, and total resistance may be reduced. However, constriction is maintained in the renal and cutaneous areas because of its dominant α effect in these areas. An increase in CO with EPI may be due to a redistribution of blood to low-resistance vessels in the muscle, but with further reduction in flow to vital organs. Cardiac dysrhythmias are a prominent hazard, and the strong chronotropic effects of EPI have limited its use in the treatment of cardiogenic shock.
EPI is commonly used in the perioperative period in anesthesia. It is often used to produce a bloodless field in dentistry, otolaryngology, and skin grafting either topically or in local and field blocks. Anesthesiologists often use it to prolong regional anesthesia (see Chapter 21). The addition of EPI to arthroscopic infusions to attain a bloodless field is another area of increased EPI usage with the development of these techniques. These infusions are usually safe in maintaining a dry operative field because the solutions are very dilute at around 1:3,000,000. However, the large volumes infused, the unpredictable absorption of the EPI, especially in denuded cancellous bone, offers the opportunity of exposure of the patient to an excessive amount of EPI over a short period despite the dilution. The dose of submuscoally injected EPI necessary to produce ventricular cardiac dysrhythmia in 50% of patients anesthetized with a 1.25 minimal alveolar concentration (MAC) of a volatile anesthetic was 10.9, 10.9, and 6.7 µg/kg during administration of halothane, enflurane, and isoflurane, respectively.34 The incidence of cardiac dysrhythmia is eliminated when this dose is halved in patients anesthetized with halothane or isoflurane. In contrast with adults, children seem to tolerate higher doses of subcutaneous EPI without developing cardiac dysrhythmia.35 EPI infusion maintains positive chronotropism in circumstances of symptomatic bradycardia when single doses of atropine do not suffice.36 At low doses, the use of EPI infusion may also induce a benefic bronchodilation effects due to its effect on β2 receptors. Nevertheless, EPI can be used at higher doses, which induces a significant increase in the arterial blood pressure and CO. Unfortunately, these relative high doses of EPI can be followed by increases in arrhythmogenic properties, including supraventricular and tachycardia, which impose an increase in the myocardial oxygen consumption; therefore, many clinicians find other alternatives.36
Table 15-10 Comparison of Relative α1 Catecholamine Responses on Peripheral Resistance and Capacitance Vesselsa
Ephedrine is one of the most commonly used noncatecholamine sympathomimetic agents. It is used extensively for treating hypotension following spinal or epidural anesthesia. Ephedrine stimulates both α and β receptors by direct and indirect actions. It is predominantly an indirect-acting pressor, producing its effects by causing NE release. Tachyphylaxis develops rapidly and is probably related to the depletion of NE stores with repeated injection. The cardiovascular effects of ephedrine (Table 15-8) are nearly identical to those of EPI, but are less potent. Its effects are sustained about 10 times longer than those of EPI. Ephedrine remains the pressor of choice in obstetrics because uterine blood flow improves linearly with blood pressure (see Chapter 43).23 This effect is probably not related to its arteriolar vasoconstriction but rather to its venoconstrictive action. Ephedrine is a weak, indirect-acting sympathomimetic agent that produces venoconstriction to a greater degree than arteriolar constriction (Table 15-10). This may be its most important and unappreciated effect. It causes a redistribution of blood centrally, improves venous return (preload), increases CO, and restores uterine perfusion. The mild β action restores HR simultaneously with improved venous return. An increased blood pressure is noted as a result rather than a cause of these events. Mild α1-arteriolar constriction does occur, but the net effect of improving venous return and HR is increased CO. Uterine blood flow is spared. This response, however, depends on the patient's state of hydration.
Isoproterenol is a potent balanced β1 and β2 receptor agonist with no vasoconstrictor effects. It increases HR and contractility while decreasing systemic vascular resistance. Although it can increase CO, it is not useful in shock because it redistributes blood to nonessential areas by its preferential effect on the cutaneous and muscular vessels. As a result, it produces variable and unpredictable results on CO and blood pressure. Isoproterenol is a potent dysrhythmogenic drug and extends myocardial ischemic areas. Deleterious effects on an evolving cardiac ischemic process include cardiac dysrhythmias, tachycardia, and reduced diastolic coronary perfusion pressure and time. Increased myocardial oxygen demand makes it an unattractive drug for patients in cardiogenic shock. However, isoproterenol is helpful in managing cardiac failure associated with bradycardia, asthma, and cor pulmonale. It is also a useful chemical pacemaker in third-degree heart block until an artificial pacemaker can be inserted or the cause can be removed, and may be one of the most important drugs used for denervated heart in cases of significant bradycardia (see Chapter 54). Isoproterenol might be useful in treating both idiopathic and secondary pulmonary hypertension. It has also been reported as useful in improving the forward flow in patients with regurgitant aortic valvular disease, but it should not be used if there is an accompanying stenosis.
Dobutamine (DBT) is a synthetic catecholamine modified from the classic inodilator isoproterenol. Isoproterenol was, in turn, synthesized from DA. Variations and similarities in structure can be seen in Figure 15-6. DBT has clear advantages over isoproterenol and DA in many clinical situations. It acts directly on β1 receptors but exerts much weaker β2stimulation than isoproterenol. It does not cause NE release or stimulate DA receptors. DBT possesses weak α1 agonism, which can be unmasked by beta-blockade as a prompt and dramatic increase in blood pressure. DBT increases HR more than EPI for a given increase in CO.32,37
DBT may decrease diastolic coronary filling pressure because of its vasodilation. However, it appears to produce coronary vasodilation in contrast to the constriction produced by DA. Dobutamine has been used effectively to improve coronary flow to differentiate, by echocardiography, responsive or unresponsive areas of dyskinesia in patients following myocardial infarction. DBT does not have any clinically important venoconstrictor activity, in contrast to DA, in which an increase in ventricular filling pressure can be noted at low doses. Clinical studies suggest that DBT is less likely to increase HR than DA for a given dose, a major concern in the patient with coronary artery disease. DBT is a coronary artery dilator, whereas DA is not. A DA-induced tachycardia, however, may be of less concern in the septic patient who commonly has a maldistribution of volume, low vascular resistance, a pre-existing refractory tachycardia, but a
previously healthy heart. The empiric preference of DA in surgical units and DBT in coronary units has been observed and is perhaps well founded. DA and DBT also have contrasting effects on the pulmonary vasculature. DA has been noted to increase pulmonary artery pressure and does not inhibit the pulmonary hypoxic response. It is not recommended for patients in right heart failure. DBT does vasodilate the pulmonary vasculature and is helpful in treating right heart failure and cor pulmonale.38,39 DBT is highly controllable, with a half-life of 2 minutes. Tachyphylaxis is rare but may be noted if given over 72 hours. The net hemodynamic effects of DBT include an increase in CO, a decrease in left ventricular filling pressure, and a decrease in systemic vascular resistance without a significant increase in chronotropism at lower doses.40
Table 15-11 Autonomic Effects of Calcium Entry Blockers in Intact Humans
DA offers advantages over many sympathomimetics in treating the low-output syndrome. It is a dose-related agonist to all three types of adrenoceptors, and the desired action can be selected by changing the infusion rate. The DA receptors are most sensitive followed by the β, and then α receptors. DA dosage regimens have been traditionally, and arbitrarily, divided into low, medium, and high doses according to its dose-receptor sensitivity (Table 15-11). Renal and mesenteric vascular dilatation and tubular cell natriuresis are mediated through the DA receptors at low-dose infusion rates of 0.5 to 2.0 µg/kg. This is often referred to as renal dose DA because of the purported enhanced renal blood flow and diuresis. However, the concept of renal dose DA may be more imagined than real, and is now considered outdated.41,42 The hemodynamic effects of low-dose DA are primarily related to vasodilatation by activation of the DA1 and DA2 receptors. Activation of presynaptic DA2 adrenoceptors adds to the vasodilating effect of the DA1 receptors by inhibiting presynaptic NE release in the renal and mesenteric vessels. The reduction of total systemic vascular resistance would be significant when one considers that 25% of the CO goes to the kidneys alone. A reduced diastolic blood pressure is often noted with a slight reflex increase in HR. Increasing the infusion rate of DA to 2 to 5 µg/kg/min begins to activate β receptors increasing the CO by increasing chronotropism and contractility with early venoconstriction (preload) and systemic vasodilatation (afterload reduction). Blood pressure may not increase despite significant increases in CO. This dose range would appear optimal for managing congestive heart and lung failure because it combines inotropism and afterload reduction with possible diuresis, but for this specific reason, inotropes without α activity are better used. Further increases in dose activate α receptors, which will increase vascular resistance and blood pressure, but further improvements in CO may be attenuated. Infusion rates of greater than 10 µg/kg/min produce intense α activity, which may override any beneficial DA or β vasodilation effect on total flow. High-dose DA behaves much like NE and, in fact, causes NE release at this dose range.
Despite the apparent dose-response divisions of DA, a wide variability of individual responses has been noted. The α-adrenergic effects can be seen in some individuals in doses as low as 5 µg/kg/min, whereas doses as high as 20 µg/kg/min may be required to obtain this effect in shocked patients. This wide variation in dose response has led to a re-examination of DA as a primary adrenergic for patients in cardiogenic shock or failure. Increased venous return may not be desirable in this situation, but DA's hemodynamic versatility continues to be useful in cardiogenic shock when combined with other complementary catecholamines such as DBT. The venoconstriction, or distributive effects, of DA are useful in surgical patients in whom third-space edema and sepsis are the most common abnormalities. DA increases mean pulmonary arterial pressure and is not recommended for sole support in patients with right heart failure, adult respiratory distress syndrome, or pulmonary hypertension.
The studied use of adrenergic combinations in patients with cardiac failure has been proposed because pathophysiology cannot be approached with the attitude that β agonism is all good and β agonism is all bad. The objective is to increase coronary perfusion and CO while decreasing afterload. No single vasoactive agent can achieve this, but these conditions can be approached with combination therapy. Because of receptor summation during combination therapy, standard rates of infusion (as outlined in Table 15-8) no longer apply. Invasive hemodynamic monitoring is mandatory for success; otherwise, iatrogenic disasters can be expected. Other conditions necessary for success with vasoactive drugs also require that the failing myocardium or vasculature must have functional reserve, the reserve can be stimulated, and perfusion can be maintained. The adrenergic effects of combined sympathomimetics, like the solo drugs, also appear to be additive and competitive for receptor sites. Summation is more consistent with current receptor pharmacology and can be used to advantage in avoiding unwanted side effects of one drug while supplementing its desired attributes with another. The summation principle obviates the necessity of knowing a large number of drugs. One need only become familiar with a few agents to manage most clinical situations. Because of summation, many combinations of vasoactive drugs have been found useful in making fine hemodynamic adjustments in the critically ill. The available sympathomimetic agents provide a wide range of hemodynamic effects particularly when combined with vasodilators. For example, if a larger positive inotropic action and less vasoconstriction are desired, DBT could be added to DA. Also, nitroprusside could be added to DA or combined with any other appropriate inodilator.43
DA and DBT are two of the most popular inodilators in use today. A comparison of these two drugs will underscore the importance of the extracardiac side effects in selecting a drug either for use alone or in combination.39,44,45,46 This comparison is particularly appropriate because DA and DBT are considered
equipotent inotropic agents, and are effective in the same dose range of 2 to 15 µg/kg/min. Their differences can be compared at low (0.5 to 4 µg/kg/min), medium (5 to 9 µg/kg/min), and high (10 to 15 µg/kg/min) doses. This comparison will illustrate the divergent effects of two drugs on preload and afterload while sharing the property of inotropism. Although they share several clinical indications, these drugs are pharmacologically distinct and not interchangeable. Their divergent properties, however, make them particularly valuable when administered in combination. Although frequently combined previously, this combination therapy is falling out of favor since they act on the same receptors and they have so many similarities of action. Therefore, most clinicians now combine an inotrope, such as DBT or milrinone, with the more potent α agonists phenylephrine, NE, or even EPI infusions, in order to compensate for the vasodilation induced by the inotropes, and to maintain an adequate perfusion pressure. DBT is a direct-acting catecholamine that produces a positive inotropic β1 effect but with minimal changes in β2 HR or vascular resistance (β2, α1 counteraction). Thus, DBT may not alter blood pressure even though CO is markedly improved (see Chapter 10).
DBT and/or milrinone are the mainstay for the treatment of decompensated cardiac failure. Although these agents do improve the CO, their use is associated with increase in the cardiac oxygen consumption, cardiac arrhythmias, and even mortality. Therefore, for patients with normal blood pressure and no evidence of hypoperfusion, there is little role for the inotropic therapy. Nevertheless, in patients with evidence of impaired organ perfusion (hypotension, decreased renal function) and low-output state, with or without congestion or pulmonary edema refractory to diuretics and vasodilators at optimal doses, there is a role for these agents, at least for short-term stabilization. Recently, a new class of drugs was developed, namely calcium sensitizing agents (levosimendan). These drugs are a unique class of positive inotropic agents that increase the sensitivity of the cardiomyocyte contractile apparatus to intracellular calcium. These may prove to be beneficial either alone or in combination with the classic inotropes in management of decompensated heart failure, but more studies are necessary to evaluate their overall benefit and long-term outcome.45,46
Fenoldopam, a benzazepine derivative, is a selective DA1 agonist with no α or β receptor activity compared to DA41 (see Chapter 56). Intravenous fenoldopam has direct natriuretic and diuretic properties and promotes an increase in creatinine clearance. It offers advantages in the acute resolution of severe hypertension compared to sodium nitroprusside, particularly if the patient has pre-existing renal impairment.47 Preservation or augmentation of renal blood flow during blood pressure reduction presents a potential for use during several situations in the perioperative period. Fenoldopam has an elimination half-life of 5 minutes. This property might well lend itself in the producing hypotensive anesthesia while preserving renal function. Human studies have demonstrated that fenoldopam is a potent direct renal vasodilator. Intravenous fenoldopam may prove to be ideal for treating conditions in which renal vasoconstriction is an expected complication. Since it has renal vasodilatory effects and it promotes increased urine output, fenoldopam has been employed in vascular anesthesia as a renal protector, especially in cases when renal arteries have been temporarily clamped. Its role in preventing development of renal dysfunction is still debatable because there are conflicting results in different studies. Therefore, Stone et al.48 and Zacharias et al.49 show in a 315-patient population that fenoldopam is not useful in preventing further deterioration of the renal function after contrast administration. A large meta-analysis concluded that there is no pharmacologic intervention that is effective in treatment of patients with acute renal injury. On the other hand, Landoni et al.,50 in a more recent and complete meta-analysis, suggest that fenoldopam reduces the risk of acute tubular necrosis, the need for renal replacement therapy, and overall mortality in patients with acute kidney injury. It is obvious that in such circumstances of conflicting results, large randomized studies are necessary to reach a valid conclusion.
The onset of action with IV fenoldopam is about 5 minutes, reaching a steady state in about 20 minutes. The drug is rapidly metabolized in the liver and excreted in the urine. The elimination half-life is about 5 minutes. There has been no evidence of tolerance in reducing blood pressure for up to 24 hours. No rebound on withdrawal has been noted. The most common adverse effects of fenoldopam are related to vasodilation, which include hypotension, flushing, dizziness, headache, and increases in HR, nausea, and hypokalemia have occurred. It should be used cautiously in patients with glaucoma as it can increase intraocular pressure. No significant drug interactions have been reported. Concomitant use with beta-blockers will reduce the effective dose of fenoldopam.
Fenoldopam is diluted in normal saline or 5% dextrose is given by continuous infusion without a bolus dose. The effective dosage range is 0.1 to 1.6 µg/kg/min. A reflex tachycardia may be produced. The dosage is titrated upward every 15 minutes according to patient response. Any change in infusion rate should be detectable within 15 minutes.
Clonidine is a centrally acting selective partial α2 adrenergic agonist (220:1 α2 to α1). It is an antihypertensive drug because of its ability to decrease central sympathetic outflow. Stimulation of α2 receptors in the vasomotor centers of the medulla oblongata is thought to produce this effect.51 It is not clear whether these are pre-or postsynaptic receptors; however, the end result is decreased SNS tone and enhanced vagal tone. Peripherally, there is decreased plasma renin activity as well as decreased EPI and NE levels. This drug has been proven to be effective in the treatment of severe hypertension and renin-dependent hypertensive disease.
Clonidine is not available for IV use. The usual daily adult oral dose is 0.2 to 0.3 mg. A transdermal clonidine patch is available for use on a weekly basis for surgical patients unable to take oral medication. Clonidine is clinically useful in anesthesiology in other ways. It has been found to produce dose-dependent analgesia when introduced into the epidural or subarachnoid space in doses of 150 to 450 µg (see Chapter 57). Clonidine can be added to local anesthetics for epidural, spinal, or regional blocks, and therefore intensifies the anesthesia. It can also be used postoperatively as it reduces the dose of other regional anesthetic components, and subsequently the possible side effects. One must be aware that clonidine can produce hypotension, bradycardia, and sedation.52 Oral clonidine (5 µg/kg) when used as a premedicant enhances the postoperative analgesia provided by intrathecal morphine without adding to the side effects of the morphine. Other additional benefits noted from a clonidine premedication include (1) blunted reflex tachycardia for intubation, (2) reduction of vasomotor liability, (3) decreased plasma catecholamines, and (4) dramatic decreases in MAC for inhaled gases or injected drugs.
Clonidine is rapidly absorbed by mouth and reaches peak plasma levels within 60 to 90 minutes. The elimination half-life is between 9 and 12 hours. It is equally excreted in the liver and kidneys. The duration of the hypotensive effect after a single dose is about 8 hours. The transdermal administration of clonidine requires about 48 hours to achieve therapeutic levels. The decrease in systolic blood pressure is more prominent than the decrease in diastolic blood pressure. There seems to be no effect on glomerular filtration rate. The perioperative administration
of clonidine either as an oral doses or as a patch for total of 4 days, has significantly reduced the incidence of myocardial ischemia and mortality up to 2 years postoperatively.
The most common side effects are sedation and a dry mouth. However, skin rashes are frequent with chronic use. Impotence may be seen occasionally, and orthostatic hypotension is rare. One of the more worrisome complications of chronic clonidine use is a withdrawal syndrome on acute discontinuation of the drug. This usually occurs about 18 hours after discontinuation. The symptoms are hypertension, tachycardia, insomnia, flushing, headache, apprehension, sweating, and tremulousness. This condition lasts for 24 to 72 hours and is most likely to occur in patients taking more than 1.2 mg/day of clonidine. The withdrawal syndrome has been noted postoperatively in patients who were withdrawn from clonidine before surgery. It can be confused with anesthesia emergence symptoms, particularly in a patient with uncontrolled hypertension.53 Absent the availability of the oral route in the surgical patient, withdrawal can be treated with clonidine transdermally or more rapidly with rectal clonidine.
Dexmedetomidine is a more selective α2 agonist than clonidine (see Chapter 56).54 Its potent α2 agonism is 1,620:1 α2 to α1. Compared with clonidine, dexmedetomidine is 7 times more selective for α2 receptors and has a shorter half-life of 1.5 hours. The loading dose (1 µg/kg) is given over 10 minutes or longer. Then an infusion is begun at 0.2 to 0.7 µg/kg/hr. Because of hemodynamic side effects, some centers omit the loading dose and start the continuous infusion. It has a more rapid onset of action (<5 minutes). The time to peak effect is 15 minutes. It can be given intravenously and has many uses in anesthesiology. It provides excellent sedation, reduces blood pressure, HR, and profoundly decreases plasma catecholamines. Little respiratory depression accompanies weaning from mechanical ventilation. It can be administered as a premedicant in cases of difficult intubations where awake fiberoptic intubation is employed. In the intensive care unit the use of clonidine is employed because of its sedating and analgesic effects without the respiratory depressive actions of other agents. There is concern for possible rebound hypertension, rebound hyperexcitability, and arrhythmias in infusions longer than 24 hours; ultimately, clinical trials are required to clarify these questions.55 A recent meta-analysis demonstrated a trend toward improved cardiac outcomes in noncardiac surgical patients who have been treated perioperatively with dexmedetomidine.56 Dexmedetomidine has been shown to be an effective anxiolytic and sedative when used as premedication. Pretreatment with dexmedetomidine, like clonidine, attenuates hemodynamic responses to intubation. Likewise, it decreases the MAC for volatile anesthetics from 35 to 50% but increases the likelihood of hypotension. Dexmedetomidine, like clonidine, increases the range of temperatures not triggering thermoregulatory defenses. It is likely to promote perioperative hypothermia, but also is effective against shivering.
Nonadrenergic Sympathomimetic Agents
Nonadrenergic sympathomimetic drugs also act indirectly by influencing the cAMP-calcium cascade, exclusive of the receptors (Fig. 15-10). The function of the second messenger (Ca2+) nearly always goes together. This concept reinforces the recent appreciation of the homogeneity of action of a wide variety of drugs previously thought to be unrelated. Sympathomimetics have more pharmacologic similarities than differences.
Vasopressin, and its congener (desmopressin) are exogenous preparations of the endogenous antidiuretic hormone (ADH). ADH and oxytocin are the two principle hormones secreted by the posterior pituitary. Target sites for ADH are the renal collecting ducts, vascular smooth muscle, and cardiac myocytes. Water absorption is passively reabsorbed from renal collecting ducts into extracellular fluid. Nonrenal actions include inotropism and intense vasoconstriction accounting for its alternative designation as vasopressin.57 Arginine vasopressin is the most active form of ADH. Historically, vasopressin has been used for (1) treatment of diabetes insipidus, (2) diagnosis of diabetes insipidus, (3) abdominal distention, and (4) as an adjunct in the treatment of gastrointestinal hemorrhage and esophageal varices. Recently, three new indications for the use of vasopressin have emerged: (1) pressure support for septic shock, (2) cardiac arrest secondary to ventricular fibrillation/ventricular tachycardia, or (3) pulseless electrical activity/asystole.58,59,60,61 Animal studies have shown, both in open- and closed-chest models, vasopressin caused larger increases in systemic vascular resistance, cerebral perfusion pressure, and coronary perfusion pressure than EPI. Vasopressin is a more effective vasoconstrictor than EPI in the presence of hypoxia and acidosis. In contrast to EPI, vasopressin does not seem to increase myocardial oxygen consumption or lactate production.61,62 The 2005 guidelines for Advanced Cardiac Life Support (ACLS) of the American Heart Association recommend that vasopressin may be used to replace the first or second dose of EPI during the pulseless arrest algorithm63 (see Chapter 59). EPI is class IIb recommendation, and vasopressin, which did not show any improvement in survival when compared with EPI, may be used instead of the first or the second dose of EPI and is considered class-indeterminate36 (see Chapter 59). Vasopressin administered for cardiac arrest is known as vasopressin injection USP. The dose in cardiac arrest is 40 IU in 40 mL IV as a single dose in a peripheral IV line. Extravasation may cause local tissue necrosis. Its use in vasodilated sepsis is by infusion pump starting at 0.04 IU/min. There are suggestions that vasopressin may be useful in addition to potent α agonists for treatment of shock, especially from relative sparing of the mesenteric vessels; these data are supported by rat studies.64 Despite a theoretical advantage of using vasopressin to decrease the catecholamines dosage in septic patients, the use of vasopressin failed to decrease mortality when compared with NE.58 In such circumstances it seems that timing of initiation of therapy is the most important parameter for survival.65,66
Adenosine, available for more than 50 years, has been recognized recently as a clinically useful drug. It is an endogenous nucleotide and is found in every cell in the body. It is composed of adenine and a pentose sugar. Production can be increased by stimuli such as hypoxia and ischemia. This ubiquitous nucleotide has potent electrophysiological effects in addition to having a major role in regulation of vasomotor tone. Adenosine is believed to have a cardioprotective effect by regulating oxygen supply and demand (see Chapter 59). The receptors in the myocardial conduction system are the most sensitive and mediate sinoatrial node slowing and AV nodal conduction delay. Adenosine hyperpolarizes atrial myocytes and decreases their action potential duration via an increase in outward K+ current. These are the ACh-regulated K+ channels.
Adenosine mimics the effects of ACh in many ways, including an extremely short plasma half-life of mere seconds. Adenosine also antagonizes the inward Ca2+ current produced by catecholamines. This antidysrhythmic mechanism of Ca2+ channel blockade is thought to be an indirect effect and important only when β stimulation is present. The primary antidysrhythmic effect of adenosine is to interrupt re-entrant AV nodal tachycardia, which most likely relates to its K+ current, rather than Ca2+ current effects. The chief indication for adenosine is paroxysmal supraventricular tachycardia, which it may terminate in a matter of seconds, adenosine being the recommended
as first line of treatement.36,67 Adenosine is to be used only cautiously in patients with Wolff-Parkinson-White syndrome with narrow complex tachycardia, and should be avoided in Wolff-Parkinson-White syndrome with atrial fibrillation as its use may increase the conduction via the atrioventricular node and induce ventricular fibrillation. One may use adenosine for re-entrant tachycardias involving the AV node, as well as right ventricular tachycardia.68 The same characteristics that make adenosine an effective therapeutic agent may also make it an ideal agent for diagnosing other types of dysrhythmia. The incidence of incorrect diagnosis of supraventricular dysrhythmia has been reported to be as high as 15% using conventional means. Approximately 10% of supraventricular tachycardias do not involve AV nodal re-entry. Adenosine will nevertheless slow AV nodal conduction in these cases, decrease the ventricular rate, and allow inspection of P waves. Thus, adenosine may be useful in unmasking atrial fibrillation or flutter when fast ventricular responses are noted.
A number of side effects have been reported with the use of adenosine, including flushing, headache, dyspnea, bronchospasm, and chest pain. The majority of these are brief (seconds) and not clinically significant. Transient new dysrhythmias (65%) will be noted at the time of cardioversion, but these disappear during the half-life of the drug. Major hemodynamic changes are rare but consist of hypotension and bradycardia. Adenosine should be given by means of a rapid IV bolus with flush because of its extremely short half-life of <10 seconds. The initial adult dose is 6 mg (100 to 150 µg/kg for pediatrics), which can be followed by 12 mg within 1 to 2 minutes if the initial dose is without effect.51 The 12-mg dose may be repeated once. The antidysrhythmic effect of adenosine occurs as soon as the drug reaches the AV node. Although both adenosine and verapamil are as effective in treating the paroxysmal supraventricular tachycardia, one must be aware of side effects before choosing one versus the other. Nevertheless, adenosine seems to be a better choice because of fewer side effects, a view that is recommended by the recent ACLS Guidelines36,69 (see Chapter 59).
Phosphodiesterase inhibitors have pharmacologic properties approaching the characteristics of the ideal inotropic agent.70,71,72 They do not rely on stimulation of β and/or α receptors. These drugs combine positive inotropism with vasodilator activity by selectively inhibiting phosphodiesterase (PDE) III. PDE I and II hydrolyze all cyclic nucleotides, whereas PDE III acts specifically on cAMP. The PDE III inhibitors interact with PDE III at the cell membrane and impede the breakdown of cAMP. cAMP levels increase and protein kinase is activated to promote phosphorylation. In cardiac muscle, phosphorylation increases the slow inward movement of calcium current, promoting increased intracellular calcium stores. Thus, inotropism increases. In vascular smooth muscle, increased cAMP activity accounts for the vasodilation, decreased peripheral vascular resistance, and lusitropism. Amrinone (currently termed inamrinone) is the prototypical PDE III inhibitor, and like nitroprusside and nitroglycerin, promotes diastolic relaxation, which promotes ventricular filling.73Milrinone is currently the most popular PDE inhibitor released for clinical use in the United States. The degree of hemodynamic effect of these drugs depends on the dose, degree of inotropic reserve, and state of cAMP depletion.
Milrinone is a derivative of amrinone. (In most centers milrinone has replaced amrinone; in general, their hemodynamic actions are similar.) It has nearly 20 times the inotropic potency of the parent compound. Milrinone is active both intravenously and orally and has beneficial short-term hemodynamic effects in patients with severe refractory congestive heart failure. Improvement of CO appears to result from a combination of enhanced myocardial contractility and peripheral vasodilation. Treatment with oral milrinone for up to 11 months has been effective and well tolerated without evidence of fever, thrombocytopenia, or gastrointestinal effects. Milrinone has been approved for short-term IV therapy of congestive heart failure.70,71,72 It is administered with a loading dose of 50 µg/kg over 10 minutes. The maintenance IV infusion rate ranges from a minimum of 0.375 µg/kg/min to a maximum of 0.75 µg/kg/min (not to exceed 1.13 µg/kg/day). Dosage must be adjusted in renal failure patients as milrinone is excreted in the urine, primarily in unconjugated form. Peak response with an IV dose occurs after 5 minutes and reveals no evidence of tolerance over short-term trials (24 hours); it is compatible with other adrenergic agonists. It is an effective inotropic agent in patients receiving beta-blockers. Its efficacy in the patient who has been digitalized has been demonstrated. Milrinone and DBT have become the mainstay of treatment for decompensated heart failure patients who require IV vasodilators and positive inotropic agents. Nevertheless, the use of such agents significantly increases mortality74 and one must be aware that these drugs may increase the risk of arrhythmias in these patients who may in fact require implantable cardioverter defibrillators.75
Glucagon is a single-chain polypeptide of 29 amino acids that is secreted by pancreatic cells in response to hypoglycemia (see Chapter 49). The liver and kidney are responsible for its degradation. Known effects of this hormone in humans include the following: (1) inhibition of gastric motility, (2) enhanced urinary excretion of inorganic electrolytes, (3) increased insulin secretion, (4) hepatic glycogenolysis and gluconeogenesis, (5) anorexia, (6) inotropic and chronotropic cardiac effects, and (7) relaxation of smooth muscle (biliary, i.e., sphincters).76 Little attention was given to glucagon until 1968, when it was demonstrated to produce positive inotropic and chronotropic effects in the canine heart. Glucagon enhances the activation of adenyl cyclase in a manner similar to that of NE, EPI, and isoproterenol. These cardiac actions of glucagon are not blocked by β blockade or catecholamine depletion. Glucagon, in contrast to the xanthines, rarely causes dysrhythmia, even in the face of ischemic heart disease, hypokalemia, and digitalis toxicity. Glucagon may possess antidysrhythmic activity in digitalis toxicity because it has been shown to enhance AV nodal conduction in patients with varying degrees of AV block. An IV dose of 1 to 5 mg of glucagon increases cardiac index, mean arterial pressure, and ventricular contractility, even in the presence of digitalis therapy. After a bolus dose, its action dissipates in approximately 30 minutes. Nausea and vomiting are common side effects in the awake patient, especially following a bolus dose. Hypokalemia, hypoglycemia, and hyperglycemia are also seen. Glucagon is also useful in treating insulin-induced hypoglycemia.
Despite the obvious benefits of glucagon in cardiac patients, its use has not become popular. This pancreatic hormone may be of hemodynamic benefit when more conventional approaches have proved refractory in the following settings: (1) low CO syndrome following cardiopulmonary bypass, (2) low CO syndrome with myocardial infarction, (3) chronic congestive heart failure, and (4) excessive β-adrenergic blockade. In cases of anaphylactic shock with significant and refractory hypotension, glucagon is extremely useful alternative agent in reversing the decreased blood pressure.77
The most important actions of the digitalis glycosides are those affecting myocardial contractility, conduction, and rhythm. The glycoside most likely to be used by the anesthesiologist is digoxin. The principal uses of
digoxin are for the treatment of congestive heart failure and to control supraventricular cardiac dysrhythmia such as atrial fibrillation. Digoxin is one of the few positive inotropes that does not increase HR. Digoxin enhances myocardial inotropism and automaticity but slows impulse propagation through the conduction tissues.51 Despite nearly two centuries of use, its mechanism of action is only modestly certain. Digitalis reciprocally facilitates calcium entry into the myocardial cell by blocking the Na+,K+ adenosine triphosphatase pump. This calcium influx may account for its positive inotropic action because this inotropic response is not catecholamine- or β receptor-dependent, and is therefore effective in patients taking β-blocking drugs. The inhibition of this enzyme transport mechanism also results in a net K+ loss from the myocardial cell. This contributes to digitalis toxicity with hypokalemia. Calcium potentiates the toxic effects of digitalis. Extreme caution should be observed when calcium is given to a patient taking digitalis or when digitalis administration is contemplated in the patient with hypercalcemia. Digitalis has been of little use in cardiogenic shock and has proved potentially injurious in patients with uncomplicated myocardial infarction because of its vasoconstrictive properties and effects on myocardial oxygen consumption in the absence of cardiomegaly. Care must be taken to rule out conditions in which the use of digitalis is of no benefit and is potentially harmful. These include mitral stenosis with normal sinus rhythm and constrictive pericarditis with tamponade. Signs and symptoms of idiopathic hypertrophic subaortic stenosis are often exacerbated by digitalis. With increased strength of contraction, the muscular obstruction can be markedly increased. The same is true for the use of digitalis in patients with infundibular pulmonic stenosis, as occurs with tetralogy of Fallot. Any augmentation of contractility may further reduce an already diminished pulmonary blood flow. Beware of digitalis toxic reactions in the older age group and in patients suffering from arterial hypoxemia, acidosis, renal compromise, hypothyroidism, hypokalemia, or hypomagnesemia, as well as in patients receiving quinidine or calcium channel blockers.
When entertaining the possibility of perioperative digitalis administration, the following points must be considered.
1. Myocardial oxygen consumption is increased in the nonfailing, nondilated heart.
2. The therapeutic-to-toxic ratio of digitalis is narrow.
3. Inotropic drugs that are less toxic and reversible are readily available.
4. Verapamil or beta-blockers are more efficacious for supraventricular tachydysrhythmias not initiated by heart failure.
5. Digitalis may cause serious dysrhythmia in the unstable patient.
6. Serum potassium concentrations may fluctuate in the surgical patient.
7. Any cardiac dysrhythmia that occurs in the presence of digitalis must be considered a toxic phenomenon.
8. Digitalis-induced cardiac dysrhythmias are difficult to treat.
9. Renal compromise will result in toxic effects with standard maintenance doses.
10. Cardioversion may be dangerous after digitalis administration.
11. After initiation of digitalis therapy, the administration of alternative drugs becomes more complicated.
Digoxin, beta-blockers, and calcium channel blockers such as diltiazem and verapamil may be used in patients with heart failure and normal ejection fraction to control the HR, especially if patients do have supraventricular tachyarrhythmias such as atrial fibrillation. Nevertheless, digoxin is not recommended for patients with heart failure, but with normal ejection fraction, as it may increase the left ventricular filling pressure, and subsequently aggravate their heart failure.78
Calcium is of great importance in the genesis of the cardiac action potential and is the key to controlling intracellular energy storage and utilization. Movement of extracellular calcium across membranes also governs the function of uterine smooth muscle as well as the smooth muscle of the blood vessels. The sympathomimetic drugs promote the transmembrane influx of calcium, whereas the beta-blockers and calcium channel blockers inhibit such movement. The American Heart Association has recommended against the use of calcium during cardiac arrest except when hyperkalemia, hypocalcemia, or calcium-channel blocker toxicity is present.79 Subsequently, the indications for calcium use are now limited to only few clinical applications (see Chapter 59). Calcium chloride is often given at the termination of cardiopulmonary bypass to offset the myocardial depression associated with hypothermic potassium cardioplegia.80 There is newer evidence that the use of calcium in the early postbypass period may induce spasm of the coronaries, including the newly grafted internal mammary artery, also causes hypercontracture of the heart cells, and therefore increases the risk for myocardial ischemia, reperfusion injury, and even myocardial infarction.81,82,83 The use of calcium salts is clearly indicated during rapid or massive transfusions of citrated blood.80
Citrate binds calcium, and rapid infusion rates of citrated blood result in myocardial depression that is reversible by calcium. Two forms of calcium salts are commonly available: calcium chloride and calcium gluconate. Traditionally, calcium gluconate has been preferred in pediatric patients and calcium chloride in adult patients. Previous data held that calcium chloride produced consistently higher and more predictable levels of ionized calcium.84 Studies have shown, however, that ionization of any of the preparations is immediate and equally effective (see Chapter 14). Calcium chloride produces only transient increases in CO and blood pressure. Bolus doses of 2 to 10 mg/kg (1.5 mg/kg/min) of calcium chloride can produce moderate improvement in contractility. The rapid administration of calcium salts, if the heart is beating, can produce bradycardia and must be used cautiously in the patient who is digitalized because of the hazard of producing toxic effects. Calcium salts will precipitate as calcium carbonate if mixed with sodium bicarbonate.
Monoamine Oxidase Inhibitors
Monoamine oxidase inhibitors (MAOIs) and the tricyclic antidepressants are used to treat psychotic depression. These drugs are not used in the practice of anesthesia but are a source of potentially serious anesthetic interactions in patients who are taking them chronically (see Chapter 23). Their use is rapidly declining as the nontricyclic antidepressants such as Prozac are more efficacious and produce fewer side effects. Few of the MAOIs or tricyclic antidepressants will be encountered in an anesthesia practice today, with the exceptions of phenelzine (Nardil) and amitriptyline (Amitril, Elavil). Their pharmacologic actions and side effects are a direct result of their effect on the cascade of catecholamine metabolism. MAOIs block the oxidative deamination of endogenous catecholamines into inactive vanillylmandelic acid. They do not inhibit synthesis. Thus, blockade of MAO would produce an accumulation of NE, EPI, DA, and 5-hydroxytryptamine in adrenergically active tissues, including the brain. The action of sympathomimetic amines is potentiated in patients taking MAOIs. Indirect-acting
sympathomimetics (ephedrine, tyramine) produce an exaggerated response as they trigger the release of accumulated catecholamines. Foods containing a high tyramine content such as cheese, red Italian wine, and pickled herring can also precipitate hypertensive crises.26 Meperidine has been reported to produce hypertensive crisis, convulsions, and coma with MAOIs. Hepatotoxicity has been reported that does not seem to be related to dosage or duration of treatment. Its incidence is low but remains a factor in selecting anesthesia.
The anesthetic management of patients taking MAOIs remains controversial. Currently, recommendations for management include discontinuation of the drugs for at least 2 weeks before surgery; however, this recommendation is not based on controlled studies but rather is the result of limited case reports that suggest potent drug interactions.
This group of antidepressant drugs is referred to as tricyclic antidepressants because of their structure. These drugs have almost replaced the MAOIs because of fewer side effects. All of these agents block uptake of NE into adrenergic nerve endings. Just as with the MAOIs, high doses of the tricyclic antidepressants can induce seizure activity that is responsive to diazepam. Neuroleptic drugs may potentiate the effects of tricyclic antidepressants by competition with metabolism in the liver. Chronic barbiturate use increases metabolism of the tricyclic antidepressants by microsomal enzyme induction. Other sedatives, however, potentiate the tricyclic antidepressants in a manner similar to that occurring with the MAOIs. Atropine also has an exaggerated effect because of the anticholinergic effect of tricyclic antidepressants. Prolonged sedation from thiopental has been reported. Ketamine may also be dangerous in patients taking tricyclic antidepressants by producing acute hypertension and cardiac dysrhythmia. Despite these serious interactions, discontinuation of these drugs before surgery is probably not necessary. The latency of onset of these drugs is from 2 to 5 weeks; however, the excretion of tricyclic antidepressants is rapid, with approximately 70% of a dose appearing in the urine during the first 72 hours. The long latency period for resumption of treatment militates against interrupted treatment. A thorough knowledge of the possible drug interactions and autonomic countermeasures now available obviates postponement.
Selective Serotonin Reuptake Inhibitors
The mechanism of action of selective serotonin reuptake inhibitors appears to be the selective inhibition of neuronal uptake of serotonin. This potentiates the behavioral changes induced by the serotonin precursor, 5-hydroxytryptophan.85 The availability of sympathetic antagonists for possible side effects during anesthesia weighs in favor of continuation of therapy versus the risk of exacerbation of a severe depression. Prozac (fluoxetine) is a popular oral nontricyclic antidepressant. Unlike desyrel, the elimination half-life of Prozac is 1 to 3 days and can lead to significant accumulation of the drug. Prozac's metabolism, like that of other compounds including tricyclic antidepressants, phenobarbital, ethanol, and pentothal, involves the P450 II D6 system. Therefore concomitant therapy with drugs also metabolized by this enzyme system may lead to drug interactions and prolongation of effect of the benzodiazepines. Buproprion is used as an antidepressant, whereas a sustained release drug is marketed as a nonnicotine aid to smoking cessation. The neurochemical mechanism of the antidepressant effect of bupoprion is not known. It does not inhibit monoamine oxidase and is a weak blocker of the neuronal uptake of serotonin and NE. It also inhibits the neuronal uptake of DA to some extent. No systematic data have been collected on the interactions of bupropion and other drugs.
Drugs that bind selectively to α-adrenergic receptors block the action of endogenous catecholamines or moderate the effects of exogenous adrenergics. The resultant effects may be ascribed together the blockade effect to α-adrenergic agonists or to unopposed α-adrenergic receptor activity. The effect is smooth muscle relaxation. The response to the vasculature may vary over a wide range in a single vascular bed, depending on its intrinsic state of constriction. Vessels with higher initial tone have a greater response to α blockade. Prominent clinical effects of α blockers include hypotension, orthostatic hypotension, tachycardia and miosis, nasal stuffiness, diarrhea, and inhibition of ejaculation. The α blockers may be classified according to binding characteristics. Phenoxybenzamine is an oral α blocker that produces and irreversible blockade. It is a relatively nonselective α blocker. Phentolamine, tolazoline, and prazosin are characterized by reversible binding and antagonism. When patients are taking these drugs chronically, one should keep in mind that the normal autonomic response to stress, inhalation anesthetics, or extensive regional anesthesia may be blunted. Elevations of catecholamines will not reflexly increase peripheral vascular resistance and may actually decrease if vascular β receptors are unopposed. α Blockers are often used in combination with diuretics and other antihypertensives. Volume depletion may not be evident on preoperative examination but become unmasked with the induction of anesthesia, resulting in the onset of a marked hypotension. This hypotension is usually responsive to volume repletion and the temporary use of a direct acting α agonist such as neosynephrine. There is no cause for discontinuation of these drugs before surgery but preloading with IV fluids is suggested to ensure adequate central volume.
Phentolamine is used almost exclusively in the presurgical treatment of pheochromocytoma (see Chapter 49). It is a competitive antagonist at α1 and α2 receptors. Phentolamine may also have some antihistaminic and cholinomimetic activity. The cholinomimetic activity may result in abdominal cramping and diarrhea, both of which are blocked by atropine. Tachycardia and hypotension are also common side effects.
Intravenously, phentolamine produces peripheral vasodilatation and a decrease in systemic blood pressure within 2 minutes and lasting from 10 to 15 minutes. Blood pressure reduction elicits baroreceptor reflexes and NE release. Cardiac arrhythmias and angina pectoris may accompany phentolamine administration. It can be given in doses of 30 to 70 µg/kg IV to produce a transient decrease in blood pressure. It can also be used as a continuous infusion to maintain blood pressure during resection of a pheochromocytoma.
Phenoxybenzamine acts as a nonselective α-adrenergic antagonist (see Chapter 49). α Blockade is 100 times more potent on postsynaptic α1 receptors than at α2 receptors. Preoperatively in preparation for removal of a pheochromocytoma, the dug is administered orally starting at 10 mg twice daily.86 The onset of α blockade is slow. This is related to the time required for structural modification of the phenoxybenzamine molecule to become active. The elimination half-life is about 24 hours. Orthostatic hypotension is prominent, especially in the presence of pre-existing hypertension or hypovolemia. CO is often increased and renal blood flow is not greatly altered except in pre-existing renal
vasoconstriction or stenosis. Coronary and cerebral vascular resistance is not changed.
Prazosin is relatively selective for α1 receptors, leaving the inhibiting effect of α2 receptor activity on NE release intact. As a result, it is less likely than nonselective α antagonists to evoke reflex tachycardia. The initial oral dose is 1 mg twice daily, then titrated to effect. Prazosin dilates both arterioles and veins. Cardiovascular effects include total body reductions in systemic vascular resistance and venous return. When combined with a diuretic it is an effective antihypertensive drug. It should not be used with clonidine or α-methyldopa, as it appears to decrease their effectiveness. Prazosin may also cause bronchodilation.
Oral α1 blockers have been found useful for benign prostatic hypertrophy and hypertension. The anesthesiologist may encounter patients taking these medications on a chronic basis and must be aware of their possible interactions with anesthetics (see Chapter 23). Doxazosin is a long-acting selective α1 blocker used for treating benign prostate hyperplasia and hypertension. The most common side effect, as with all α blockers, is orthostatic hypotension and dizziness. Tamsulosin is another α blocker that is used for benign prostate hyperplasia. It is not indicated for hypertension but it is capable of producing orthostatic hypotension.
β-Adrenergic blockers were introduced in the 1960s. These sympatholytic agents have dominated cardiovascular pharmacology. They are among the most common drugs used in the treatment of cardiac disease and hypertension. A variety of drugs are available with β-blocking activity that may be distinguished by differing pharmacokinetic and pharmacodynamic properties. Examples of some of the drugs available and their diversity of actions are listed in Table 15-12. Beta-blockers can be classified according to whether they are selective or nonselective on the β1 or β2 receptor and whether they possess intrinsic sympathomimetic activity. For example, a beta-blocker with selective properties for the β1 receptor would bind to the cardiac receptors, whereas a nonselective beta-blocker would bind to both β1 (cardiac) and β2 (vascular, bronchial smooth muscle and metabolic) receptors. Nonselective β-antagonists are referred to as first-generation beta-blockers. These include propranolol, nadolol, sotalol, and timolol. Second-generation drugs are those considered selective for β1-adrenergic blockade. These include atenolol, esmolol, and metoprolol. Over the past decade, and because of their selectivity, the use of beta-blockers has expanded to include the treatment of congestive heart failure. Recently, a new beta-blocker subcategory has been developed, respectively, beta-blocker with vasodilatory properties, such as in a new beta-blocker, nebivolol.87
Beta-blockers are an important class of agents that are indicated for treatment of coronary artery disease, hypertension, heart failure, and tachyarrhythmias. They have a primary role in treatment of patients after a myocardial infarction.88 Beta-blockers have a direct effect on reducing the mortality in patients with heart failure due to left ventricular systolic dysfunction (bisoprolol, carvedilol, and metoprolol). Recently, a fourth agent has been used with similar favorable results, and this is nebivolol.89,90 Nebivolol is a beta-blocker with an excellent β selectivity, and endothelium-dependent vasodilation secondary to L-arginine/nitric oxide pathway. Therefore, this novel drug has hemodynamic advantages and a better profile for side effects. Recent trials demonstrated a reduced morbidity and mortality in elderly patients with chronic heart failure, which makes this drug a very interesting option for the future treatment of cardiac disease because it is currently only available in Europe.87,91 Beta-blockers reduce the incidence of perioperative myocardial infarction; there is an increased interest in using these agents perioperatively in high-risk patients undergoing vascular and other high-risk surgical procedures92 (see Chapter 42).
Selective β-blockade is of great benefit in treatment of patients with obstructive airway disease, diabetes, or peripheral vascular disease. However, it must be emphasized thatspecificity is a relative term and not absolute. Nonselective blocking effects may be seen in all tissues if higher blood levels are reached with “selective” drugs. For example, the use of β1-selective blockers in patients with obstructive or reactive airway disease remains controversial. Patients with reactive airway disease may develop serious reductions in ventilatory function even with β1-selective antagonists, but these circumstances are rare, so these drugs can be employed for large categories of patients. Other drugs are available for treatment of supraventricular arrhythmias and hypertension in asthmatic patients. Sympathetic activation generally results in increased circulating glucose levels secondary to enhanced glycogenolysis, lipolysis, and gluconeogenesis. Administration of β2 blockers to insulin-dependent diabetics reduces their ability to recover from hypoglycemic episodes (seeChapter 49).
In patients receiving chronic beta-blocker therapy, the drug should be continued throughout the perioperative and postoperative period92 (see Chapter 42). Acute withdrawal of β-antagonists may produce a hemodynamic withdrawal syndrome and induce tachycardia.26 HR is a major determinant of myocardial oxygen demands. Tachycardia is known to increase the risk of poor outcome in patients with ischemic heart disease; therefore, hemodynamic control of HR and blood pressure (work) is important in reducing perioperative risk. Several studies have shown the benefits of prophylactic β-blockade with atenolol in patients at risk for ischemic cardiac disease.93 The reduction in perioperative morbidity and mortality in these groups of patients was significant.94,95,96,97,98,99 Recent data suggest that the use of beta-blocker alone is not effective, unless tight HR control is present (<80 beats per minute perioperatively). For this purpose a combination of drugs may be required; further studies are underway that may indeed establish the best clinical practice.95,97,100,101,102,103,104
Several of the β blockers listed in Table 15-12 also have a local anestheticlike effect on myocardial membranes at high doses. This effect is similar to that of quinidine in that phase 0 of the cardiac action potential is depressed slowing conduction. This membrane-stabilizing activity is caused by the D-isomer, whereas the L-isomer is responsible for β blocking activity. The clinical significance of membrane-stabilizing activity is unclear.
Propranolol is the prototypical β-blocking drug against which all others are compared. It is nonselective and has no intrinsic sympathomimetic activity but does have membrane-stabilizing activity at higher doses. It is available in both IV and oral forms. The IV dose is usually 0.5 to 1 mg repeated every 5 minutes up to a total of 5 mg with careful titration to effect.51 It is highly lipophilic and is metabolized by the liver to more water-soluble metabolites, one of which, 17-OH propranolol, has weak β-blocking activity. There is a significant first-pass effect by the liver after oral administration of the drug. It is highly protein-bound, and the free drug level may be altered by other highly bound drugs. The elimination half-life is approximately 4 hours, but the pharmacologic half-life is around 10 hours. Hemodynamic effects include decreased HR and contractility. The major factors contributing to the decrease in blood pressure by propranolol are decreased CO and renin release. Systemic vascular resistance may increase on acute administration owing to blockade of β2 receptors in the peripheral vasculature. With chronic administration, however, peripheral vascular resistance decreases. This is thought to be secondary to decreased renin release and, possibly, decreased
central SNS outflow. Complications with the use of propranolol include bradycardia, heart block, worsening of congestive heart failure, bronchospasm, and sedation.105 During anesthesia with halothane, it may cause severe bradydysrrhythmias. Because it is not cardioselective, most clinicians are moving away from using propranolol, and instead are using the selective alternatives such as metoprolol, or atenolol.
Table 15-12 β-Adrenergic Blocking Drugs
Metoprolol is a relatively selective β-blocking drug with β-blocking effects at moderate and high doses. It has neither intrinsic sympathomimetic activity nor membrane-stabilizing activity. It has a possible advantage in patients with reactive airway disease at oral doses up to 100 mg/day. The initial IV dose is 1.25-5 mg every 6 to 12 hours. For myocardial infarction the dose is 2 to 5 mg every 2 minutes for three doses, followed by 50 mg orally every 6 hours, with careful monitoring of the heart rate while the loading dose is being administered.51 It is mostly metabolized in the liver, with only about 5% excreted unchanged in the urine. The elimination half-life is 3.5 hours. It is available in IV as well as oral form; therefore, it is commonly recommended prior to surgery and anesthesia.89
Atenolol is similar to metoprolol in that it is relatively cardioselective and has no intrinsic sympathomimetic activity or membrane-stabilizing activity. It is less lipophilic, however, and is eliminated primarily by renal excretion. The starting dose is 5 mg over 5 minutes IV, and 25 to 50 mg/day oral administration.51 The elimination half-life is 6 to 7 hours. The lack of first-pass metabolism results in more predictable blood levels after oral dosing. The main advantage of this drug is its once a day dosing.93,106
Esmolol has several uses in the perioperative period.107 The most unique feature of the drug is the ester function incorporated into the phenoxypropanolamine structure. This allows for rapid degradation by esterases in the red blood cells and a resultant pharmacologic half-life of 10 to 20 minutes. Esmolol is cardioselective and appears to have little effect on bronchial or vascular tone at doses that decrease HR in humans. It has been used successfully in low doses in patients with asthma but caution is again advised when using beta-blockers in these patients. The IV bolus dose is 0.25 to 0.5 mg/kg, and a continuous infusion loading dose is 500 µg/kg/min over 1 to 2 minutes, with a maintenance dose of 50 to 200 µg/kg/min.51
Esmolol is metabolized rapidly in the blood by an esterase located in the red blood cell cytoplasm. It is different from the plasma cholinesterase and is not inhibited to a significant degree by physostigmine or echothiophate but is markedly inhibited by sodium fluoride. There are no apparent important clinical interactions between esmolol and other ester-containing drugs. At the highest infusion rates (500 µg/kg/min), esmolol does not prolong neuromuscular blockade by succinylcholine. Esmolol has proven to be useful in the perioperative period because of its capability to be administered intravenously and its short half-life. This feature permits a trial of β blockade in doubtful situations. Esmolol has been shown to blunt the response to intubation of the trachea and is moderately effective in treating postoperative hypertension.108,109,110 Most reported studies in humans have used doses of 50 to 500 µg/kg/min. The most beneficial approach seems to be a loading dose of 500 µg/kg over 30 seconds, followed by continuous infusion of 50 to 300 µg/kg/min. Peak blockade appears to occur within 5 minutes. On discontinuation of the infusion, serum levels decline with an elimination half-life of 9 minutes.
Timolol is also noncardioselective with little intrinsic sympathomimetic activity and no membrane-stabilizing activity. It is the only beta-blocker used as the L-isomer rather than the racemic mixture. It is 5 to 10 times as potent as propranolol. Hepatic metabolism accounts for approximately 66% of its elimination, and another 20% is found unchanged in the urine. The elimination half-life is 5.6 hours, and the pharmacologic half-life is approximately 15 hours. It was first used topically for treatment of glaucoma but is now used in hypertension and has been shown to decrease the risk of reinfarction and death following myocardial infarction. Its hemodynamic effects and side effects are similar to those of other beta-blockers. The anesthesiologist should also be aware that timolol eye drops may be absorbed systemically and cause bradycardia and hypotension that are refractory to treatment with atropine.111
Other beta-blockers include drugs such as nadolol (noncardioselective beta-blocker), acebutolol (cardioselective beta-blocker with intrinsic sympathomimetic activity and membrane-stabilizing activity), pindolol (nonselective beta-blocker with membrane-stabilizing activity and intrinsic sympathomimetic activity), betaxolol (cardiac selective), penbutolol (nonselective with some intrinsic sympathetic activity), carteolol (nonselective) are used for treatment of hypertension or HR control.
Labetalol is an antihypertensive drug with blocking activity at both α and β receptors. The relative α/β-blocking effects depend on the route of administration. After oral administration, the ratio of α/β effectiveness is 1:3; however, when given intravenously, it is 1:7. The α effects are primarily on α1 receptors, whereas the β effects on nonselective. Hemodynamic effects consist primarily of decreased peripheral resistance and decreased or unchanged HR with little change in CO. Serum renin activity is decreased. Maintenance of lower HRs in the presence of decreased systemic blood pressure is beneficial in controlling the myocardial oxygen supply/demand ratio and is a major benefit of labetalol in patients with coronary artery disease.
Labetalol is eliminated by hepatic glucuronide conjugation. The elimination half-life after IV administration is 5.5 hours and 6 to 8 hours after oral use. Elimination is not markedly prolonged in-patients with hepatic or renal failure. Another advantage of the drug is the ability to convert from IV to oral forms of the same drug after the patient is stable. For treatment of hypertension when used as a bolus, the initial dose is 2.5 to 10 mg IV over 2 minutes, then repeat every 10 minutes to a total of 30 mg. When used as a continuous infusion, it is usually started at 0.5 to 2.0 mg/min and titrated to effect. Because there is an enhanced effect by inhalation anesthetics, these doses should be decreased when used intraoperatively.
Complications and contraindications are similar to those for the beta-blockers. Labetalol should be used with caution in patients with compromised myocardial function because it may worsen heart failure. Also, owing to β-blocking activity, the drug may induce bronchospasm in asthmatics. As with other beta-blockers, abrupt withdrawal is not recommended. Labetalol is one of the favorites of many anesthesiologists for use in the perioperative period because it rapidly decreases both blood pressure, and to some extent, also the HR, it can be used as a bolus, and ultimately achieves normotension within a few minutes of initial administration.112,113
Calcium Channel Blockers
Calcium is regarded as the universal messenger in cells and plays a critical role in a number of biologic processes. It is
involved in blood coagulation, a broad array of enzymatic reactions, the metabolism of bone, neuromuscular transmission, the electrical activation of various excitable membranes, as well as endocrine secretion and muscle contraction. Calcium initiates several physiologic events in the specialized automatic and conducting cells in the heart. It is involved in the genesis of the cardiac action potential and it links excitation to contraction and controls energy stores and utilization. Movement of extracellular calcium across membranes also governs the function of smooth muscle in bronchi and in coronary, pulmonary, and systemic arterioles. Its roles in adrenergic effector response have been outlined in detail (seeAdrenergic Receptors). Membrane calcium channels are known to provide a pathway for calcium influx across cell membranes that differ from calcium efflux movements associated with active pumps or exchange. The inward calcium channel exhibits two distinguishing properties: (1) selectivity in that they have the ability to distinguish between ion species, and (2) excitability in that they have the property of responding to changes in membrane potential. Separate, ion-specific channels for sodium and calcium influx exist. The status of these channels can vary to produce three kinetic states: resting, activated, and inactivated.
Figure 15-16. Structural formulas of the calcium entry blockers demonstrate dissimilar structures consistent with their dissimilar electrophysiologic and pharmacologic properties. They also share some similarities but cannot be considered therapeutically interchangeable. Nifedipine and nitrendipine are structurally similar and are both potent vasodilators.
Classification of calcium channel blockers has been difficult since their discovery. They were initially thought to be β-adrenergic blocking drugs because of their sympatholytic action. Later they were called calcium antagonists. It is clear, however, that these drugs are not true pharmacologic antagonists of calcium. Instead, they interact with the cell membrane to control the intracellular concentration of calcium. The correct terminology for this group of drugs appears to be calcium channel blockers. The molecular structures of three clinically useful calcium entry blockers are seen in Figure 15-16. These drugs produce vasodilatation, depress cardiac conduction velocity (dromotropism), depress contractility (inotropism), and decrease HR (chronotropism). All calcium channel blockers do this, but with varying degrees of potency in the intact human and in vitro (Table 15-11). Thus, despite their similarities, these drugs cannot be considered therapeutically interchangeable. The useful pharmacologic effects of the calcium channel blockers have been confined almost solely to the cardiovascular system.99 The drugs are all absorbed via the gastrointestinal tract, but the extensive first-pass hepatic extraction of verapamil limits its bioavailability orally (Table 15-13). Onset of action is equivalent for all three
drugs and is consistent with rapid membrane transport. All three drugs are extensively protein-bound and subject to the effect of changes in plasma protein concentration and competition from other protein-bound drugs and metabolites, but final elimination of verapamil and nifedipine is primarily renal.
Table 15-13 Comparative Pharmacology of Calcium Entry Blockers
Verapamil is a calcium channel blocker that is administered intravenously for terminating supraventricular tachydysrhythmias. Nearly all forms of supraventricular tachydysrhythmias are caused by re-entry using either the sinoatrial or the AV node as part of the circuit. Verapamil terminates these cardiac dysrhythmias by decreasing nodal conductivity and converting the unidirectional block of re-entry to a bidirectional block. Verapamil does not alter the action potential upstroke in fibers whose resting membrane potential is more negative than -60 mV, that is, fast-action potentials. (It does slow or prevent depolarization in cardiac tissue with a resting membrane potential that is less negative than -50 mV, that is, calcium-dependent upstroke.) Verapamil, therefore, has profound effects on pacemaker cells, which depend on the calcium current for depolarization. It depresses the rate of sinus discharge, reduces conduction velocity, and increases refractoriness of the AV node. A dose-dependent increase in the PR interval and AV interval is produced on the electrocardiogram. This has been described as a quinidinelike effect similar to that produced by class IA antidysrhythmic drugs (e.g., procainamide), which are also effective for supraventricular dysrhythmia. In contrast to procainamide, verapamil does not increase the QRS or QT interval because it lacks activity on the sodium-dependent action potentials.
Verapamil is a first-line drug for treatment of supraventricular tachydysrhythmias (Table 15-11) (see Chapter 59). The incidence of successful termination of paroxysmal atrial tachycardia with verapamil in adults has approached 90%. It is also effective in treating atrial fibrillation and atrial flutter by either converting to a sinus rhythm or slowing the ventricular response. The ventricular rate will slow as a result of decreased conduction velocity through the AV node even when conversion is not produced. Caution must be exercised in treating patients when the underlying cause of the atrial tachycardia, atrial fibrillation, or atrial flutter is the Wolff-Parkinson-White syndrome.36 Verapamil may terminate the tachydysrhythmia by its specific depressant effects on the AV node, which is one limb of the re-entrant pathway. It may also increase conduction velocity in the accessory tract, in which case the HR may actually increase. Verapamil has no adverse effects on bronchial asthma or obstructive lung disease and may be selected over propranolol in patients with these conditions. It should be avoided in patients with sick sinus syndrome, AV block, and the presence of heart failure, unless the heart failure is the result of a supraventricular tachycardia. Verapamil has been effective in terminating ventricular tachycardias and premature depolarizations in about two thirds of the treatment trials when other drugs have failed, and can be used also as an antihypertensive.78,114
The important side effects of verapamil are directly related to its predominant pharmacologic action (Table 15-11). It may produce unwanted AV conduction delays and bradycardia, resulting in cardiovascular collapse. Verapamil must be used carefully, if at all, in the presence of propranolol. The combined effect has produced complete heart block in animals and humans. It must be used carefully in digitalized patients for the same reason. No such interactions exist with nifedipine. The combination of β blockade and nifedipine may be beneficial in patients with ischemic heart disease because the reflex tachycardia seen with nifedipine can be countered with β blockade.
Nifedipine is the most potent calcium entry blocker when tested in isolated tissue preparations. It is an equipotent cardiac depressant and vasodilator. Depression of inotropism and cardiac conduction, however, is not evident in the intact human. It does not affect baroreflex mechanisms and, as a result, the marked vasodilation is accompanied by increased SNS tone and afterload reduction (Table 15-11).26 A compensatory tachycardia may result, and CO may actually increase as a result of the afterload reduction. The most specific therapeutic application for nifedipine is coronary vasospasm (variant of Prinzmetal's angina; see Chapter 41). It has been more successful than nitroglycerin for this purpose because it produces a more profound and predictable coronary vasodilation. It has also been extremely useful in other types of ischemic heart disease ranging from unstable angina to myocardial infarction. The decrease in myocardial oxygen demand that results from the reduced afterload and reduced left ventricular volume appears to be the mechanism for the relief of angina. Coronary vasodilation is another factor, but it is not known if this is the antianginal effect in patients with coronary artery disease. The dilating effect may last only 5 minutes, but the antianginal effect may last more than 1 hour. As an antihypertensive the usual dosage is oral administration of 10 to 20 mg/day.51
The hemodynamic effects of diltiazem lie somewhere between those of verapamil and nifedipine. It is less potent than either of these two agents. Diltiazem is a good coronary artery dilator but a poor peripheral vasodilator. It often produces bradycardia and delayed conduction, and reflex tachycardia is not a problem. It appears to be an effective oral drug for the treatment of coronary disease in which cardiac dysrhythmias are troublesome. Cardiac dysrhythmias are noticeably a part of the clinical picture in patients suffering from coronary spasm. Intravenous administration of diltiazem is effective therapy for supraventricular tachycardias including paroxysmal supraventricular tachycardia, atrial fibrillation, atrial flutter, and re-entrant tachycardias. Like verapamil, diltiazem acts by prolonging AV nodal conduction. The peripheral vascular effects of diltiazem, though, are less severe, making it a more desirable therapeutic choice in most cases. A bolus dose of 0.25 mg/kg is administered over 2 minutes and may be repeated at 0.35 mg/kg if necessary after 15 minutes. An infusion of 5 to 15 mg/hr may be necessary to maintain the reduction of HR The new 2005 ACLS Guidelines recommends use of calcium channel blockers for a variety of supraventricular arrhythmias, and because of diminished peripheral vasodilation, which implies limited effect on the arterial blood pressure, diltiazem appears to be one of the best options for management of tachyarrhythmias36 (see Chapter 59).
Nicardipine hydrochloride is a calcium channel blocker that can be administered orally and intravenously. It is the only calcium channel blocker that can be titrated intravenously to be used as an antihypertensive agent, the usual dose being 1 to 2 µg/kg/min or 5 mg/hr.51 Nicardipine is a smooth muscle relaxant producing vasodilation of peripheral and coronary arteries. It has a rapid onset of action, and the major effects last 10 to 15 minutes. Toxic metabolic products are not produced. It has minimal cardiodepressant effects and does not decrease the rate of the sinus node pacemaker or slow conduction through the AV node, but one should use it cautiously in patients having acute myocardial ischemia. Renal failure does not affect the dosage, but the dosage should be reduced in the elderly and those with hepatic dysfunction. It is compatible with most
crystalloid solutions. Side effects of nicardipine include headache, lightheadedness, flushing, and hypotension. Reflex tachycardia is not a frequent finding with nicardipine, as is the case with nitroprusside, hydralazine, or nifedipine.112,113,115
Nimodipine is highly lipophilic. It has a greater vasodilating effect on cerebral arteries than on vessels elsewhere because of its lipophilism, which promotes crossing the blood–brain barrier. Clinical studies demonstrate a favorable effect on the severity of neurologic deficits caused by cerebral vasospasm following subarachnoid hemorrhage. However, no radiographic evidence has been presented that nimodipine either prevents or relieves spasm of these arteries. The mechanism for clinical improvement is not known. It is an oral drug that is rapidly absorbed, with a T-terminal half-life of approximately 8 to 9 hours. The usual dose is 60 mg every 4 hours for 21 days.51 Earlier elimination rates are much more rapid, which results in a need to redose every 4 hours. The bioavailability of an oral dose is only 13%. Dosage should be reduced in patients with hepatic dysfunction. The primary indication for nimodipine is for the improvement of neurologic deficits caused by vasospasm following subarachnoid hemorrhage from a ruptured cerebral aneurysm.112,113,116
Calcium Channel Blockers and Anesthesia
Evidence indicates that halothane depresses slow-channel kinetics. All of the potent inhalation anesthetics behave in a similar fashion in that they depress myocardial contractility and vascular tone in a dose-related manner. Most studies indicate that the calcium entry blockers and inhalation anesthetics exert additive effects on the inward calcium current.117Opioid anesthetics do not appear to add anything to the effects of the calcium entry blockers. Calcium channel blockers appear to augment the effects of both depolarizing and nondepolarizing muscle relaxants.118 These observations serve as a word of caution because their clinical significance has not been defined. Prolonged apnea and relaxation have been reported when verapamil was used to treat a supraventricular tachycardia in a patient with Duchenne's muscular dystrophy.119 One must be aware that calcium channel blockers may have side effects such as hypotension, in cases of overdosage, headaches, facial flushing, dizziness, ankle edema, constipation, and may even induce angina; therefore, their administration in perioperative period, when dehydration is a common occurrence, should be closely monitored.120 Calcium entry blockers should be continued until the time of surgery to maintain control of angina pectoris, hypertension, or cardiac dysrhythmia.101 In addition, the use of calcium channel blockers in the perioperative period appears to induce a beneficial effect of decreasing cardiac complications unrelated to cardiac surgical procedures121 (see Chapter 23). Verapamil may increase the toxicity of digoxin, the benzodiazepines, carbamazepine, oral hypoglycemics, and possibly quinidine and theophylline.122 Cardiac failure, AV conduction disturbances, and sinus bradycardia may be more frequent with concurrent use of beta-blockers, and severe hypotension and bradycardia may occur with bupivacaine. Decreased lithium effect and lithium neurotoxicity have both been reported with the concurrent use of verapamil.123 The effects of verapamil may also be increased by cimetidine.
Most antihypertensive drugs blunt the ANS or its effector organs or cause reflex increases in ANS outflow. Anesthetic agents may also inhibit ANS tone to some degree and might therefore have additive effects with antihypertensive drugs. In addition, patients with hypertension may exhibit greater lability in blood pressure intraoperatively and rebound hypertension in the postoperative period. A rational approach to their perioperative use includes decisions as to holding or continuing them preoperatively, possible interactions with anesthetic drugs, and resumption of treatment postoperatively.
Angiotensin-Converting Enzyme Inhibitors
The renin-angiotensin system is integrally related to the ANS in controlling blood pressure (Fig. 15-12; see Chapter 49). The central role of the renin-angiotensin-aldosterone system in the regulation of fluid balance and hemodynamics was not fully appreciated until the discovery and clinical application of inhibitors of the angiotensin-converting enzyme (ACE). Captopril, enalapril, and lisinopril inhibit converting enzyme and thereby prevent the conversion of angiotensin I to the active angiotensin II. These drugs have been highly effective in the treatment of all levels of essential hypertension as well as renovascular and malignant hypertension. The cardiovascular effects normally involve only decreased peripheral vascular resistance. CO may remain normal or increase while the filling pressure remains unchanged. Thus, these drugs have been effective in the management of congestive heart failure as well.40 There is usually no increase in SNS tone in response to the lowered blood pressure. ACE inhibition generally results in reductions in angiotensin-aldosterone, NE, and plasma antidiuretic hormone. This suppression is accompanied by a decrease in aldosterone and an improvement in cumulative plasma potassium levels, which are beneficial in both congestive heart failure and hypertension. It can be concluded that the major humoral responses to chronic congestive heart failure, even overlooking the effects of the diuretics, are affected by the release of angiotensin, aldosterone, and increased SNS tone. Captopril, the first orally active compound, has proven highly effective in the treatment of all levels of hypertension and congestive heart. Enalapril is a second-generation (nonsulfhydryl) ACE inhibitor. The omission of the sulfhydryl group possibly diminishes side effects. Both captopril and enalapril combine a high degree of clinical efficacy with a low rate of side effects. Both are eliminated via renal excretion and should be given in reduced doses in patients with renal dysfunction. Captopril has a shorter half-life and requires more frequent dosing than enalapril. Enalapril has to be converted by esterase in the liver and other tissues into the active compound enalaprilat. Lisinopril is one of these ACE inhibitors that is absorbed as the active form and is very long acting.
The ACE inhibitors are associated with few side effects and are popular in treating hypertension. Captopril may produce reversible neutropenia, dermatitis, and angioedema. Enalapril produces syncope, headache, and dizziness in about 1% of elderly patients. All ACE inhibitors may cause hypotension in patients who are hypovolemic and taking diuretic therapy. The hypotensive effects are also enhanced by the concomitant use of calcium channel blockers. The ACE inhibitors blunt the hypokalemic effects of thiazide diuretics and may magnify the potassium-sparing effects of spironolactone, triamterene, and amiloride. In addition, nonsteroidal anti-inflammatory drugs, including aspirin, may magnify the potassium-retaining effects of ACE inhibitors. ACE-I is now a mainstay in treatment of patients with heart failure and decreased ejection fraction, since it increases their survival.74For patients with heart failure and normal left ventricular ejection fraction, the first line of treatment is loop diuretics in combination with beta-blockers and (ACE) inhibitors.99 In the perioperative period, the ACE inhibitors have been associated with significant hypotension, which at times such as when separating from cardiopulmonary
bypass requires additional vasopressors to sustain systemic blood pressure.124
A new class of drugs, namely angiotensin–receptor blockers, was developed by inhibiting directly the effects of the hormone angiotensin II. These medications have been developed with the hope that, being similar to an ACE inhibitor, one could expect the same effectiveness, with fewer side effects such as cough, angioneurotic edema, and rash.125Alternatively, there are data that this class of drugs may have some beneficial effects on decreasing the renal deterioration in diabetic patients.126
Hydralazine is the most commonly used vasodilator and can be given by the intramuscular, intravenous, and oral routes to achieve an optimum blood pressure control. It relaxes smooth muscle tone directly, without interacting with adrenergic or cholinergic receptors. The mechanism of action is unknown. It is most potent in coronary, splanchnic, renal, and cerebral vessels, causing increased blood flow in each of these organs. The decrease in cardiac afterload is beneficial, but, unfortunately, there is usually a concomitant reflex tachycardia that may be severe. It is commonly combined with a beta-blocker such as propranolol. Hydralazine is metabolized by hepatic acetylation, and oral bioavailability may be low owing to first-pass metabolism. The elimination half-life is about 4 hours, but the pharmacologic half-life is much longer as a result of avid binding of the drug to smooth muscle. The effective half-life is approximately 100 hours. Side effects include a lupuslike syndrome, drug fever, skin rash, pancytopenia, and peripheral neuropathy. The IV dose for perioperative use is 5 to 10 mg in an IV bolus every 15 to 20 minutes until blood pressure control is achieved. It may also be given 10 to 40 mg intramuscularly, but the response is slower.78,112,127
Sodium nitroprusside is an extremely potent vasodilator that is available only for IV administration (see Chapter 41). It acts directly on smooth muscle, causing both arterial and venous dilation. The action of sodium nitroprusside on both venous and arterial sides of the circulation causes decreases in cardiac preload as well as afterload.99,128 This results in decreased cardiac work; however, it has been suggested that sodium nitroprusside may further compromise ischemic myocardium in the presence of occlusive coronary artery disease by shunting blood away from the ischemic zone.129 Other potential and deleterious side effects include pulmonary vasodilation with an increased ventilation-perfusion mismatch and with resultant hypoxia, and temporary decrease in platelet function.51,130 Sodium nitroprusside is useful during the perioperative period. It lowers blood pressure within 1 to 2 minutes, with the effect dissipating within 2 minutes after infusion is stopped. It is extremely potent and should be administered through a central venous line by infusion pump while continuously monitoring arterial pressure. The starting dose is 0.25 to 0.5 µg/kg/min. It can be increased slowly as needed to control blood pressure, but chances for toxicity are greater if the dose of 2 µg/kg/min is exceeded. The dose required for steady-state-induced hypotension is variable. The hypotensive effects of sodium nitroprusside may be potentiated by inhalation anesthetics and blood loss; therefore, close perioperative monitoring is essential. It is commonly used to induce hypotension for decreasing blood loss in patients predisposed to major hemorrhage.112
Chemically, sodium nitroprusside consists of a ferrous iron atom bound with five cyanide molecules and one nitric group. The ferrous iron reacts with sulfhydryl groups in red blood cells and releases cyanide. Cyanide is reduced to thiocyanate in the liver and excreted in the urine. The half-life of thiocyanate is 4 days, and it accumulates in the presence of renal failure.
Administration of high doses of sodium nitroprusside can result in cyanide toxicity. The cyanide molecule binds to cytochrome oxidase, interfering with electron transport and causing cellular hypoxia. Toxicity can be recognized by the triad of tachyphylaxis (increasing tolerance to the drug dose), elevated mixed venous Pao2, and metabolic acidosis. The possible treatments of cyanide toxicity consist of (1) administration of amyl nitrate (by inhalation or directly into the anesthesia circuit), (2) infusion of sodium nitrite, and (3) administration of sodium thiosulfate.
Nitroglycerin, or glyceryl trinitrate, is a venodilator used to treat myocardial ischemia (see Chapter 41). Its predominant action is on venules, causing increased venous capacitance and decreased cardiac preload. Effects on the arterial side are minimal except at very high doses. The usual IV dose is 1 to 3 µg/kg/min. On IV administration, effects can be seen within 2 minutes, and they usually resolve within 5 minutes of discontinuing the drug. Side effects are minimal, and there is no potential for cyanide toxicity as with nitroprusside. Use of nitroglycerin for control of perioperative hypertension has been reported but because of its relatively weak arteriolar action it is not as useful as other drugs as an antihypertensive agent.99,128 In obstetric patients with pre-eclampsia, however, it may be chosen over nitroprusside to circumvent potential cyanide toxicity to the fetus.131
Nesiritide is a recombinant form of a human B-type natriuretic peptide. It is identical with the endogenous hormone liberated by the ventricles in situations characterized by volume overload and increased wall tension. Nesiritide acts on guanylate cyclase similar to nitric oxide, and therefore induces beneficial effects on hemodynamics by venous and arterial vasodilation, including coronary vasodilation. It is more effective than nitroglycerin in decreasing the right atrial pressure, pulmonary capillary wedge pressure, systemic vascular resistance, and ultimately improves the CO. The possible side effects include hypotension, headache, and renal dysfunction. The dose is 2 µg/kg bolus, continued with continuous infusion of 0.01 µg/kg/min that may be increased to a maximum of 0.03 µg/kg/min, with the most significant side effect being hypotension. The biologic effects last longer than expected from the drug's half-life. Nesiritide is beneficial for rapid improvement of dyspnea, and can be used in patients with decompensated heart failure, in addition to diuretic therapy for rapid improvement of symptoms; but again the possibility of worsening renal function, together with possible worsening 30-day mortality in a recent study, made its safety questionable.31,40,128
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Editors: Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K.; Cahalan, Michael K.; Stock, M. Christine