Noradrenergic Transmission

The neurochemical steps that mediate noradrenergic neurotransmission are summarized in Figure 11-1. The first step involves the transport of tyrosine into the neuron followed by its conversion to 4-dihydroxy-phenylalanine (l-DOPA) by the rate-limiting enzyme tyrosine hydroxylase. l-DOPA is rapidly decarboxylated to dopamine (DA) by aromatic l-amino acid decarboxylase (ALAAD), also known as DOPA decarboxylase. In dopaminergic neurons within the central nervous system (CNS), this is the last step in the synthetic process, and DA is released as a neurotransmitter. Noradrenergic neurons in the CNS and peripheral sympathetic nervous system contain an additional enzyme, DA β-hydroxylase, which converts DA to NE. This enzyme is located in synaptic vesicles, so DA must be actively transported into these vesicles before conversion to NE.

FIGURE 11–1 Prejunctional and postjunctional sites of action of drugs that modify noradrenergic transmission at a sympathetic neuroeffector junction. l-Tyrosine is actively transported into the neuron, where it is converted to l-DOP A by tyrosine hydroxylase (TH). This reaction is followed by the action of aromatic l-amino acid decarboxylase (ALAAD) to convert l-DOPA to DA, which is actively transported into synaptic vesicles, where it is converted by DA β-hydroxylase (DBH) to norepinephrine (NE). The arrival of an action potential at the varicosity causes Ca⁺⁺ influx, which promotes the exocytotic release of NE. After release, NE can activate postjunctional α₁, α₂, or β receptors or prejunctional α₂ receptors. Activation of prejunctional α₂ receptors inhibits the further release of NE. The action of NE is terminated by transport back into the neuron by high-affinity uptake (Uptake 1), where it can be repackaged into synaptic vesicles or metabolized by monoamine oxidase (MAO) to inactive products. NE is also removed by diffusion and transport into the postjunctional cell (Uptake 2), where it is metabolized to normetanephrine by catechol-O-methyltransferase (COMT). Sites at which drugs act to enhance or mimic noradrenergic transmission are identified by numbers in circles.

Drugs that enhance or mimic noradrenergic transmission:

1. Facilitate release (e.g., amphetamine)

2. Block reuptake (e.g., cocaine)

3. Receptor agonists (e.g., phenylephrine)

Drugs that reduce noradrenergic transmission:

4. Inhibit synthesis (e.g., 4a, α-methyltyrosine; 4b, carbidopa; 4c, disulfiram)

5. Disrupt vesicular transport and storage (e.g., reserpine)

6. Inhibit release (e.g., guanethidine)

7. Receptor antagonists (e.g., phentolamine)

When the action potential depolarizes the nerve terminal, voltage-gated Ca⁺⁺ channels open, allowing Ca⁺⁺ to enter the neuron and cause the vesicles to release NE. At the neuroeffector junction, NE binds to adrenergic receptor subtypes on both the presynaptic and postsynaptic membranes, with different organs containing different receptor subtypes. Activation of α₂-“autoreceptors” on the presynaptic neuronal membrane causes feedback inhibition and reduces further NE release. The signaling mechanisms occurring after adrenergic receptor activation are discussed in Chapter 9.

After NE has activated its receptors, its action is terminated primarily by a high-affinity reuptake system (termed “uptake 1” in Fig. 11-1), which transports NE back into the neuron for repackaging and eventual re-release. A smaller fraction of the NE in the synapse diffuses away from the receptors and can be taken up by a lower affinity extraneuronal process (termed “uptake 2” in Fig. 11-1). Some of the NE taken back into the sympathetic neurons by reuptake can be oxidatively deaminated by monoamine oxidase (MAO) located on the external mitochondrial membrane. The biologically inactive deaminated metabolites enter the circulation and are excreted in the urine. The NE that is transported into the postjunctional cell is O-methylated by catechol-O-methyltransferase (COMT) to normetanephrine. The high-affinity reuptake of NE into presynaptic terminals is the major mechanism that terminates its actions, although COMT and MAO also play important roles in metabolizing circulating NE and Epi and some exogenously administered sympathomimetic amines.

In addition to the synthesis and release of NE by sympathetic neurons, NE is also synthesized in and released from chromaffin cells in the adrenal medulla. These cells usually contain another enzyme, phenylethanolamine-N-methyltransferase, which converts NE to Epi. Chromaffin cells are innervated by sympathetic preganglionic cholinergic neurons and release catecholamines into the blood, where they are transported to various organs to act on adrenergic receptors. Circulating catecholamines, whether administered as drugs or released from the adrenal medulla, are also removed by high-affinity uptake into sympathetic nerves or metabolized, as discussed.

Drugs modify the activity of sympathetic neurons by increasing or decreasing the noradrenergic signal (see Fig. 11-1). Sympathomimetics may mimic noradrenergic transmission by acting directly on postsynaptic adrenergic receptors (e.g., phenylephrine), by facilitating NE release (e.g., amphetamine) or by blocking neuronal reuptake (e.g., cocaine). Amphetamine and cocaine have intense effects on the CNS and are drugs of abuse with severe addiction liability (Chapter 37).

Sympatholytics reduce noradrenergic transmission by inhibiting synthesis (e.g., α-methyltyrosine), disrupting vesicular storage (e.g., reserpine), inhibiting release (e.g., guanethidine), or directly blocking receptors (e.g., phentolamine).

Activation of Adrenergic Receptors

Over the last half century it has become clear that the actions of NE and Epi are mediated through multiple adrenergic receptor subtypes (see Chapter 9). We now know that there are nine different subtypes of adrenergic receptors, each encoded by separate genes, which are grouped into three major families (α₁, α₂, β), each containing three different members. Of these, only four (α₁, α₂, β₁, and β₂) are currently important in clinical pharmacology; therefore they are the major focus of this chapter. Both NE and Epi activate most adrenergic receptors with similar, but not identical, potencies, although NE is much less potent than Epi at the β₂-subtype. Isoproterenol (ISO) is a synthetic analog of NE and Epi and selectively activates only β receptors. Differences in the pharmacological profiles of different adrenergic receptors are illustrated in Figure 11-2, where dose-response curves for the actions of these catecholamines on different tissues are depicted.

FIGURE 11–2 Dose-response curves (arbitrary scales) show relative potencies of three catecholamines in experimental muscle preparations. Changes in the force of contraction or relaxation for each muscle is shown after addition of progressively increasing concentrations of each catecholamine. NE, Norepinephrine; Epi, epinephrine; ISO, isoproterenol.

Adrenergic receptor activation increases the contraction of cardiac muscle and induces smooth muscle to either contract or relax, depending on the receptor subtype(s) present. Contraction of arterial strips is mediated by α₁ receptors, where the relative potencies of the three catecholamines are Epi ≥ NE >>> ISO. Relaxation of bronchial smooth muscle is mediated by β₂ receptors, with the relative potencies being ISO > Epi >>> NE. Contraction of cardiac muscle is mediated by β₁ receptors, with the relative potencies being ISO > Epi = NE. The presence of different receptor subtypes in these three tissues is further demonstrated in Figure 11-3 by examining the effects of selective antagonists. Phentolamine, a competitive antagonist at α₁ receptors, causes a parallel shift to the right of NE-induced contractions of arterial strips (see Fig. 11-3, A) but does not affect the other two responses. Propranolol, a competitive antagonist at both β₁ and β₂ receptors, causes a parallel shift to the right of responses mediated by bronchial β₂ receptors (see Fig. 11-3, B) and cardiac β₁ receptors (see Fig. 11-3, C), without affecting the α₁ receptor response.

FIGURE 11–3 Changes in force of contraction or relaxation (arbitrary scale) of different tissues hung in separate tissue baths after addition of increasing concentrations of catecholamine in absence and presence of a fixed concentration of an α (phentolamine) or β (propranolol) receptor blocking drug. NE, Norepinephrine; ISO, isoproterenol.

Adrenergic α₂ receptors are found on platelets, in the CNS, and postsynaptically in several other peripheral tissues (blood vessels, pancreas, and enteric cholinergic neurons). As mentioned, activation of α₂ receptors on the terminals of sympathetic neurons reduces NE release. These receptors are also found both presynaptically and postsynaptically on neurons in brain, and activation of these receptors reduces central sympathetic outflow.

Direct-Acting Sympathomimetics

Direct-acting adrenergic receptor agonists mimic some of the effects of sympathetic nervous system activation by binding to and activating specific receptor subtypes (see Fig. 11-1, site 3). For example, as mentioned, ISO selectively activates β receptors, phenylephrine selectively activates α₁ receptors, and clonidine selectively activates α₂ receptors. Similarly, dobutamine and albuterol are relatively specific agonists at β₁ and β₂ receptors, respectively. The structures of some clinically important adrenergic receptor agonists are shown in Figure 11-4.

FIGURE 11–4 Structures of some direct-acting sympathomimetic agonists. Asterisk indicates asymmetrical carbon.

Indirect-Acting Sympathomimetics

Indirect-acting sympathomimetics do not activate receptors directly but facilitate the release of NE from sympathetic neurons or block high-affinity reuptake. Thus they act presynaptically to facilitate adrenergic neurotransmission. Amphetamine and related drugs produce their sympathomimetic effects by facilitating NE release (see Fig. 11-1, site 1); the effects of these drugs in the CNS are described in Chapter 37. On the other hand, cocaine and tricyclic antidepressants, such as desipramine, exert their sympathomimetic effects by blocking high-affinity reuptake (see Fig. 11-1, site 2). The structure and characteristics of cocaine are discussed in Chapter 37, with similar information for tricyclic antidepressants given in Chapter 30.

Because neuronal reuptake, and not metabolism, is the primary mechanism for terminating the actions of NE and Epi, it is not surprising that drugs that inhibit the metabolism of these amines show little or no sympathomimetic actions. On the other hand, inhibitors of MAO (e.g., pargyline) or COMT (e.g., tolcapone) can enhance the actions of other synthetic sympathomimetic amines that are substrates for these enzymes, with some important toxicological implications. For example, the actions of tyramine, a sympathomimetic amine present in a variety of foods, are greatly enhanced in patients treated with MAO inhibitors (see Chapter 30), and the pharmacokinetics of l-DOPA, used for the treatment of Parkinson’s disease, are increased when administered concurrently with a COMT inhibitor (see Chapter 28).

An indirect-acting sympathomimetic amine that releases NE must penetrate the noradrenergic neuron before it can act. Nonpolar, lipid-soluble drugs such as amphetamine can diffuse across neuronal membranes, whereas polar, water-soluble compounds such as tyramine must rely on high-affinity uptake by the NE transporter. Thus drugs that inhibit the NE transporter will reduce or block the effects of tyramine but will enhance the effects of Epi, which acts directly on the adrenergic receptors. Cocaine also causes a prompt increase in the response to Epi by blocking the reuptake system, whereas reserpine disrupts amine transport from the cytoplasm into synaptic vesicles (see Fig. 11-1, site 5). Therefore reserpine has only small effects on responses to direct-acting sympathomimetics.

Sympatholytics

Direct and Reflex Cardiovascular Actions of Adrenergic Agents

The sympathetic nervous system plays an important role in regulating the cardiovascular system; thus adrenergic drugs have pronounced effects on this system. These drugs alter the rate and force of contraction of the heart and the tone of blood vessels (and, consequently, blood pressure) through activation of adrenergic receptors on cardiac and vascular smooth muscle cells. Compensatory reflex adjustments occur as a result of these responses, and these reflexes must be considered to understand the overall actions of adrenergic drugs on the heart and blood vessels.

Mean arterial blood pressure does not fluctuate widely because of feedback mechanisms that evoke compensatory responses to maintain homeostasis (Fig. 11-5). Baroreceptors are stretch receptors located in the walls of the heart and blood vessels that are activated by distention of the blood vessels. Increased blood pressure increases impulse traffic in afferent baroreceptor neurons that project to vasomotor centers in the medulla. Impulses generated in the baroreceptors inhibit the tonic discharge of sympathetic neurons projecting to the heart and blood vessels and activate vagal fibers projecting to the heart. When phenylephrine, which contracts vascular smooth muscle, is administered, peripheral resistance and blood pressure increase (Fig. 11-6). In turn, this increase in pressure increases afferent baroreceptor neuronal activity, thereby reducing sympathetic nerve activity and increasing vagal nerve activity. Consequently, heart rate decreases (bradycardia). Drugs such as histamine, which relax vascular smooth muscle, decrease blood pressure, reducing impulse traffic in afferent buffer neurons. Consequently, sympathetic nerve activity increases and vagal nerve activity decreases, resulting in an increased heart rate (tachycardia).

FIGURE 11–5 Baroreceptor control of blood pressure and heart rate. SNS, Sympathetic nervous system; PNS, parasympathetic nervous system.

FIGURE 11–6 Responses to intravenous injections of drugs that cause vasoconstriction (phenylephrine) or vasodilation (histamine) by acting directly on vascular smooth muscle.

In summary, drugs causing vasoconstriction secondarily cause reflex slowing of the heart, whereas drugs causing vasodilation produce reflex tachycardia. Thus the actions of adrenergic drugs on the cardiovascular system include both the direct actions of the drug on effector organs and compensatory reflex actions.

Direct-Acting Sympathomimetics

Epi is the prototype of direct-acting sympathomimetic drugs because it activates all known adrenergic receptor subtypes. The effects of direct-acting sympathomimetic drugs on selected tissues and organ systems are discussed in this section, with the effects of the prototype Epi first, followed by those of more selective sympathomimetics as compared with the prototype.

Metabolic Effects

Epi exerts many metabolic effects, some of which are the result of its action on the secretion of insulin and glucagon. The predominant action of Epi on islet cells of the pancreas is inhibition of insulin secretion from pancreatic β cells through activation of α₂ receptors and stimulation of glucagon secretion from pancreatic α cells through activation of β₂ receptors.

The major metabolic effects of Epi are increased circulating concentrations of glucose, lactic acid, and free fatty acids. In humans these effects are attributable to the activation of β receptors at liver, skeletal muscle, heart, and adipose cells (Fig. 11-7). Adrenergic β receptor activation results in G_s protein-mediated activation of adenylyl cyclase. The resulting increase in cyclic adenosine monophosphate (cAMP) leads to a series of phosphorylation events, culminating in activation of phosphorylase and lipase. Lipase catalyzes breakdown of triglycerides in fat to free fatty acids. The characteristic “calorigenic action” of Epi, which is reflected in a 20% to 30% increase in O₂ consumption, is caused partly by the breakdown of triglycerides in brown adipose tissue and subsequent oxidation of the resulting fatty acids. In liver, phosphorylase catalyzes the breakdown of glycogen to glucose. In muscle, glycogenolysis and glycolysis produce lactic acid, which is released into the blood. Release of glucose from the liver is accompanied by the efflux of K⁺, so that Epi induces hyperglycemia and a brief period of hyperkalemia due to activation of hepatic α adrenergic receptors. The hyperkalemia is followed by a more pronounced hypokalemia, as the K⁺ released from the liver is taken up by skeletal muscle as a result of activation of muscle β₂ adrenergic receptors.

FIGURE 11–7 Mechanisms by which epinephrine (and other β receptor agonists) exerts metabolic effects in adipose, liver, heart, and skeletal muscle cells.

Indirect-Acting Sympathomimetics

The sympathomimetic actions of some drugs stem from their ability to cause the release of NE from sympathetic neurons or block the neuronal reuptake of NE. Some of these drugs (e.g., amphetamine, cocaine) have noticeable CNS stimulant actions (see Chapter 37).

Tyramine is present in a variety of foods (e.g., ripened cheese, fermented sausage, wines) and is also formed in the liver and GI tract by the decarboxylation of tyrosine. Tyramine is an indirect-acting agent that is taken up by sympathetic nerve terminals and displaces NE from vesicles into the synaptic cleft via reverse transport of the NE uptake 1 transporter (not by exocytosis). Normally, significant quantities of tyramine are not found in blood or tissues, because tyramine is rapidly metabolized by MAO in the GI tract, liver and other tissues including sympathetic neurons. However, in patients treated with MAO inhibitors for depression, increased circulating concentrations of tyramine may be achieved, particularly after the ingestion foods containing large concentrations of tyramine, leading to the massive release of NE and a severe hypertensive response. Thus patients treated with MAO inhibitors should avoid eating foods containing tyramine (see Chapter 30).

Ephedrine and amphetamine are related chemically to Epi (Fig. 11-8) but exert their sympathomimetic effects mainly by facilitating the release of NE. Ephedrine is a mixture of four isomers: D- and l-ephedrine and d– and l-pseudoephedrine. l-Ephedrine is the most potent, but the racemic mixture is often used, as is d-pseudoephedrine. Ephedrine is not metabolized by COMT or MAO and thus has a prolonged duration of action. Ephedrine exerts a direct action on β₂ receptors and has some limited usefulness as a bronchodilator. It also readily crosses the blood-brain barrier. Ephedrine was widely used as a dietary supplement for its stimulant and appetite-suppressant properties (see Chapter 7) but has now been removed from the market in the United States because of increasing reports of adverse effects.

FIGURE 11–8 Structures of some indirect-acting sympathomimetics compared with epinephrine. Asterisk indicates asymmetrical carbon.

Pseudoephedrine has fewer central stimulant actions than ephedrine and is widely available as a component of over-the-counter preparations used as a decongestant for relief of upper respiratory tract conditions that accompany the common cold. Its use has been subject to legal restrictions because it can be chemically modified to yield an abused substance (methamphetamine). It is often combined with analgesics, anticholinergics, antihistaminics, and caffeine. Pseudoephedrine is thought to act as a decongestant both by indirectly releasing NE and by activating α₁ adrenergic receptors, constricting nasal blood vessels.

Methamphetamine and amphetamine exist as d– and l-optical isomers. On peripheral sympathetic neurons, d– and l-amphetamine are equipotent, but in the CNS, the d-isomer is three to four times more potent than the l-isomer. Amphetamine is used therapeutically only for its central stimulant action (see Chapter 37), and only the d-isomer is used to minimize peripheral sympathomimetic actions. Amphetamine facilitates the release and blocks the reuptake of NE. However, the central stimulant actions of amphetamine appear to result from its ability to cause DA release (see Chapter 37). Cocaine is structurally distinct but has similar central stimulant and sympathomimetic actions. It also blocks the neuronal reuptake of NE and DA; however, unlike amphetamine, it does not facilitate neurotransmitter release.

α Receptor Antagonists

Phentolamine is a prototypical competitive antagonist at α receptors, meaning that blockade can be surmounted by increasing agonist concentration (Fig. 11-9). Phenoxybenzamine, on the other hand, binds covalently to α receptors and produces an irreversible blockade that cannot be overcome by addition of more agonist (see Fig. 11-9).

FIGURE 11–9 Comparison of the effects of a reversible (phentolamine) and an irreversible (phenoxybenzamine) inhibitor of α receptors. Changes in the force of contraction of arterial strips were recorded after addition of increasing concentrations of NE in the absence and in the presence of low and high concentrations of phentolamine and low and high concentrations of phenoxybenzamine. The broken lines are larger doses of the antagonist.

Phenoxybenzamine and phentolamine have similar affinities for α₁ and α₂ receptors. They cause vasodilation by blocking sympathetic activation of blood vessels, an effect proportional to the degree of sympathetic tone. Adrenergic α receptor antagonists cause only small decreases in recumbent blood pressure but can produce a sharp decrease during the compensatory vasoconstriction that occurs on standing because reflex sympathetic control of capacitance vessels is lost. This can result in orthostatic or postural hypotension accompanied by reflex tachycardia, although tolerance to this effect occurs with repeated use.

The effects of α receptor blockade on mean blood pressure and heart rate in response to NE and Epi are illustrated in Figure 11-10. The intravenous injection of NE and Epi produces a brief increase in blood pressure by activating α₁ receptors in blood vessels. A reflex decrease in sympathetic and increase in vagal tone to the heart occur (see Fig. 11-5), but reflex bradycardia may be masked by direct activation of cardiac β₁ receptors. In the case of NE, bradycardia is often seen because systolic and diastolic pressure both increase. Because of such complex and opposing actions, the effects of these compounds on heart rate can vary. Blockade of α receptors with phentolamine lowers blood pressure but is accompanied by a reflex increase in heart rate. NE now has little effect on blood pressure and does not cause reflex bradycardia, whereas heart rate is increased by stimulation of cardiac β₁ receptors. When Epi is administered, the former pressor response is converted to a strong depressor response because vasodilatation resulting from β₂ receptor activation is unmasked. Epi now causes pronounced tachycardia by direct activation of cardiac β₁ receptors as well as a reflex tachycardia after the blood pressure decrease. Thus, when α receptors are blocked, the actions of Epi resemble those of the pure β receptor agonist ISO.

FIGURE 11–10 Effects of intravenous injections of NE and Epi on mean blood pressure and heart rate before and after blockade of α receptors by phentolamine. (Note: the heart rate data [red line] appears above the blood pressure on the right part of the graph (beyond the dashed line).

The tachycardia that occurs after administration of α receptor antagonists is attributable in part to blockade of presynaptic α₂ receptors on sympathetic neurons (Fig. 11-11). Activation of these receptors inhibits NE release, and this feedback inhibition is disrupted when α₂ receptors are blocked. This has little consequence when the postsynaptic receptors are α₁, because the α receptor antagonists mentioned also block these receptors. In the heart, however, the postsynaptic receptors are β₁. Thus effects of sympathetic activation are enhanced when α₂ receptors are blocked, increasing NE release and enhancing reflex tachycardia (see Fig. 11-11, B).

FIGURE 11–11 Comparison of the actions of phentolamine (α₁ and α₂ receptor antagonist) and prazosin (α₁ receptor antagonist) at noradrenergic neuroeffector junctions in cardiac muscle (β₁ receptors) and vascular smooth muscle (α₁ receptors).

Prazosin, terazosin, doxazosin, tamsulosin, and alfuzosin are selective α₁ receptor antagonists with similar pharmacological profiles but some differences in pharmacokinetics. By blocking α₁ receptors in arterioles and veins, these drugs reduce peripheral vascular resistance and lower blood pressure; accordingly, they are used in treating hypertension. Selective α₁ receptor antagonists cause less tachycardia than nonselective α receptor antagonists, because the α₂ receptors, which reduce NE release, are not blocked by these drugs (see Fig. 11-11, C). Adrenergic α₁ receptor antagonists also relax smooth muscle in the prostate and bladder neck and thereby relieve urinary retention in benign prostatic hyperplasia. Tamsulosin, terazosin, and alfuzosin are commonly prescribed for this condition.

The major side effects of α receptor antagonists are related to a reduced sympathetic tone at α receptors. These effects include orthostatic hypotension, tachycardia (less common with selective α₁ receptor antagonists), inhibition of ejaculation, and nasal congestion. Other adverse effects are not related to their ability to block α receptors; for example, phentolamine stimulates the GI tract, causing abdominal pain and diarrhea.

β Receptor Antagonists

Propranolol is the prototypical nonselective β receptor antagonist. Newer compounds differ primarily in their duration of action and subtype selectivity. Propranolol is a competitive antagonist at both β₁ and β₂ receptors. Like all adrenergic receptor blocking drugs, its pharmacological effects depend on the activity of the sympatho-adrenal system. When impulse traffic in sympathetic neurons and circulating concentrations of NE and Epi are high (e.g., during exercise), the effects of the drugs are more pronounced. The most profound effects of propranolol are on the cardiovascular system. Propranolol blocks the positive chronotropic and inotropic responses to β receptor agonists and to sympathetic activation. It reduces the rate and contractility of the heart at rest, but these effects are more dramatic during exercise. The drug may precipitate acute failure in an uncompensated heart. Propranolol, but not some other β receptor antagonists, also has a direct membrane-stabilizing action (local anesthetic action), which may contribute to its cardiac antiarrhythmic effect.

When administered acutely, propranolol does not greatly affect blood flow because vascular β receptors are not tonically activated, although compensatory reflexes cause slightly increased peripheral resistance. Propranolol administered over the long term is an effective antihypertensive agent. How it lowers blood pressure is not completely understood, but it is believed to result from several actions, including reduced cardiac output, reduced release of renin from the juxtaglomerular apparatus, and possibly some actions in the CNS.

Propranolol also blocks the metabolic actions of β receptor agonists and activation of the sympatho-adrenal system. It inhibits increases in plasma free fatty acids and glucose from lipolysis in fat and glycogenolysis in liver, heart, and skeletal muscle. This can pose a problem for diabetics by augmenting insulin-induced hypoglycemia. However, selective β₁ receptor antagonists are less likely to augment insulin-induced hypoglycemia. Adrenergic β receptor antagonists also reduce the premonitory tachycardia associated with insulin-induced hypoglycemia, so diabetic patients taking them must learn to recognize sweating (induced by activation of cholinergic sympathetic neurons) as a symptom of low blood glucose.

Propranolol causes few serious side effects in healthy people but can do so in patients with various diseases; heart failure is the main threat. Propranolol is usually contraindicated in patients with sinus bradycardia, partial heart block, or compensated congestive heart failure. Sudden withdrawal of propranolol from patients who have received this drug over the long term can cause “withdrawal symptoms” such as angina, tachycardia, and dysrhythmias. Rebound hypertension may occur in such patients taking propranolol to control blood pressure. These withdrawal symptoms probably result from the development of β receptor supersensitivity and can be minimized by gradually reducing the dose of the drug.

The ability of propranolol to increase airway resistance is of little clinical importance in healthy people but can be very hazardous in patients with obstructive pulmonary disease or asthma. Selective β₁ receptor antagonists (see later discussion) should be used in these patients, although even these drugs should be used with caution, because they are not completely inactive at β₂ receptors.

Nadolol is a nonselective β receptor-blocking drug that is less lipid soluble than propranolol and less likely to cause CNS effects. It has a significantly longer duration of action than most other β receptor antagonists. Timolol is another nonselective β receptor antagonist administered orally for treating hypertension and angina pectoris or as an ophthalmic preparation for treating glaucoma.

Carteolol, pindolol, and penbutolol are nonselective β receptor antagonists that have modest intrinsic sympathomimetic properties. These drugs cause less slowing of resting heart rate and fewer abnormalities of serum lipid concentrations than other β receptor antagonists, and it has been suggested that they also produce less up regulation of β receptors. These drugs generally cause less severe withdrawal symptoms and are used to treat hypertension.

Labetalol and carvedilol are competitive antagonists of α₁, β₁, and β₂ receptors. Consequently, they have hemodynamic effects similar to those of a combination of propranolol (β₁ and β₂ receptor blockade) and prazosin (α₁ receptor blockade). Unfortunately, side effects are also similar to those of both drugs (e.g., orthostatic hypotension, nasal congestion, bronchospasm). However, these drugs are potent antihypertensive agents.

At low doses, acebutolol, atenolol, metoprolol, and esmolol are more selective in blocking β₁ receptors on cardiac muscle than in blocking β₂ receptors on bronchiolar smooth muscle. They are less likely than nonselective β receptor antagonists to increase bronchoconstriction in patients with asthma. These β₁ receptor antagonists are useful in treating hypertension and angina pectoris. Esmolol is a selective β₁ receptor antagonist that is rapidly metabolized by esterases in red blood cells and has a very short t_1/2. It is used for the emergency treatment of sinus tachycardia and atrial flutter or fibrillation.

Drugs that Interfere with Sympathetic Neuronal Function

Drugs that disrupt the synthesis, storage, or release of NE have been used primarily in the treatment of hypertension; however, they are no longer widely used. Guanethidine is the prototype of this class of drugs, which impairs release of NE from postganglionic sympathetic neurons. Related drugs include guanadrel, bretylium, and reserpine, which depletes sympathetic neurons of stored NE. These drugs reduce sympathetic tone in a relatively nonspecific manner, causing substantial side effects, including reduced blood pressure, heart rate, and cardiac output and increased GI motility and diarrhea. Because of their side effects and the availability of better drugs, these drugs are no longer widely used.

Drugs that Reduce Central Sympathetic Outflow

The activity of peripheral sympathetic neurons is regulated in a complex manner by neuronal systems located in the lower brainstem. These central neurons, in turn, are regulated in part by α₂ receptors. Clonidine is the prototype α₂ receptor agonist. It is lipid soluble and penetrates the blood-brain barrier to activate α₂ receptors in the medulla, resulting in diminished sympathetic outflow. Clonidine lowers blood pressure by reducing total peripheral resistance, heart rate, and cardiac output. It does not interfere with baroreceptor reflexes and does not produce noticeable orthostatic hypotension. Accordingly, clonidine lowers blood pressure in patients with moderate to severe hypertension and produces less orthostatic hypotension than drugs acting in the periphery. However, side effects of clonidine may include dry mouth, sedation, dizziness, nightmares, anxiety, and mental depression. Various signs and symptoms related to sympathetic nervous system overactivity (hypertension, tachycardia, sweating) may occur after withdrawal of long-term clonidine therapy; thus the dose of clonidine should be reduced gradually. Clonidine is also used to ameliorate signs and symptoms associated with increased activity of the sympathetic nervous system that accompany withdrawal from long-term opioid use.

Guanabenz and guanfacine are other α₂ receptor agonists that act centrally to inhibit sympathetic tone with a relative sparing of cardiovascular reflexes. Guanfacine is longer acting, less likely to reduce cardiac output, and less sedating than clonidine.

Methyldopa is an analog of the catecholamine precursor l-DOPA that is transported into noradrenergic neurons, where it is converted to α-methyl-NE (Fig. 11-12). α-Methyl-NE partially displaces NE in synaptic vesicles, where it is released in place of NE. This compound selectively activates α₂ receptors to cause hypotensive actions, which appear to be attributable to α-methyl-NE in the brain not in the periphery.

FIGURE 11–12 Metabolism of α-methyldopa in central noradrenergic nerve terminals.

Drugs that Inhibit Catecholamine Synthesis

Metyrosine (α-methyltyrosine) inhibits tyrosine hydroxylase in the brain, periphery, and adrenal medulla, thereby reducing tissue stores of DA, NE, and Epi. Metyrosine is used in the treatment of patients with pheochromocytoma not amenable to surgery. Its most prevalent side effect is sedation.

Carbidopa, a hydrazine derivative of methyldopa, inhibits ALAAD. Unlike methyldopa, carbidopa does not penetrate the blood-brain barrier and therefore has no effect in the CNS. Because ALAAD is ubiquitous, is present in excess, and does not control the rate-limiting step in catecholamine synthesis, clinical doses of carbidopa have no appreciable effect on the endogenous synthesis of NE in sympathetic neurons. They do, however, reduce the conversion of exogenously administered l-DOPA to DA outside the brain, rendering carbidopa useful for the adjunctive treatment of Parkinson’s disease (see Chapter 28).